methods of prediction and prevention of pre-eclampsia - health

Methods of prediction and prevention ofpre-eclampsia: systematic reviews of accuracy and effectiveness literature witheconomic modelling

CA Meads, JS Cnossen, S Meher, A Juarez-Garcia,G ter Riet, L Duley, TE Roberts, BW Mol, JA van der Post, MM Leeflang, PM Barton, CJ Hyde, JK Gupta and KS Khan

Health Technology Assessment 2008; Vol. 12: No. 6

HTAHealth Technology AssessmentNHS R&D HTA Programmewww.hta.ac.uk

March 2008

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Methods of prediction and prevention ofpre-eclampsia: systematic reviews ofaccuracy and effectiveness literature witheconomic modelling

CA Meads,1* JS Cnossen,2 S Meher,3 A Juarez-Garcia,4

G ter Riet,2,5 L Duley,6 TE Roberts,4 BW Mol,7

JA van der Post,7 MM Leeflang,8 PM Barton,4

CJ Hyde,1 JK Gupta9 and KS Khan9

1 Department of Public Health and Epidemiology, University of Birmingham, UK

2 Department of General Practice, Academic Medical Center, Amsterdam, The Netherlands

3 University of Liverpool, Liverpool Women’s Hospital, UK4 Department of Health Economics, University of Birmingham, UK5 Horten Centre, University of Zurich, Switzerland 6 Bradford Institute for Health Research, Bradford Royal Infirmary, UK7 Department of Obstetrics and Gynaecology, Academic Medical Center,

Amsterdam, The Netherlands8 Department of Clinical Epidemiology and Biostatistics, Academic Medical

Center, Amsterdam, The Netherlands9 Birmingham Women’s Hospital, UK

* Corresponding author

Declared competing interests of authors: L Duley was a member of the steeringcommittee and author on the Barbados 1998 aspirin trial and the Vitamins in Pregnancy (VIP)trial and was co-investigator in the PARIS review. CJ Hyde is a member of the Editorial boardfor Health Technology Assessment but was not involved in the editorial process for this report.

Published March 2008

This report should be referenced as follows:

Meads CA, Cnossen JS, Meher S, Juarez-Garcia A, ter Riet G, Duley L, et al. Methods ofprediction and prevention of pre-eclampsia: systematic reviews of accuracy and effectivenessliterature with economic modelling. Health Technol Assess 2008;12(6).

Health Technology Assessment is indexed and abstracted in Index Medicus/MEDLINE, ExcerptaMedica/EMBASE and Science Citation Index Expanded (SciSearch®) and Current Contents®/Clinical Medicine.

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The research reported in this issue of the journal was commissioned by the HTA Programme as projectnumber 01/64/04. The contractual start date was in January 2004. The draft report began editorial reviewin August 2006 and was accepted for publication in August 2007. As the funder, by devising acommissioning brief, the HTA Programme specified the research question and study design. The authorshave been wholly responsible for all data collection, analysis and interpretation, and for writing up theirwork. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and wouldlike to thank the referees for their constructive comments on the draft document. However, they do notaccept liability for damages or losses arising from material published in this report.The views expressed in this publication are those of the authors and not necessarily those of the HTA Programme or the Department of Health.

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Objectives: To investigate the accuracy of predictivetests for pre-eclampsia and the effectiveness ofpreventative interventions for pre-eclampsia. Also to assess the cost-effectiveness of strategies(test–intervention combinations) to predict and prevent pre-eclampsia.Data sources: Major electronic databases weresearched to January 2005 at least. Review methods: Systematic reviews were carriedout for test accuracy and effectiveness. Qualityassessment was carried out using standard tools. Fortest accuracy, meta-analyses used a bivariate approach.Effectiveness reviews were conducted under theauspices of the Cochrane Pregnancy and ChildbirthGroup and used standard Cochrane review methods.The economic evaluation was from an NHSperspective and used a decision tree model.Results: For the 27 tests reviewed, the quality ofincluded studies was generally poor. Some testsappeared to have high specificity, but at the expense ofcompromised sensitivity. Tests that reached specificitiesabove 90% were body mass index > 34, �-foetoprotein and uterine artery Doppler (bilateralnotching). The only Doppler test with a sensitivity ofover 60% was resistance index and combinations ofindices. A few tests not commonly found in routinepractice, such as kallikreinuria and SDS-PAGE

proteinuria, seemed to offer the promise of highsensitivity, without compromising specificity, but thesewould require further investigation. For the 16effectiveness reviews, the quality of included studieswas variable. The largest review was of antiplateletagents, primarily low-dose aspirin, and included 51trials (36,500 women). This was the only review wherethe intervention was shown to prevent both pre-eclampsia and its consequences for the baby. Calciumsupplementation also reduced the risk of pre-eclampsia, but with some uncertainty about the impacton outcomes for the baby. The only other interventionassociated with a reduction in RR of pre-eclampsia wasrest at home, with or without a nutritional supplement,for women with normal blood pressure. However, thisreview included just two small trials and its resultsshould be interpreted with caution. The cost of most ofthe tests was modest, ranging from £5 for blood testssuch as serum uric acid to approximately £20 forDoppler tests. Similarly, the cost of most interventionswas also modest. In contrast, the best estimate ofadditional average cost associated with an average case of pre-eclampsia was high at approximately £9000. The results of the modelling revealed that prior testing with the test accuracy sensitivities andspecificities identified appeared to offer little as a way of improving cost-effectiveness. Based on the


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Abstract

Methods of prediction and prevention of pre-eclampsia:systematic reviews of accuracy and effectiveness literature with economic modelling

CA Meads,1* JS Cnossen,2 S Meher,3 A Juarez-Garcia,4 G ter Riet,2,5 L Duley,6

TE Roberts,4 BW Mol,7 JA van der Post,7 MM Leeflang,8 PM Barton,4 CJ Hyde,1

JK Gupta9 and KS Khan9

1 Department of Public Health and Epidemiology, University of Birmingham, UK2 Department of General Practice, Academic Medical Center, Amsterdam, The Netherlands3 University of Liverpool, Liverpool Women’s Hospital, UK4 Department of Health Economics, University of Birmingham, UK5 Horten Centre, University of Zurich, Switzerland 6 Bradford Institute for Health Research, Bradford Royal Infirmary, UK7 Department of Obstetrics and Gynaecology, Academic Medical Center, Amsterdam, The Netherlands8 Department of Clinical Epidemiology and Biostatistics, Academic Medical Center, Amsterdam, The Netherlands9 Birmingham Women’s Hospital, UK* Corresponding author

evidence reviewed, none of the tests appearedsufficiently accurate to be clinically useful and theresults of the model favoured no-test/treat-allstrategies. Rest at home without any initial testingappeared to be the most cost-effective ‘test–treatment’combination. Calcium supplementation to all women,without any initial testing, appeared to be the secondmost cost-effective. The economic model providedlittle support that any form of Doppler test hassufficiently high sensitivity and specificity to be cost-effective for the early identification of pre-eclampsia. Italso suggested that the pattern of cost-effectivenesswas no different in high-risk mothers than the low-riskmothers considered in the base case. Conclusions: The tests evaluated are not sufficientlyaccurate, in our opinion, to suggest their routine use inclinical practice. Calcium and antiplatelet agents,primarily low-dose aspirin, were the interventionsshown to prevent pre-eclampsia. The most cost-effective approach to reducing pre-eclampsia is likely to

be the provision of an effective, affordable and safeintervention applied to all mothers without priortesting to assess levels of risk. It is probably prematureto suggest the implementation of a treat-allintervention strategy at present, however the feasibilityand acceptability of this to women could be explored.Rigorous evaluation is needed of tests with modest costwhose initial assessments suggest that they may havehigh levels of both sensitivity and specificity. Similarly,there is a need for high-quality, adequately poweredrandomised controlled trials to investigate whetherinterventions such as advice to rest are indeed effectivein reducing pre-eclampsia. In future, an economicmodel should be developed that considers not just pre-eclampsia, but other related outcomes, particularlythose relevant to the infant such as perinatal death,preterm birth and small for gestational age. Such amodelling project should make provision for primarydata collection on the safety of interventions and theirassociated costs.

Abstract

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v

Glossary and list of abbreviations ............. vii

Executive summary .................................... ix

1 Objectives and background ....................... 1Aims ............................................................ 1Description of underlying health problem ...................................................... 1Objectives of this project ............................ 6

2 Systematic review methods ...................... 9Protocol development ................................ 9The research question ................................ 9Methods for test accuracy reviews .............. 9Methods for Cochrane reviews .................. 14Modifications to the protocol and originalgrant proposal ............................................ 16Methods for economic evaluation .............. 16Project reporting ........................................ 16

3 Test accuracy reviews ................................ 17Study selection ........................................... 17Examinations .............................................. 18Investigations – blood ................................ 18Investigations – urine ................................. 31Investigations – haemodynamic ................. 35Discussion of test accuracy ......................... 46

4 Clinical effectiveness reviews .................... 53Study selection ........................................... 53Presentation of results ................................ 53Antenatal care interventions ...................... 53Lifestyle interventions ................................ 53Nutrition and dietary interventions ........... 59Pharmacological interventions ................... 71Discussion of results of clinical effectiveness reviews ................................... 78

5 Economic evaluation .................................. 85Methods for economic evaluation .............. 85Results of economic evaluation .................. 94Discussion of results of economic evaluation ................................................... 100

6 Conclusions ................................................ 107Introduction ............................................... 107Main findings ............................................. 107Strengths of the report ............................... 107Limitations of the project .......................... 107Overall conclusion ...................................... 108

Recommendations for practice .................. 108Recommendations for research ................. 108

Acknowledgements .................................... 111

References .................................................. 113

Appendix 1 Protocol for the effectivenessreviews ........................................................ 121

Appendix 2 Test accuracy search strategy ....................................................... 123

Appendix 3 Data extraction form ............. 125

Appendix 4 Effectiveness reviews genericsearch strategy ............................................ 133

Appendix 5 Cochrane review subgroupcategorisation and list of outcomes ........... 135

Appendix 6 Comparison between proposeddiagnostic and screening tests and treatments for pre-eclampsia to besystematically reviewed and final systematicreviews completed ...................................... 139

Appendix 7 Test accuracy tables ofmethodological and reporting characteristics of included studies ............. 141

Appendix 8 Diagnostic test quality charts 169

Appendix 9 Effectiveness reviews tables ofmethodological and reporting characteristics of included studies ............. 177

Appendix 10 Data extraction sheet foreconomics section ....................................... 215

Appendix 11 Economic evaluation case 6results ......................................................... 217

Appendix 12 References for reviews ......... 219

Health Technology Assessment reportspublished to date ....................................... 251

Health Technology Assessment Programme ................................................ 267

Contents

GlossaryAneuploidy The condition of having lessthan or more than the normal diploid numberof chromosomes.

Extra Domain A and B in fibronectinmolecule Although fibronectin is encoded byonly one gene, this protein exists in a numberof variant isoforms due to alternate splicingand/or post-translational modifications.

I2 statistic Indication of heterogeneity ofstudies in a forest plot.

Multiples of median When two analyticalmethods agree, or differ by a proportionalamount, conversion to multiples of median canbe used to simplify the clinical interpretation ofresults.

List of abbreviationsACTH adrenal corticotrophic hormone

AFP �-foetoprotein

APEC Action on Pre-Eclampsia

AUN any unilateral notching

BMI body mass index

BNF British National Formulary

CEAC cost-effectiveness acceptabilitycurve

CI confidence interval

DHEA-s dehydroepiandrosterone sulfate

DIC disseminated intravascularcoagulation

E3 unconjugated oestriol

ED-A, ED-B extra domain A and B infibronectin molecule

fDNA foetal DNA

FN fibronectin

fp, fn false positive, false negativenumbers

HCG human chorionic gonadotrophin

HELLP haemolysis, elevated liverenzymes and low platelets

ICER incremental cost-effectivenessratio

IPD individual patient data

MoM multiples of median

NICU neonatal intensive care unit

NNT number-needed-to-treat

NPV negative predictive value

PMS premenstrual syndrome

PE pre-eclampsia


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Glossary and list of abbreviations

continued

Technical terms and abbreviations are used throughout this report. The meaning is usually clear fromthe context, but a glossary is provided for the non-specialist reader. In some cases, usage differs in the

literature, but the term has a constant meaning throughout this review.

List of abbreviations continuedPPV positive predictive value

PSA probabilistic sensitivity analysis

RCT randomised controlled trial

RD risk difference

ROC receiver–operator characteristic

RR relative risk

SD standard deviation

SDS-PAGE sodium dodecyl sulfatepolyacrylamide gelelectrophoresis

SPSS Statistical Package for the SocialSciences

sROC summary receiver–operatorcharacteristic

SUA serum uric acid

tp, tn true positive, true negativenumbers

UCCR urinary calcium/creatinine ratio

UCE urinary calcium excretion

WHO World Health Organization

Glossary and list of abbreviations

All abbreviations that have been used in this report are listed here unless the abbreviation is well known (e.g. NHS), or it has been used only once, or it is a non-standard abbreviation used only in figures/tables/appendices in which case the abbreviation is defined in the figure legend or at the end of the table.

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BackgroundPre-eclampsia is part of a spectrum of conditionsknown as the hypertensive (high blood pressure)disorders of pregnancy and is defined ashypertension and proteinuria detected for the firsttime in the second half of pregnancy (after20 weeks’ gestation). Pre-eclampsia complicates2–8% of pregnancies and may have serious effects on mother and child, which makes it animportant threat to public health in bothdeveloped and developing countries. Once womenare identified to be at high risk, they can betargeted for more intensive antenatal surveillanceand prophylactic interventions. This reportcontains a health technology assessment of currentstrategies for risk stratification and prevention toguide clinical practice and future research in thisfield.

ObjectivesThe aim of the project was to identifycombinations of test and treatments that wouldpredict and help prevent pre-eclampsia. Thisstudy completed three distinct pieces of work tocontribute to this goal:

● a series of systematic reviews on the accuracy oftests for the prediction of pre-eclampsia

● a series of systematic reviews of effectiveness ofinterventions with potential to reduce thenumber of cases of pre-eclampsia

● a health economic evaluation, including aneconomic model, of the combined effect of testsand interventions and their cost-effectiveness.

MethodsProtocols were developed for test accuracy andeffectiveness systematic reviews which used up-to-date review methods, including searches withoutlanguage restrictions, study quality assessment andmeta-analysis where appropriate. Although therewas a slight variation between the search end-dateof different systematic reviews, searches weregenerally conducted to January 2005 at least. Fortest accuracy reviews, literature was identified from

several sources, including databases: PubMED(MEDLINE), EMBASE (Ovid), The CochraneLibrary (DARE, CCTR), MEDION, contact withexperts including the Cochrane Pregnancy andChildbirth Group and checking of reference listsof accuracy review articles and papers that wereeligible for the systematic reviews included in thisreport. Included were cohort and case–controlstudies of pregnant women where the test underreview was performed before the 25th week ofgestation and compared with the referencestandard of pre-eclampsia and a 2 × 2 table wasreported or could be calculated. Qualityassessment was based on QUADAS criteria. Meta-analyses used a bivariate approach.

Effectiveness reviews were conducted under theauspices of the Cochrane Pregnancy andChildbirth Group. Studies were identified from theCochrane Central Register of Controlled Trials(CENTRAL), the Cochrane Pregnancy andChildbirth Group’s trials register, MEDLINE,EMBASE, handsearches of 30 journals andconference proceedings and reference lists of trialreports. Included were randomised or quasi-randomised controlled trials of the relevantintervention compared with placebo, no treatmentor usual care in pregnant women that measuredpre-eclampsia as an outcome. Quality assessmentwas as described in the Cochrane Handbook.Meta-analyses estimating relative risk (RR) wereconducted in Review Manager software, using afixed effects models or random effects ifheterogeneity was detected.

For the economic evaluation, the model structureused was a decision tree constructed in DATATreeage software. An NHS perspective was chosen.Four options (test no-one and treat all, test all andtreat no-one, test all and treat only with positivetest and test all and treat all) were compared withtest no-one and treat no-one. Inputs to the modelwere test accuracy and effectiveness systematicreview meta-analysis results, test accuracy andintervention costs, cost of pre-eclampsia as anoutcome and the prevalence of pre-eclampsia. The primary analysis used point estimates of keyparameters of all tests and the most effectiveinterventions. Extensive deterministic andprobabilistic sensitivity analyses were conducted.

Executive summary

Executive summary

x

The outputs were incremental cost-effectivenessratios for test and treatment combinations.

ResultsMain findings of test accuracy reviewsThere were 27 tests reviewed [body mass index(BMI), �-foetoprotein, cellular and totalfibronectin, foetal DNA, haemoglobin,haematocrit, human chorionic gonadotrophin,oestriol, uric acid, urinary calcium excretion,urinary calcium/creatinine ratio, several forms ofproteinuria/albuminuria and several flow velocitywaveforms of Doppler uterine artery]. The qualityof studies and the accuracy of tests were generallypoor. Some tests appeared to have high specificity,but at the expense of compromised sensitivity.Only a few tests reached specificities above 90%.These were BMI > 34, �-foetoprotein and uterineartery Doppler (bilateral notching). The onlyDoppler test with a sensitivity of over 60% wasresistance index and combinations of indices.Kallikreinuria had a sensitivity of over 80%.Cellular and total fibronectin and kallikreinuriawere found to have specificities above 90%.However, these estimates were based on singlestudies. Also, a few tests not commonly found inroutine practice, such as kallikreinuria and sodiumdodecyl sulfate polyacrylamide gel electrophoresisproteinuria, seemed to offer the promise of highsensitivity, without compromising specificity, butthese too would require further investigation.

Main findings of effectiveness reviewsSixteen systematic reviews of interventions arepresented in this report, of which 15 providedestimates of effectiveness in preventing pre-eclampsia. The quality of included studies wasvariable; many reviews included only small, poor-quality trials and a small number of reviewsincluded large, well-designed trials. The largestreview was of antiplatelet agents, primarily low-dose aspirin, and included 51 trials (36,500women). This was the only review where theintervention was shown to prevent both pre-eclampsia [RR 0.81, 95% confidence interval (CI)0.75 to 0.88] and its consequences for the baby(death, preterm birth and small for gestationalage). Calcium supplementation also reduced therisk of pre-eclampsia (12 trials, 15,206 women, RR0.48, 95% CI 0.33 to 0.69) but with someuncertainty about the impact on outcomes for thebaby. The only other intervention associated witha reduction in RR of pre-eclampsia was rest athome, with or without a nutritional supplement,for women with normal blood pressure. However,

this review included just two small trials (106women) and its results should be interpreted withcaution. Although the review of antioxidant agents(vitamins C and E in particular) presented herereports a reduction in the relative risk of pre-eclampsia, two large trials have subsequentlyreported their results. In the recently updatedCochrane review, the effect on pre-eclampsia is nolonger statistically significant.

Main findings from the economicevaluationThe cost of most of the tests was modest, rangingfrom £5 for blood tests such as serum uric acid toapproximately £20 for Doppler tests. Similarly, thecost of most interventions was also modest. Incontrast, the best estimate of additional averagecost associated with an average case of pre-eclampsia was high at approximately £9000.

The results of the modelling revealed that priortesting with the test accuracy sensitivities andspecificities identified appeared to offer little as away of improving cost-effectiveness. Based on theevidence reviewed, none of the tests appearedsufficiently accurate to be clinically useful and theresults of the model favoured no-test/treat-allstrategies.

The treatments included in the main analysis wererest at home, antiplatelets, antioxidants andcalcium as these were the interventions where theRRs and 95% CIs showed they were unlikely to beassociated with a worse outcome of pre-eclampsiafrequency. However, if the results of the updatedCochrane review on antioxidants had beenavailable when the economic model was run,antioxidants would not have been so included.

Rest at home without any initial testing was themost cost-effective ‘test–treatment’ combination,delivering the greatest reduction in number ofcases of pre-eclampsia at virtually zero additionalcost (to the NHS). Calcium supplementation to allwomen, without any initial testing, was the secondmost cost-effective. The costs averted as a result ofthis reduction in cases of pre-eclampsia greatlyexceed the cost of the calcium supplementation.Paradoxically, antiplatelet agents, the treatmentabout which there was greatest certainty ofeffectiveness, did not feature among the cost-effective options highlighted. This was because thesize of the effect on number of cases of pre-eclampsia prevented, on current evidence, wassmaller than the effect of rest at home and calciumsupplementation. Thus, the very low costassociated with antiplatelet agents was outweighed

by the higher number of pre-eclampsia cases andthe high associated cost. Calcium was more costlycompared with antiplatelets but had fewer cases ofpre-eclampsia and was therefore shown to berelatively much more cost-effective by theeconomic model.

All three main predictions of the economic modelwere affected by uncertainty. However, effectivetreatments (RR <0.7) with modest costs (<£50)applied to all women without prior testing werelikely to be preferred from the perspective of cost-effectiveness. Threshold analyses conducted in theeconomic model suggested that tests with upperrange costs would need substantially improvedsensitivities (assuming best level of specificityachieved in any test was maintained). Theeconomic model provided little support that anyform of Doppler test has sufficiently highsensitivity and specificity to be cost-effective forthe early identification of pre-eclampsia. Theeconomic model also suggested that the pattern ofcost-effectiveness was no different in high-riskmothers than the low-risk mothers considered inthe base case.

ConclusionsNone of the tests evaluated is sufficiently accurate,in our opinion, to suggest its routine use inclinical practice. Calcium and antiplatelet agents,primarily low-dose aspirin, are the interventionsshown to prevent pre-eclampsia. The most cost-effective approach to reducing pre-eclampsia is

likely to be the provision of an effective, affordableand safe intervention applied to all motherswithout prior testing to assess levels of risk.However, we believe that it is probably prematureto suggest the implementation of a treat-allintervention strategy such as advice to rest orpharmacological interventions such as low-doseaspirin or calcium supplementation at present.However, the feasibility and acceptability towomen of offering universal application ofinterventions could be explored. Someconsideration needs to be given to whether thehealth service should continue to do certain testswhose main perceived value is to help identify pre-eclampsia when their usefulness is questionable.

Recommendations for furtherresearchRigorous evaluation is needed of tests with modestcost whose initial assessments suggest that theymay have high levels of both sensitivity andspecificity. Similarly, there is a need for high-quality, adequately powered randomised controlledtrials to investigate whether interventions such asadvice to rest are indeed effective in reducing pre-eclampsia. In future, an economic model should bedeveloped which considers not just pre-eclampsia,but other related outcomes, particularly thoserelevant to the infant such as perinatal death,preterm birth and small for gestational age. Such amodelling project should make provision forprimary data collection on the safety ofinterventions and their associated costs.


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AimsThe aims of this project were to investigate theaccuracy of predictive tests for pre-eclampsia andthe effectiveness of preventative interventions for pre-eclampsia, and also to assess the cost-effectiveness of strategies (test–interventioncombinations) to predict and prevent pre-eclampsia.

Description of underlying healthproblemNature of pre-eclampsia and definitionsPre-eclampsia (sometimes called toxaemia) is partof a spectrum of conditions known as thehypertensive (high blood pressure) disorders ofpregnancy. These disorders have a continuum withnormal pregnancy. In pregnant women,hypertension is usually defined as systolic bloodpressure of at least 140 mmHg and/or diastolicblood pressure of at least 90 mmHg. Pre-eclampsiais defined as hypertension accompanied byproteinuria,1 which usually occurs during thesecond half of pregnancy.2 Proteinuria duringpregnancy is defined as 300 mg of protein, ormore, in a 24-hour urine collection (whichcorrelates with 30 mg/dl or a spot ratio of�30 mg/ml).

There are four main categories of hypertensivedisorders in pregnancy which are now widelyagreed:

● Pre-eclampsia. Pre-eclampsia is defined ashypertension and proteinuria detected for thefirst time in the second half of pregnancy (after20 weeks’ gestation).

● Gestational hypertension or pregnancy-induced hypertension. This is hypertensiondetected for the first time during the secondhalf of pregnancy (after 20 weeks’ gestation) inthe absence of proteinuria. It usually resolveswithin 3 months after delivery. Gestationalhypertension that does not resolve after deliveryshould be reclassified as chronic hypertension.

● Chronic hypertension. This is hypertensionknown to be present before pregnancy, ordetected before 20 weeks’ gestation. It is

classified as essential hypertension if there is nounderlying cause and secondary hypertension ifthere is an underlying cause such as renal,cardiac or endocrine disease. Chronichypertension may present for the first time asgestational hypertension.

● Pre-eclampsia superimposed on chronichypertension. Women with chronichypertension may then develop pre-eclampsia.This is diagnosed where there is new onset ofproteinuria, or sudden worsening of eitherhypertension or proteinuria, or development ofother signs and symptoms of pre-eclampsiaafter 20 weeks’ gestation.

Attempts to classify the hypertensive disorders ofpregnancy have, in the past, been confusing andsometimes misleading. More recently, there hasbeen a shift towards standardising definitions, andensuring they are relevant for both clinicalpractice and research. Internationally, there is nowconsiderable agreement between the variouswidely used recommendations for classification.1,3,4

The suggestion that a change in blood pressure ismore important than any absolute level5 is nolonger included due to lack of evidence that it isrelated to outcome.1,3,4 Oedema was originally oneof the triad of signs of pre-eclampsia, but this hasnow been excluded from the definition.1,3,6 This ismainly because oedema is a common feature ofnormal pregnancy, can only be assessedsubjectively and does not define a group at risk ofpoor outcome. Oedema may be absent in somewomen with severe pre-eclampsia and eclampsia.

During normal pregnancy, cardiac outputincreases by about 40% in the first trimester. Bloodpressure remains relatively unchanged in the firsttrimester, falling by about 5–10 mmHg in thesecond trimester, and rising back to pre-pregnancylevels by term. Kidney function also increasesduring normal pregnancy leading to increasedprotein excretion.

When measuring blood pressure, any rise foundshould be confirmed by a second measurement,ideally at least 4 hours later. Blood pressureshould be measured with an auscultatory device, asoscillometric techniques systematically under-record during pregnancy.7 The debate over which


1


Chapter 1

Objectives and background

auscultatory sound to use for assessment ofdiastolic blood pressure, muffling (Korotkoff phaseIV) or disappearance (Korotkoff phase V), has beenresolved, and Korotkoff V is now recommended asmore reliable.4,8 When measuring proteinuria, ifonly a single midstream urine sample is available,this correlates with 30 mg/dl, 1+ or more on adipstick or a spot urine protein/creatinine ratio ofat least 30 mg/mmol.3,4

For many women, developing pre-eclampsia can bea difficult and unexpected experience, especially ifthey become ill or deliver too early9 or their babydies. Women with mild pre-eclampsia generallyhave no symptoms. Women with severe pre-eclampsia or very high blood pressure may feelunwell with symptoms such as headache, upperabdominal pain or visual disturbances.

AetiologyThere has been an exponential increase in basicscience literature exploring aetiology of pre-eclampsia, yet it remains a ‘disease of theories’.Many aetiological (genetic, nutritional,immunological and infectious) andpathophysiological (abnormal placentation,oxidative stress and endothelial dysfunction)pathways have been proposed as causal hypothesesfor pre-eclampsia.10 Some of these are describedbelow.

The placenta is believed to play a key role in pre-eclampsia. Pre-eclampsia occurs only in thepresence of a placenta, and its resolution beginswith the removal of the placenta at delivery. Pre-eclampsia can occur when there is no foetus, as ina molar pregnancy,11 and when the pregnancy isnot in the uterus, as in an abdominal pregnancy.12

Abnormal implantation of the placenta13 andexcessive placental tissue have both beenimplicated as the underlying pathology in pre-eclampsia.

Pre-eclampsia is thought to occur as a result ofinadequate blood supply to the placenta. Innormal pregnancy, as the placenta implants in theuterus important changes take place in the bloodvessels to ensure that the growing placenta andfoetus have adequate blood supply from themother. As the normal placenta implants itinvades the spiral arterioles in the uterus,replacing their endothelial lining and remodellingthem into large diameter vessels with a largecapacity to handle blood flow to the placenta.14 Inpre-eclampsia, these vascular adaptations may bepatchy or fail to extend into the deeper layers ofthe uterus,13 resulting in small-diameter, high-

resistance blood vessels that are unable to meetthe increasing demand for blood supply to theplacenta. Alternatively, implantation may benormal but there may be a relative reduction inplacental perfusion if the placenta is large, andnormal uterine blood flow is then inadequate toperfuse this large placenta, for example in amultiple pregnancy. Implantation and vascularchanges are complete by 20–22 weeks’ gestation.Hence, although pre-eclampsia is usuallydiagnosed in the second half of pregnancy, theantecedents are present much earlier.

Current thinking is that inadequate blood supplyto the placenta leads to the release of unknownfactors or materials into the maternal circulation.These factors then activate or injure theendothelial cells, resulting in endothelialdysfunction (abnormal functioning of endothelialcells).15 Several pathways for this link betweenreduced perfusion of the placenta and endothelialdysfunction have been proposed. One hypothesisis that reduced placental perfusion may give riseto oxidative stress. In an environment whereoxidants exceed neutralising antioxidant,16

excessive formation of free radicals leads to lipidperoxidation and cell membrane damage.17

Alternatively, lack of oxygen in the placenta maytrigger the release of small proteins, known ascytokines, that start an inflammatory response inthe endothelium.18 Another proposed mediatorfor the endothelial cell injury is micro fragmentsof placental tissue. These are transferred into thematernal circulation, and have been shown to alterendothelial function in laboratory studies.19

Endothelial dysfunction results in a series ofchanges associated with narrowing of the bloodvessels and an increased tendency to blood clots.These include reduced production of vasodilatorsand anticoagulants (such as prostacyclin and nitricoxide), increased production of vasoconstrictorsand platelet aggregators (such as thromboxane A2and endothelin), increased responsiveness ofendothelium to the vasopressor angiotensin II andan elevation in the proteins of the coagulationcascade (such as von Willebrand factor). In additionto widespread vasoconstriction and activation ofplatelets and the coagulation system, these changeslead to leakage of fluid out of the blood vessels andinto surrounding tissues, causing oedema and areduction in the circulating blood volume. There isthen inadequate blood flow to many of the woman’sorgans, especially the kidneys, liver and brain. It isthe vasoconstriction, micro-clots, and reducedcirculating blood volume that result in the clinicalmanifestations of pre-eclampsia.


2

However, reduced perfusion of the placenta is notsufficient to explain pre-eclampsia. The abnormalimplantation may interact with maternalconstitutional factors (genetic, environmental andbehavioural) to produce the syndrome of pre-eclampsia. The contributions of reduced perfusionand maternal factors may be balanced differentlyin different pregnancies. For example, profoundlyreduced perfusion could lead to pre-eclampsia inwomen with minimal predisposing risk, whereasfor others the maternal constitution might presentsuch a high risk that even minimal reduction ofplacental perfusion was sufficient.

Despite a growing understanding of thepathophysiology of pre-eclampsia, the underlyingaetiology remains unclear. Factors that appear tohave a role include the placenta, maternalimmune response, genetic predisposition,maternal vascular disease and diet. Whether anindividual woman will develop this syndromeprobably depends on which of these factors shehas and how they interact.

Normal pregnancy requires adaptation of thematernal immune response, so that the foetus,who also carries the father’s genes, is not rejectedas foreign tissue. It has been suggested that forsome women pre-eclampsia may occur becausethis adaptation is inadequate, for example in afirst pregnancy with a new partner.20 Insubsequent pregnancies with the same partner, theimmune response is more complete, and the riskof pre-eclampsia is therefore lower. Even a firsttrimester miscarriage or termination providessome protection.21

Risk factors with a particularly high associationwith pre-eclampsia (more than a one in 10 risk)include maternal diabetes,22–24 chronichypertension22,23,25 and renal disease.26

Thrombophilias and autoimmune disease have astrong association with severe early-onset pre-eclampsia.27 Obstetric factors associated with highrisk are multiple pregnancy,23,28 history of pre-eclampsia in a previous pregnancy, especially ifsevere or early onset,22,29,30 and a currenthydropic11 or molar pregnancy.31 Other factorslinked with pre-eclampsia, but associated with asomewhat lower risk, include firstpregnancies,3,23,31 young (less than 20 years) orolder age (more than 35 years),23,24 a familyhistory of pre-eclampsia32,33 and obesity.23,34,35

Pre-eclampsia tends to run in families, suggestingthat genetic predisposition may be a factor. Therisk is higher for sisters and daughters of women

who had eclampsia and pre-eclampsia.32,33

A number of genes are currently under evaluationfor possible links with pre-eclampsia.36

Medical conditions associated with vascular (bloodvessel) disease also increase the risk of a womandeveloping pre-eclampsia. For example, the risk isdoubled with diabetes37 and one-fifth of womenwith chronic hypertension develop pre-eclampsia.25 In addition, the thrombophilias areassociated with severe early-onset pre-eclampsia.27

This is a group of conditions with a tendency forthrombosis or blood clotting. They include proteinS deficiency, activated protein C resistance andautoimmune diseases such as antiphospholipidsyndrome and systemic lupus erythematosus.Recently, a raised blood level of homocysteine, ametabolite of the amino acid methionine, hasbeen linked to pre-eclampsia,38 although asystematic review of the relevant literature castdoubt on the likelihood of these being a causalassociation.39

Certain dietary factors have been linked to pre-eclampsia. For example, Mayan Indians inGuatemala, who traditionally soak their corn inlime before cooking, have a high calcium intakeand a low incidence of pre-eclampsia andeclampsia. This led to the hypothesis that anincrease in calcium intake during pregnancy mightreduce the incidence of pre-eclampsia amongwomen with low calcium intake. Similarly, theobservation that Greenland Inuits who eat a lot ofoily fish have a low incidence of pre-eclampsiaprovided the basis for the hypothesis that fish oilmight prevent this condition.40 Other dietaryfactors that have been suggested to have a role inpreventing pre-eclampsia include magnesium,zinc, selenium, antioxidants such as vitamin C andE, folic acid, garlic and rhubarb.

It is clear that basic science literature has not sofar provided a deep enough understanding of thebiological mechanisms of disease in pre-eclampsia.This raises questions about the completeness ofour basic knowledge and soundness of ourinterpretation of the available scientificinformation on disease mechanisms.10 Systematicreviews have largely not been applied to studydisease mechanisms and aetiology. The WHOprogramme to conquer pre-eclampsia has initiatedsystematic reviews to study aetiopathogenesis ofpre-eclampsia.41

EpidemiologyHypertension is common during pregnancy.Around 10% of women will have their blood


3


pressure recorded as above normal at some pointbefore delivery. Pre-eclampsia complicates 2–8% ofpregnancies;2 however, the incidence variesaccording to risk factors. Among unselectedwomen, the incidence rate of pre-eclampsia isestimated to be 2.5% [95% confidence interval(CI) 1.9 to 3.4%] from the control group eventrate in a trial of antiplatelet agents for preventingpre-eclampsia and its complications.42 Amongprimiparous women it is estimated to be 4.7%(95% CI 4.3 to 5.3%) by pooling control groupevent rates in five trials of antiplatelet agents forpreventing pre-eclampsia.43–47 Among high-riskwomen (e.g. previous pre-eclampsia or foetalgrowth restriction, pre-existing hypertension,nephropathy or diabetes, multiple pregnancy) it isestimated to be 10% (95% CI 9.3 to 10.8%) bypooling control group event rates in six trials ofantiplatelet agents for preventing pre-eclampsia.48–53 Overall, 15–25% of women withgestational hypertension progress to pre-eclampsia.54

PrognosisFor women who have hypertension alone,pregnancy outcome is similar to that for womenwith normal blood pressure. Once proteinuriadevelops, the outcome may be compromised. Pre-eclampsia can develop into severe pre-eclampsiaand/or eclampsia. The clinical features or tests inpre-eclampsia that predict the risk of complicationsneed delineation through systematic review. Arecent review of the literature on the predictivevalue of serum uric acid showed imprecise, poor-quality evidence,55 a feature likely to be prevalentin other related prognostic literature.

There is no widely accepted definition of severepre-eclampsia. Nevertheless, it is generally agreedthat two or more of the following indicate severedisease: severe hypertension (blood pressure atleast 160 mmHg systolic or 110 mmHg diastolic),severe proteinuria [usually at least 3 g (range2–5 g) of protein in 24 hours or 3+ on dipstick],reduced urinary volume (less than 400–500 ml in24 hours), neurological disturbances such asheadache, visual disturbances, and exaggeratedtendon reflexes, upper abdominal pain, pulmonaryoedema (fluid in the lungs), impaired liverfunction tests, high serum creatinine, low platelets,intrauterine growth restriction or reduced liquorvolume.3,4,56 Eclampsia is the occurrence ofseizures in a woman with pre-eclampsia.

Severe pre-eclampsia can lead to problems in theliver, kidneys and brain and to abnormalities ofthe clotting system. Rare but particularly serious

complications include eclampsia, stroke,haemolysis, elevated liver enzymes and lowplatelets (HELLP) syndrome and disseminatedintravascular coagulation (DIC). These seriouscomplications are associated with an increased riskof maternal death.57 As the placenta is alsoinvolved in pre-eclampsia, there are also increasedrisks for the baby. The most common are poorgrowth due to inadequate blood supply throughthe damaged placenta, and problems associatedwith prematurity, due either to planned early birthto protect the mother or the baby, or to thespontaneous onset of preterm labour.

Although the outcome following pre-eclampsia oreclampsia is good for most women, theseconditions remain major causes of maternalmortality. There is also growing evidence thatwomen who have had gestational hypertension orpre-eclampsia may be at increased risk later in lifeof hypertension, stroke and, to a lesser extent,ischaemic heart disease.58,59 For the babies, pre-eclampsia is an antecedent for up 12% withgrowth restriction at birth60 and for 19% ofpreterm births.61 Being born too early, or withgrowth restriction, is associated with an increasedrisk of developmental delay and chronic ill healthin childhood.

Burden of diseaseOver half a million women die each year frompregnancy-related causes, and 99% of these deathsoccur in the developing world.2 However, thereremain considerable gaps in burden of diseasestudies in the geographical coverage of causes ofmaternal mortality. An estimated 10–25% ofmaternal deaths in developing countries areassociated with pre-eclampsia or eclampsia62

(Table 1), as are 15% of the direct obstetric deathsin the UK63 and USA.56 Perinatal mortality is alsoincreased following pre-eclampsia.63,64

There is less information about morbidity foreither mother or baby, but it is likely that this toois high. For example, pre-eclampsia accounts foran estimated one-fifth of antenatal admissions,65

two-thirds of referrals to day-care assessmentunits66 and one-quarter of obstetric admissions tointensive care units.67 Psychological morbidityfollowing a difficult pregnancy or labour orperinatal death is well documented,68 althoughthere is little information specific to pre-eclampsia.

Current service provisionScreening for women at risk of pre-eclampsia is animportant part of antenatal care. Routine


4

screening for pre-eclampsia is based onmeasurement of blood pressure and urinalysis forproteinuria. Once women have been identified asat high risk, they can be targeted for moreintensive antenatal surveillance and prophylacticinterventions such as early delivery. Most currentstrategies for risk assessment are based on theobstetric and medical history and clinicalexamination. Pregnant women are assessed attheir first antenatal clinic (prior to 12 weeks ifpossible) for risk factors for pre-eclampsiaincluding age, nulliparity, long pregnancy interval,prior history of pre-eclampsia, high body massindex (BMI), history of diabetes mellitus andhypertension. If a woman has any of the riskfactors, an increased schedule of blood pressurescreening is provided. Otherwise, they have bloodpressure measurement and urinalysis forproteinuria at 16, 25, 28, 31, 34, 36, 38 and40 weeks. No other blood tests to detect pre-eclampsia are recommended and routine Dopplerultrasound scans of the uterine or umbilical arteryare not recommended.69

Primary prevention is preventing the onset of adisease, for example prevention of any signs orsymptoms of pre-eclampsia. Secondary preventionis the reversing, stopping or slowing of itsprogress, for example prevention of proteinuria ina woman with gestational hypertension. Tertiaryprevention is the prevention of complications inestablished disease, for example, prevention ofeclampsia in a woman with pre-eclampsia. Thisproject is mainly concerned with primaryprevention.

As the cause of pre-eclampsia is not completelyunderstood, it is difficult to develop rationalstrategies for prevention. Current strategies forprevention focus on antenatal surveillance,modification of lifestyle, dietary interventions andpharmacological therapy. Certain lifestyle choicesmay influence risk of hypertension, such aswhether to exercise, how much to rest in bed andwhether to modify the salt content in the diet. Asthese would normally be a matter of personal

preference, it is important that anyrecommendation that women modify their lifestyle should be based on adequate evidence.70

Antenatal care is a complex package of care. Thecomponents of this package vary considerably,depending on a range of factors such as country,setting and the characteristics of the individualwoman. Evaluation of antenatal care shouldinclude evaluation of individual components, suchas how to measure blood pressure or proteinuria,comparisons of packages with differentcomponents and frequencies and comparisons ofdifferent settings and providers of care. Thisproject focuses on developing cost-effectiveprevention strategies for the UK NHS.

Various hypotheses have been put forward to linkpre-eclampsia with specific dietary deficiencies,either before or during pregnancy. For example,calcium71 and fish oil supplementation weresuggested based on observations of an associationbetween dietary intake and the incidence of pre-eclampsia in various communities. Zinc72 andmagnesium supplements73 were suggested asinterventions that might optimise normalphysiological function during pregnancy.Antioxidants such as vitamin C and E, seleniumand garlic have been suggested to counteractoxidative stress. Folic acid may correct raisedblood levels of homocysteine.

A wide range of drugs have been advocated forprimary and secondary prevention of pre-eclampsia. For example, diuretics were popularwhen oedema was considered to be an importantsymptom of pre-eclampsia. Antiplatelet agentswere suggested based on the hypothesis that theywould increase production of the vasodilatorprostacyclin and reduce the vasoconstrictorthromboxane, hence reducing the risk of pre-eclampsia.74 Anticoagulants have also beensuggested for women at particularly high risk,such as those with thrombophilias.75

Antihypertensive drugs are widely used for womenwith gestational or chronic hypertension in the


5


TABLE 1 Proportion of maternal deaths attributed to hypertensive disorders according to geographical regions

Region Number of Number of maternal deaths Proportion of maternal deaths data sets (denominator) caused by hypertensive disorders

(%)

Developed countries 5 2,823 16.1Africa 8 4,508 9.1Asia 11 16,089 9.1Latin America and Caribbean 10 11,777 25.7

hope that early control of blood pressure mayprevent progression to pre-eclampsia.76 Recently,there has been interest in nitric oxide, avasodilator and inhibitor of platelet aggregation.77

There is also considerable interest in this areafrom women’s consumer groups. A small,unpublished survey was conducted betweenDecember 2005 and January 2006 by Action onPre-Eclampsia (APEC) in direct response to theHTA effectiveness review project, which requestedconsumer feedback on the importance toconsumers of each of the effectiveness reviewtopics. APEC runs a helpline that receives between3500 and 4000 information requests per year, ofwhich approximately 20% are related toprevention of pre-eclampsia. The potential topicsfor the survey were reviewed by three members ofAPEC staff who run the APEC Helpline andinformation lines (via the telephone and website),who rated the importance of the topic toconsumers. Staff members were also asked toreport the most commonly asked questions.Responses were collated and rated as 2 (commonquestion), 1 (occasionally asked question) and 0(never asked – consumers unaware). In general,women were reported to be particularly concernedabout things that they can do themselves (such aslifestyle and dietary interventions), but there werealso questions about their healthcare professionals’actions (pharmacological interventions/antenatalcare interventions). The results from the surveyare given in Table 2.

This project will evaluate whether screening testscan be incorporated along with these interventionsinto a cost-effective prevention strategy. There aresurprisingly few reliable evidence summaries onthe individual risk factors for pre-eclampsia2,78

and how these might interact. Similarly, theevidence concerning accuracy of variousphysiological, ultrasonographic and biochemicalscreening tests for predicting pre-eclampsia needto be systematically reviewed.

Objectives of this projectThis research project was undertaken to meet thefollowing objectives:

1. To determine, among women in earlypregnancy, the accuracy of various tests (history,examination and investigations) for predictingthe later development of pre-eclampsia andrelated complications (see Table 3 for a list oftests).

2. To determine the effectiveness and safety ofpreventative interventions for pre-eclampsiaand its complications (see Table 4 for a list ofinterventions).

3. To determine the cost-effectiveness of testingand subsequent prevention strategies in termsof both human and financial costs.

The relationship of our objectives to the range ofwork required in this area is shown in Figure 1.


6

2*

1*

3*

Update and completion ofCochrane effectiveness

reviews

Tests to predictcomplications and

interventions to preventthem from occurring

COMPLICATIONSe.g. Eclampsia

Research notincluded as

part of this projectEconomic modelling

Reviews of test accuracyfor prediction ofpre-eclampsia

Interventions to prevent progression topre-eclampsia

e.g. aspirin treatment

e.g. accuracy of uterine arteryDoppler, plasma uric acid

of cost-effectiveness of testing and subsequent preventative strategies

e.g. MgSO4

*Numbers correspond to objectives outlined in the text above.

FIGURE 1 Methods of predicting and preventing pre-eclampsia: an overview of objectives of this project


7


TABLE 2 Consumer priorities

Review Gradinga Comment

Lifestyle interventionsRest for preventing pre-eclampsia in 2 More specifically, what is impact of working/stress in women women with normal blood pressure (a) with increasing blood pressure that has not reached threshold

or (b) women who have had pre-eclampsia and feeling guilty. Restmay have been advised by GP

Bed rest with or without hospitalisation 2for hypertension in pregnancy

Exercise and other physical activity for 0preventing pre-eclampsia

Aerobic exercise during pregnancy 0 Only asked as a normal antenatal question unrelated to pre-eclampsia

Dietary and nutritional interventionsAntioxidants (vitamin C and E only) 2 Are they safe? Do they work? Women are self-medicating

Altered protein and energy intake 2 Specifically related to Brewer diet women find via the Internet

Garlic 1

Magnesium 1 Only in relation to MgSO4 and whether dietary Mg may havehelped

Folate 1

Calcium 1

Fish oil and other prostaglandin precursors 1

Chinese herbal medicine (including rhubarb) 0

Zinc 0

Altered dietary salt 0

Pharmacological interventionsAntiplatelet agents – specifically aspirin 2 Often asked if it is safe/effective after GP or consultant says it

makes no difference. Potential for self-prescribing

Oral beta-blockers for mild to moderate 2 Questions concern long-term treatment and impact for hypertension asthmatics rather than severity of hypertension

Antihypertensive drugs for mild to moderate 1 Questions are more general; not related to severity of hypertension hypertension

Antihypertensive drugs for women with 0normal/borderline hypertension

Diuretics 0

Nitric oxide donors and precursors 0

Progesterone 0

Heparin in women with thrombophilia 0

Antenatal care interventionsAm I having the right pattern of antenatal 2 This is a high priority additional question and is commonly askedcare for my higher risk pregnancy? by women who have had pre-eclampsia

Self blood pressure monitoring versus 1 Questions about the value of home monitoring for women conventional blood pressure monitoring (particularly who have had pre-eclampsia)

Patterns of antenatal care for low-risk 1 Women are generally concerned about long interval between pregnancies 16 and 28 weeks, not specifically regarding pre-eclampsia

Antenatal day-care units versus hospital 1 Occasionally asked by a women who has been admittedadmission for women with complicated pregnancies

Ambulatory versus conventional methods 0for monitoring blood pressure

a Grading: 2, common question; 1, occasional question; 0, never asked – consumers unaware.Reproduced with permission from APEC.

Protocol developmentGeneric protocols were developed for undertakingthe review work, one for systematic reviews of test accuracy studies and the other for thedevelopment and maintenance of Cochranereviews evaluating interventions for prevention ofpre-eclampsia.79 These protocols outlined acommon set of methods for the selection andassessment of studies and included a standard listof outcomes to be assessed. More details about theeffectiveness reviews protocol can be found inAppendix 1.

The research questionThe following structured question was addressed:

● Population Normotensive women inearly pregnancy at risk ofdeveloping hypertensivedisorders of pregnancy.

● Index tests See Table 3.● Reference standard Pre-eclampsia confirmed by

presence of hypertensionand proteinuria (andoedema as reported in olderprimary studies beforedefinitions were revised).

● Interventions See Table 4.● Outcomes Pre-eclampsia, perinatal

deaths, small-for-gestational age babies,preterm birth, need forhospitalisation, neonatalintensive care and relatedhealthcare costs.

Methods for test accuracy reviews Search strategyLiterature was identified from several sources,including

● general health and biomedical databases:PubMED (MEDLINE), EMBASE (Ovid)

● specialist electronic databases: The CochraneLibrary (DARE, CCTR), MEDION

● contact with experts including the CochranePregnancy and Childbirth Group

● checking of reference lists of review articles andpapers that were eligible for the systematicreviews included in this report.

The aim was to find all studies on all tests thatpredict or are believed to predict pre-eclampsia,using a single comprehensive search strategy.Therefore, search terms related to pre-eclampsiawere combined with methodological filters foridentification of aetiological and diagnostic teststudies (see Appendix 2 for details). MEDLINE(PubMED) and EMBASE were searched frominception to February 2004. Other databases weresearched from inception to December 2003.Experienced clinical librarians performed thesearches and their updates (last update 30 May2005). No language restrictions were applied. Acomprehensive master database of articles relevantto any predictive test was constructed usingReference Manager 10.0 software.

Inclusion criteriaThe criteria for study inclusion in the systematicreviews on predictive accuracy were as follows:

● Population: Any pregnant women in primary,secondary or tertiary care, at any level of risk ofdeveloping pre-eclampsia. Studies wereincluded that tested women at risk ofdeveloping pre-eclampsia before 25 weeks ofgestation. When gestational age at the time ofthe index test varied, the mean gestational age,as calculable from the descriptive statistics, hadto be less than 25 weeks. If gestational age wasunclear the study was excluded.

● Setting: Any setting including general practice,midwifery, outpatient clinics or based onnational or regional registers.

● Predictive tests (index tests): See Table 3. Testsused for the prediction of pre-eclampsia wereprioritised on the basis of clinical relevance andafter consultation with persons knowledgeableof NHS needs (we consulted with the Chair ofthe NHS Antenatal Sourcing Subgroup:Professor M Whittle; personal communication,November 2004. Foetal DNA was added to ouroriginal list based on the advice received.) Weexcluded studies that tested all women then


9


Chapter 2

Systematic review methods

selected only some for follow-up on the basis ofa specific range of index test results.

● Reference standard: Pre-eclampsia, using avariety of definitions. Pre-eclampsia was definedas hypertension (�140/90 mmHg) withproteinuria (total protein of �300 mg in a 24-hour urine collection, or �30 mg/dl in asingle sample of urine, or �1+ on a dipstick)developing for the first time after 20 weeks’gestation, with or without generalised oedema.For women with chronic hypertension, pre-

eclampsia was defined as a sudden worsening ofhypertension and/or proteinuria, or other signsand symptoms of pre-eclampsia after 20 weeks’gestation. When authors did not provide detailsof how pre-eclampsia was verified, pre-eclampsiarates as reported were accepted. At the stage ofdata extraction, the extent that pre-eclampsiadefinition complied with recent consensus wasassessed.3,4,80 All studies that compared a test orstrategy with a reference standard according tointernational standards or variations of the


10

TABLE 4 Cochrane effectiveness reviews updated in this project

Category

Antenatal care interventions Ambulatory versus conventional methods for monitoring blood pressure

Lifestyle interventions Bed rest with or without hospitalisation for hypertensionExercise for prevention of hypertensionRest in women with normal blood pressure

Dietary and nutritional interventions Altered dietary salt intakeAntioxidantsCalcium supplementation during pregnancy for preventing hypertensive disorders

and related problemsNutritional adviceBalanced protein/energy intakeIsocaloric balanced protein supplementationEnergy/protein restrictionGarlicMagnesiumMarine oil and other prostaglandin precursor supplementation during pregnancy for

reducing pre-eclampsia

Pharmacological interventions Antihypertensive drug therapy for mild to moderate hypertensionAntiplatelet agents for preventing pre-eclampsia and its complicationsDiuretics for preventing pre-eclampsiaNitric oxide and precursorsProgesterone

TABLE 3 Tests for predicting pre-eclampsia in early pregnancy reviewed in this project

Category

History None but data for tests subgrouped according to historical risk factors wherever possible

Examination BMI

InvestigationsBlood �-Foetoprotein (AFP)

Serum fibronectin (total and cellular)Foetal DNA (fDNA)Haemoglobin/haematocritHuman chorionic gonadotrophin (HCG)OestriolSerum uric acid

Urine Urinary calcium excretion, urinary calcium to creatinine ratioUrinary proteinuria (24-hour or spot tests for total proteinuria, albuminuria, microalbuminuria,

albumin to creatinine ratio, kallikrein, SDS-PAGE proteins)

Haemodynamic Uterine artery Doppler (any/unilateral notching, bilateral notching, combinations of waveforms, pulsatility index, resistance index, other ratios)

SDS-PAGE, sodium dodecyl sulfate polyacrylamide gel electrophoresis.

definition in pregnant women were included.3,4

The prediction of clinical consequences of pre-eclampsia was not part of this work.

● Study design: Diverse study designs wereincluded such as prospective cohorts, historiccohorts and (nested) case–control studies, all ofwhich could be matched or unmatched ondifferent variables. Studies had to report resultsso that a 2 × 2 table cross-classifying abnormaland normal test results and the occurrence ornon-occurrence of pre-eclampsia could becalculated. Excluded were all cross-sectionalstudies in which the distribution of a non-stableindicator (often a blood constituent) amongwomen with pre-eclampsia was compared withthat of non-pre-eclamptic women. With anystudy design, the description of thedistributions of test results among pre-eclampticand non-pre-eclamptic women for clearly non-(log)-normal test results could not betransformed into proper 2 × 2 tables and weretherefore excluded.

● Subgroups: Severe pre-eclampsia was defined ashypertension (systolic blood pressure�160 mmHg and/or diastolic blood pressure�110 mmHg) with proteinuria (total protein�2.0 g in a 24-hour urine collection or �3+ ona dipstick), with or without oedema. Also adistinction was made between early-onset(<34 weeks’ gestation) and late-onset(�34 weeks’ gestation) pre-eclampsia, but toofew studies provided this information.

Study selectionThe study selection process consisted of threesteps. First, titles and/or abstracts of all citations inthe master database (that is, irrespective of testtype) were assessed by one reviewer. If a citationwas considered potentially relevant, the full-textpaper was retrieved for further consideration.Reviewers were instructed to include the paper ifthere was any doubt, thus enhancing the sensitivityof the initial selection step. Second, for eachparticular review, a search based on keywords intitles and abstracts in the master database wasperformed to find all studies on the test at issue.One reviewer again scrutinised titles and/orabstracts of studies on the particular test to ensure(almost) independent duplicate selection. Onlypapers that were judged as irrelevant twice werenot ordered as full-text papers and all otherpapers were retrieved. Third, inclusion wasperformed independently by two reviewers whoassessed against the selection criteria detailedabove. Disagreements were resolved by consensusor by arbitration by a third reviewer whenconsensus could not be reached.

The reviewing team were fluent in English, Frenchand German so could select papers, extract dataand assess quality of papers in these languages.When necessary, papers in other languages,including Bulgarian, Chinese, Italian, Japanese,Russian and Spanish, were translated.

Data extractionClinical, methodological and statistical dataextraction was conducted independently induplicate, using a predesigned and piloted formthat changed only slightly between different indextests. Data extraction was carried out using theStatistical Package for the Social Sciences (SPSS)database and/or paper forms. See Appendix 3 fora list of data items extracted.

Disagreements between reviewers were resolved byconsensus or by arbitration by a third reviewer, ifdisagreement persisted. In case of serial index testmeasurements during pregnancy, a 2 × 2 data tablewas constructed for each serial measurement.Where multiple publications of the same study wereidentified, each publication was examined to ensurethat all relevant information for that particularstudy was recorded. However, only the mostcomplete report was used for extracting results.

Pairs of data extraction forms or SPSS files werechecked for discrepancies. After disagreementswere resolved information was entered into adedicated SPSS database. Relevant variables werechecked using descriptive statistics to detectimplausible values or outliers. Extreme or outlyingvalues were checked against the original dataextraction forms and against the originalpublications if necessary to further exclude thepossibility of data-entry errors.

Quality assessmentQuality items were included in the data extractionform (see Appendix 3). The following aspects ofmethodological quality of included test accuracystudies were assessed:81,82

● study design● consecutive recruitment/random sample● blinding of test results (both index and

reference tests)● greater than 90% verification of diagnosis● incidence of pre-eclampsia less than 4%● prospective data collection● adequate index test description● adequate reference standard.

Note that items on study design and incidence arenot strictly related to internal validity, but help the


11


reader to put the findings in context. Study designwas extracted and reported in tables. Study qualitywas assessed independently by two reviewers. Anydisagreements were resolved by consensus or byarbitration by a third reviewer, if disagreementpersisted.

The following items were included in qualitydiagrams in study summaries and assessed usingthe three criteria listed under each item:

● Consecutive recruitmentYes – adequate patient recruitment was presentwhen there was a consecutive series of patientsor the study used random sampling.Unclearly reported – selection criteria and patientrecruitment were not clearly reported so that onecould not tell what selection criteria were used.No – recruitment was considered inadequatewhere it was specifically described and was notconsecutive or random.

● Blinding of the test results (index test orreference test)Yes – adequate blinding was present when it wasexplicitly stated that the results of each test wereinterpreted unaware of the results of the othertest or when it might be inferred that they wereinterpreted before the other test results wereavailable as applies to the index test result inprospective cohort studies.Unclearly reported – no description of whethereither test was interpreted under blindconditions.No – inadequate blinding was present if it wasclear from the text that neither test result wasinterpreted under blind conditions.

● Verification of diagnosisYes – adequate verification of diagnosis waspresent where at least 90% of the womenoriginally subjected to the index test andfulfilling the inclusion criteria were followed upand had verification by the reference standard.Unclearly reported – where the numbers ofwomen excluded or lost to follow up were notcalculable.No – inadequate where the follow-up level wasbelow 90%.

● Incidence of pre-eclampsia <4%We dichotomised the item ‘incidence of pre-eclampsia’ using an incidence cut-off value of4% in cohort studies (and based on theunderlying cohort in nested case–controlanalyses where possible). This was done becausein cohort studies with more than 10,000women, which reflect more or less unselectedpopulations, the incidence of pre-eclampsiavaried between 1.3 and 3.2%.83–85

Yes – unselected (low risk) patient spectrumwhere incidence of pre-eclampsia <4%.Unclearly reported – we could not determine theincidence of pre-eclampsia in the study.No – selected patient spectrum where incidenceof pre-eclampsia was �4%.The intention was to do subgroup analysis forhigh- and low-risk populations.

● Prospective data collectionYes – this was adequate when it was clear thatthe research protocol for the study had beenwritten before data collection took place(prospective).Unclearly reported – we could not tell whether thedata collection was conducted prospectively orretrospectively.No – this was inadequate when there wasretrospective data collection or there was amixture of prospective and retrospective datacollection.

● Adequate description of index testYes – adequate description of index test if thegestational age at the time of testing, type oftest (e.g. assay/manufacturer) and cut-off levelwere all reported. For the Doppler review thecriteria were type of Doppler, type of machineand probe used, level of high-pass filter, angleof insonation, size of sampling gate, number ofconsecutive waveforms measured, one or bothuterine arteries, description of site ofmeasurement, measurement parameter and cut-off level used, route (transvaginal ortransabdominal).Unclearly reported – unclear description was thedescription of one or more items in addition togestational age and cut-off level but not anadequate description.No – inadequate, gestational age and cut-offlevel reported only.

● Adequate reference standardYes – adequate reference standard if strictly inaccordance with current internationallyaccepted standards of definition of pre-eclampsia.Unclearly reported – unclear, if hypertensionand/or proteinuria were not clearly defined interms of cut-off level such as >140/90 mmHg orproteinuria >0.3 g in 24 hours.No – inadequate, when the definition of pre-eclampsia included other items such as a rise insystolic or diastolic blood pressure orhyperuricaemia or oedema, or when criteriawere more loose or stringent.Adequacy of the reference standard for studiesthat reported on severe pre-eclampsia as anoutcome was based on the definition of severepre-eclampsia.


12

Methods of statistical analysisSummary measures for predictive accuracyThe main focus of each review was a summaryestimate of predictive accuracy as expressed by itssensitivity and specificity and their 95% CIs, for thestudies that gave 2 × 2 tables. A secondary aim wasto identify (clinically relevant) sources ofheterogeneity, if any. If the calculation of a summaryestimate was deemed not meaningful, individualstudy results were depicted using forest plots andreceiver–operator characteristic (ROC) plots only.

Data exploration and statistical analysisIn each review, we used forest plots and ROC plotsto display the precision by which sensitivity andspecificity had been measured in each study andto illustrate the variation in estimates betweenstudies. The 95% CIs were calculated using theexact binomial method, according to Wilson.86

Extreme values, outliers and threshold phenomena(data points on a typical convex ROC curve) wereexplored. If appropriate, we used a bivariate meta-regression model to meta-analyse estimates ofsensitivity and specificity.87,88 Therefore, at leasttwo studies with comparable data on test resultshad to be included. Rather than using a singleoutcome measure per study, such as the diagnosticodds ratio in the summary receiver–operatorcharacteristic (sROC) approach, the bivariate modelpreserves the two-dimensional nature of diagnosticdata by directly analysing the logit transformedsensitivity, log[sensitivity/(1 – sensitivity] andspecificity, log[specificity/(1 – specificity)], of eachstudy in a single model. This model estimates andincorporates the correlation that might existbetween logit sensitivity and specificity withinstudies due to possible differences in thresholdbetween studies. The bivariate model uses arandom effects approach for both sensitivity andspecificity, allowing for heterogeneity beyondchance due to clinical or methodologicaldifferences between studies. In addition, themodel acknowledges the difference in precision bywhich sensitivity and specificity have beenmeasured in each study. This means that studieswith a larger number of patients with the targetcondition receive more weight in the calculation ofthe summary estimate of sensitivity, whereasstudies with more patients without the targetcondition are more influential in the pooling ofspecificity. The model requires logittransformation of the sensitivity and specificity. Astandard correction of adding 0.5 to all four cellsof the 2 × 2 table was applied when eithersensitivity or specificity was 100%. The modelproduces the following results: a random effectestimate of the mean sensitivity and specificity

with corresponding 95% CIs, the amount ofbetween-study variation for sensitivity andspecificity separately and the strength and shapeof the correlation between sensitivity andspecificity. The results have been transformed back(anti-logit) to the original scale and used tocalculate sROC curves with their 95% CIs. Wherepossible, covariates were added to the model totest explicitly whether either sensitivity, specificityor both are different in clinically cogent subgroupsof studies. When possible the analysis aimed toestimate valid measures of predictive accuracytaking into account confounding by anymethodological flaws. In the first instance,attempts were always made to quantify the extentto which the accuracy measures varied by clinicalsubgroups, such as early versus laterdetermination. STATA SE 9.0 (StataCorp, CollegeStation, TX, USA) was used for calculations exceptto fit the various bivariate models, for which theProc Mixed procedure in SAS version 9.1 forWindows (SAS Institute, Cary, NC, USA) was used.

Data descriptionFor each test, information on individual studieswas summarised using:

● A table with methodological and reportingcharacteristics of the included studies. Thenumber of women analysed was based on thetotal number of women tested before the 25thweek of gestation in each study. The incidenceof pre-eclampsia was based on the number ofanalysed cases divided by the total number ofwomen at baseline (cohort studies and nestedcase–control studies). Results (such as age) aregiven as mean [± standard deviation (SD)] forthe whole group unless stated otherwise.

● A table with individual quality and reportingitems of the included studies. Symbols used inthe table were classified as follows: +, studycomplies with item; –, study does not complywith item; ?, item unclearly or not reported.

● A summary of quality and reporting items ofthe included studies. Data were presented as100% stacked bars, where figures in the stacksrepresent the number of studies. The item‘study design’ is stated in the table with qualityand reporting characteristics.

● Forest plots of sensitivities (%) andspecificities (%) and 95% CIs. Studies areranked according to decreasing specificity(within subgroups). Numbers of womenanalysed are tp/(tp + fn) for sensitivity andtn/(fp + tn) for specificity (fp, fn = falsepositive, false negative numbers; tp, tn = truepositive, true negative numbers).


13


● An ROC plot. Estimates of predictive accuracyfrom individual studies are shown (separate forsubgroups if appropriate) and where possible ansROC curve (according to the bivariate method)was drawn. In the sROC plots the vertical axisshows sensitivity, and the horizontal axis shows1 – specificity.

● A table with subgroup analyses (if applicable).Significance level p < 0.10.

Methods for Cochrane reviewsSearch strategyThe Cochrane Pregnancy and Childbirth Group'strials register was searched. This register ismaintained by the Trials Search Coordinator andcontains trials identified from:

● quarterly searches of the Cochrane CentralRegister of Controlled Trials (CENTRAL)

● monthly searches of MEDLINE● handsearches of 30 journals and proceedings of

major conferences● weekly current awareness search of a further

37 journals.

Details of the search strategies for CENTRAL andMEDLINE, the list of handsearched journals andconference proceedings and the list of journalsreviewed via the current awareness service can befound under the heading ‘Specialized register’within the information about the CochranePregnancy and Childbirth Group at The CochraneLibrary (http://www.mrw.interscience.wiley.com/cochrane/clabout/articles/PREG/frame.html). Trialsidentified through the searching activitiesdescribed above were given a code (or codes)depending on the topic. The codes were linked toreview topics. The Trials Search Coordinatorsearches the register for each review using thesecodes rather than keywords.

In addition, CENTRAL (The Cochrane Library)and EMBASE (2002 to current) were searchedusing a generic search strategy to identify trialsrelated to pre-eclampsia (see Appendix 4) in orderto find trials that were not already listed in thetrial register. For individual reviews this searchcould be expanded by including additional termsspecific to the intervention being assessed. Thejournal Hypertension in Pregnancy was alsohandsearched for the years 2000–5. Reference listsof trial reports were checked for additionalcitations. Trial reports were also obtained throughpersonal communication with trialists or experts inthe area. There were no language restrictions forany aspect of the search.

Inclusion criteria1. Population: Pregnant women, regardless of

gestation at trial entry. The only participantexclusions were where women had given birthprior to trial entry or if they had established pre-eclampsia. In the Cochrane reviews, women weregrouped according to normal blood pressure orhypertension (see Appendix 5 for details) butthese subgroups have not been reported here.

2. Intervention: Any intervention or combinationof interventions to prevent the occurrence ofpre-eclampsia (see Table 4). Where appropriatefor specific reviews, maximum and/or minimumintervention dosages were justified and specified.Based on current understanding of the aetiologyof pre-eclampsia, it is implausible that veryshort-term interventions could have clinicallyimportant effects on pre-eclampsia. Therefore,the minimum duration of the interventionplanned at trial entry was 7 days. If single-dosestudies or those with a planned intervention ofless than 7 days were included, this was justifiedand discussed in the individual review.

3. Comparator: Placebo or no intervention.Where one intervention was compared withanother intervention in the Cochrane reviews,these results were not used in this report.

4. Outcomes: For the purposes of this report, thefollowing outcomes were included:(a) For the woman – pre-eclampsia: defined

where possible as hypertension (bloodpressure �140 mmHg systolic or�90 mmHg diastolic) with proteinuria(�300 mg protein in a 24-hour urinecollection or �30 mg/dl in a single sampleor �1+ on dipstick). The definition doesnot include oedema. For a woman withchronic hypertension and proteinuria attrial entry, pre-eclampsia is defined assudden worsening of proteinuria and/orhypertension, or other signs and symptomsof pre-eclampsia after 20 weeks’ gestation.

(b) For the baby – death: including all deathsbefore birth and up to 1 year after birth, orthe closest outcome to this reported in thesystematic review. Preterm birth: defined asbirth before 37 completed weeks’ gestation.Small for gestational age: defined asgrowth below the third centile, or lowestcentile reported.A range of other outcomes were reportedin the Cochrane reviews but have not beenreported here. Details of these are availablein Appendix 5.

5. Study design: Randomised controlled trials(RCTs) evaluating any interventions forprevention of pre-eclampsia and its


14

complications. Studies with a quasi-randomdesign, such as allocation by alternation, day ofweek or hospital numbers, were included insome reviews. If a systematic review did includesuch studies, the subgroup results excludingstudies with a quasi-random design were alsoused in a subgroup analysis.Studies were excluded if:(a) more than 20% loss to follow-up or

withdrawal of participants (b) more than 20% of analysis not in the groups

to which the participants were randomised(c) large difference (more than 10%) in loss of

participants between groups.6. Subgroups. A large number of subgroups were

investigated in the Cochrane reviews and wereincluded in the generic protocol but have notbeen reported here because they were not usedto inform the economic model. Details of thesubgroups can be found in Appendix 5.

Study selectionEach citation was assessed for inclusion in a reviewby at least two reviewers independently. Anydifferences in opinion were resolved by discussion.If agreement could not be reached, the full textcopy was obtained and if necessary translated intoEnglish. If agreement still could not be reachedbased on the full text copy, further information wassought from the study authors. If the study authorscould not be contacted, a third party was consulted.

Data extractionData on study characteristics, methodologicalquality and results were extracted on to dataextraction sheets by at least two reviewers anddiscrepancies were resolved through discussion. Ifagreement was not reached, that item wasexcluded until further clarification was availablefrom the authors. Where data for one or moremain outcome were missing, authors were contactedwhenever possible to obtain more information.The information was entered on to ReviewManager software (RevMan 2003) and checked foraccuracy by at least one other reviewer.

Quality assessmentThe quality of each included trial was assessedindependently by at least two reviewers using thecriteria outlined in the Cochrane Handbook.89

Each study was assessed for method of randomallocation, quality of the concealment ofallocation, completeness of follow up and blindingin the assessment of outcome.

1. Allocation concealmentA quality category for concealment of allocation

was assigned to each trial, using the followingcriteria:(a) adequate concealment of allocation, such

as telephone randomisation, consecutivelynumbered sealed opaque envelopes.

(b) unclear whether adequate concealment ofallocation

(c) inadequate concealment of allocation suchas random number tables, sealed envelopesthat are not numbered or opaque.

Where the method of allocation concealment isunclear, whenever possible attempts were madeto contact authors to provide further details.

2. Completeness of follow-upCompleteness of follow-up was assessed usingthe following criteria: (a) less than 5% loss to follow-up or withdrawal

of participants(b) 5% to 10% loss to follow-up or withdrawal

of participants(c) more than 10% and up to and including

20% loss to follow-up or withdrawal ofparticipants. For most of the individualreviews, where information was missing,clarification was sought from the authors.For the purposes of this report, wherereviews did not include information aboutfollow-up (antiplatelets, energy and proteinintake), this has been recorded in theabsent/unclear/unreported category andindividual trialists were not contacted.

3. BlindingBlinding was assessed using the followingcriteria:(a) Blinding of patients (yes/no/unclear)(b) Blinding of caregiver (yes/no/unclear)(c) Blinding of outcome assessment

(yes/no/unclear).

For this report, the quality of the studies for eachsystematic review was summarised in tables whichwere then used to create the quality diagram foreach clinical effectiveness summary. Four categorieswere used: randomisation method (stated versusnot stated or unclear), allocation concealment(present versus not present or unclear), blinding(any blinding versus none) and more than 80%follow-up (present versus not present or unclear).These were assessed using the characteristics ofincluded studies published in each effectivenessreview. If the characteristic of the trial in thecharacteristics table was marked as unclearlyreported, that item was marked as unclear in thequality table. Individual trials were not examined.Data extraction from the Cochrane review tables ofcharacteristics was carried out by two reviewers anddiscrepancies resolved by discussion.


15


Methods of statistical analysisStatistical analyses were carried out using Revman(Revman 2003). Information was analysed basedon the group to which the participants wererandomised, regardless of whether they receivedthe allocated intervention or not. For dichotomousdata, results are presented as summary relativerisk (RR) with 95% CI.

The I2 statistic was used to assess heterogeneitybetween trials. In the absence of significantheterogeneity, results are pooled using a fixedeffect model. If substantial heterogeneity wasdetected (I2 > 50%), possible causes were exploredand subgroup analyses for the main outcomesperformed. Heterogeneity that was not explainedby subgroup analyses was modelled using randomeffects analysis, where appropriate

Methods of reportingThe full Cochrane review has been reported hererather than the trials that reported the pre-eclampsia outcome only. This is because we alsoreport here baby outcomes of death, preterm birthand small for gestational age. Where the resultshave RR 0.9–1.1 and the 95% CIs cross 1, wedescribe the results as having no clear effect onpre-eclampsia. If the RR is more extreme than thisbut the 95% CIs cross 1, we describe the pointestimate of effect but explain that these findingscould have been accounted for by chance alone.Where the 95% CIs do not cross 1, we describe theresults as unlikely to be accounted for by chancealone.

Modifications to the protocol andoriginal grant proposalFollowing approval of this HTA project, two keysystematic reviews appeared in the literature that

impacted on our plans.78,90 Moreover, as welearned more about the subject after commencingthe reviews, the knowledge gained was used toupdate our protocols. We sought input from theHTA programme at a monitoring visit (June 2005)concerning protocol modification. In all instancesof modification to the original proposal/protocol,our decisions were driven by new knowledge aboutmethods and definitions. We did not haveknowledge of results among included studies untilafter changes were implemented into the protocols.The comparison between proposed diagnostic andscreening tests and treatments for pre-eclampsia tobe systematically reviewed in the protocol andoriginal grant proposal and the final systematicreviews completed can be seen in Appendix 6.

Methods for economic evaluationSee the section ‘Methods for economic evaluation’(p. 85) for a description of the methods used forthe economic evaluation. This is because themethods include a description of inputs to theeconomic model that relies on informationprovided in Chapters 3 and 4.

Project reportingThe results of the three main parts of this review(test accuracy systematic reviews, effectivenesssystematic reviews and economic modelling) arereported separately with a discussion section foreach. Additional information (results anddiscussion) for effectiveness reviews is available inthe Cochrane Library. The final section of thereport considers all of the findings to drawconclusions overall. Recommendations for practiceand research appear individually in each sectionand in the concluding chapter.


16

Study selectionAt the final update of 30 May 2005 there were16,813 potentially relevant citations identified.These citations were screened for relevance to

each of the 11 systematic review categories andretrieved if relevant. The numbers of included andexcluded studies for each of the systematic reviewsare shown in Table 5.


17


Chapter 3

Test accuracy reviews

TABLE 5 Process from initial search to final inclusion for accuracy reviews

Papers retrieved for Reasons for exclusiondetailed evaluationa

Index test

Body mass indexd NA NA 13 2 1 1 11�-Foetoprotein 117f 79 8 75 44 6 7 1 15 2 12Fibronectin 136f 66 – 62 1 12 4 27 17 1 4

Cellulare 2Totale 3

fDNA 52 33 – 30 15 6 – 5 3 1 3Haemoglobin/haematocrit 1057 79 1 78 50 10 10 3 5 – 2Human chorionic gonadotrophin 572f 149 3 136 85 17 9 1 21 3 16Oestriol 431f 77 1 75 57 5 5 2 3 2 3Uric acid 664f 186 6 187 139 40 5 3 5Calcium/creatinine 1025f 195 5 192 146 22 6 12 4 2 8

Urinary calcium excretione 4Urinary calcium creatinine ratioe 6

Proteinuria/albuminuria 1718f 117 – 100 63 7 3 12 4 11 17Doppler uterine artery 1072 229 3 166 69 23 26 22 16 13 63

Any/unilateral notchinge 19Bilateral notchinge 22Combinations of FVWe 25Pulsatility indexe 8Resistance indexe 25Other ratiose 7

FVW, flow velocity waveform; NA, not applicable; PIH, pregnancy-induced hypertension.a Based on topic specific search in Reference Manager.b Including 2 × 2 tables with artificial test positive/test negative ratio.c Other reasons for exclusion include duplicate publication, unobtainable, no translation available, no cut-off used.d Review based on O’Brien and colleagues, Epidemiology 2003;14:368–74, where large cohort studies were available for

precise estimation of accuracy.e Italicised index tests are reviews performed after search immediately above mentioned.f Search until October 2004.

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ExaminationsBody mass indexPre-existing physical characteristics of pregnantwomen, such as BMI before pregnancy, have beenproposed as potential risk factors for pre-eclampsia. BMI is calculated as weight (kg) perheight squared (m2) and is categorised asunderweight (BMI < 20), normal weight (BMI20–25), overweight (BMI > 25) and obese(BMI > 30). In particular, maternal obesity isassociated with an increased risk of adversepregnancy outcomes.

The review of diagnostic accuracy of BMI included11 studies (452,615 women) (see Appendix 7).The quality of the studies is shown in Figure 2 andAppendix 8. Sensitivities and specificities areshown in Figure 3 and ROC space in Figure 4.Pooled estimates of sensitivity and specificity usedin decision modelling were as follows:

● BMI � 34: 18% (95% CI 15 to 21%) and 93%(95% CI 87 to 97%)

● BMI > 29: 23% (95% CI 15 to 33%) and 88%(95% CI 80 to 93%)

● BMI > 24.2: 41% (95% CI 29 to 53%) and 75%(95% CI 62 to 84%)

● BMI < 19.8: 11% (95% CI 8 to 16%) and 80%(95% CI 73 to 86%).

Investigations – bloodMaternal serum �-foetoproteinDetermination of maternal serum �-foetoprotein(AFP) is used worldwide for screening of foetalaneuploidy and anomalies as part of the triple testand marker for neural tube defects. Freeavailability of this information has encouragedresearchers to assess its predictive value for pre-eclampsia. AFP is a glycoprotein produced by theyolk sack and foetal gastrointestinal tract.Maternal serum AFP levels rise until 32 weeks ofgestation, whereas foetal AFP peaks at 10–13 weeksand then declines progressively until term.Elevated AFP levels are associated with open spinabifida and anencephaly, whereas in Down’ssyndrome pregnancies AFP levels stabilise at15–20 weeks of gestation.

The review of diagnostic accuracy of AFP included12 studies (137,097 women) (see Appendix 7).The quality of the studies is shown in Figure 5 andAppendix 8. The sensitivities and specificities areplotted in Figure 6 and ROC space in Figure 7.Studies are classified by (1) counting all casesversus severe cases of pre-eclampsia only (Ratyand colleagues, Stamilio and colleagues; forreferences referred to only within individualsystematic reviews, see Appendix 12), (2) cut-offvalue 2.5 multiples of median (MoM) (top four


18

4

5

7

5

6

2

6

5

7

6

2

11

11

0 20 40 60 80 100

Adequate reference standard

Adequate test description

Prospective data collection

Incidence of pre-eclampsia <4%

Over 90% verification of diagnosis

Blinding of test results

Consecutive recruitment

Compliance with quality item (%)

Yes Unclearly reported No

Numbers within stacked bars are numbers of studies

FIGURE 2 Quality and reporting assessment of studies on BMI


19


0 20 40 60 80 100

Sensitivity (95% CI)

0 20 40 60 80 100

Specificity (95% CI)

OBESEBianco >34.9 vs 19-27 (85/442)

Sibai >33.9 (53/326)OVERWEIGHT

Ros >29 (18/126)Thadhani >29.9 (10/83)Steinfeld >28.9 (15/129)

Baeten >29.9 (1321/6512)Sebire >29.9 (97/326)

Sibai >29.9 (97/326)Bowers >29 (5/14)

Ogunyemi >29 (25/46)NORMAL WEIGHTLee >24.2 (74/415)

Knuist >26 (5/28)Ros >26 (37/126)

Thadhani >24.9 (22/83)Baeten >24.9 (2915/6512)

Sibai >25.9 (166/326)Sebire >24.9 (1213/2451)

Ogunyemi >26 (38/46)Bowers >26 (7/14)

UNDERWEIGHTSibai <20 (20/326)

Ogunyemi <19.8 (3/46)Ros <19.8 (11/126)

Baeten <20 (731/6512)Knuist <19.8 (7/28)

Thadhani <21 (22/83)Lee <19.8 (80/415)

OBESE(10956/11484)

(3616/3984)OVERWEIGHT

(2170/2292)(16083/17128)

(2142/2295)(81415/89872)

(253933/284762)(3238/3984)

(187/267)(358/536)

NORMAL WEIGHT(27288/29320)

(1805/2052)(1981/2292)

(13189/17128)(65508/89872)

(2507/3984)(175685/284762)

(293/536)(126/267)

UNDERWEIGHT(3536/3984)

(461/536)(1953/2292)

(71710/89872)(1637/2052)

(11545/17128)(19521/29320)

1st A

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FIGURE 3 BMI (prepregnancy) sensitivities, specificities and 95% CIs. Studies are categorised in subgroups by cut-off values, whichare stated to the right of first author’s name. For references referred to only within individual systematic reviews, see Appendix 12.

0

0.2

0.4

0.6

0.8

1.0

0 0.2 0.4 0.6 0.8 1.0

1 – Specificity

Sens

itivi

ty

FIGURE 4 BMI plotted in ROC space. Diamonds represent obesity, squares overweight, triangles normal weight and circles underweight.

studies) versus 2.0 MoM (other studies). None ofthe subgroup analyses for AFP were statisticallysignificant (see Table 6). We used pooled estimatesof sensitivity and specificity of 9% (95% CI 5 to16%) and 96% (95% CI 94 to 98%), respectively, ineconomic modelling.

Cellular and total fibronectinWomen destined to develop pre-eclampsia arereported to have higher plasma fibronectin (FN)

concentrations than (pregnant) controls. FN is aglycoprotein of which several subtypes exist.Inflammation, vascular injury and malignancy aregenerally associated with increased expression ofthe extra domain A (ED-A) (also called ED-1+ oroncofoetal FN) and ED-B (also called ED-2+)forms of FN, particularly in the blood vessel walls.ED-A (oncofoetal) FN is also released by theplacenta and has been used as a predictor forpreterm birth. ED-A and ED-B are both called


20

9

7

6

51

5

3

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7

4

2

5

3

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0 20 40 60 80 100

Compliance with quality item (%)Yes Unclearly reported No

FIGURE 5 Quality and reporting assessment of studies on AFP.

0 20 40 60 80 100 0 20 40 60 80 100

Sensitivity (95% CI) Specificity (95% CI)

CUTOFF 2.5 MOMMorssink (2/40)Yaron (82/1894)

Wenstrom (5/53)Jauniaux (8/11)

CUTOFF 2.0 MOMLeung (1/21)Pouta (1/34)

Milunsky (19/223)Waller (63/673)

Capeless (0/7)Simpson (3/63)

SEVERE PERaty (3/10)

Stamilio (4/49)

CUTOFF 2.5 MOM(1941/1968)

(56627/58146)(4401/4561)

(21/30)CUTOFF 2.0 MOM

(980/994)(591/603)

(12752/13263)(47932/50335)

(328/351)(544/587)

SEVERE PE(1220/1232)(1822/1949)

FIGURE 6 AFP sensitivities, specificities and 95% CIs

cellular FN and contain only 5% of all FN inplasma whereas total FN contains all subtypes of FN.

The review of test accuracy of cellular FN includedtwo studies (135 women) and total FN includedthree studies (373 women) (see Appendix 7). Thequality of the four studies in total (one studyreported both cellular and total FN) is shown inFigure 8 and Appendix 8. Sensitivities andspecificities are shown in Figures 9 and 10 and

ROC space in Figures 11 and 12. We were unableto derive meaningful pooled estimates ofsensitivity and specificity. Three studies reportedon several cut-off values, all shown in the forestplots and ROC plots. For cellular FN we used asensitivity of 50% (95% CI 29.9 to 70.1%) at thehighest specificity achieved of 96% (95% CI 79 to99%) for economic modelling, measured in thesecond trimester at a cut-off value of 5.0 μg/ml.For total FN we used a sensitivity of 65% (95% CI44 to 83%) at the highest specificity achieved of


21


0

0.2

0.4

0.6

0.8

1.0

0 0.2 0.4 0.6 0.8 1.0

1 – Specificity

Sens

itivi

ty

FIGURE 7 AFP plotted in ROC space. The ROC space has triangles representing studies with severe pre-eclampsia as outcome, solidline representing the sROC curve and dashed lines representing the 95% CI of the sROC curve.

TABLE 6 Subgroup analysis (significance level p < 0.10) for maternal serum AFP testing based on 12 studies

Covariate Sensitivity (%) (95% CI) p-Value Specificity (%) (95% CI) p-Value

Pooled estimates (no. of studies) 9 (5 to 16) 96 (94 to 98)Severity of pre-eclampsia 0.528 0.618

Overall (10) 8 (4 to 16) 96 (93 to 98)Severe (2) 14 (3 to 46) 97 (89 to 99)

Cut-off value 0.491 0.6552.0 MoM (8) 8 (3 to 17) 97 (93 to 98)2.5 MoM (4) 12 (4 to 31) 95 (88 to 98)

Incidence 0.177 0.329<4% (6) 7 (3 to 14) 97 (94 to 99)�4% (5) 15 (6 to 32) 95 (88 to 98)

Type of immunoassay 0.649 0.166Radio (3) 7 (2 to 21) 97 (91 to 99)Enzyme (4) 13 (4 to 33) 93 (84 to 97)Fluorescent (2) 15 (3 to 54) 99 (95 to 100)Not reported (3)a 7 (2 to 25) 96 (89 to 99)

a The category ‘Not reported’ was not used in calculating p-values.


22

3

4

4

3

1

4

1

4

4








0 20 40 60 80 100


FIGURE 8 Quality and reporting assessment of studies on cellular and total FN

0 20 40 60 80 100Sensitivity (95% CI)

0 20 40 60 80 100Specificity (95% CI)

1st A

utho

r, cu

toff

(num

ber

of w

omen

ana

lyse

d)

1st TRIMESTER cFNLockwood, 4.0 (2/6)Lockwood, 3.2 (4/6)Lockwood, 2.8 (6/6)

2nd TRIMESTER cFNLockwood, 5.8 (7/20)

Chavaria, 4.5 (9/26)Lockwood, 4.2 (16/20)Chavarria, 3.6 (18/26)

Lockwood, 3.2 (18/20)Chavarria, 2.7 (25/26)

1st TRIMESTER cFN(8/8)(6/8)(5/8)

2nd TRIMESTER cFN(23/23)(51/52)(18/23)(39/52)(13/23)(20/25)

FIGURE 9 Cellular FN sensitivities, specificities and 95% CIs. Numbers to the right of author’s name are cut-off values in �g/ml.

0 20 40 60 80 100Sensitivity (95% CI)

1st A

utho

r, cu

toff

(num

ber

of w

omen

ana

lyse

d) 1st TRIMESTER tFNLockwood, 4.15 (1/6)Lockwood, 393 (3/6)

Paarlberg, 240 (14/26)Lockwood, 370 (4/6)Lockwood, 347 (5/6)2nd TRIMESTER tFN

Soltan, 393(11/17)Lockwood, 400 (5/20)Lockwood, 380 (9/20)

Lockwood, 350 (11/20)Paarlberg, 230 (18/26)

Lockwood, 230 (14/20)

1st TRIMESTER tFN(6/8)

(6/86)(129/202)

(5/8) (5/8)

2nd TRIMESTER tFN(67/71)(21/23)(20/23)(17/23)

(135/202)(10/23)

0 20 40 60 80 100Specificity (95% CI)

FIGURE 10 Total FN sensitivities, specificities and 95% CIs. Numbers to the right of author’s name are cut-off values in mg/l.

94% (95% CI 86 to 98%) at a cut-off value of293 μg/ml for economic modelling.

Foetal DNAPre-eclampsia is associated with an underlyingplacental lesion which facilitates increasedtrafficking of foetal cells and the release of cell-freefoetal DNA (fDNA). A marked increase in theconcentration of circulating cell-free fDNA hasbeen found in the plasma of women with pre-eclampsia compared with normotensive women. Inplasma of pregnant women carrying male foetuses,sequences from the SRY gene were amplified todistinguish fDNA from maternal DNA.

The review of diagnostic accuracy of fDNA includedthree studies (351 women) (see Appendix 7). The quality of the studies is shown in Figure 13and Appendix 8. Sensitivities and specificities are shown in Figure 14 and the ROC space in Figure 15. We used pooled estimates of sensitivityand specificity of 50% (95% CI 31 to 69%) and 88%(95% CI 80 to 93%), respectively, for economicmodelling. Each study was represented once in thepooled estimates [cut-off values: Cotter andcolleagues >50,000 copies/ml, Farina andcolleagues 10% false positive rate (FPR) and Leungand colleagues �33.5 genome-equivalents(Geq)/mi].


23


0

0.2

0.4

0.6

0.8

1.0

0 0.2 0.4 0.6 0.8 1.0

1 – Specificity

Sens

itivi

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FIGURE 11 Cellular FN plotted in ROC space. Diamonds represent results from Lockwood and colleagues and triangles Chavarria andcolleagues.

0

0.2

0.4

0.6

0.8

1.0

0 0.2 0.4 0.6 0.8 1.0

1 – Specificity

Sens

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FIGURE 12 Total FN plotted in ROC space. Diamonds represent results from Lockwood and colleagues, squares Paarlberg andcolleagues and triangle Soltan and colleagues.


24

3

1

3

2

1

2

1

1

1

1

2

12Adequate reference standard







0 20 40 60 80 100


FIGURE 13 Quality and reporting assessment of studies on foetal DNA

0 20 40


60 80 100 0 20 40


60 80 100

Cotter >55,000 (34/88)

Cotter <50,000 (72/88)

Cotter <10,000 (83/88)

Farina 5% FPR (26)

Farina 10% FPR (3/6)



Leung �33.5 Geq/ml (12/18)

(159/176)

(114/176)

(57/176)

(28/30)

(27/30)

(25/30)

(24/30)

(27/33)

1st A

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t-of

f (n

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FIGURE 14 fDNA sensitivities, specificities and 95% CIs

0

0.2

0.4

0.6

0.8

1.0

0 0.2 0.4 0.6 0.8 1.0

1 – Specificity

Sens

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FIGURE 15 fDNA plotted in ROC space. Diamonds represent results from Cotter and colleagues, squares Farina and colleagues andtriangle Leung and colleagues.

Haemoglobin/haematocritPre-eclampsia, when it is severe, can be associatedwith a reduced cardiac output combined with anincreased systemic vascular resistance and lowplasma volume in comparison with normalpregnancy. Endothelial dysfunction and damagemay lead to capillary leakage of plasma towardsthe interstitium and therefore low plasma volumeand an increase in haematocrit and haemoglobin.

The review of diagnostic accuracy of haemoglobinand haematocrit included one study forhaemoglobin (546 women) and one study forhaematocrit (707 women) (see Appendix 7). Thequality of the studies is shown in Figure 16 andAppendix 8. The sensitivities and specificities areshown in Figure 17 and the ROC space in

Figure 18. Both studies were of poor quality so nofurther statistical analysis was possible and noresults were used in economic modelling.

Maternal serum human chorionicgonadotrophinMaternal serum HCG is used worldwide forscreening of foetal aneuploidy, such as Down’ssyndrome, and anomalies as part of the triple test.This has also made the investigation of itspredictiveness of pre-eclampsia possible. MaternalHCG levels seem to be increased in the secondtrimester in pregnancies that subsequently developpre-eclampsia. HCG is a glycoprotein composed oftwo non-covalently linked subunits, � and �, and isproduced mainly by the syncytiotrophoblast cellsof the placenta after the luteo-placental shift (end


25


1

1

2

1

2

2

1

1

1

2








0 20 40 60 80 100



FIGURE 16 Quality and reporting assessment of studies on haemoglobin and haematocrit

0 20 40 60 80 100


0 20 40 60 80 100


HAEMOGLOBIN

Heilmann (13/38)

HAEMATOCRIT

Goh >34% (10/38)

Goh >41% (28/38)

HAEMOGLOBIN

(590/669)

HAEMATOCRIT

(467/508)

(106/508)

1st A

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FIGURE 17 Haemoglobin and haematocrit sensitivities, specificities and 95% CIs

of first trimester). HCG peaks at 8–10 weeks andthen declines to reach a plateau at 18–20 weeks ofgestation.

The review of diagnostic accuracy of maternalHCG included 16 studies (72,732 women) (seeAppendix 7). The quality of the studies is shownin Figure 19 and Appendix 8. Sensitivities andspecificities are shown in Figure 20. Table 7shows the results of subgroup analyses for HCG

where type of immunoassay affected bothsensitivity and specificity. The ROC space is shownin Figure 21, where triangles represent studies with severe pre-eclampsia as outcome, the solidline represents the sROC curve and dashed lines represent the 95% CI of the sROC curve. We used pooled estimates of sensitivity andspecificity of 24% (95% CI 16 to 35%) and 89%(95% CI 86 to 92%), respectively, in economicmodelling.


26

0

0.2

0.4

0.6

0.8

1.0

0 0.2 0.4 0.6 0.8 1.0

1 – Specificity

Sens

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FIGURE 18 Haemoglobin and haematocrit plotted in ROC space. Squares represent results from Goh and colleagues and diamondHeilmann and colleagues.

6

9

12

1

12

32

8

1

2

14

2

11

2

2

2

1

1042

6








0 20 40 60 80 100


FIGURE 19 Quality and reporting assessment of studies on maternal HCG


27


0 20 40Sensitivity (95% CI)

60 80 100 0 20 40Specificity (95% CI)

60 80 100

1st A

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sed)

2nd TRIMESTER hCGYaron (76/1387)Morssink (4/40)

Lambert (10/60)Heinonen (26/243)

Lee (26/95)Aquilina (11/35)

Muller (11/34)Ashour (34/194)

Luckas (4/19)Onderoglu (7/15)

Vaillant (11/16)Pouta (6/30)

Jauniaux (8/11)1st TRIMESTER hCG

Haddad (0/3)Yaron (10/27)

SEVERE PELee (19/56)

Stamilio (5/49)

2nd TRIMESTER hCG(42404/44178)

(1877/1968)(284/299)

(4718/5047)(883/957)(548/605)

(5176/5742)(5336/5944)

(367/411)(473/547)(356/418)(510/607)

(19/30)1st TRIMESTER hCG

(150/177)(1261/1595)SEVERE PE

(915/996)(1735/1949)

FIGURE 20 Maternal HCG sensitivities, specificities and 95% CIs. Note that Lee and colleagues reported on both pre-eclampsia andsevere pre-eclampsia.

TABLE 7 Subgroup analysis (significance level p < 0.10) for maternal HCG testing based on 16 studies

Covariate Sensitivity (%) p-Value Specificity (%) p-Value(95% CI) (95% CI)

Pooled estimates (no. of studies) 24 (16 to 35) 89 (86 to 92)Definition of pre-eclampsia 0.474 0.435

Internationally accepted (2) 22 (8 to 47) 91 (82 to 96)Other variations (11) 31 (20 to 44) 88 (83 to 91)Unclearly/not reported (3)a 10 (4 to 24) 93 (88 to 97)

Severity of pre-eclampsia 0.796 0.819Overall (15) 26 (17 to 37) 89 (86 to 92)Severe (2) 22 (6 to 54) 90 (80 to 96)

Cut-off value 0.728 0.2522.0 MoM (9) 23 (14 to 37) 89 (84 to 92)2.3 or 2.5 MoM (5) 20 (9 to 38) 92 (87 to 95)Not reported in MoM (2)a 58 (20 to 88) 85 (71 to 93)

Type of immunoassay 0.011 0.037Radio (3) 12 (5 to 25) 93 (89 to 96)Enzyme (5) 45 (28 to 64) 87 (81 to 92)Fluorescent (2) 28 (10 to 57) 82 (69 to 90)Not reported (6)a 17 (9 to 29) 91 (86 to 94)

Gestational age at testing 0.772 0.105�14 weeks (14) 24 (15 to 35) 90 (87 to 93)<14 weeks (2) 28 (7 to 67) 82 (67 to 91)


Serum unconjugated oestriolDetermination of serum unconjugated oestriol isused worldwide for screening of foetal aneuploidyand anomalies as part of the triple test. Given therole of the placenta in determining the maternalserum level of this hormone, its predictive value in pregnancies with placental dysfunction such as in pre-eclampsia have also been investigated.Oestriol is produced by the placenta by conversionof foetal 16-�-hydroxydehydroepiandrosteronesulfate to androgens, which are subsequentlyaromatised to oestriol. It is first detected at8 weeks of gestation. Early in pregnancy,dehydroepiandrosterone sulfate (DHEA-S)production by the foetal adrenal gland isindependent of foetal adrenal corticotrophichormone (ACTH); in the second trimester ACTHis required for adrenal function. Henceforward,90% of oestriol production is accounted for byDHEA-S derived from the foetal adrenal glands.Either a placental or a foetal pathologicalcondition, alone or in combination, could beassociated with low serum oestriol levels.

The review of diagnostic accuracy of serumunconjugated oestriol included three studies(26,811 women) (see Appendix 7). The quality ofthe studies is shown in Figure 22 and Appendix 8.Sensitivities and specificities are shown in Figure 23and the ROC space in Figure 24. We used pooled

estimates of sensitivity and specificity of 26% (95%CI 9 to 56%) and 82% (95% CI 61 to 93%),respectively, in economic analysis.

Serum uric acidHigh blood uric acid levels have been found to beassociated with pre-eclampsia since 1917, but arealso associated with other pathophysiologicalstates. Renal impairment and an increasedbreakdown of purines in the ischaemic placentaleading to overproduction of uric acid may explainincreased serum uric acid (SUA) levels in (future)pre-eclamptic patients. In normal pregnancy, aftera decrease in SUA concentration, SUA levels risein the third trimester, possibly due to increasedfoetal production, decreased binding to albuminand a decline in uric acid clearance. The NationalHeart, Lung and Blood Institute recommendedthe determination of SUA in high-risk womenpresenting with normal blood pressure.

The review of test accuracy of serum uric acidincluded five studies (514 women) (seeAppendix 7). The quality of the studies is shownin Figure 25 and Appendix 8. The sensitivities andspecificities are shown in Figure 26 and ROC spacein Figure 27. We used pooled estimates ofsensitivity and specificity of 36% (95% CI 22 to53%) and 83% (95% CI 73 to 90%), respectively, ineconomic analysis.


28

0

0.2

0.4

0.6

0.8

1.0

0 0.2 0.4 0.6 0.8 1.0

1 – Specificity

Sens

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FIGURE 21 Maternal HCG plotted in ROC space. The ROC space has triangles representing studies with severe pre-eclampsia asoutcome, solid line representing the sROC curve and dashed lines representing the 95% CI of the sROC curve.


29


2

1

2

2

1

111

1

2

1

2

2

1

1








0 20 40 60 80 100


FIGURE 22 Quality and reporting assessment of studies on serum unconjugated oestriol

Yaron (71/777)

Kowalczyk (5/13)

Stamilio (21/49)

0 20 40


60 80 100

(22060/23727)

(220/296)

(1374/1949)

0 20 40


60 80 1001st A

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ana

lyse

d)

FIGURE 23 Serum unconjugated oestriol sensitivities, specificities and 95% CIs. Note that Stamilio and colleagues reported on severepre-eclampsia as an outcome.

0.2

0.4

0.6

0.8

1.0

0 0.2 0.4 0.6 0.8 1.0

1 – Specificity

0.0

Sens

itivi

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FIGURE 24 Serum unconjugated oestriol plotted in ROC space. The ROC space has a solid line representing the sROC curve anddashed lines representing the 95% CI of the sROC curve.


30

5

1

2

1

5

4

1

4

1

4

3

4








0 20 40 60 80 100


FIGURE 25 Quality and reporting assessment of studies on serum uric acid

0 20 40 60 80 100


0 20 40 60 80 100


1st A

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ana

lyze

d)

Jauniaux (3/11)

Salako (0/5)

Conde-Agudelo (4/13)

Winocour (5/9)

Jacobsen (2/4)

(27/30)

(13/16)

(288/374)

(10/13)

(37/39)

FIGURE 26 SUA sensitivities, specificities and 95% CIs. Note that Jacobson and colleagues used a cut-off of rise above baselinerather than absolute value.

0

0.2

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0.6

0.8

1.0

0 0.2 0.4 0.6 0.8 1.0

1 – Specificity

Sens

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FIGURE 27 SUA plotted in ROC space. The ROC space has solid line representing the sROC curve and dashed lines representing the95% CI of sROC curve.

Investigations – urineUrinary calcium excretion/urinarycalcium creatinine ratioIn normotensive pregnancies, renal excretion ofcalcium increases, reaching maximum levels in thethird trimester. In normal pregnancy, urinarycalcium excretion (UCE) is 350–620 mg/day,compared with 100–250 mg/day in non-pregnantwomen. Several studies have reported a decreasedUCE in pre-eclampsia compared withnormotensive pregnancies. UCE represents a

balance between glomerular filtration and tubular(re)absorption; the latter may be increased in pre-eclampsia. The urinary calcium/creatinine ratio(UCCR) at 24–34 weeks was suggested to bepredictive of pre-eclampsia.

The review of test accuracy of urinary calciumexcretion included four studies (705 women) andurinary calcium creatinine ratio included sixstudies (1345 women) (see Appendix 7). Thequality of the studies is shown in Figures 28 and 29and Appendix 8. The sensitivities and specificities


31


1 2 1








0 20 40 60 80 100


3 1

2 2

1 3

4

1 3

1 3

FIGURE 28 Quality and reporting characteristics of studies on urinary calcium excretion

1 4 1








0 20 40 60 80 100


3 3

1 1 4

2 4

6

1 1 4

6

FIGURE 29 Quality and reporting assessment of studies on urinary calcium/creatinine ratio

are shown in Figure 30 and ROC space inFigures 31 and 32. We used pooled estimates ofsensitivity and specificity for UCE of 57% (95% CI24 to 84%) and 74% (95% CI 69 to 79%),respectively, in economic analysis. We used pooledestimates of sensitivity and specificity for UCCR of50% (95% CI 36 to 64%) and 80% (95% CI 66 to89%), respectively, in economic analysis.

ProteinuriaRoutine proteinuria urinalysis is conducted inantenatal clinics from first booking but there islittle guidance to support this for pre-eclampsiaprediction. Proteinuria measurement includes totalprotein or total albumin excretion in 24 hours,

microalbuminuria, albumin/creatinine ratio,dipsticks for spot proteinuria or albuminuria andmore unusual proteins such as kallikrein andsodium dodecyl sulfate polyacrylamide gelelectrophoresis (SDS-PAGE) proteins.

The review of diagnostic accuracy included 11studies (4388 women), of which four reported totalproteinuria (2228 women), two reportedalbuminuria (88 women), two reportedmicroalbuminuria (190 women) and one eachreported microalbuminuria/creatinine ratio (1422 women), kallikrein (307 women) and SDS-PAGE proteins (153 women) (seeAppendix 7). The quality of the studies is


32

0 20 40 60 80 100


0 20 40 60 80 100


UCESanchez-Ramos (7/8)

Nisell 19-21 wks (3/11)Nisell 11-13 wks (2/11)

Baker (4/13)Suarez (11/15)

UCCRSoltan (9/17)Rogers (4/8)

Conde-Agudelo (4/13)Kazerooni (6/8)

Suarez (10/15)Baker (4/13)

UCE(76/91)20/26)

(19/26)(351/487)

(35/54)UCCR

(67/71)(172/191)(292/374)

(73/94)

(37/54)(268/487)

1st A

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FIGURE 30 UCE and UCCR sensitivities, specificities and 95% CIs

0

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0.6

0.8

1.0

0 0.2 0.4 0.6 0.8 1.0

1 – Specificity

Sens

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FIGURE 31 UCE shown in ROC space. The ROC space has solid line representing the sROC curve and dashed lines representing the95% CI of the sROC curve.


33


shown in Figure 33 and Appendix 8. Sensitivitiesand specificities are shown in Figure 34 and ROC space in Figure 35. Pooled estimates ofsensitivity and specificity used in decisionmodelling were as follows: total proteinuria, 35% (95% CI 13 to 68%) and 89% (95% CI 79 to

94%); total albuminuria, 70% (95% CI 45 to 87%)and 89% (95% CI 79 to 94%); microalbuminuria,62% (95% CI 23 to 90%) and 68% (95% CI 57 to77%); and albumin/creatinine ratio, 19% (95% CI12 to 28%) and 75% (95% CI 73 to 77%),respectively.

0

0.2

0.4

0.6

0.8

1.0

0 0.2 0.4 0.6 0.8 1.0

1 – Specificity

Sens

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FIGURE 32 UCCR shown in ROC space. The ROC space has solid line representing the sROC curve and dashed lines representing the95% CI of the sROC curve.

5 6








0 20 40 60 80 100



11

8 1 2

1 3 7

8 2 1

8 3

2 9

FIGURE 33 Quality and reporting assessment of studies of proteinuria


34

0 20 40 60Sensitivity (95% CI)

80100 0 20 40 60Specificity (95% CI)

80100

TOTAL PROTEINURIADelmis (106/193)

Sibai 1 (22/193)Sibai 2 (14/73)

Combs (47/67)ALBUMINURIAWinocour (7/9)Ekbom 2 (5/8)

MICROALBUMINURASoltan (7/17)

Gonzalez (23/29)MICROALB/CREAT

Masse (19/101)KALLIKREINURIAMillar <75 (6/12)

Millar <200 (10/12)Millar <100 (10/12)

SDS PAGE PROTEINURIAWinkler (29/29)

TOTAL PROTEINURIA(473/499)(511/570)(276/310)(184/244)

ALBUMINURIA(13/14)(50/57)

MICROALBUMINURA(51/71)(47/73)

MICROALB/CREAT(991/1321)

KALLIKREINURIA(295/295)(294/295)(294/295)

SDS PAGE PROTEINURIA(85/124)

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FIGURE 34 Proteinuria tests sensitivities, specificities and 95% CIs

0

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1 – Specificity

Sens

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FIGURE 35 Proteinuria tests shown in ROC space. Diamonds represent total proteinuria, small squares represent albuminuria, largesquare microalbumin/creatinine ratio, triangles microalbuminuria, circle SDS-PAGE proteinuria and crosses kallikreinuria.

Investigations – haemodynamicUterine artery DopplerDoppler ultrasound has been demonstrated to bea reliable, non-invasive method of examininguteroplacental perfusion. Alterations in flowvelocity waveforms measured in the uterinearteries are associated with an increased risk forsubsequent development of pre-eclampsia (and/orfoetal growth restriction). There are six reviews ofDoppler diagnostic tests which correspond to thesix ways of reading a Doppler test:

1. A unilateral notch refers to an early diastolicnotch measured in either the left or right mainuterine artery; any notch refers to either aunilateral early diastolic notch or bilateralnotches measured in the main uterine arteries.

2. Bilateral notching refers to early diastolicnotches measured in both main uterine arteries.

3. All single ratios such as S/D ratio, A/C ratio andnotch index.

4. The pulsatility index of the main uterine arteryis calculated as peak systolic flow minus end

diastolic flow divided by mean flow [= (A – B)/M].

5. The resistance index of the main uterine arteryis calculated by peak systolic flow minus enddiastolic flow divided by peak systolic flow[(A – B)/A].

6. Several flow velocity waveforms, single orcombined, have been investigated for theprediction of pre-eclampsia. In this review,combinations of notching and resistance index,notching and pulsatility index, notching andother ratios are reported.

Any or unilateral notching of the main uterinearteriesThe review of diagnostic accuracy of any orunilateral notching included 19 studies (14,345women) (see Appendix 7). The quality of thestudies is shown in Figure 36 and Appendix 8. Thesensitivities and specificities are shown inFigure 37. Table 8 shows the results of subgroupanalysis. The ROC space is shown in Figure 38,where the solid line represents the sROC curveand dashed lines represent 95% CIs. Studies with


35









0 20 40 60 80 100



105 4

19

8 11

8 3 4

1 18

10 1 8

11 7 1

FIGURE 36 Quality and reporting assessment of studies on Doppler any/unilateral notching

TABLE 8 Subgroup analysis (significance level p < 0.10) for any/unilateral notching of the main uterine artery


Pooled estimates (no. of studies) 63 (51 to 74) 82 (74 to 87)Incidence 0.647 0.025

<4% (8) 66 (47 to 81) 88 (81 to 93)�4% (12) 61 (43 to 76) 75 (65 to 84)

0

0.2

0.4

0.6

0.8

1.0

0 0.2 0.4 0.6 0.8 1.0

1 – Specificity

Sens

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1.0

FIGURE 38 Doppler any or unilateral notching plotted in ROC space. The ROC space has a solid line representing the sROC curve anddashed lines representing the 95% CI of the sROC curve.


36

0 20 40 60 80 100


0 20 40 60 80 100


ANY NOTCHING(602/654)(201/234)(126/148)

(3498/4132)(552/654)(252/303)(723/874)(226/279)

(70/87)(60/84)(50/75)(35/53)

(77/124)(198/329)(121/205)

(81/148)(23/48)

(277/596)(102/231)

UNILATERAL NOTCHING(1902/1981)

(93/97)(1108/1160)

(612/654)(578/654)

(2265/2564)(1749/2013)

ANY NOTCHINGAntsaklis 24 (16/21)

Geipel (twin) 21 (9/22)Venkat-raman 23 (6/16)

Prefumo 21 (13/17)Antsaklis 20 (17/21)Phupong 24 (7/19)

Marchesoni 22 (20/26)Ohkuchi 20 (6/9)Aardema 22 (1/7)

Coleman 23 (20/32)Frusca 24 (3/3)Frusca 24 (3/3)

Schwarze 24 (6/7)Schwarze 23 (14/17)

Schwarze 21 (8/10)Venkat-raman 17 (10/16)

Axt-Fliedner 23 (3/4)Harrington 14 (3/4)

Carbillon 13 (10/12)UNILATERAL NOTCHING

Bower 24 (35/45)Konchak 20 (5/6)

Harrington 20 (10/44)Antsaklis 24 (7/21)Antsaklis 20 (7/21)

Audibert 22 (20/51)Bower 20 (37/45)

1st A

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FIGURE 37 Doppler any or unilateral notching of the main uterine arteries: sensitivities, specificities and 95% CIs. Studies areclassified by any notching versus unilateral notching. Numbers to the right of the author’s name indicate (average) gestational age attesting. Note that some authors reported data at several gestational ages.

several measurements are represented once only.We used pooled estimates of sensitivity andspecificity of 63% (95% CI 51 to 74%) and 82%(95% CI 74 to 87%), respectively, in decisionmodelling.

Bilateral notching of the main uterine arteriesThe review of diagnostic accuracy of Dopplerbilateral notching included 22 studies (29,395women) (see Appendix 7). The quality of thestudies is shown in Figure 39 and Appendix 8.Sensitivities and specificities are shown in Figure 40.Table 9 shows the results of subgroup analysis. TheROC space is shown in Figure 41, where the solidline represents sROC curve and dashed linesrepresent 95% CIs. Studies with severalmeasurements are represented once only. We usedpooled estimates of sensitivity and specificity of48% (95% CI 34 to 62%) and 92% (95% CI 87 to95%), respectively, in decision modelling.

Single ratios such as systolic/diastolic (S/D) ratio,albumin/creatinine (A/C) ratio and notch indexThe review of diagnostic accuracy of single ratiossuch as S/D ratio, A/C ratio and notch indexincluded three studies (659 women) for S/D ratio,four studies (1335 women) for A/C ratio and onestudy (625 women) for notch index (seeAppendix 7). The quality of the studies is shownin Figure 42 and Appendix 8. Sensitivities andspecificities are shown in Figure 43. Table 10 showsthe results of subgroup analysis. The ROC space isshown in Figure 44. The subgroup sensitivities andspecificities with their 95% CIs are for the S/Dratio 49% (30 to 69%) and 80% (60 to 92%), forthe A/C ratio 71% (55 to 83%) and 82% (72 to89%) and for notch index 12% (2 to 46%) and78% (61 to 88%), respectively. We used pooledsensitivities and specificities of 55% (95% CI 37 to72%) and 80% (95% CI 73 to 86%), respectively, indecision modelling.


37









0 20 40 60 80 100



74

22

10 14

16 6

22

156 1

14 6 2

14 4

FIGURE 39 Quality and reporting assessment of studies on Doppler bilateral notching

TABLE 9 Subgroup analysis (significance level p < 0.10) for bilateral notching of the main uterine arteries



<4% (9) 47 (28 to 68) 95 (89 to 97)�4% (14) 45 (27 to 63) 89 (80 to 94)


38

0 20 40 60 80 100 0 20 40 60 80 100

Sensitivity (95% CI) Specificity (95% CI)

Mires 23 (8/863)Mires 19 (23/363)

Harrington 20 (24/44)Yu 23 (4/21)

Albaiges 24 (21/65)Audibert 22 (11/51)

Geipel 21 (4/22)Antsaklis 24 (9/21)

Prefumo 21 (11/17)Marchesoni 22 (16/26)

Venkat-raman 23 (4/16)Carbillon 23 (5/12)

Antsaklis 20 (10/21)Ohkuchi 20 (5/9)

Papageorghiou 23 (45/113)Kurdi 20 (13/21)Uludag 19 (9/10)

Frusca 24 (3/3)Coleman 23 (9/32)

Geipel 21 (2/2)Schwarze 24 (4/6)

Schwarze 24 (8/17)Schwarze 21 (4/10)

Venkat-raman 17 (6/16)Axt-Fliedner 23 (1/4)

Harrington 14 (27/30)Zimmerman 23 (6/6)

Geipel 21 (0.1)

(6192/6216)(6131/6216)(1136/1160)

(322/330)(1636/1692)(2460/2564)

(224/234)(623/654)

(3933/4132)(830/874)(139/148)(215/231)(607/654)(256/279)

(7055/7738)(821/925)

(62/70)(65/75)(72/84)(41/48)

(105/125)(273/329)(169/205)(121/148)

(34/48)(418/596)

(25/49)(6/13)

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FIGURE 40 Doppler bilateral notching of the main uterine arteries: sensitivities, specificities and 95% CIs. Numbers to the right of first author’s name are average gestational ages (weeks) for time of testing. Note that some authors reported on several gestational ages.

0.2

0.4

0.6

0.8

1.0

0 0.2 0.4 0.6 0.8 1.0

1 – Specificity

Sens

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0

FIGURE 41 Doppler bilateral notching plotted in ROC space. The ROC space has a solid line representing the sROC curve and dashedlines representing the 95% CI of the sROC curve.


39









0 20 40 60 80 100



71

7

3 5

6 2

2 6

71

4 3 1

1

FIGURE 42 Quality and reporting assessment of Doppler single ratios

0 20 40 60 80 100


0 20 40 60 80 100


S/D RATIOSchulman S/D (10/19)

Aquilina A/B (31/40)Saccini S/D (12/25)

A/C RATIONorth A/C (8/15)

Ohkuchi A/C (7/9)Ferrier A/C (2/4)

Aquilina A/C (34/40)NOTCH INDEX

(high risk) Aardema NI (1/7)(low risk) Aardema NI (0/5)

S/D RATIO(46/52)

(332/510)(8/13)

A/C RATIO(381/431)(242/179)

(37/47)(345/510)

NOTCH INDEX(70/87)

(395/526)

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FIGURE 43 Doppler single ratios: sensitivities, specificities and 95% CIs. Aquilina is one paper with two indices (AB and AC ratio).

TABLE 10 Subgroup analysis (significance level p < 0.10) for single ratios of the uterine artery. Aquilina’s A/B ratio was not used incalculating pooled estimates to avoid duplicate inclusion of numbers of women


Pooled estimates (no. of studies) 55 (37 to 72) 80 (73 to 86)Type of ratio 0.095 0.861

S/D (3) 49 (30 to 69) 80 (60 to 92)A/C (4) 71 (55 to 83) 82 (72 to 89)Notch index (2) 12 (2 to 46) 78 (61 to 88)



40

0

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0 0.2 0.4 0.6 0.8 1.0

1 – Specificity

Sens

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FIGURE 44 Doppler single ratios plotted in ROC space








0 20 40 60 80 100



71

8 1

4 5

8 1

9

71 1

6 2 1

8

FIGURE 45 Quality and reporting assessment of pulsatility index of the main uterine artery

Doppler uterine artery – pulsatility index The review of test accuracy studies of Dopplerpulsatility index included nine studies (reported ineight papers) (14,697 women) (see Appendix 7).The quality of the studies is shown in Figure 45 andAppendix 8. Sensitivities and specificities are shownin Figure 46. Table 11 shows the results of subgroup

analysis. The ROC space is shown in Figure 47,where the solid line represents the sROC curve anddashed lines represent 95% CIs. Studies with severalmeasurements are represented only once. We usedpooled estimates of sensitivity and specificity of 48%(95% CI 29 to 69%) and 87% (95% CI 75 to 94%),respectively, in decision modelling.


41


0 20 40Sensitivity (95% CI) Specificity (95% CI)

60 80100 0 20 40 60 80 100

PERCENTILE CUTOFFYU >95th (7/21)

Martin >95th (2.35) (17/63)Zeeman >95th (4/11)

Yu >95th (1.6) (56/60)ABSOLUTE CUTOFF

ALBAIGES >1.45 (23/65)Papageorghiou >1.63 (46/113)

Aardema, low risk >1.3 (0/5)Sato >1.2 (13/16)

Aardema, high risk >1.3 (1/7)

PERCENTILE CUTOFF(319/330)

(2844/2982)(29/41)

(404/623)ABSOLUTE CUTOFF

(1624/1692)(7383/7738)

(410/536)(228/317)

(59/87)

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FIGURE 46 Doppler pulsatility index of the main uterine artery: sensitivities, specificities and 95% CIs. Studies are classified by (1)early (cut-off 16 weeks, Martin and colleagues) versus late gestational age and (2) cut-off level [95th centile versus absolute values(bottom five)].

TABLE 11 Subgroup analysis (significance level p < 0.10) for pulsatility index



< 4% (4) 31 (12 to 62) 93 (83 to 97)�4% (5) 59 (31 to 82) 79 (59 to 90)

0

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Sens

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FIGURE 47 Doppler pulsatility index of the main uterine artery plotted in ROC space. The ROC space has a solid line representingthe sROC curve and dashed lines representing the 95% CI of the sROC curve.

Doppler uterine artery – resistance indexThe review of test accuracy studies of Dopplerresistance index of the main uterine arteryincluded 26 studies (reported in 25 papers) (5761women) (see Appendix 7). The quality of thestudies is shown in Figure 48 and Appendix 8.(Note: one study recorded low- and high-riskwomen separately and has been counted as twostudies in the quality diagrams.) Sensitivities andspecificities are shown in Figure 49. Table 12 showsthe results of subgroup analysis. The ROC space isshown in Figure 50, where the solid line represents

sROC curve and dashed lines represent the 95%CI of the sROC curve. Studies with data forseveral cut-off values were included only once. Weused pooled estimates of sensitivity and specificityof 66% (95% CI 54 to 76%) and 80% (95% CI 74to 85%), respectively in decision modelling.

Combinations of flow velocity waveformsThe review of diagnostic accuracy of combinationsof notching and resistance index, notching andpulsatility index, notching and other ratiosincluded 18 studies (11,778 women) for resistance


42








0 20 40 60 80 100



78

20 5 1

8 18

16 6 2

214 1

158 4

8 17 1

16 2

FIGURE 48 Quality and reporting assessment of resistance index of the main uterine artery

TABLE 12 Subgroup analysis (significance level p < 0.10) for resistance index of the main uterine artery


Pooled estimates (no. of studies) 66 (54 to 76) 80 (74 to 85)Definition of pre-eclampsia 0.902 0.499

Internationally accepted (8) 62 (39 to 80) 84 (73 to 91)Other variations (14) 60 (45 to 74) 80 (72 to 86)Unclearly/not reported (4) 74 (42 to 92) 85 (69 to 93)



index and/or notching, three studies (9959women) for pulsatility index and/or notching andfour studies (1159 women) for S/D ratio and/ornotching (see Appendix 7). The quality of thestudies is shown in Figure 51 and Appendix 8.Sensitivities and specificities are shown in Figure 52.Table 13 shows the results of subgroup analysis.The ROC space is shown in Figure 53. All studiesare represented only once in the analysis. The

sensitivities and specificities with their 95% CIs fornotching and resistance index were 67% (56 to77%) and 86% (82 to 90%), for notching andpulsatility index 38% (17 to 65%) and 95% (88 to98%) and for notching and other ratios 60% (30 to84%) and 79% (62 and 89%), respectively. We usedpooled sensitivities and specificities of 64% (95%CI 54 to 74%) and 86% (95% CI 82 to 90%),respectively, in decision modelling.


43


0 20 40 60 80 100Sensitivity (95% CI)

0 20 40 60 80 100Specificity (95% CI)

ABSOLUTE CUTOFFNorth >0.57 (4/15)

Valensise >0.58 (8/9)Frusca >0.58 (4/8)

Schwarze >0.58 (both (7/17)Valensise >0.58 (8/9)

Coleman >0.58 (both) (13/32)Axt-Fliedner >0.58 (both) (2/4)

Pattinson >0.58 (6/7)Parretti >0.58 (mean) (28/36)Schwarze >0.58 (any) (14/17)

Frusca >0.58 (3/3)Tranquilli >0.58 (8/14)

Coleman >0.58 (any) (29/31)Axt-Fliedner >0.58 (any) (2/4)

Arenas >0.59 (8/11)Soregaroll >0.6 (9/9)

Sato >0.6 (12/16)Schwarze >0.7 (both) (3/17)

Axt-Fliedner >0.7 (both) (1/4)Coleman >0.7 (both) (7/32)Schwarze >0.7 (both) (7/17)Axt-Fliedner >0.7 (any) (1/4)Coleman >0.7 (any) (16/32)

PERCENTILE CUTOFFNorth >90th (4/15)Caruso >90th (9/9)Caruso >90th (4/5)

Caforio >90th low risk (3/3)Ferrier >90th (2/4)

Caforio >90th high risk (41/42)Caforio >90th low risk (3/3)

Caforio >90th high risk (39/42)Ohkuchi >91st (6/9)

Geipel >95th singl.ref. (4/22)Chan >95th (4/23)

Konchak >9th (5/6)Gelpel >95th twin ref (8/22)

OTHER CUTOFFFrusca >2SD (3/3)

Rizzo n.r. (6/16)Aquilina n.r. (35/40)

ABSOLUTE CUTOFF(387/432)(245/263)(379/411)(284/329)(152/183)

(65/84)(36/48)(32/46)

(73/108)(208/329)

(32/53)(31/61)(36/85)(19/48)

(227/308)(186/262)(219/325)(325/329)

(46/48)(79/84)

(289/329)(42/48)(60/84)

PERCENTILE CUTOFF(382/431)

(27/33)(18/23)

(395/527)(35/47)

(208/293)(369/527)(202/293)(236/279)(230/234)(297/311)

(91/97)(206/234)

OTHER CUTOFF(53/75)(32/48)

(332/510)

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FIGURE 49 Doppler resistance index of the main uterine artery: sensitivities, specificities and 95% CIs. Studies are classified byincreasing cut-off value (absolute versus percentile versus other), which is stated to the right of the first author’s name.


44

0

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0.4

FIGURE 50 Doppler resistance index plotted in ROC space. The ROC space has solid line representing the sROC curve and dashedlines representing the 95% CI of the sROC curve.








0 20 40 60 80 100



73

21 4

11 16

16 6 3

164 5

13 12

19 3

232

FIGURE 51 Quality and reporting assessment of Doppler combinations of flow velocity waveforms


45


RI +/– NOTCHINGChan (5/23)

Coleman, both RI > 0.7 (6/32)Driul (23/39)

Harrington (34/44)Aquilina (21/35)

Geipel (7/22)Harrington, low risk (1/2)

Driul (4/10)Frusca (1/3)

Harrington (38/48)Bower, severe PE (23/29)

North (8/15)Bower, moderate PE (14/16)

Bower, mild PE (2/7)Geipel, high risk (9/11)

Geipel, low risk (5/6)Subtil (14/24)

Harrington, high risk (19/20)RI > 0.7, Coleman (13/32)

Kurdi (15–21)Valensise (6/7)

Coleman, RI > 0.58 (20/32)Campbell, 24–26 wk (13/13)

Frusca (4/4)Campbell, 19–21 wk (13/13)

PI +/– NOTCHINGYu (4/21)

Albaiges, PI and notch (15/65)Albaiges, PI or notch (29/65)

Papageorghiou (64/113)S/D or DS +/– NOTCHING

Morris (8/36)Soutif (3/4)

Benifla (4/4)Haddad (5/5)

RI +/– NOTCHING(301/311)

(79/84)(60/64)

(1084/1160)(563/605)(217/234)(416/456)(723/830)

(46/53)(2037/2389)(1723/2029)

(365/430)(1727/2042)(1724/2051)

(39/47)(135/164)

(923/1146)(120/150)

(66/84)(724/925)

(7/9)(60/84)

(173/251)(18/32)

(99/251)PI +/– NOTCHING

(327/330)(1668/1692)(1592/1692)(6870/7738)

S/D or DS +/– NOTCHING(665/732)(264/311)

(18/24)(22/43)

0 20 40Sensitivity (95% CI)

60 80 100 0 20 40Specificity (95% CI)

60 80 100

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FIGURE 52 Doppler combinations of flow velocity waveforms of the main uterine artery: sensitivities, specificities and 95% CIs.Studies are classified by (1) resistance index and/or notching, (2) pulsatility index and/or notching, (3) S/D or D/S ratio and/or notching.Note that some studies reported data for several subgroups (e.g. resistance index cut-off value; severity of pre-eclampsia; high- or low-risk population; gestational age), which in these cases is stated to the right of the first author’s name.

TABLE 13 Subgroup analysis (significance level p < 0.10) for combinations of flow velocity waveforms of the main uterine artery. Allstudies are represented only once in the analysis


Pooled estimates (no of studies) 64 (54 to 74) 86 (82 to 90)Combination of FVW 0.136 0.024

RI and/or notching (20) 67 (56 to 77) 86 (81 to 90)PI and/or notching (3) 38 (17 to 65) 95 (88 to 98)S/D or D/S and/or notching (4) 60 (30 to 84) 79 (62 to 89)


FVW, flow velocity waveform; PI, pulsatility index; RI, resistance index.

Discussion of test accuracySummary of test accuracy findingsThe main results are summarised in Figures 54 and55. The results indicate that the quality of studiesand accuracy of tests were generally poor. Sometests have high specificity, but sensitivities tend to below. Over 90% of studies were published in English.

The total number of women included in thereviews ranged from 135 (cellular FN) to 452,615(BMI), with a median of 4388 women(proteinuria). The number of women included pertest accuracy study ranged from 14 (FN) to287,213 (BMI). The number of studies per testthat were meta-analysed was generally small with amedian of seven (range 2–25) (see Table 5).Uterine artery Doppler was a notable exception,with a total of 63 studies on its evaluation.However, only coherent Doppler subgroups weremeta-analysed, based on the many differentindices used for interpretation of Doppler, andthese groups were smaller (range 7–25). In theevaluation of many tests, including total FN,fDNA, haemoglobin/haematocrit, oestriol, SUA,urinary calcium excretion and many types ofproteinuria, the limited number of studies and thelimited number of cases with pre-eclampsia perstudy seriously constrained conclusions.

The overall quality of studies within reviews wasvariable. There were deficiencies in many areas ofmethodology (see Figure 54). No test had

universally high-quality data. The interpretationsof the accuracy data on all tests were negativelyaffected by poor reporting and potential threats tovalidity identified in assessment of study quality.In particular, studies suffered in blinding, testdescription and reference standard adequacy.Thus, when assessing results, we often could notbe confident about the reported predictive abilityof tests. Many studies included patients across theclinical risk spectrum, but did not provide separateresults for specific parts of the spectrum, such aswomen without any particular risk factors. On theother hand, over half of the studies had pre-eclampsia incidences greater than 4%. Consequently,the material we studied sometimes gave anopportunity to study variation of test accuracybetween low and high(er) incidence populations.

For most of the tests evaluated, results were pooledusing the (random effects) bivariate method. Thismethod accounts for statistical heterogeneity leftunexplained after attempts, where feasible, toidentify its sources in clinical subgroups,diagnostic modality variations and/ or qualityitems. However, in the case of fibronectin wedeemed meta-analysis misleading in the light ofextreme variations in test thresholds within studiesand resultant heterogeneity in the estimation ofaccuracy. Here, only results of individual studiescould be considered useful for clinical application.Figure 55 is the forest plot of sensitivity andspecificity that we believe to be suitably valid for consideration in clinical decision-making


46

0

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FIGURE 53 Doppler combinations of flow velocity waveforms and/or early diastolic notching plotted in ROC space. Diamondsrepresent resistance index and/or notching, squares represent pulsatility index and/or notching and triangles represent S/D ratios and/or notching.


47





Incidence of pre-eclampsia <4%*




0 20 40 60 80 100



732

144 2517

72 6 112

109 31

11938 29

92 78 16

121 33

52

Note: Some studies are reported twice because of inclusion in several reviewsNumbers within stacked bars are numbers of studies*Studies with high- and low-risk populations are counted separately

46

11420

FIGURE 54 Quality of all tests reviewed for prediction of pre-eclampsia

69 (60 to 77)

0 20 40 60 80 100

Doppler combinations of FVWDoppler resistance indexDoppler pulsatility index Doppler other ratiosDoppler bilateral notchingDoppler any/unilateral notchingSDS-PAGE proteinuria 100 (88 to 100)KallikreinuriaMicroalbumin/creatinine ratioMicroalbuminuriaTotal albuminuria Total proteinuriaUrinary calcium/creatinine ratioUrinary calcium excretionSerum uric acidOestriolHCGFoetal DNAFibronectin totalFibronectin cellularAFPBMI < 19.8BMI > 24.2BMI > 29

0 20 40 60 80 100

BMI > 34

2526

97

2219

1112246453

16311

127982

228965761

146972069

2939514345

153307

1422190

8822281345705514

2681172732

351293

43137097152720440214410823

16236

11 (8 to 16) 41 (29 to 53) 23 (15 to 33) 18 (15 to 21)

64 (54 to 74) 66 (54 to 76) 48 (29 to 69) 55 (37 to 72) 48 (34 to 62) 63 (51 to 74)

19 (12 to 28) 62 (23 to 90) 70 (45 to 87) 35 (13 to 68) 50 (36 to 64) 57 (24 to 84) 36 (22 to 53) 26 (9 to 56) 24 (16 to 35) 50 (31 to 69) 65 (42 to 83) 50 (30 to 70) 9 (5 to 16)

83 (52 to 98)

80 (73 to 86) 75 (62 to 84)88 (80 to 93)93 (87 to 97)

86 (82 to 90)80 (74 to 85)87 (75 to 94)80 (73 to 86)92 (87 to 95)82 (74 to 87)

75 (73 to 77)68 (57 to 77)89 (79 to 94)89 (79 to 94)80 (66 to 89)74 (69 to 79)83 (73 to 90)82 (61 to 93)89 (86 to 92)88 (80 to 93)94 (86 to 98)96 (79 to 99)96 (94 to 98)

98 (98 to 100)

Sensitivity Specificity

Sn (95% CI)TestNo. ofstudies

No. ofwomen Sp (95% CI)

FIGURE 55 Forest plot of accuracy estimates put forward for decision analysis

of each of the tests reviewed. These results havebeen put forward for decision-analytic modelling.

In general, tests in early pregnancy for predictinglater development of pre-eclampsia tended tohave better specificity than sensitivity, althoughthe precision of estimation varied considerably.Specificity (true negative rate) of a test is theproportion of those women who did not developpre-eclampsia later who were initially identified assuch. A highly specific test has a very lowproportion of false positive results. Thus, whensuch a test produces a positive result it tends torule in later development of disease (if sensitivityis moderate and prevalence is not too high).Sensitivity (true positive rate) of a test is theproportion of those women who really developedpre-eclampsia later in pregnancy who are initiallyidentified as such. A highly sensitive test has a verylow proportion of false negative results. Thus,when such a test produces a negative result ittends to rule out later development of pre-eclampsia (if specificity is moderate andprevalence is not too low).

Screening typically involves use of a confirmatorytest after initial testing, prior to the institution oftherapy. In this project, this use of confirmatorytests is not the case as testing is used to identify arisk group in which preventative interventions(both intensive monitoring and treatments) will beemployed directly after test results are known. Inthis situation, for a test to serve as a good tool forscreening, it should perform well in bothsensitivity and specificity. However, there oftentends to be a trade-off between sensitivity andspecificity and the preferable balance dependslargely on the outcomes of disease and morbidityand costs associated with the intervention. Givenalso the consequences of false positive results(both costs of intensive monitoring and treatment-associated morbidity among normal women), it isimportant that test specificity is suitably high. Thisis because erroneously providing interventions towomen falsely labelled as positive leads tounwarranted inconvenience, expense andmorbidity when pre-eclampsia would not havedeveloped later in pregnancy anyway. Given theconsequences of false negative results (both costsand morbidity of cases left untreated), it isimportant that the test sensitivity is suitably high.This is because erroneously withholding effectiveinterventions from women falsely labelled asnegative leads to excessive morbidity and expensewhen disease develops later in pregnancy. Ifavailable effective interventions are convenient,inexpensive, and without adverse effects (to both

mother and child), it is better to have the accuracytrade-off in favour of sensitivity than specificity.

Figure 55 demonstrates that when considering thepoint estimates and imprecision in theirestimation, most tests perform either poorly or thelevel of their performance is uncertain. Only a fewtests reached specificity above 90%. These wereBMI >34, AFP, FN (cellular and total), kallikreinand uterine artery Doppler (bilateral notching).Concerning Doppler sensitivity, only Doppler(any/unilateral notching, resistance index andcombinations) were over 60% sensitive.Kallikreinuria and SDS-PAGE proteinuria seemedto offer the promise of high sensitivity at over80%, without compromising specificity, but wouldrequire further investigation because thesefindings are based on results from single studiesonly. Depending on the level of effectiveness ofvarious interventions (Chapter 4) and theirassociated inconvenience, costs and morbidity, athreshold analysis (Chapter 5) will be required todetermine what levels of sensitivity and specificityare required to make testing cost-effective in theprevention of pre-eclampsia.

Provisos/limitations arising fromproblems with primary dataThe interpretations of the accuracy data on testsare affected by threats to validity identified inassessment of study quality. There was no test thathad universally high-quality data. The overallquality of studies within reviews was variable, withdeficiencies in many areas of methodology (seeFigure 54). Association between design qualitycomponents and diagnostic performance has beenstudied empirically.81,91 A rationalistic approach isthat study design (and execution) issues requiretheir proper (honest) reporting before anymeasures of diagnostic performance (whatevertheir magnitude) count as scientific evidence.

Studies often did not conform to the standards ofreporting for diagnostic studies.82 In particular,they suffered in blinding, test description andreference standard adequacy. The extent to whichthese deficiencies have impacted on accuracyestimates depends on a number of factors. There isa 15–26-week time separation between predictivetesting and its verification by the referencestandard in pre-eclampsia. In this situation,blinded assessment of the reference standard maynot be as major an issue if the predictive testresults were collected for an unrelated purpose,for example Down’s syndrome screening, and wereforgotten by the time pre-eclampsia appeared inthe course of pregnancy. This problem would be


48

further diminished if, during the study, healthcareproviders did not employ the hypothesis that thetest result carried information on the occurrenceof pre-eclampsia. We would have liked to seesufficient information for others to be able toreplicate tests and for us to be able to categorisepatients according to new disease classifications forhypertensive disorders of pregnancy. This wasoften not possible. Our expectations of the level ofdetail that should be provided about test andreference standard in the primary studies wereperhaps unrealistic given that initiatives toimprove reporting are recent phenomena.

It was often not possible to be certain about thedefinition of pre-eclampsia used in studies. Therewas a lack of information on the exact techniqueof blood pressure measurement and Korotkoffthreshold for abnormality or whether theproteinuria was in the absence of urinary tractinfection and pre-existing renal disease or whetherthere was normalisation of blood pressure within6 weeks of giving birth. Moreover, there wasgenerally no specification of clinically importantdetails of pre-eclampsia such as whether it wasearly or late and severe or non-severe. We hadplanned to perform subgroup analyses accordingto time of onset and severity of pre-eclampsia,wherever possible (see the section ‘Methods fortest accuracy reviews’, p. 11) but lack of dataprecluded this for most of the diagnostic testsreviewed. The poverty of reporting also impactedon assessment for the risk of treatment paradox:i.e. giving effective treatments to test positivepatients may lead to potential non-occurrence ofpre-eclampsia, making an otherwise reasonabletest appear inaccurate. However, the treatmentsthat exist are mostly of not proven effectiveness(see Chapter 4).

Spectrum bias refers to the possibility that a test’ssensitivity and/or specificity vary between groupsof patients with different illness severity92,93 Inother words, spectrum bias refers to variationacross subgroups (or, to use the technical term,effect measure modification). However, the issue ofdiagnostic confounding by other diagnostic testinformation has so far been overlooked.(Confounding here refers to when one or morediagnostic tests have predictive abilities that arerelated to each other and to the outcome so that itis difficult to assess the independent prediction(the added value of one, given the other) fromeach of the tests on the diagnosis of the outcome).Unfortunately, the issue of diagnostic confoundingmay only be dealt with by multivariable analysis ofthe primary study data or individual patient data

(IPD) meta-analyses.94 Interestingly, the latterapproach was taken increasingly in Dopplerstudies after 2004. The tests could have beenstudied using IPD meta-analysis but this wouldhave required access to raw data from studies,which was not within the scope of our work andwould have required considerable additionalresources. Such multivariable analysis wouldgenerate probabilities of pre-eclampsia for a seriesof patient characteristics (a predictive profile) thatincorporate test results. If no multivariableanalysis is planned, such confounding may becounteracted by the selection of patient groupsthat are homogeneous as to their other diagnosticcharacteristics (patient history and obstetric riskprofile in multiparous women). However, such anapproach is difficult given the large number ofpieces of diagnostic information that usually exist(such as age, parity, co-morbidities and BMI).

Strikingly, there was a virtual absence ofcorrelation between strictness of patient entrycriteria and the incidence of pre-eclampsiabetween studies. This could be because entrycriteria were haphazard such that the intendedpopulation was different to the sample enrolled.This could also be because of geographical,genetic, nutritional and other variations thatpredispose women to pre-eclampsia. To bepractical, we therefore defined subgroupsaccording to a 4% incidence threshold (see thesection ‘Methods for test accuracy reviews’, p. 12),but studies often did not provide separate resultsfor the low-risk subgroup. Over half of the studieshad pre-eclampsia incidence of greater than 4%.Consequently, to some extent, the material that westudied gave an opportunity to study test accuracyin low- and high(er)-incidence populations. Theresults did not always provide informationconcerning prediction in purely low-risk groups.

Provisos/limitations arising from reviewmethodsThe selection of tests for review of their accuracywas based largely on the opinion of the researchteam, including practising obstetricians, also withadvice from a small external group. To addscientific validity to the selection process, aDelphic survey of practice might have been moreappropriate. The reviews were carried out using acomprehensive search strategy so as to minimisethe risk of missing studies. Nevertheless, theamount of research identified per test was ofteninsufficient to produce precise estimates ofaccuracy. With the exception of the Doppler test,the evaluation of many tests, particularly total FN,


49


fDNA, haemoglobin/haematocrit, oestriol, SUA,urinary calcium excretion and many types ofproteinuria, was limited due to imprecision. Inparticular, the estimate that suffered most in thisrespect was sensitivity, as its precise estimationrequires large absolute numbers of pre-eclampsiacases.94 Thus, when assessing their results wecould not always be confident about the range ofreported predictive ability of tests.

Our review made explicit the deficiencies in thequality of studies.81,82,91 We would have liked tohave based our inferences on high-quality studiesbut often numbers of studies per test were toosmall or reporting was too unclear to achieve this.We had planned subgroup analyses according tostudy quality, population clinical risk level, diseaseseverity and possible variations in test(sub)modalities used, for example different assaytechniques for the same test. Ideally we wouldhave liked to obtain estimates of accuracy forclinically relevant subgroups or test modalitiesadjusted for study quality. Our experience that thisis very difficult has recently been formallyacknowledged.95 Due to the low number ofincluded studies, subgroup analyses (either clinicalor quality based) were often not possible or wouldhave had low power to identify differences.Subgroup analyses on severe pre-eclampsia in theAFP and HCG reviews did not appear to make anydifference in the pooled estimates.

Due to variations in test thresholds fordetermining abnormality, generating summariesof findings was not straightforward. The bivariatemethod deals with this by estimating thecorrelation between sensitivity and specificity.When information is scarce, however, suchestimations may be imprecise. For some tests, anduterine artery Doppler in particular, the samestudy provided estimates of more than onediagnostic indicator (e.g. resistance index andnotching). This precluded valid statisticalcomparison of these indices due to violation of theprinciple that the compared study samples arestatistically independent. Recently, this issue wasaddressed in the literature, but the solution wasbased on the use of odds ratios, which has otherdrawbacks.96 We made a systematic attempt (seethe section ‘Methods for test accuracy reviews’,starting on p. 9) at translating results in asummary ROC space into clinically relevantinformation. For pooling test results, the bivariatemethod was particularly suitable as it takes intoaccount the relationship between sensitivity andspecificity that may exist due to threshold effects.Since it also uses a random effects approach,

unexplained statistical heterogeneity was formallytaken into account. We could not explore reasonsfor heterogeneity in detail largely because poorreporting and the small number of studies per testwould have rendered the use of statistical methodssuch as meta-regression underpowered. As mostpooled results amalgamated heterogeneousindividual estimates, these should be interpretedwith caution. Given also the uncertain impact ofstudy design issues on the magnitudes ofsensitivity and specificity,91 our view is that thesummaries that we generated provide the bestavailable results for clinical interpretation at thetime of completing our work.

Provisos/limitations arising from thingsnot doneFor some tests, we found so few studies that nomeaningful analyses could be carried out (such ashaemoglobin and haematocrit). Where studieswere available, absence of primary data in keyareas and limitations of reviews including few,generally poor studies limited our ability toexplore the information collated as completely aswe would have liked. As an example, incompleteanalyses when repeated measurement of indextests had been performed (such as for proteinuria)precluded the possibility of taking a monitoringperspective which is critical in antenatal care,particularly among high-risk cases. Some studiesreported mean ± SD for non-Gaussiandistributions of index test results and did notprovide 2 × 2 tables. Such information had to beexcluded from our reviews. One of the keyconclusions is that better quality primary studies,especially in new evaluations of new tests, arerequired.

It has already been highlighted above how reviewscould have benefited from the use of advancedtechniques such as meta-regression analysis andIPD meta-analysis had more (better reported)studies per test or more resources been available.Despite these deficiencies, in comparison withprevious comprehensive work by the WHO90

reviewing tests for pre-eclampsia, this reviewcovered more tests and found more studies. Theresults here are more precise than in the previouswork cited and currently provide the best availableevidence for clinical interpretation.

Findings in the light of limitationsScreening typically involves use of a confirmatorytest after initial testing, prior to institution oftherapy. In our project, this is not the case astesting is used to identify a risk group in whichpreventative interventions (both intensive


50

monitoring and treatments) will be employeddirectly after test results are known. Given thequality, level and precision of the accuracyevidence, no single test has emerged as a frontrunner in the quest to predict and prevent pre-eclampsia. The test that seems to offer thepromise of both high sensitivity and highspecificity is kallikreinuria but it would requirefurther investigation. Tests that offer highspecificity, such as BMI >34, AFP, fibronectin anduterine artery Doppler (bilateral notching), havethe potential to minimise unwarrantedinconvenience, expense and morbidity associatedwith false positive results when disease would nothave developed later in pregnancy anyway. Testswith high sensitivity, such as Doppler (resistanceindex and combinations), have the potential toreduce costs and morbidity of cases left untreatedassociated with false negative results.

Ramifications for the economic modelHow accuracy results are incorporated into themodel includes dealing with challenges relating tothe systematic review process (covered above) andpatient preferences. One of the key issuesconcerning screening or predictive tests in thisproject is that, if available, effective interventionsare convenient, inexpensive and without particularrisk of harm or side-effects (to both mother andchild); high sensitivity is more important thanhigh specificity. It is worth speculating that inpreventing pre-eclampsia, it is difficult from aclinical and patient perspective to distinguishbetween false positive and false negative testresults and so from this perspective the optimaltest will be one which minimises both false positive(high specificity) and false negative (highsensitivity) results. As we have observed that teststend to have higher specificity than sensitivity,they are unlikely to improve cost-effectivenesswhen used in combination with inexpensive, safeand effective treatments (e.g. aspirin). Dopplertesting for predicting and preventing pre-eclampsia is particularly badly affected by cost-effectiveness analysis incorporating the costs andeffects of treatment, when its perceived valuedepends on also predicting other things (growthrestriction and perinatal mortality). There is asmall risk of overlooking potentially cost-effectivetest accuracy results compatible with the includeddata, particularly maximised sensitivity, which mayhave been overlooked by focusing on summariesproduced by bivariate analyses. For example, if weplot the sensitivity and specificity input into themodel on the relevant ROC spaces for uterineartery Doppler (resistance index), the values do

not appear to be completely representative of thedata actually obtained from the included studies.This is largely because populations and testthresholds vary. We have only put forward data inFigure 55 for decision-analytic modelling, which webelieve provide the most robust estimates.Ultimately, the threshold analysis (Chapter 5)shows what levels of sensitivity and specificity willbe required to make testing cost-effective inprevention of pre-eclampsia.

Recommendations for practiceGiven the generally low sensitivities of the testsevaluated, a practical recommendation forclinicians for prevention of pre-eclampsia is toconsider refraining from testing, but to initiatepreventative treatment.

Recommendations for research● The development of new tests or markers

should be followed by new, more robustlydesigned test accuracy studies with sufficientpower to estimate test sensitivity.

● Such studies should preferably evaluate theadded value of new tests using statisticalanalyses that incorporate information whichphysicians document through the clinicalhistory (risk profile).

● Power and validation of so-developed predictivemodels (mathematical risk functions) mayinvolve (prospective) IPD diagnostic meta-analyses.

● The choice of tests for systematic review may beguided by a Delphic survey of practice.

● Combinations not evaluated, such as bloodpressure and proteinuria, should be evaluated.

● Any new evaluations must be undertaken in thesetting in which they will be applied.

Conclusions of test accuracy reviews The quality of studies and accuracy of tests weregenerally poor (Figure 54). Some tests appear tohave high specificity, but at the expense ofcompromised sensitivity. Only a few tests reached apooled specificity above 90%. These were BMI>34, AFP and uterine artery Doppler (bilateralnotching). Concerning Doppler sensitivity, onlyDoppler (resistance index and combinations) wasover 60% sensitive. Cellular and total FN andkallikreinuria were found to have a specificityabove 90% based on single estimates. A few testsnot commonly found in routine practice, such askallikreinuria and SDS-PAGE proteinuria, seemedto offer the promise of high sensitivity, withoutcompromising specificity, but would requirefurther investigation.


51


Study selectionOverall, of 1803 citations identified as potentiallyeligible for the Cochrane reviews (see Figure 56and Table 14), 315 RCTs were incorporated intoreviews (see Tables 15–17).

Presentation of resultsThe Cochrane systematic reviews are grouped byinterventions based on Antenatal care, Lifestyle,Dietary and Pharmacological interventions. Thecharacteristics of included studies, methodologicalquality of included studies, results and input to thedecision analysis-based economic model aredescribed for each review. The primary outcomewas pre-eclampsia and this was the input to theeconomic model. The pre-eclampsia complicationsalso reported here are death of the baby, pretermbirth and the baby being small for gestational age.These outcomes could not be incorporated intothe economic model at the current stage of itsdevelopment. Other outcomes includingsafety/side-effects/adverse events reviewed but notincluded in this report can be found in theCochrane Library. Similarly, excluded studies foreach review can be found in the Cochrane Library.

Antenatal care interventionsAmbulatory versus conventionalmethods for monitoring blood pressureduring pregnancyBlood pressure measurement plays a central rolein the screening and management of hypertensionduring pregnancy. In recent years, the validity ofconventional (clinic) blood pressure measurementhas been questioned and it has been suggestedthat ambulatory automated devices, providingmultiple measurements usually over a 24-hourperiod, might be more reliable.

The review of ambulatory versus conventionalmethods for monitoring blood pressure97 did notidentify any RCTs.

Lifestyle interventionsBed rest with or without hospitalisationfor hypertension during pregnancyWomen with high blood pressure are often advisedto rest in bed either at home or in hospital. It issuggested that this might help to reduce themother’s blood pressure and so provide benefitsfor the baby. However, there may be adverse


53


Chapter 4

Clinical effectiveness reviews

TABLE 14 Generic search: reasons for excluding potentially eligible citations

Source Not eligible Excluded after further assessment

CENTRAL 700 173 93 261 44 64 3 5 1 – 1 2 8

EMBASE 647 54 461 98 15 17 – 1 – – 1 – 1

Hypertension 150 5 121 – 1 16 – – – 7 – – 0in Pregnancya

HDP, hypertensive disorders of pregnancy; PCG, Pregnancy and Childcare Group; PE, pre-eclampsia.a Handsearch.

Tota

l cit

atio

ns

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of P

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wom

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to t

race

Full trial reportsretrieved fordetailedevaluation


54

Search for existing Cochrane reviews and protocols

9 core+ reviews + protocols5 reviews 4 protocols

5 updated reviewsambulatory BP monitoringaltered dietary saltcalcium supplementationantiplatelet agentsantihypertensive drugs

4 protocols converted into reviewsbed rest for hypertensionmarine oilsantioxidant agentsdiuretic drugs

5 new reviews†

exerciserest for normal BP garlicnitric oxideprogesterone

4 excluded as substantial overlap with another included reviewvitamin Cvitamin E�-blockersaerobic exercise

7 non-core+ reviewsantenatal daycare unitspatterns of antenatal caremagnesiumfolate zincheparinenergy and protein intake

85 excluded Reasons: 66 PE not reported 13 not prevention of PE 6 historic interest* only

CDSR, issue 1, 2004105 potentially eligible citations 84 reviews + 21 protocols

264 included

8 included

Search for trial citations

CENTRAL – 700 citationsgeneric search Feb 04updated April 05

EMBASE – 647 citationsgeneric search for years Jan 02to April 04

Hypertension in Pregnancy150 citationshandsearch of journal2000–2005

Other review specific searches – 31for details, see individual reviews

Personal communication – 10 Reference lists – 1

PCG register – 264 citationsreview specific searches Oct 04updated when preparing review

692 excludedfor reasons, see Table 14

692 excludedfor reasons, see Table 14

646 excluded for reasons, see Table 14

0 included

11 included

315 citations incorporated into reviews

* Interventions not currently used clinically, or reviews which have been withdrawn and replaced by modified versions.+ Core reviews/protocols were updated or completed within the project. Non-core reviews/protocols were included in the search strategy and updated where possible. † New reviews conducted using methods outlined in the Generic ProtocolBP, blood pressure; CDSR, Cochrane Database of Systematic Reviews; PE, pre-eclampsia

20 included reviews + protocols 1 included

31 included

FIGURE 56 Search strategy for effectiveness reviews


55


TABLE 15 How the 315 citations were incorporated into each review for new reviews

Intervention Full papers retrieved Excluded Includeda

for evaluation

Reason for exclusion

Nitric oxide donors and 13 10 2 1 – 7 – – 2 3 2 6 6precursors

Exercise 14 7 – 6 1 11 9 – – – 2 3 3

Garlic 2 1 – – 1 1 – 1 – – – 1 1

Rest at home 15 14 – 1 – 13 – 1 – 12 – 2 2

Progesterone 10 6 – 3 1 5 4 – – – 1 5 2

Total citations 54 37 17

a Includes trials that are completed, ongoing and those that are awaiting further clarification from authors regarding inclusioninto the review.

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TABLE 16 How the 315 citations were incorporated into each review for protocols converted into reviews

Intervention Papers retrieved for evaluation Excluded Includeda


Antioxidant agents 36 25 1 10 – 15 2 2 3 6 2 21 15

Marine oils 41 37 – 4 – 20 2 6 6 3 3 21 10

Bedrest for women with hypertension 14 14 – – – 9 – 1 6 2 – 5 4

Total citations 125 72 53


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effects; for example, some women may find itstressful, it may contribute to blood clots in the legsand it can put a burden on the woman’s family.

The Cochrane review of bed rest with or withouthospitalisation in the secondary prevention of pre-eclampsia98 included four RCTs (449 women) (seeAppendix 9, Table 83). Two of these includedwomen with hypertension but no proteinuria99,100

and two included women with unspecifiedproteinuric hypertension101,102 (which were notdirectly relevant to this project).

All participants were women with a singletonpregnancy between 26 and 38 weeks’ gestation attrial entry. Two trials recruited both primigravidand multigravid women,99,100 and the other twodid not report on parity. The women had diastolicblood pressure between 90 and 110 mmHg. Onetrial also specified systolic pressure of at least140 mmHg. No trials reported on whether womenwere using antihypertensive therapy at trial entry.Two trials compared strict bed rest in hospital with

some rest in hospital101,102 and the other twocompared some bed rest in hospital with normalactivity at home.99,100 Characteristics of the studiescan be seen in Appendix 9.


56

TABLE 17 How the 315 citations were incorporated into each review for updated reviews

Intervention Trials New papers retrieved Excluded Includeda

already in for evaluationreview


Calcium 11 18 14 13 – – 1 6 – – 1 – 5 8 4 (3) 4supplementation

Altered dietary salt 2 5 6 6 – – – 1 – – – – 1 5 – 5

Antiplatelet drugs 51 51 39 26 5 1 7 19 9 1 5 2 2 20 8 (7) 12

Antihypertensive 40 35 77 76 1drugs

Ambulatory BP – – 0 – – – – 0 – – – – – 0 – –monitoring

Total citations 136


Incl

uded

Excl

uded

(fo

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ason

s, s

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ach

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ew)

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ls

3

1

3

1

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3

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3

0 50 100

More than 80%follow-up

Blinding

Allocationconcealment

Randomisationmethod

Absent/unclear/unreportedPresent


FIGURE 57 Quality of RCTs of bed rest in the secondaryprevention of pre-eclampsia

The quality of the four studies is shown inFigure 57. Allocation concealment was adequate inthree trials99–101 but unclear in the fourth.102 Onetrial stated that only the assessment of babyoutcomes was blinded.99 Blinding was notmentioned in the other reports, although blindingof participants would not have been possible. Twotrials reported no losses to follow-up99,101 andanother102 excluded 13% of women from theanalysis. Reasons for exclusion included womennot complying with their allocated treatment. Thefourth trial100 excluded 26% of women.

There was no clear effect of bed rest comparedwith normal activity at home in the secondaryprevention of pre-eclampsia with an RR 0.98 (95%CI 0.80 to 1.20) (Figure 58). The perinataloutcome results are shown in Table 18. Bed restwas not used in decision analysis as the review ison secondary rather than primary prevention ofpre-eclampsia.

Exercise or other physical activity forpreventing pre-eclampsia and itscomplicationsThe belief that women should remain physicallyactive during pregnancy is prevalent in many

cultures, and can be traced back to ancient times.In the late twentieth century, as more women werecomfortably off, and with the spread of labour-saving machines to do household tasks, theconcept of antenatal exercises developed. Theseexercises aim to prepare the woman for the birth.With changes in lifestyle in modern times, sportand exercise have also become major leisureactivities for women. In addition, womenincreasingly have paid employment outside thehome that may include physical activity. Whenthey become pregnant, women are often anxiousabout the safety to themselves and their unbornchild of continuing these activities. Although thereis a range of possible effects of exercise and otherphysical activity during pregnancy, this reviewdeals primarily with those related to prevention ofpre-eclampsia and its consequences.

The review of exercise or other physical activity forpreventing pre-eclampsia and its complications103

included two RCTs (45 women). In one,104 womenhad gestational diabetes, in the other105 they hadeither mild hypertension or a previous personal orfamily history of hypertension. All women wererandomised between 18 and 34 weeks’ gestation tomoderate/high-intensity aerobic exercise or


57


Studyor subcategory

Some restn/N

Routine activityn/N

RR (fixed)95% CI

Weight(%)

RR (fixed)95% CI

Crowther 1992 69/110 69/108 100.00 0.98 (0.80 to 1.20)

Total (95% CI) 110 108 100.00 0.98 (0.80 to 1.20)

Total events: 69 (some rest), 69 (routine activity)Test for heterogeneity: not applicableTest for overall effect: Z = 0.18 (p = 0.86)

0.1 0.2 0.5 1 2 5 10 Favourssome rest

Favours routineactivity

Review: Bed rest with or without hospitalisation for hypertension during pregnancyComparison: 02 Some rest in hospital versus routine activity at homeOutcome: 02 Pre-eclampsia

FIGURE 58 Forest plot of the effects of bed rest in the secondary prevention of pre-eclampsia

TABLE 18 Effects of bed rest on perinatal outcomes

Outcome No. of trials Rest n/N Activity n/N RR 95% CI I2 (%)

Death of baby 1 2/110 1/108 1.96 0.18 to 21.34 NAPreterm birth (<37 weeks) 1 13/110 24/108 0.53 0.29 to 0.99 NASmall for gestational age 1 15/110 15/108 0.98 0.51 to 1.91 NA

NA, not applicable.

normal activity. The exercise was moderate- tohigh-intensity walking or cycling for30–45 minutes 3–4 times per week for 10 weeks oruntil delivery. Characteristics of the studies can beseen in Appendix 9.

The quality of the studies is shown in Figure 59.One study105 was high quality, with adequateallocation concealment, blinding of outcome

assessment and no losses to follow-up. Theother104 had adequate concealment of allocation,but with no blinding of outcome assessment and12% of participants excluded from the analysis.

Exercise (aerobic exercise) had a trend towardsbeing more effective than normal activity inpreventing pre-eclampsia with an RR of 0.31 (95%CI 0.01 to 7.09), but these findings could havebeen accounted for by chance alone (Figure 60).Because of the wide CIs, the effect of aerobicexercise relative to normal activity is highlyuncertain. This result is compatible with bothincreased and decreased incidence of pre-eclampsia being associated with aerobic exercise.The perinatal outcome results are shown inTable 19. Exercise was not used in decision analysisas the results are based on small numbers withonly one participant having the outcome ofinterest and because the trials were in women athigher risk of pre-eclampsia.

Rest for preventing pre-eclampsia andits complications in women with normalblood pressureRestriction of activity and rest have traditionallybeen advocated during pregnancy for a variety of


58

2

1

2

2

1


Blinding


Randomisationmethod

0 50 100



FIGURE 59 Quality of RCTs of exercise for preventing pre-eclampsia and its complications

Review: Exercise or other physical activity for preventing pre-eclampsia and its complicationsComparison: 01 Regular aerobic exercise versus normal physical activityOutcome: 01 Pre-eclamspia

Studyor subcategory

Exercisen/N

Controln/N

RR (fixed)95% CI

Weight(%)

RR (fixed)95% CI Order

USA 1997 0/15 1/14 100.00 0.31 (0.01 to 7.09) 0USA 2000 0/8 0/8 Not estimable 0

Total (95% CI) 23 22 100.00 0.31 (0.01 to 7.09)Total events: 0 (exercise), 1 (control)Test for heterogeneity: not applicableTest for overall effect: Z = 0.73 (p = 0.47)

0.01 0.1 1 10 100

Favoursexercise

Favourscontrol

FIGURE 60 Forest plot of the effects of exercise for preventing pre-eclampsia and its complications

TABLE 19 Effects of exercise on perinatal outcomes

Outcome No. of trials Exercise n/N Normal activity n/N RR 95% CI I2 (%)

Death of baby 1 0/8 0/8 – –Preterm birth 2 1/23 1/22 1.00 0.07 to 13.37 NASmall for gestational age 1 1/8 1/8 3.00 0.14 to 64.26 NA

NA, not applicable.

indications, including prevention and treatment ofhypertension. Surveys conducted in Canada andthe USA on obstetrician and physicianmanagement of hypertensive disorders inpregnancy suggest that advice to stop work and/orto rest more is common when blood pressure israised. This advice is based largely on findingsfrom case–control studies and the observation thatwhen women are walking or moving about theyhave a higher systolic blood pressure than whenthey have been sitting for some time.

The review of rest for preventing pre-eclampsiaand its complications in women with normal bloodpressure106 included two RCTs (106 women). Onecompared rest alone with unrestricted activitywhere rest was in the left lateral recumbentposition for 4 hours daily until delivery. If meanarterial pressure increased by at least 9 mmHg,the duration of rest was increased to 6 hours perday. The other trial compared rest plus nutritionalsupplementation (soy protein, calcium and linoleicacid) with unrestricted activity plus placebo (irontablets) where rest was in the left lateral positionfor 15 minutes twice daily until delivery. Allparticipants were at moderate risk of pre-eclampsia. Women were enrolled between 28 and32 weeks’ gestation. Neither study reportedbaseline activity of the women at trial entry: inone,107 some participants were in paidemployment, but the physical activity in thisemployment is not stated; in the other,108 the onlyinformation is that women in the control groupdid not have regular daytime rest. One trialcompared 4 hours per day of rest with unrestrictedactivity.107 For both trials, rest was lying in the leftlateral position at home, but not necessarily inbed. Neither required women to stop working.Neither trial reported compliance with the adviceto rest. Although in one study107 participants werevisited by nurses to ensure compliance with rest,what the nurses observed during these visits is notreported. Characteristics of the studies can be seenin Appendix 9.

The quality of the two studies is shown inFigure 61. Clearly, blinding of participants to restwas not possible, although the caregivers wereblinded in one trial. Neither study reportedwhether the outcome assessment was blinded.

On average, rest was more effective thanunrestricted activity in preventing pre-eclampsia(Figure 62 overleaf). We used RR 0.05 (95% CI0.00 to 0.83) (rest alone) and RR 0.13 (95% CI0.03 to 0.51) (rest combined with other nutrientsupplements) for primary prevention of pre-

eclampsia in decision analysis. No results wereavailable for perinatal outcomes (see Table 20overleaf).

Nutrition and dietary interventionsAltered dietary salt for preventing pre-eclampsia and its complicationsIn the early part of the twentieth century, a low saltdiet was often recommended as treatment foroedema, in both pregnant and non-pregnantpeople. At that time oedema was included in thedefinition of pre-eclampsia, although it is nowrecognised to be part of normal pregnancy as itaffects 80% of pregnant women. This led to theidea that restricting salt intake might treat, andalso prevent, pre-eclampsia. By the 1940s, a lowsalt diet was widely recommended duringpregnancy, particularly for women with pre-eclampsia. In the late 1950s and early 1960s, thispractice began to be questioned, and it was evensuggested that a high salt intake might prevent ortreat pre-eclampsia. Subsequently, interest in saltconsumption during pregnancy has largely fadedaway. In most parts of the world women are nolonger advised by clinicians to alter their salt intakeduring pregnancy. A notable exception is in TheNetherlands where, until relatively recently, thispractice remained widespread. Nevertheless, somelay literature aimed at pregnant women continuesto advocate salt restriction during pregnancy.

The review of altering dietary salt in the primaryprevention of pre-eclampsia109 included two RCTs(631 women). Women in these trials werenulliparous. In one all women werenormotensive110 and in the other they had adiastolic blood pressure of at least 85 mmHg at


59


2

2

2

2


Blinding


Randomisationmethod

0 50 100



FIGURE 61 Quality of RCTs of rest for preventing pre-eclampsia and its complications in women with normal bloodpressure

trial entry.111 Both studies compared advice torestrict dietary salt (to 20 or 50 mmol/day) withadvice to continue normal dietary salt.Compliance was assessed by checking urinarysodium excretion. Although this was higher thanthe target level for the low-sodium group, sodiumexcretion was still lower than for the normal dietgroup. Characteristics of the studies can be seen inAppendix 9.

The quality of these studies is shown in Figure 63.Follow-up was complete in one study, in the other10% of women were excluded primarily from thelow-salt group as women did not want to use therecommended diet. Blinding of participants was


60

Review: Rest for preventing pre-eclampsia and its complications in women with normal blood pressureComparison: 01 Rest alone versus unrestricted activityOutcome: 01 Pre-eclampsia

Studyor subcategory

Restn/N

Controln/N

RR (fixed)95% CI

Weight(%)


Spinapolice 1983 0/16 9/16 100.00 0.05 (0.00 to 0.83) 0

Total (95% CI) 16 16 100.00 0.05 (0.00 to 0.83)Total events: 0 (rest), 9 (control)Test for heterogeneity: not applicableTest for overall effect: Z = 2.09 (p = 0.04)

0.0010.01 0.1 1 10 1001000

Favours rest Favours control

Review: Rest for preventing pre-eclampsia and its complications in women with normal blood pressureComparison: 02 Rest plus nutrient supplementation versus unrestricted activity plus placeboOutcome: 01 Pre-eclampsia

Studyor subcategory

Rest and nutrientsn/N

Controln/N

RR (fixed)95% CI

Weight (%)


Harrera 1993 2/37 16/37 100.00 0.13 (0.03 to 0.51) 0

Total (95% CI) 37 37 100.00 0.13 (0.03 to 0.51)Total events: 2 (rest and nutrients), 16 (control)Test for heterogeneity: not applicableTest for overall effect: Z = 2.92 (p = 0.004)

0.01 0.1 1 10 100Favours restand nutrients

Favourscontrol

FIGURE 62 Forest plot of the effects of rest in the primary prevention of pre-eclampsia

TABLE 20 Effects of rest on perinatal outcomes

Outcome No. of trials Rest n/N Unrestricted activity n/N RR 95% CI I2 (%)

Death of baby 0Preterm birth 0Small for gestational age 0

2

1 1

1 1

1 1


Blinding


Randomisationmethod

0 50 100



FIGURE 63 Quality of RCTs of altering dietary salt in theprimary prevention of pre-eclampsia

not possible. In one study, the caregiver wasblinded to urinary sodium concentrationmeasurements.

Advice to restrict dietary salt had a trend towardsbeing less effective than advice to continue normaldietary salt in preventing pre-eclampsia, but thesefindings could have been accounted for by chancealone. Because of the wide CIs, the effect ofaltered dietary salt relative to normal diet is highlyuncertain. This result is compatible with bothincreased and decreased incidence of pre-eclampsia being associated with advice to restrictdietary salt. We used RR 1.11 (95% CI 0.46 to2.66) for primary prevention of pre-eclampsia indecision analysis (Figure 64). The perinataloutcome results are shown in Table 21.

Antioxidants for preventing pre-eclampsiaAntioxidants are loosely defined as any substancethat, when present in low concentrationscompared with that of an oxidisable substrate,significantly delays or inhibits oxidation of thatsubstrate. Antioxidants protect proteins andenzymes from oxidation and destruction by free radicals, and help to maintain cellularmembrane integrity. Recently, the observation that women with pre-eclampsia have decreasedplasma and placental concentrations ofantioxidants has led to the proposal that placental

underperfusion may mediate a state of oxidativestress.

The review of vitamin (vitamin C, vitamin E and�-carotene), mineral (selenium) and non-vitaminantioxidants (glutathione peroxidase, catalase,superoxide dismutase)112 included seven RCTs(6082 women). [Since this report was finished, twolarge trials have been published. The recentlyupdated Cochrane Antioxidant review alsoexcludes the quasi-randomised trial. The updatedreview included 10 RCTs (nine for the pre-eclampsia outcome, RR = 0.73 (95% CI 0.51 to1.06).] Most women (5572, 95%) were atmoderate/low risk at trial entry. Two trials (351women) recruited women before 20 weeks’gestation,113,114 and another reported recruitingwomen “during late pregnancy”, which probablymeant after 20 weeks’ gestation.115 The remainingstudies all recruited women both before and after20 weeks’ gestation; one specified 16–22 weeks’gestation,116 while others merely stated below24 weeks’, below 26 weeks’ or below 29 weeks’gestation. One or more vitamins were theantioxidant most commonly evaluated (5982women). The vitamins evaluated were vitamin Conly (one trial),117 vitamins C plus E only (twotrials),113,116 vitamin C plus multivitamin and iron,calcium, iodine, manganese, copper, vitamin A, Band D (one trial)118 and vitamins C and E with fishoil and aspirin (one trial).119 The other two


61


Studyor subcategory

Low saltn/N

Normal saltn/N

RR (fixed)95% CI

Weight(%)

RR (fixed)95% CI

Netherlands 1997 2/110 10.9389.97Netherlands 1998 8/184

1/1328/117

Total (95% CI) 294 309 100.00

2.40 (0.22 to 26.12)0.96 (0.37 to 2.51)

1.11 (0.46 to 2.66)Total events: 10 (low salt), 9 (normal salt)Test for heterogeneity: �2 = 0.48, df = 1 (p = 0.49), I2 = 0Test for overall effect: Z = 0.73 (p = 0.47)

0.1 0.2 0.5 21 5 10Favours low salt

Favours normal salt

FIGURE 64 Forest plot of the effects of altering dietary salt in the primary prevention of pre-eclampsia

TABLE 21 Effects of altering dietary salt on perinatal outcomes

Outcome No. of trials Low salt n/N Normal salt n/N RR 95% CI I2 (%)

Death of baby 2 2/206 1/203 1.92 0.18 to 21.03 NAPreterm birth 1 9/110 10/132 1.08 0.46 to 2.56 NASmall for gestational age 1 15/110 12/132 1.50 0.73 to 3.07 NA

antioxidants were the mineral selenium115 and thenon-vitamin antioxidant lycopene.114 Seven trialsreported pre-eclampsia as an outcome, althoughthree did not say how they defined pre-eclampsia.One study reported “toxaemia” and defined this

as “hypertension occurring with albuminuria”.118

Characteristics of the studies can be seen inAppendix 9.

The quality of these studies is shown in Figure 65.One study was quasi-randomised, with womenallocated treatments according to alternate lists;allocation concealment was thereforeinadequate.118 Two trials reported outcome for allwomen according to treatment allocation, andanother three did not mention any losses tofollow-up. In the two remaining trials, losses tofollow-up were 8 and 11%. For three trials women,caregivers and researchers were blinded to theintervention. Another trial stated it was “double-blind” in the text, and a fourth used the term“triple-blind”. Blinding was not mentioned inreports of the remaining two trials. The sixproperly randomised trials used a placebo control.The quasi-random study did not use a placebo.

On average, antioxidants were more effective thanplacebo in preventing pre-eclampsia (Figure 66).


62

2


Blinding


Randomisationmethod

0 50 100



3

6

4

4

1

3 4

3

FIGURE 65 Quality of RCTs of antioxidants in the primaryprevention of pre-eclampsia

Study Antioxidant(s)n/N

Controln/N

RR (fixed)95% CI

Weight(%)

RR (fixed)95% CIor subcategory

01 Studies with random allocation Beazley 2002 9/52 9/48 4.25 0.92 (0.40 to 2.13) Chappell 1999 11/141 24/142 10.87 0.46 (0.24 to 0.91) Han 1994 0/52 4/48 2.13 0.10 (0.01 to 1.86) Rivas 2000 1/63 14/64 6.31 0.07 (0.01 to 0.54) Sharma 2003 10/116 24/135 10.08 0.48 (0.24 to 0.97) Steyn 2002 3/100 3/100 1.36 1.00 (0.21 to 4.84)

Subtotal (95% CI) 524 537 35.01 0.45 (0.31 to 0.66)Total events: 34 [antioxidant(s)], 78 (control)Test for heterogeneity: �2 = 8.02, df = 5 (p = 0.16), I2 = 37.6%Test for overall effect: Z = 4.08 (p < 0.0001)

02 Studies with quasi-random allocation People’s League 1942 100/2510 143/2511 64.99 0.70 (0.55 to 0.90)

Subtotal (95% CI) 2510 2511 64.99 0.70 (0.55 to 0.90)Total events: 100 [antioxidant(s)], 143 (control)Test for heterogeneity: not applicableTest for overall effect: Z = 2.81 (p = 0.005)

Total (95% CI) 3034 3048 100.00 0.61 (0.50 to 0.75)Total events: 134 [antioxidant(s)], 221 (control)Test for heterogeneity: �2 = 9.32, df = 6 (p = 0.16), I2 = 35.6%Test for overall effect: Z = 4.62 (p < 0.00001)

0.001 0.01 0.1 1 10 100 1000

Favours antioxidants

Favourscontrol

Review: Antioxidants for preventing pre-eclampsiaComparison: 01 Any antioxidants versus control or placeboOutcome: 01 Pre-eclampsia (subgroups by whether random or quasi-random allocation)

FIGURE 66 Forest plot of the effects of antioxidants in the primary prevention of pre-eclampsia

We used RR 0.61 (95% CI 0.50 to 0.75) forprimary prevention of pre-eclampsia in decisionanalysis. The perinatal outcome results are shownin Table 22.

Calcium supplementation duringpregnancyAn inverse relationship between calcium intakeand hypertensive disorders of pregnancy was firstdescribed in 1980, based on epidemiological andclinical studies, and led to the hypothesis that anincrease in calcium intake during pregnancy mightreduce the incidence of high blood pressure andpre-eclampsia among women with low calciumintake. Low calcium intake may cause high bloodpressure by stimulating either parathyroidhormone or renin release, thereby increasingintracellular calcium in vascular smooth muscleand leading to vasoconstriction. A possible modeof action for calcium supplementation is that itreduces parathyroid release and intracellularcalcium, and so reduces smooth musclecontractility. By a similar mechanism, calciumsupplementation could also reduce uterine smooth muscle contractility and prevent pretermlabour and delivery. Calcium might also have anindirect effect on smooth muscle function byincreasing magnesium levels. A theoretical risk ofincreased renal tract stone formation with calciumhas not been substantiated and no other adverseeffects of calcium supplementation have beendocumented.

The review of calcium supplementation in theprimary prevention of pre-eclampsia71 included 12 RCTs (15,206 women). About one-third of thewomen had adequate calcium intake whereas theremainder had low calcium intake (5275 adequate,10,253 low calcium intake). Most of the information was from two large trials.120,121 Mostwomen were low risk at trial entry (14,923 low risk,605 high risk). The dose of calcium evaluated wasprimarily 1.5–2 g as calcium carbonate (eighttrials),121–128 gluconate (one trial)129 or elementalcalcium (three trials),130–132 treatment was started at anywhere between 20 and 32 weeks until delivery and this was compared with placebo.


The quality of the studies is shown in Figure 67.Overall, these trials were high quality, with the twolarge trials being well conducted. For one smallstudy there is a large discrepancy in the size of thetwo allocated groups,129 the reason for which isunclear.

Calcium supplementation was more effective thanplacebo in preventing pre-eclampsia and thesefindings are unlikely to be accounted for by chancealone (Figure 68 overleaf). There was significantheterogeneity so a random effects model was usedin meta-analysis. We used RR 0.48 (95% CI 0.33 to0.69) in decision analysis. The perinatal outcomeresults are shown in Table 23 overleaf.

Energy and protein intake in pregnancyObservational studies have reported that bothgestational weight gain and energy intake arestrongly and positively associated with foetalgrowth, and possibly associated with a reduced riskof preterm birth. Moreover, these associations arestronger in undernourished women, that is, thosewith low prepregnancy weight-for-height. TheDutch Famine Study found a clear reduction infoetal growth, but no effect on gestational


63


TABLE 22 Effects of antioxidants on perinatal outcomes

Outcome No. of trials Antioxidant Control RR 95% CI I2 (%) p-Valuen/N n/N

Neonatal death 2 36/2542 27/2534 1.33 0.81 to 2.19 0 0.45Preterm birth (<37 weeks) 3 76/293 54/290 1.38 1.04 to 1.82 0 0.94Small for gestational age 3 49/309 81/325 0.64 0.47 to 0.87 0 0.52


Blinding


Randomisationmethod

0 50 100



7

12

9

5

9 3

3

FIGURE 67 Quality of RCTs of calcium supplementation duringpregnancy

duration when pregnant women were forced bythe Germans in 1944 and 1945 to reduce theirenergy intake during the third trimester. Non-randomised trials of ‘balanced’ energy/proteinsupplementation (i.e. supplements in whichprotein provides less than 25% of the total

energy content) have reported beneficial effects on foetal growth, although the evidence fromproperly randomised trials suggests more modest benefits. Trials of interventions to increase foetal growth have taken on greaterinterest in light of recent evidence that higher


64

Review: Calcium supplementation during pregnancy for preventing hypertensive disorders and related problemsComparison: 01 Routine calcium supplementation in pregnancy by baseline dietary calciumOutcome: 02 Pre-eclampsia

Studyor subcategory

Calciumn/N

Placebon/N

RR (random)95% CI

Weight(%)

RR (random)95% CI Order

01 Adequate calcium diet Villar 1987 1/25 3/27 2.55 0.36 (0.04 to 3.24) 1 Villar 1990 0/90 3/88 1.49 0.14 (0.01 to 2.67) 2 Crowther 1999 10/227 23/229 11.86 0.44 (0.21 to 0.90) 3 CPEP 1997 158/2163 168/2173 19.86 0.94 (0.77 to 1.16) 4

Subtotal (95% CI) 2505 2517 35.76 0.62 (0.32 to 1.20)Total events: 169 (calcium), 197 (placebo)Test for heterogeneity: �2 = 6.20, df = 3 (p = 0.10), I2 = 51.6%Test for overall effect: Z = 1.43 (p = 0.15)

02 Low calcium diet L-Jaramillo 1990 0/22 8/34 1.64 0.09 (0.01 to 1.48) 1 S-Ramos 1994 4/29 15/34 8.56 0.31 (0.12 to 0.84) 2 L-Jaramillo 1989 2/55 12/51 5.07 0.15 (0.04 to 0.66) 3 Purwar 1996 2/97 11/93 4.90 0.17 (0.04 to 0.77) 4 L-Jaramillo 1997 4/125 21/135 8.01 0.21 (0.07 to 0.58) 5 Belizan 1991 15/579 23/588 13.06 0.66 (0.35 to 1.26) 6 WHO 2006 171/4151 186/4161 19.92 0.92 (0.75 to 1.13) 7

Subtotal (95% CI) 5058 5096 61.16 0.36 (0.18 to 0.70)Total events: 198 (calcium), 276 (placebo)Test for heterogeneity: �2 = 23.85, df = 6 (p = 0.0006), I2 = 74.8%Test for overall effect: Z = 3.03 (p = 0.002)

03 Dietary calcium not specified Niromanesh 2001 1/15 7/15 3.08 0.14 (0.02 to 1.02) 0

Subtotal (95% CI) 15 15 3.08 0.14 (0.02 to 1.02)Total events: 1 (calcium), 7 (placebo)Test for heterogeneity: not applicableTest for overall effect: Z = 1.94 (p = 0.05)Total (95% CI) 7578 7628 100.00 0.48 (0.33 to 0.69)Total events: 368 (calcium), 480 (placebo)Test for heterogeneity: �2 = 33.90, df = 11 (p = 0.0004), I2 = 67.5%Test for overall effect: Z = 3.88 (p = 0.0001)

0.01 0.1 1 10 100

Favourstreatment

Favourscontrol

FIGURE 68 Forest plot of the effects of calcium supplementation in the primary prevention of pre-eclampsia

TABLE 23 Effects of calcium supplementation on perinatal outcomes

Outcome No. of trials Calcium Placebo RR 95% CI I2 (%) p-Valuen/N n/N

Death of the baby 10 177/7548 200/7593 0.89 0.73 to 1.09 0Preterm birth (<37 weeks)a 10 703/7347 763/7404 0.81 0.64 to 1.03a 57.2 0.02Small for gestational age 3 164/6543 149/6548 1.10 0.88 to 1.37 0

a Random effects model, as I2 57%.

birth weight for gestational age is associated withreduced risks for type 2 diabetes, hypertensionand coronary heart disease in late adulthood.High-protein dietary supplementation (i.e.supplementation in which the protein provides atleast 25% of its total energy content) mayadversely affect pregnancy outcome. Isocaloricprotein supplementation denotes a supplement inwhich the protein content is ‘balanced’, that is,provides less than 25% of its total energy content,but replaces an equivalent amount of energy in the diet. Before 1970, clinicians frequentlycounselled pregnant women to restrict their foodintake in an attempt to prevent pre-eclampsia,despite the absence of evidence that such advicewas beneficial. Moreover, evidence fromobservational studies (including the Dutch Famine Study) strongly suggests that suchrestriction (among non-obese women, at least) isassociated with impairment in foetal growth. Noevidence points to specific effects of protein (asopposed to energy) restriction, althoughprescription of a well-balanced diet that restrictsenergy intake will also lead to a reduction inprotein intake.

The review of energy and protein intake inpregnancy looked at five related interventions –nutritional advice during pregnancy (five trials,1134 women), balanced protein/energysupplementation in pregnancy (13 trials, 4665women), high protein supplementation inpregnancy (two trials, 1076 women), isocaloricbalanced protein supplementation in pregnancy(three trials, 966 women) and energy/proteinrestriction in pregnant women with high weight-for-height or weight gain (three trials, 384 women)and included 23 trials in total.133 (Since this reportwas finished, the Cochrane Energy and Proteinreview has been updated; there were no newincluded studies so the results have not changedfor the pre-eclampsia outcome.) The trials of highprotein supplementation in pregnancy did notreport pre-eclampsia. Participants varied in thetrials between well nourished women and thosewho were nutritionally vulnerable. Theinterventions within each category variedconsiderably. Controls were mainly no interventionexcept for eight trials where some form of placebowas used.134–141 Characteristics of the studies canbe seen in Appendix 9.

The quality of the 23 studies is shown in Figure 69.Alternate allocation or quasi-random methods ofallocation were used in six trials.137,142–146 Nodetails on follow-up were given in this systematicreview.

Nutritional advice had a trend towards being moreeffective than no advice but these findings couldhave been accounted for by chance alone, RR 0.89(95% CI 0.42 to 1.88). Isocaloric balanced proteinsupplementation was as effective as control, RR1.00 (95% CI 0.57 to 1.75). Balancedprotein/energy intake had a trend towards beingless effective than control but these findings couldhave been accounted for by chance alone, RR 1.20(95% CI 0.77 to 1.89). Energy/protein restrictionalso had a trend towards being less effective thannormal diet but these findings could have beenaccounted for by chance alone, RR 1.13 (95% CI0.59 to 2.18) (Figures 70–73). The perinataloutcome results are shown in Tables 24–27. Becauseof the wide CIs, the effect of energy and proteinintake relative to comparator is highly uncertain.These results are compatible with both increasedand decreased incidence of pre-eclampsia beingassociated with energy and protein intakeinterventions. Energy and protein intake reviewresults were not used in decision analysis becauseof the possibility of harm from two of theinterventions, one showing no apparent effect andthe remaining result based on one trial only.

Garlic for preventing pre-eclampsia andits complicationsGarlic (Allium sativum) is part of the Allium, oronion, family and is used in both traditionalChinese and Ayurvedic medicine. The traditionalmedicinal uses of garlic include prevention ofinfection and treatment of colds, influenza,bronchitis, whooping cough, gastroenteritis,dysentery and skin problems. More recently, it hasbeen suggested that garlic may have lipid-loweringproperties which may be beneficial for thetreatment of arteriosclerosis and diabetes and forthe prevention of myocardial infarction. The


65



Blinding


Randomisationmethod

0 50 100



5

23

18

5

2 21

18

FIGURE 69 Quality of RCTs of energy and protein intake inpregnancy


66

Study Treatmentn/N

Controln/N

RR (fixed)95% CI

Weight%

RR (fixed)95% CI

Hankin 1982 17/96 8/40

96 40

100.00 0.89 (0.42 to 1.88)

100.00 0.89 (0.42 to 1.88)Total events: 17 (treatment), 8 (control)Test for heterogeneity: not applicable

Total (95% CI)

Test for overall effect: Z = 0.32 (p = 0.8)

0.1 0.2 0.5 1 2 5 10Favours

treatmentFavourscontrol

Review: Energy and protein intake in pregnancyComparison: 01 Nutritional advice during pregnancyOutcome: 03 Pre-eclampsia

FIGURE 70 Forest plot of the effect of nutritional advice during pregnancy to prevent pre-eclampsia

Study Treatmentn/N

Controln/N

RR (fixed)95% CI

Weight(%)

RR (fixed)95% CI

Girija 1984 0/10 0/10

258 258

0.0 Not estimableMora 1978 25/221 17/222 60.2 1.48 (0.82 to 2.66)Ross 1938 9/27 11/26 39.8 0.79 (0.39 to 1.58)

100.00 1.20 (0.77 to 1.89)Total events: 34 (treatment), 28 (control)Test for heterogeneity: �2 = 1.89, df = 1 (p = 0.17), I2 = 47.0%

Total (95% CI)


0.1 0.2 0.5 1 2 5 10Favours


Review: Energy and protein intake in pregnancyComparison: 02 Balanced protein/energy supplementation in pregnancyOutcome: 03 Pre-eclampsia

FIGURE 71 Forest plot of balanced protein and energy supplementation in pregnancy to prevent pre-eclampsia

TABLE 24 Effects of nutritional advice on perinatal outcomes

Outcome No. of trials Nutritional Placebo RR 95% CI I2 (%) p-Valueadvice n/N n/N

Neonatal death 1 5/221 4/227 1.28 0.35 to 4.72 NAPreterm birth (<37 weeks) 2 9/238 18/211 0.46 0.21 to 0.98 0.83Small for gestational age 1 12/205 12/199 0.97 0.45 to 2.11 NA

TABLE 25 Effects of balanced energy and protein supplementation on perinatal outcomes

Outcome No. of trials Balanced Placebo RR 95% CI I2 (%) p-Valueenergy/protein n/N

n/N

Neonatal death 4 23/1153 33/1053 0.62 0.37 to 1.05 0.81Preterm birth (<37 weeks) 5 97/1225 118/1211 0.83 0.65 to 1.06 0.94Small for gestational age 6 142/1757 193/1639 0.68 0.56 to 0.84 0.66


67


Study Treatmentn/N

Controln/N

RR (fixed)95% CI

Weight(%)

RR (fixed)95% CI

Mardones 1988 23/391 23/391

391 391

100.00 1.00 (0.57 to 1.75)

100.00 1.00 (0.57 to 1.75)Total events: 23 (treatment), 23 (control)Test for heterogeneity: not applicable

Total (95% CI)

Test for overall effect: Z = 0.32 (p = 1)

0.1 0.2 0.5 1 2 5 10Favours


Review: Energy and protein intake in pregnancyComparison: 04 Isocaloric balanced protein supplementation in pregnancyOutcome: 05 Pre-eclampsia

FIGURE 72 Forest plot of isocaloric balanced protein supplementation in pregnancy to prevent pre-eclampsia

Study Treatmentn/N

Controln/N

RR (fixed)95% CI

Weight(%)

RR (fixed)95% CI

Campbell 1978 6/51 9/51

142 142

60.0 0.67 (0.26 to 1.74)Campbell 1983 11/91 6/91 40.0 1.83 (0.71 to 4.75)

100.00 1.13 (0.59 to 2.18)Total events: 17 (treatment), 15 (control)Test for heterogeneity: �2 = 2.16, df = 1 (p = 0), I2 = 53.8%

Total (95% CI)


0.1 0.2 0.5 1 2 5 10Favours


Review: Energy and protein intake in pregnancyComparison: 05 Energy/protein restriction in pregnant women with high weight-for-height or gainOutcome: 01 Pre-eclampsia

FIGURE 73 Forest plot of energy and protein restriction in high weight for height or weight gain during pregnancy to prevent pre-eclampsia

TABLE 26 Effects of isocaloric protein supplementation on perinatal outcomes

Outcome No. of trials Isocaloric Placebo RR 95% CI I2 (%)protein n/N n/N

Neonatal death 1 1/391 2/391 0.50 0.05 to 5.49 NAPreterm birth (<37 weeks) 1 40/391 38/391 1.05 0.69 to 1.60 NASmall for gestational age 1 171/391 127/391 1.35 1.12 to 1.61 NA

TABLE 27 Effects of energy and protein restriction on perinatal outcomes

Outcome No. of trials Energy/protein Placebo RR 95% CI I2 (%)restriction n/N

n/N

Death of the baby 0Preterm birth (<37 weeks) 1 2/91 4/91 0.50 0.09 to 2.66 NASmall for gestational age 0

suggestions that garlic may lower blood pressure,reduce oxidative stress and/or inhibit plateletaggregation have led to the hypothesis that garlicmay have a role in the prevention of pre-eclampsia. Many commercial preparations ofgarlic are available but garlic’s active compoundallicin is unstable, so the bioavailability of allicinremains uncertain.

The review of garlic for preventing pre-eclampsiaand its complications147 included one RCT (100women).148 This study included primigravidwomen at 28–32 weeks at moderate risk of pre-

eclampsia, was conducted in Iran and evaluatedgarlic in tablet form. Characteristics of the studycan be seen in Appendix 9.

The quality of the study is shown in Figure 74.There is no information about how therandomisation sequence was prepared or theallocation concealed. Follow-up was reported forall women. A placebo was used, although garlicodour was reported by one-third of the women inthe active group. There was no other blinding.

Garlic had a trend towards being more effectivethan placebo in preventing pre-eclampsia, butthese findings could have been accounted for bychance alone (Figure 75). We used RR 0.78 (95%CI 0.31 to 1.93) for primary prevention of pre-eclampsia in decision analysis. The perinataloutcome results are shown in Table 28.

Magnesium supplementation inpregnancyMagnesium is one of the essential mineralsneeded by humans in relatively large amounts. Itworks with many enzymes to regulate bodytemperature and synthesise proteins, in additionto maintaining electrical potentials in nerves andmuscle membranes. Magnesium occurs widely inmany foods; dairy products, breads and cereals,vegetables and meats are all good sources. It istherefore not surprising that frank magnesium


68

TABLE 28 Effects of garlic on perinatal outcomes

Outcome No. of trials Rest n/N Activity n/N RR 95% CI I2 (%)

Death of the baby 1 0/50 0/50 – – –Preterm birth (<37 weeks) 1 NA NA – – –Small for gestational age 1 NA NA – – –


Blinding


Randomisationmethod

0 50 100



1

1

1

1

FIGURE 74 Quality of RCTs of garlic for preventing pre-eclampsia and its complications

Review: Garlic for preventing pre-eclampsia and its complicationsComparison: 01 Garlic versus placebo/no interventionOutcome: 01 Pre-eclampsia

Studyor subcategory

Garlicn/N

Controln/N

RR (fixed)95% CI

Weight(%)


Iran 2001 7/50 9/50 100.00 0.78 (0.31 to 1.93) 0

Total (95% CI) 50 50 100.00 0.78 (0.31 to 1.93)Total events: 7 (garlic), 9 (control)Test for heterogeneity: not applicableTest for overall effect: Z = 0.54 (p = 0.59)

0.1 0.2 0.5 1 2 5 10

Favours garlic Favours control

FIGURE 75 Forest plot of the effects of garlic for preventing pre-eclampsia and its complications

deficiency has never been reported to occur inhealthy individuals who eat varied diets. Dietaryintake studies during pregnancy consistentlydemonstrate that many women, especially thosefrom disadvantaged backgrounds, have intakes ofmagnesium below recommended levels. It hasbeen reported that magnesium supplementationduring pregnancy was associated with a reducedrisk of foetal growth retardation and pre-eclampsia. Higher magnesium intake is associatedwith increased birth weight.

The review of magnesium supplementation inpregnancy included seven RCTs (2689 women).Participants were a mixture of women with high-and low-risk pregnancies and at high and low riskof having a low magnesium diet. The magnesiumwas given as oxide,149 citrate,150 gluconate (twoRCTs)151,152 and aspartate (three RCTs)153–155 witha variety of doses that may or may not becomparable. Comparator was either placebo (sixRCTs) or no treatment (one RCT).150


The quality of the studies is shown in Figure 76.The largest trial was a cluster randomised trial thatdid not take intra-cluster correlation effects intoaccount in the statistical analysis.153 Another was a

quasi-randomised trial in that participants wereallocated to groups by using their date of birth.155

Magnesium supplementation had a trend towardsbeing more effective than comparator inpreventing pre-eclampsia but these findings couldhave been accounted for by chance alone(Figure 77). We used RR 0.87 (95% CI 0.57 to 1.32)for primary prevention of pre-eclampsia indecision analysis. The perinatal outcome resultsare shown in Table 29.


69



Blinding


Randomisationmethod

0 50 100



4 3

61

5 2

6 1

FIGURE 76 Quality of RCTs of magnesium supplementation inpregnancy

Study Treatmentn/N

Controln/N

RR (fixed)95% CI

Weight(%)

RR (fixed)95% CI

Angola 1992 2/50 5/50

235 239

12.6 0.40 (0.08 to 1.97)Memphis 1989 32/185 35/189 87.4 0.93 (0.60 to 1.44)

100.00 0.87 (0.57 to 1.32)Total events: 34 (treatment), 40 (control)Test for heterogeneity: �2 = 1.02, df = 1 (p = 0.31), I2 = 2.0%

Total (95% CI)


0.1 0.2 0.5 1 2 5 10Favours


Review: Magnesium supplementation in pregnancyComparison: 01 Magnesium vs control – all studiesOutcome: 08 Any pre-eclampsia

FIGURE 77 Forest plot of the effects of magnesium in the primary prevention of pre-eclampsia

TABLE 29 Effects of magnesium supplementation on perinatal outcomes

Outcome No. of trials Magnesium Control RR 95% CI I2 (%) p-Valuen/N n/N

Death of baby prior to discharge 3 5/893 3/908 1.59 0.42 to 6.05 0Preterm birth (<37 weeks) 5 86/1125 121/1150 0.73 0.57 to 0.94 56.5 0.06Small for gestational age 3 72/865 104/876 0.70 0.53 to 0.93 32.6 0.23

Marine oil and other prostaglandinprecursor supplementation duringpregnancyThe use of fish oil supplements during the secondhalf of pregnancy has been proposed as a possiblestrategy to prevent pre-eclampsia and pretermbirth and to increase birthweight. Marine oils area rich source of the n-3 long-chainpolyunsaturated fatty acids (omega-3 fatty acids).These are precursors to the 3-series prostaglandinsand have been shown to modulate inflammatoryand vascular effects. Since pre-eclampsia isassociated with vasoconstriction and endothelialdamage, it is plausible that marine oil fatty acidscan down-regulate these responses through directcompetition with the thromboxane A2 precursorarachidonic acid. Other agents, such as eveningprimrose oil, contain the fatty acid called �-linolenic acid, which is a precursor to the 1-series prostaglandins. These prostaglandins havea similar hypothesis for their mode action to thosederived from n-3 (marine oil) fatty acids. They aretherefore included in this review.

The review of marine oil and other prostaglandinprecursor supplements156 included six RCTs (2783women). All six compared a supplement, or foodcontaining marine fatty acids, with either placeboor no supplement. Four trials used oil derivedfrom fish157–160 and another used a combination ofevening primrose oil and fish oil.149 The sixthassessed consumption of eggs enriched withdocosahexaenoic acid, by feeding an algal oil toegg-laying hens.161 Most trials started

supplementation after 16 weeks’ gestation. Threeincluded women with high-risk pregnancies.158–160


The quality of these studies is shown in Figure 78.Only one study did not use a placebo for thecontrol group.149 Trials that assessed the success ofblinding indicate that the majority of womentaking marine oil could guess their groupallocation, largely because of belching and anunpleasant taste associated with taking the fish oilsupplements.

Marine oil and other prostaglandin precursorsupplements show a trend towards being more


70


Blinding


Randomisationmethod

0 50 100



5 1

3 3

6

5 1

FIGURE 78 Quality of RCTs of marine oil and other prostaglandinprecursor supplements in the primary prevention of pre-eclampsia

Review: Marine oil, and other prostaglandin precursor, supplementation for pregnancy uncomplicated by pre-eclampsia or intrauterine growth restriction (Editorial process 310106)Comparison: 01 Prostagladin precursor supplementation versus none or placebo – all womenOutcome: 02 Pre-eclampsia (hypertension with proteinuria)

Studyor subcategory

Marine oiln/N

Controln/N

RR (fixed)95% CI

Weight(%)

RR (fixed)95% CI

Angola 1992 2/50 5/50 9.92 0.40 (0.08 to 1.97)Denmark 1992 0/266 5/267 10.89 0.09 (0.01 to 1.64)England 1995 15/113 18/119 34.79 0.88 (0.47 to 1.66)Europe 2000 25/398 23/420 44.40 1.15 (0.66 to 1.99)

Total (95% CI) 827 856 100.00 0.86 (0.5 to 1.27)Total events: 42 (marine oil), 51 (control)Test for heterogeneity: �2 = 4.25, df = 3 (p = 0.24), I2 = 29.3%Test for overall effect: Z = 0.74 (p = 0.46)

0.001 0.01 0.1 1 10 100 1000

Favourstreatment

Favourscontrol

FIGURE 79 Forest plot of the effects of marine oil and other prostaglandin precursor supplements in the primary prevention of pre-eclampsia

effective than placebo or no supplement inpreventing pre-eclampsia but these findings couldhave been accounted for by chance alone(Figure 79). We used RR 0.86 (95% CI 0.59 to 1.27)for primary prevention of pre-eclampsia indecision analysis. The perinatal outcome resultsare shown in Table 30.

Pharmacological interventionsAntihypertensive drug therapy for mildto moderate hypertension duringpregnancy During the early weeks of normal pregnancyblood pressure falls, climbing slowly in laterpregnancy to reach pre-pregnancy levels at term.This complicates the diagnosis of hypertensionduring pregnancy. The role of antihypertensivetherapy for pregnant women with mild tomoderate hypertension is unclear. As there is noimmediate need to lower blood pressure, therationale for treatment is that it will prevent ordelay progression to more severe disease, therebybenefiting the woman and/or her baby andreducing consumption of health service resources.In addition to reducing blood pressure, the beliefhas been that these drugs reduce the risk ofpreterm delivery and placental abruption andimprove foetal growth. A wide variety of drugshave been advocated, and each group hasdifferent potential side-effects and adverse events.

The review of antihypertensive drugs for mild tomoderate hypertension in pregnancy76 included40 RCTs (3797 women). [Since this report wasfinished, a new version of the CochraneAntihypertensives review has been published. Thisincluded 46 RCTs, 28 compared with placebo/notreatment (22 for the pre-eclampsia outcome). Theresults were RR = 0.97 (95% CI 0.81 to 1.13).]Twenty-two RCTs (2815 women) comparedantihypertensive with placebo/no antihypertensiveand 17 RCTs (1182 women) compared oneantihypertensive drug with another; these are notdiscussed further here. The dose for several agentsvaried considerably between studies, in bothamount and duration of therapy. Most studiesrecruited women during the second or third

trimester of pregnancy. Characteristics of thestudies can be seen in Appendix 9.

The quality of the studies is shown in Figure 80(note that RCTs’ percentage follow-up was notgiven in the review). Concealment of allocationwas reported as adequate for just five of thetrials.162–166 None of the trials comparing drugwith no treatment mentioned blinding in theassessment of outcome.

There was no clear effect of antihypertensivedrugs compared with placebo/no treatment inpreventing proteinuria/pre-eclampsia (Figure 81).We used RR 0.99 (95% CI 0.84 to 1.18) forprevention of pre-eclampsia in decision analysis.The perinatal outcome results when comparedwith placebo/no treatment are shown in Table 31.

Antiplatelet agents for preventing pre-eclampsia and its complicationsIt is thought that activation of platelets and theclotting system may occur early in the course ofpre-eclampsia, before clinical symptoms develop.Deficient intravascular production of prostacyclin,a vasodilator, with excessive production ofthromboxane, a platelet-derived vasoconstrictorand stimulant of platelet aggregation have alsobeen demonstrated to occur in pre-eclampsia.


71


TABLE 30 Effects of marine oil and other prostaglandin precursor supplements on perinatal outcomes

Outcome No. of trials Marine oil n/N Control n/N RR 95% CI I2 (%)

Neonatal death 3 7/1136 6/1167 1.17 0.41 to 3.29 0Preterm birth (<37 weeks) 5 205/947 228/969 0.92 0.79 to 1.07 0Small for gestational age 1 208/685 185/689 1.13 0.96 to 1.34 NA


Blinding


Randomisationmethod

0 50 100



9 13

5 17

157

22

FIGURE 80 Quality of RCTs of antihypertensive drug therapyfor mild to moderate hypertension for prevention of pre-eclampsia


72

Review: Antihypertensive drug therapy for mild to moderate hypertension during pregnancyComparison: 01 Any antihypertensive drug versus none (subgrouped by class of drug)Outcome: 04 Proteinuria/pre-elampsia

Study Treatmentn/N

Controln/N

RR (fixed)95% CI

Weight(%)

RR (fixed)95% CI

01 Beta blocker versus none Israel 1992 Sweden 1984 UK 1982 UK 1983 UK 1989 UK 1992 USA 1987a

Subtotal (95% CI)Test for heterogeneity �2 = 7.07, df = 6 (p = 0.3146)Test for overall effect Z = –2.14 (p = 0.03)

02 Beta blocker + other drug versus none Caribbean Is. 1990 Sweden 1985

Subtotal (95% CI)Test for heterogeneity �2 = 0.48, df = 1 (p = 0.4901)Test for overall effect Z = 0.66 (p = 0.5)

03 Methyldopa versus none UK 1976 USA 1987

Subtotal (95% CI) Test for heterogeneity �2 = 0.02, df = 1 (p = 0.8932)Test for overall effect Z = 0.50 (p = 0.6)

04 Methyldopa versus none UK 1968 USA 1949

Subtotal (95% CI) Test for heterogeneity �2 = 0.60, df = 1 (p = 0.4367)Test for overall effect Z = 1.04 (p = 0.3)

05 Beta blocker or methyldopa versus none USA 1990

Subtotal (95% CI)Test for heterogeneity �2 = 0.00, df = 0Test for overall effect Z = 0.37 (p = 0.7)

06 Calcium channel blocker versus none Italy 1998 Sweden 1995 USA 1992

Subtotal (95% CI)Test for heterogeneity �2 = 0.52, df = 0 (p = 0.7718)Test for overall effect Z = 2.81 (p = 0.005)

07 Alpha blocker versus none South Africa 1991


08 Regular antihypertensive therapy Ireland 1991


Subtotal (95% CI)Test for heterogeneity �2 = 26.62, df = 18 (p = 0.0863)Test for overall effect Z = –0.10 (p = 0.9)

1/29 6/26 4/64 3/51 31/70 13/51 10/92

68/383

7/78 10/86

17/164

6/117 5/13

11/130

15/52 1/29

16/81

30/173

30/173

29/125 18/47 16/98

63/270

1/12

1/12

1/17

1/17

207/1230

3/28 6/26 9/6210/5345/7417/63 6/94

96/400

7/76 6/82

13/158

5/125 4/12

9/137

17/48 3/29

20/77

14/90

14/90

18/11810/5410/99

38/271

5/20

5/20

6/19

6/19

20/1172

1.53.04.54.9

21.77.62.9

46.1

3.53.0

6.6

2.42.1

4.5

8.81.5

10.3

9.1

9.1

9.24.64.9

18.8

1.9

1.9

2.8

2.8

100.0

0.32 (0.04 to 2.91)1.00 (0.37 to 2.70)0.43 (0.14 to 1.33)0.31 (0.09 to 1.07)0.73 (0.53 to 1.00)0.94 (0.51 to 1.76)1.70 (0.65 to 4.49)

0.76 (0.59 to 0.98)

0.97 (0.36 to 2.65)1.59 (0.60 to 4.17)

1.26 (0.63 to 2.51)

1.28 (0.40 to 4.09)1.15 (0.40 to 3.31)

1.22 (0.55 to 2.71)

0.81 (0.46 to 1.44)0.33 (0.04 to 3.02)

0.74 (0.43 to 1.30)

1.11 (0.62 to 1.99)

1.11 (0.62 to 1.99)

1.52 (0.89 to 2.59)2.07 (1.06 to 4.03)1.62 (0.77 to 3.38)

1.68 (1.17 to 2.41)

0.33 (0.04 to 2.52)

0.33 (0.04 to 2.52)

0.19 (0.02 to 1.39)

0.19 (0.02 to 1.39)

0.99 (0.84 to 1.18)

0.1 0.2Favours treatment Favours control

5 101

FIGURE 81 Forest plot of antihypertensive drug therapy compared with placebo/no treatment for mild to moderate hypertension

These observations led to the hypotheses thatantiplatelet agents, and low-dose aspirin inparticular, might prevent or delay thedevelopment of pre-eclampsia and that, forwomen who already have the disorder, the risk ofadverse events might be reduced.

The review of antiplatelet agents for the primaryprevention of pre-eclampsia74 included 51 RCTs(36,500 women). [Since this report was finished,the Cochrane Antiplatelet review has beenupdated. This included 59 trials, 46 for the pre-eclampsia outcome RR = 0.83 (95% CI 0.77 to0.89).] The antiplatelets were mostly aspirin at adose of between 50 and 150 mg/day (mostly either60–100 mg/day). In four trials aspirin was givenwith dipyridamole167–170 and in one it was givenwith vitamin C and E.171 One trial gavedipyridamole with heparin172 and one gaveozagrel hydrochloride.173 Treatments were startedat anywhere between 12 and 34 weeks and werecontinued until between 34 weeks and delivery(where specified). Comparator was placebo mostly,but one-fifth of the trials used no treatment.Characteristics of the studies can be seen inAppendix 9.

The quality of the studies is shown in Figure 82.On average, antiplatelet agents were moreeffective than placebo or no antiplatelet agent in

preventing pre-eclampsia and these results areunlikely to be accounted for by chance alone(Figure 83 overleaf). We used RR 0.81 (95% CI0.75 to 0.88) for primary prevention of pre-eclampsia in decision analysis. The perinataloutcome results are shown in Table 32 on p. 75.

Diuretics for preventing pre-eclampsiaDiuretics are commonly used to treat hypertensionin non-pregnant individuals. They were alsoformerly used in pregnancy to treat high bloodpressure and delay or prevent pre-eclampsia onset.As diuretics promote excretion of sodium anddecrease oedema and blood pressure in non-pregnant people, it was assumed that they wouldbe beneficial in preventing pre-eclampsia. Thesustained blood pressure-lowering effect of thiazidediuretics is thought to involve mobilisation ofexcess sodium from the arteriolar wall, withwidening of the vessel lumen. This mighttheoretically be of benefit in the pathologicalvasoconstriction which is an importantcharacteristic of pre-eclampsia. The use of diureticsin pregnancy became controversial, with increasingevidence of the reduction of plasma volume in pre-eclampsia. There have also been case reports ofmaternal side-effects of diuretics in pregnancyincluding low potassium and sodium levels,decreased carbohydrate tolerance (increasedtendency to diabetes) and pancreatitis.

The review of diuretics for preventing pre-eclampsia174 included five RCTs (1836 women).Participants were both primiparous andmultiparous women and were randomised fromthe first to the third trimester. Two trials includedwomen with normal blood pressure only175,176 oneincluded women with chronic hypertension only177

and two did not report on blood pressure at trialentry.178,179 Two trials stated they excluded womenwith proteinuria.175,176 One trial included womenbased on presence of excessive weight gain oroedema.176 Thiazide diuretics were evaluated in alltrials: chlorothiazide (three studies)176,178,179

hydrochlorothiazide (one study)175 andunspecified thiazide diuretics (one study).177 Thesewere compared with placebo in four studies andagainst no treatment in one study.177 Restricted


73


TABLE 31 Effects of antihypertensive drug therapy compared with placebo/no treatment on perinatal outcomes

Outcome No of trials Anti-hypertensive Placebo/no treatment RR 95%CI I2 (%)n/N n/N

Foetal or neonatal deaths 23 30/1409 44/1318 0.71 0.46 to 1.09 NAPreterm birth (<37 weeks) 12 252/912 241/826 1.00 0.87 to 1.15 NASmall for gestational age 17 147/1124 118/1035 1.13 0.91 to 1.42 NA


Blinding


Randomisationmethod

0 50 100



23 28

18 33

465

5 51

FIGURE 82 Quality of RCTs of antiplatelet agents in theprimary prevention of pre-eclampsia


74

Review: Antiplatelet agents for preventing pre-eclampsia and its complicationsComparison: 01 Antiplatelet agents versus placebo/no antiplatelet (subgrouped by maternal risk)Outcome: 02 Proteinuric pre-eclampsia

Study Antiplatelet agentn/N

Controln/N

RR (fixed)95% CI

Weight(%)

RR (fixed)95% CI

01 Moderate-risk women Australia 1993 Australia 1996a Australia 1992 Barbados 1998 Brazil 1996 China 1996 China 1999 CLASP 1994 Colrado 1993 EPREDA 1993 ERASME 2003 Finland 1997 Israel 1994 Italy 1993 Jamaica 1998 Netherlands 1986 S Africa 1988 Spain 1997 Tanzania 1995 Thailand 1996 UK 1990 UK 1995 USA 1993 USA 1993a

Subtotal (95% CI)Total events: 717 (antiplatelet agents), 831 (control)Test for heterogeneity �2 = 47.94, df = 23 (p = 0.003) I2 = 52.0%Test for overall effect Z = 3.24 (p = 0.001)

02 High-risk women Australia 1995a Australia 1996 Australia 1997 Finland 1993 Finland 2002 France 1985 France 1990 Germany 2000 India 1994 India 1999 Israel 1989 Israel 1990 Italy 1999 Japan 1999 Netherlands 1989 USA 1994 USA 1998 Venezeula 2000 Zimbabwe 1998

Subtotal (95% CI)Total events: 323 (antiplatelet agents), 443 (control)Test for heterogeneity �2 = 35.78, df = 18 (p = 0.008) I2 = 49.7%Test for overall effect Z = 4.74 (p < 0.00001)

Total (95% CI) Total events: 1040 (antiplatelet agents), 1274 (control)Test for heterogeneity �2 = 85.59, df = 42 (p = <0.0001) I2 = 50.9%Test for overall effect Z = 5.31 (p < 0.00001)

1/55 4/52 0/22 40/1819 32/476 4/40 3/118267/3992 6/48 5/156 28/1632 4/13 0/24 12/497215/3023 0/23 4/30 3/50 0/64 9/651 1/48 5/58 5/302 69/1485

14678

0/9 1/27 5/58 9/97 2/43 0/48 1/46 3/22 6/46 14/79 1/34 6/23 18/103 5/20 0/5 3/24231/1254 1/63 17/113

2114

16792

5/55 7/50 6/19 46/1822 30/494 12/44 7/75302/3982 9/42 8/73 26/1637 2/13 2/23 9/423189/3028 7/23 4/14 7/50 6/63 19/697 10/52 7/60 17/302 94/1500

14539

6/11 1/25 5/50 11/100 10/43 6/45 4/45 2/21 19/48 36/81 7/31 6/24 21/104 12/20 1/5 5/25254/1249 14/64 23/117

2108

16647

0.40.60.53.62.30.90.7

23.60.70.92.00.20.20.8

14.70.60.40.50.51.40.70.51.37.3

65.4

0.50.10.40.80.80.50.30.21.52.80.60.51.60.90.10.4

19.91.11.8

34.6

100.0

0.20 (0.02 to 1.66)0.55 (0.17 to 1.76)0.07 (0.00 to 1.11)0.87 (0.57 to 1.32)1.11 (0.68 to 1.79)0.37 (0.13 to 1.05)0.27 (0.07 to 1.02)0.88 (0.75 to 1.03)0.58 (0.23 to 1.50)0.29 (0.10 to 0.86)1.08 (0.64 to 1.83)2.00 (0.44 to 9.08)0.19 (0.01 to 3.80)1.13 (0.48 to 2.67)1.14 (0.94 to 1.38)0.07 (0.00 to 1.10)0.47 (0.14 to 1.60)0.43 (0.12 to 1.56)0.08 (0.00 to 1.32)0.51 (0.23 to 1.11)0.11 (0.01 to 0.81)0.74 (0.25 to 2.20)0.29 (0.11 to 0.79)0.74 (0.55 to 1.00)

0.85 (0.77 to 0.94)

0.09 (0.01 to 1.45)0.93 (0.06 to 14.03)0.86 (0.26 to 2.81)0.84 (0.37 to 1.95)0.20 (0.05 to 0.86)0.07 (0.00 to 1.25)0.24 (0.03 to 2.10)1.43 (0.27 to 7.73)0.33 (0.14 to 0.75)0.40 (0.23 to 0.68)0.13 (0.02 to 1.00)1.04 (0.39 to 2.77)0.87 (0.49 to 1.53)0.42 (0.18 to 0.96)0.33 (0.02 to 6.65)0.63 (0.17 to 2.33)0.91 (0.77 to 1.06)0.07 (0.01 to 0.54)0.77 (0.43 to 1.35)

0.73 (0.64 to 0.83)

0.81 (0.75 to 0.88)

0.1 0.2 0.5 2 5 10Favours antiplatelet Favours control

FIGURE 83 Forest plot of the effects of antiplatelet agents in the primary prevention of pre-eclampsia

salt intake was advised in all five studies, althoughthere was a wide range (salt intake of 1.8–5 g/day).Characteristics of the studies can be seen inAppendix 9.

The quality of the studies is shown in Figure 84.Four studies were double blinded and one was notblinded.177 Follow-up for two studies wascomplete,176,177 but the remaining three studieshad losses to follow-up ranging from 8 to 14%.

Diuretics had a trend towards being more effectivethan placebo/no treatment in preventing pre-eclampsia, but these findings could have beenaccounted for by chance alone (Figure 85). We usedRR 0.68 (95% CI 0.45 to 1.03) for primaryprevention of pre-eclampsia in decision analysis.The perinatal outcome results are shown in Table 33.


75



Blinding


Randomisationmethod

0 50 100



5

5

14

5

FIGURE 84 Quality of RCTs of diuretics for preventing pre-eclampsia

TABLE 32 Effects of antiplatelet agents on perinatal outcomes

Outcome No. of trials Antiplatelets Control RR 95% CI I2 (%) p-Valuen/N n/N

Foetal and neonatal deaths 38 401/17040 470/16970 0.84 0.74 to 0.96 0 0.63Preterm birth (<37 weeks) 28 2574/15950 2743/15895 0.93 0.89 to 0.98 0 0.64Small for gestational age 32 978/12211 1041/12099 0.92 0.85 to 1.00 27.3 0.08

Review: Diuretics for preventing pre-eclampsia (Version 05)Comparison: 01 Diuretic versus placebo/no treatmentOutcome: 01 Pre-eclampsia

Studyor subcategory

Diureticn/N

Controln/N

RR (fixed)95% CI

Weight(%)

RR (fixed)95% CI

Order

Fallis 1964 4/34 18/40 32.48 0.26 (0.10 to 0.70) 0Kraus 1966 15/506 20/524 38.58 0.78 (0.40 to 1.50) 0Sibai 1984 1/10 1/10 1.96 1.00 (0.07 to 13.87) 0Weseley 1962 14/131 14/136 26.97 1.04 (0.52 to 2.09) 0

Total (95% CI) 681 710 100.00 0.68 (0.45 to 1.03)Total events: 34 (diuretic), 53 (control)Test for heterogeneity: �2 = 5.27, df = 3 (p = 0.15), I2 = 43.0%Test for overall effect: Z = 1.80 (p = 0.07)

0.1 0.2 0.5 1 2 5 10Favours diuretic

Favourscontrol

FIGURE 85 Forest plot of the effects of diuretics for preventing pre-eclampsia

TABLE 33 Effects of diuretics on perinatal outcomes

Outcome No. of trials Diuretics Control RR 95% CI I2 (%) p-Valuen/N n/N

Perinatal death 5 22/1016 26/820 0.72 0.40 to 1.27 0Premature birth 2 17/345 9/120 0.67 0.32 to 1.41 2.1 0.31Small for gestational age 1 0/10 0/10 Not estimable – – –

Nitric oxide donors and precursors forpreventing pre-eclampsia and itscomplicationsIn 1987, nitric oxide was first identified as anendothelium-derived factor associated with vascularrelaxation. Although it is now known to have a widerange of biological functions, interest in its possiblerole in pre-eclampsia has been generated largelybecause nitric oxide mediates many functions of theendothelium, including vasodilatation and inhibitionof platelet aggregation. Nitric oxide is believed tocontribute, at least in part, to the physiologicalvascular adaptations of normal pregnancy.Therefore, reduced availability of nitric oxide mayhave a role in the pathophysiology of pre-eclampsia.Drugs that can be converted by the body into nitricoxide (known as nitric oxide donors) are widelyavailable, and have been used for years astherapeutic agents in cardiovascular diseases such asangina and hypertension. Commonly used nitricoxide donors include glyceryl trinitrate, isosorbidemononitrate, isosorbide dinitrate, S-nitroglutathioneand sodium nitroprusside. They may be taken in arange of ways such as oral or sublingual tablets,aerosol spray under the tongue, skin patches or byintravenous injection.

The review of nitric oxide donors and precursorsfor preventing pre-eclampsia and itscomplications180 included six RCTs (310 women).Four small trials (198 women) compared nitricoxide donors or precursors with placebo or nointervention and two trials compared nitric oxidedonors or precursors with alternative agents(nifedipine,181 antiplatelet agents182) and are notdiscussed further here. The four trials includedwomen at moderate to high risk of developingpre-eclampsia: one trial each of gestationalhypertension,183 either gestational hypertension orpre-eclampsia,184 chronic hypertension and a pasthistory of early onset pre-eclampsia185 or foetalgrowth restriction and normal blood pressure andan abnormal Doppler scan.186 Gestation atrandomisation was less than 16 weeks in onetrial,185 more than 24 weeks in two trials184,186 andnot reported for one trial.183 Three trialsevaluated glyceryl trinitrate transdermal patchesand one evaluated the nitric oxide precursor L-arginine.184 Characteristics of the studies can beseen in Appendix 9.

The quality of the studies is shown in Figure 86.Patients and caregivers were blinded to theintervention in two studies, only the caregiver wasblinded in one study183 and blinding was notmentioned in the remainder.185 Follow-up wascomplete in two studies, 8% of the women were

excluded from analysis in one study184 and theother did not report completeness of follow-up.185

Nitric oxide had a trend towards being moreeffective than placebo or no intervention inpreventing pre-eclampsia, but these findings couldhave been accounted for by chance alone(Figure 87). We used RR 0.83 (95% CI 0.49 to 1.41)for primary prevention of pre-eclampsia indecision analysis. The perinatal outcome resultsare shown in Table 34.

Progesterone for preventing pre-eclampsia and its complicationsProgesterone is a hormone which plays anessential role in reproduction, both in theregulation of the menstrual cycle and in themaintenance of pregnancy. It is used for a rangeof gynaecological problems such as heavy uterinebleeding, fertility control and postmenopausalhormone replacement. In addition, it has beensuggested that progesterone may have a role inthe treatment of premenstrual syndrome (PMS),threatened miscarriage and preterm birth. In thepast, administration of progesterone has beensuggested for prevention and treatment of pre-eclampsia. The hypothesis that progesteronereduced the risk of pre-eclampsia was tested butthe use of progesterone for prevention of pre-eclampsia has never become widespread in clinicalpractice.

The review of progesterone for preventing pre-eclampsia and its complications187 included oneRCT (128 women).188 This RCT had women withnormal blood pressure at 16–28 weeks’ gestation.Progesterone 100 mg was given daily or onalternate days for 1 week by intramuscular


76


Blinding


Randomisationmethod

0 50 100



3 1

3 1

22

3 1

FIGURE 86 Quality of RCTs of nitric oxide for preventing pre-eclampsia and its complications

injection, with the subsequent dosage (between50 mg alternate days and 300 mg daily) dependingon changes in intensity of “toxaemic” symptoms oftiredness, depression, nausea, irritability andheadache. Women in the control group wereoffered simple treatments such as alkalis, analgesics,sedatives and antihistamines for the relief of their“toxaemic” symptoms. How many women neededthese is not reported. Characteristics of the studiescan be seen in Appendix 9.

The quality of the study is shown in Figure 88.Twenty-two participants (15%) were excluded fromthe analyses.

Progesterone had a trend towards being moreeffective than placebo in preventing pre-eclampsia


77


Review: Nitric oxide donors and precursors for preventing pre-eclampsia and its complicationsComparison: 01 Nitric oxide donors and precursors versus placebo/no interventionOutcome: 01 Pre-eclampsia

Studyor subcategory

Nitric oxiden/N

Placebo/controln/N

RR (fixed)95% CI

Weight(%)

RR (fixed)95% CI

Order

01 Nitric oxide donors Davis 2001 1/7 3/9 11.48 0.43 (0.06 to 3.28) 0 Lees 1998 5/21 4/19 18.37 1.13 (0.35 to 3.60) 0 Picciolo 2000 12/38 7/30 34.21 1.35 (0.61 to 3.01) 0

Subtotal (95% CI) 66 58 64.06 1.12 (0.61 to 2.08)Total events: 18 (nitric oxide), 14 (placebo/control)Test for heterogeneity: �2 = 1.07, df = 2 (p = 0.59), I2 = 0%Test for overall effect: Z = 0.37 (p = 0.71)

02 Nitric oxide precursors Facchinetti 2002 3/27 7/19 35.94 0.30 (0.09 to 1.02) 0

Subtotal (95% CI) 27 19 35.94 0.30 (0.09 to 1.02)Total events: 3 (nitric oxide), 7 (placebo/control)Test for heterogeneity: not applicableTest for overall effect: Z = 1.93 (p = 0.05)

Total (95% CI) 93 77 100.00 0.83 (0.49 to 1.41)Total events: 21 (nitric oxide), 21 (placebo/control)Test for heterogeneity: �2 = 4.77, df = 3 (p = 0.19), I2 = 37.1%Test for overall effect: Z = 0.69 (p = 0.49)

0.1 0.2 0.5 1 2 5 10

Favours nitric oxide Favours control

FIGURE 87 Forest plot of the effects of nitric oxide for preventing pre-eclampsia and its complications

TABLE 34 Effects of nitric oxide on perinatal outcomes

Outcome No. of trials Nitric oxide Control RR 95% CI I2 (%) p-Valuen/N n/N

Death of the baby 2 0/65 2/49 0.25 0.03 to 2.34 0 0.23Preterm birth 3 5/86 13/68 0.48 0.21 to 1.07 0 0.07Small for gestational age 2 9/59 10/49 0.78 0.36 to 1.70 0 0.53


Blinding


Randomisationmethod

0 50 100



1

1

1

1

FIGURE 88 Quality of RCTs of progesterone for preventing pre-eclampsia and its complications

but these findings could have been accounted forby chance alone (Figure 89). We used RR 0.21(95% CI 0.03 to 1.77) for primary prevention ofpre-eclampsia in decision analysis. The perinataloutcome results are shown in Table 35.

Discussion of results of clinicaleffectiveness reviewsSummary of effectiveness findingsOverall, the study quality for these trials(Figure 90) was variable or poorly reported. As thelarge trials tended to be of higher quality, however,high-quality results were available for the majorityof women in the small number of reviews withthese trials. There were deficiencies in the fourmain quality areas investigated here and nointervention had universally high-quality data.The number of trials included in the meta-analyses was relatively small – for 11 of the 15reviews there were fewer than 10 trials and eighthad five trials or fewer. The review of antiplateletagents was a notable exception with 51 trials. As inthe summary of test accuracy reviews, in theevaluation of many interventions, includingexercise, advice to rest, advice to restrict dietarysalt, garlic supplementation and progesterone

treatment, the limited number of studies and thelimited number of women with pre-eclampsia perstudy were limiting factors. The difficulties withstudy quality and small sample sizes in many ofthem meant that interpretation of effectivenessresults was often difficult.

The effect on the RR of pre-eclampsia across thereviews is presented in Figure 91. Only fourinterventions showed a statistically significantreduction: rest at home, antioxidant agents,calcium supplementations and antiplatelet agents.For rest at home for women with normal bloodpressure, the 95% CIs are wide and there are noresults on outcomes for the baby (death, pretermbirth or small for gestational age). Forantioxidants, the findings presented here indicatethat they are effective in preventing pre-eclampsia(although the updated Cochrane review, whichincluded two large, recently published trials,reported a smaller effect size that was no longerstatistically significant). Calcium supplementationwas effective at preventing pre-eclampsia, butwithout any clear impact on perinatal outcomes.Antiplatelet agents, primarily low-dose aspirin, areassociated with a modest reduction in pre-eclampsia, which is reflected in similar modestreductions in adverse outcomes for the baby.


78

Review: Progesterone for preventing pre-eclampsia and its complicationsComparison: 01 Progesterone versus placebo/no treatmentOutcome: 01 Pre-eclampsia

Studyor subcategory

Progesteronen/N

Controln/N

RR (fixed)95% CI

Weight(%)

RR (fixed)95% CI

Order

Dalton 1962 1/62 5/66 100.00 0.21 (0.03 to 1.77) 0

Total (95% CI) 62 66 100.00 0.21 (0.03 to 1.77)Total events: 1 (progesterone), 5 (control)Test for heterogeneity: not applicableTest for overall effect: Z = 1.43 (p = 0.15)

0.01 0.1 1 10 100

Favours progesterone

Favourscontrol

FIGURE 89 Forest plot of the effects of progesterone for preventing pre-eclampsia and its complications

TABLE 35 Effects of progesterone on perinatal outcomes

Outcome No. of trials Progesterone Control RR 95% CI I2 (%)n/N n/N

Perinatal death 1 1/62 3/66 0.35 0.04 to 3.32 NAPreterm birth 0Small for gestational age 0


79





Incidence of pre-eclampsia <4%*




0 20 40 60 80 100



732

144 2517

72 6 112

109 31

11938 29

92 78 16

121 33

52

Note: Some studies are reported twice because of inclusion in several reviewsNumbers within stacked bars are numbers of studies*Studies with high- and low-risk populations are counted separately

46

11420

FIGURE 90 Quality of all effectiveness review included studies

0.01 0.1 0.2 0.5 1 2 5 10

Progesterone 0.21 (0.03 to 1.77)

Nitric oxide donors and precursors 0.83 (0.49 to 1.41)Diuretics 0.68 (0.45 to 1.03)

Antiplatelets 0.81 (0.75 to 0.88)

Antihypertensives v none 0.99 (0.84 to 1.18)

Marine oils 0.86 (0.59 to 1.27)Magnesium 0.87 (0.57 to1.32)

Garlic 0.78 (0.31 to1.93)Energy/protein restriction 1.13 (0.59 to 2.18)

Isocaloric balanced protein supplementation 1.00 (0.57 to 1.75)Balanced protein/energy intake 1.20 (0.77 to 1.89)

Nutritional advice 0.98 (0.42 to 1.88)

Calcium 0.48 (0.33 to 0.69)

Antioxidants 0.61 (0.50 to 0.75)Altered dietary salt 1.11 (0.46 to 2.66)Rest alone for normal BP 0.05 (0.00 to 0.83)

Exercise 0.31 (0.01 to 7.09)Bed rest for high BP 0.98 (0.80 to 1.20)Ambulatory BP

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FIGURE 91 Forest plot of summary of results of clinical effectiveness reviews

The best pattern of antenatal care for higher-riskpregnancy is a frequently asked question fromwomen at risk of pre-eclampsia (see Table 2, p. 7),yet there were no systematic reviews on mostaspects of antenatal care. The single reviewlooking at alternative strategies for assessing bloodpressure during pregnancy found no trials.

Lifestyle issues, such as how much to rest orexercise, are usually a matter for personal choice.Whether to rest or give up work are commonconcerns for women at risk of pre-eclampsia (seeTable 2, p. 7). For women with normal bloodpressure who are at moderate risk, it remainsunclear whether advice to rest, from 28 weeks’gestation onwards, with or without nutrientsupplementation, is beneficial overall. For womenwith gestational hypertension, rest in hospitalseems to be associated with a reduction in the RRof severe hypertension and perhaps also ofpreterm birth. Nevertheless, these findings needconfirmation in larger studies, along with morereliable information about other potential benefitsand hazards. In addition, there is little reliableinformation about the potential effects of exercise,whether recreational, domestic or occupational,for women at risk of pre-eclampsia. In the absenceof such evidence, women should be reassured thatthey can make their own choice about how muchto rest or exercise during pregnancy.

A range of dietary interventions have beensuggested as possibly having a role in theprevention of pre-eclampsia. There is no clearevidence that advice to alter salt intake duringpregnancy has any beneficial effect in preventionof pre-eclampsia or its consequences. Saltconsumption during pregnancy should thereforeremain a matter of personal preference. Theinitial optimism that antioxidants, particularly thecombination of vitamin C and E, would reduce therisk of pre-eclampsia has, so far, not beenconfirmed by two recent large trials. Results offurther ongoing trials are awaited. In themeantime, these agents cannot be recommendedfor clinical practice. Calcium supplementation isassociated with a reduction in pre-eclampsia,although this was not reflected in reductions inperinatal outcomes. Nevertheless, calciumsupplementation is probably worthwhile,particularly for women with low dietary intake.Dietary advice, protein/energy supplementation orrestriction could not be supported, based oncurrent evidence. There is insufficient evidence forany reliable conclusions about the potentialbenefits or harms of garlic. The review ofmagnesium supplementation also found not

enough high-quality evidence to recommend thisintervention. For marine oil, and otherprostaglandin precursor supplements duringpregnancy, large reductions in the risk of pre-eclampsia, preterm birth, low birth weight orsmall-for-gestational age are unlikely, althoughmore moderate reductions have not beenexcluded.

Various pharmacological agents have also beenadvocated for women at risk of pre-eclampsia. Forwomen with mild to moderate hypertensionduring pregnancy, it remains unclear whetherlowering blood pressure with antihypertensivedrug therapy is overall worthwhile. Whether thereduction in the risk of severe hypertension isconsidered sufficient to warrant treatment is adecision that should be made by women inconsultation with their obstetrician. Antiplateletagents, primarily low-dose aspirin, are associatedwith moderate–small reductions in the RR of pre-eclampsia and the main outcomes for the baby;namely death before discharge, preterm birth andbeing small for gestational age. Low-dose aspirinappears to be reasonably safe. Women at high riskshould be offered low-dose aspirin. From a publichealth perspective, it may also be worthconsidering for more widespread use, should thisbe found to be cost-effective. It is unclear whetherdiuretics prevent pre-eclampsia. There isinsufficient evidence for reliable conclusions aboutwhether nitric oxide donors and precursorsprevent pre-eclampsia and its complications. Somenitric oxide donors also have a high risk ofheadache. Similarly, it remains unclear whetherprogesterone prevents pre-eclampsia. None ofthese agents can therefore be recommended forclinical practice.

In the summary diagram forest plot (Figure 91) allof the clinical effectiveness results that wereincluded in this report are presented. Twelve ofthese were used in decision analysis-basedeconomic modelling (see Table 37, p. 88) and theremainder not used for a variety of reasons (seeTable 47, p. 105).

Provisos/limitations arising fromproblems with primary dataThe overall quality in the four main areasinvestigated were relatively poor and nointervention had universally high-quality data.Also, the number of trials that were meta-analysedwas relatively small – for 11 of the 15 reviews therewere fewer than 10 trials and eight had five trialsor fewer. The reviews of calcium and antiplateletagents were notable exceptions. As in the summary


80

of test accuracy reviews, in the evaluation of manyinterventions, including exercise, rest at home,advice to restrict dietary salt, garlicsupplementation and progesterone treatment, thesmall number of studies and the low number ofcases with pre-eclampsia per study were limitingfactors. The sample size needed to demonstrateclinically meaningful differences for detectingmodest effects was often inadequate as studies hadbeen sized using over-optimistic estimates ofpossible effects of interventions on pre-eclampsia.In general, due to the limitations in quality andreliability (small numbers of studies and women)of the data reviewed, often there was a lack ofevidence to assess effectiveness rather than goodevidence of lack of effect.

Only four interventions were associated with astatistically significant decrease in pre-eclampsiacases. As discussed above, there are problems withthe reviews of all of these interventions:

● The review of rest at home included only twosmall trials of poor quality, so at least some ofthe reported effect on pre-eclampsia may reflectbias and/or random errors, rather than a trueeffect of rest at home. Also, such a largereduction in risk associated with rest at homefrom 28 weeks’ gestation onwards seemsimplausible. In order to interpret the results forwomen, information on compliance with rest athome and on the women’s baseline activitylevel, is needed. Information about othersubstantive outcomes, including potentialhazards, is also required before there can be anycertainty about the overall benefits and harms.Although physical activity is inevitably reduced,some women may find the experience stressfuland disruptive. Rest may also have financialimplications for the women, their families andfor society, particularly if it means leaving paidemployment earlier than expected

● The review of antioxidants included a mixtureof interventions – vitamin antioxidants such as vitamins C and E, mineral antioxidants such as selenium and non-vitamin antioxidantssuch as lycopene. It is conceivable that theseinterventions may have differing effects. Most ofthe results, however, refer to a combination ofvitamins C and E. The meta-analysis results forpre-eclampsia did show some heterogeneity, butthe I2 value was not above 50%. However, testsfor heterogeneity do not have high power, sothe results should be viewed with some caution.Importantly, the antioxidant review reportedhere is now out of date as two large trialsevaluating vitamin C and E were published in

2006 and have now been incorporated into theupdated Cochrane review which becameavailable after the economic modelling wascompleted. The additional trials had the effectof reducing the point estimate of effectivenessof antioxidants and the results are no longerstatistically significant.

● Calcium supplementation appears effective forprevention of pre-eclampsia, but to date theevidence as to whether this is reflected inimprovement in substantive outcome for thebaby is inconclusive. The heterogeneity inresults of the calcium trials seems to be largelyassociated with study size, with the small studieshaving the most positive results. As the smallstudies tended to recruit high-risk women, atleast some of the heterogeneity may beexplained by calcium having a greater effect forhigh-risk women. An alternative explanationmay be publication bias. No small ‘negative’studies have been identified, which is surprisingas at least some would be expected, and tendsto support the hypothesis of publication bias.However, there are probably still too few studiesto establish whether publication bias ishappening. Over 15,000 women have beenrecruited to trials evaluating calciumsupplementation. Allocation to at least 1 gcalcium was associated with a halving of the RRof pre-eclampsia. However, women with anadequate dietary intake of calcium were the onlysubgroup for which this did not achievestatistical significance. The greatest reduction inrisk was for women at high risk and for thosewith low baseline dietary calcium intake. Thissuggests that calcium supplementation may beof more benefit for women with an inadequatediet, as found more frequently in economicallypoorer countries. Where women are generallywell nourished, as in the UK, calciumsupplementation may have a more limited role.

● For the antiplatelet review, there were very fewtrials in low-risk populations (event rate incontrol arm less than 2.5%). When a sensitivityanalysis was done on this, the lowest risk grouphad a slightly smaller effect size. Funnel plotsfor this review have consistently beenasymmetric, suggesting that small negative trialsmay be missing. Most small positive trials werepublished in the 1980s and early 1990s. Itremains possible that small negative trialsconducted at that time have still not beenpublished. Interestingly, the more recent smallstudies are also largely positive. The funnel plotfor pre-eclampsia therefore continues to beasymmetric. However, the funnel plot for dataon stillbirths and neonatal deaths is more


81


symmetrical. Also, publication bias is not theonly cause of funnel plot asymmetry, as it canbe due to differences in maternal characteristicsin small compared with large trials.

Provisos/limitations arising from reviewmethodsThe main strength of this report is that all of theincluded systematic reviews are Cochrane reviews,which follow a rigorous methodology. Thestrengths of this approach include acomprehensive search strategy, restriction torandomised (or for some reviews randomised andquasi-randomised) trials, peer reviewed andpublished protocol, peer-reviewed reviews, regularupdating and a system for feedback. TheCochrane Pregnancy and Childbirth Groupeditorial process includes internal and externalpeer review, statistical review and review by aconsumer panel. Because of time constraints, forfour of the current reviews, the currently availableversion was used for the economic modellingbecause the updated results were not available.These were energy and protein, antioxidants,antihypertensives and antiplatelets. For three ofthese reviews, the updated results differed verylittle from the previous results and so the updatewould not have had any effect on the result of thesubsequent economic evaluation. For theantioxidant review, the new update substantiallychanged the results and this has been flagged upthroughout this report. The effect of this wouldhave been to alter the results of any economicevaluation away from a recommendation tosuggest antioxidants as a cost effective option.

● The systematic review of energy and proteinintake was originally published in 2003. Theupdated version did not include any extra trials.

● The systematic review on antioxidants wasoriginally published in 2005. The updatedversion had three extra trials (with 4385women). The addition of these trials shifted theestimate of RR from 0.61 (95% CI 0.50 to 0.75)to 0.73 (95% CI 0.51 to 1.06).

● The systematic review of antihypertensivesincluded in this report was originally publishedin 2000. The updated version had six extratrials for the comparison of any hypertensiveversus placebo/no treatment. The addition ofthese trials had little impact on the estimate ofRR of pre-eclampsia, which in the 2000 reviewwas 0.99 (95% CI 0.84 to 1.18) and in the 2006update was 0.97 (95% CI 0.83 to 1.13).

● The systematic review on antiplatelet agentsincluded in this review was originally publishedin 2003. The updated version had seven extra

trials. The addition of these trials had littleimpact on the estimate of RR of pre-eclampsia,which in the 2003 review was 0.81 (95% CI 0.75to 0.88) and the 2006 update was 0.83 (95 %CI0.77 to 0.89).

As Cochrane reviews are regularly updated, thesearch strategy for this report did not start from asingle time-point. This made the construction ofthe QUOROM-style diagram complex, particularlyfor numbers of excluded studies, as shown inFigure 56, p. 54. Also, the updating process meansthat versions of the Cochrane reviews referred toin this report may quickly change and no longerbe available in the public domain as the updatesare published. Therefore, an archive of theversions used in this report has been kept, whereasthe most up-to-date versions of the Cochranereviews will be available in the Cochrane Library.

Several of the Cochrane reviews reported hereinclude a range of similar interventions within asingle review, rather than reporting eachintervention separately. Where there might bepotential differences in the effects of the differentinterventions, the Cochrane reviews have dealtwith this by using subgroup analyses to investigateheterogeneity. Some of these subgroups have beenshown in the forest plots presented in the report,for example with antihypertensives. Cochranereview authors judged it reasonable to combineresults across subgroups where there was no clearevidence of statistical heterogeneity, as in theantioxidant and antiplatelet reviews.

In this report, we have presented the quality of theincluded trials within each review as a singlediagram. Inevitably, this results in loss of detailregarding quality aspects of each trial. However,the quality of included trials is fully reportedwithin each review in the Cochrane Library.Individual trial quality assessment is most usefulwithin a review for indicating studies which may bemore open to bias than others and less welladapted to indicating parameters which may beunderpinned by relatively weak evidence. It wasthe latter, however, which was more important inthis project.

Provisos/limitations arising from thingsnot doneThe original project plan included a wide list ofpotential interventions that could have beensystematically reviewed (see Table 49, p. 140). Wealso asked a consumer group for informationabout the questions that women were asking oftheir help line (see Table 2, p. 7). As this


82

information was not available until late in theproject, it was not feasible to use it to prioritisetopics for review. Such an approach would havebeen of considerable benefit to both women andclinicians and should be considered in the future.A key limitation of this report is that we did nothave space to report on a wide variety of otherrelevant outcomes including those on adverseevents or side-effects of treatments included in theCochrane reviews. There is potential for some ofthe treatments reviewed to have serious side-effects that could outweigh the advantages if theyprevented pre-eclampsia. We did not include allCochrane reviews that reported pre-eclampsia asan outcome because some are subsets of otherCochrane reviews, such as the review on beta-blockers in pregnancy,189 which is also reported inthe antihypertensives review.

Findings in the light of limitationsThe quality assessment of the trials included inthis report suggested that trials of goodmethodology have been done and many of theseare large, but in general most trials haveimportant deficiencies in terms of bothmethodology and small sample size. Theselimitations have hampered the search for effectivetreatments to prevent pre-eclampsia. We havegood evidence on the effectiveness of a fewinterventions that aim to reduce pre-eclampsia.However, the limitations introduce considerableuncertainty on other interventions. This arisesfrom lack of evidence about the effect on pre-eclampsia or because of differing effects onoutcomes beyond pre-eclampsia and because ofvariability in the size of effect between studies.

Ramifications for the economic modelThe implications of the finding on effectivenessfor the economic evaluation are multiple. Thereviews with apparently the most beneficial effectswere entered into the model. However, concernsabout the quality and sparcity of the data(particularly for interventions such as rest athome) need to be considered when interpretingthe model results. This is discussed in greaterdetail at the end of Chapter 5.

Recommendations for practiceAnti-platelet agents, particularly low-dose aspirin,produce moderate but consistent and importantreductions in pre-eclampsia and its consequencesfor the baby. This information should be discussedwith women at risk of pre-eclampsia to help themmake informed decisions about their antenatalcare. Potential side-effects of this treatment havenot been addressed here. Further details are

available in the Cochrane review on antiplateletagents. There is a possibility that calciumsupplementation should be offered to women,particularly with low dietary calcium intake.Otherwise there are few recommendations forpractice.

Recommendations for researchThere needs to be a closer match between theinterests and clinical needs of pregnant womenabout the questions they would like answered (seeTable 2, p. 7) and the clinical trials and systematicreviews currently being undertaken.

As calcium supplementation appears to beeffective for the prevention of pre-eclampsia, themost effective and acceptable methods of dietarycalcium fortification could be investigated.

Until the cause of pre-eclampsia is fullyunderstood, developing potentially effectiveinterventions to prevent this important conditionremains problematic. As pre-eclampsia is a multi-system disorder, effectiveness also needs to beassessed by the impact on other outcomes for boththe woman and the child. These include the threeneonatal outcomes included in the effectivenesssection, neonatal deaths, preterm births and smallfor gestational age, but also other measures ofserious morbidity for the mother and the long-term outcome for mother and child.

The lifestyle interventions such as rest fornormotensive women and exercise are ofconsiderable interest to women. These meritgood-quality, adequately powered RCTs whichmeasure all relevant clinical outcomes, side-effects,costs and acceptability to women.

Given the difficulty with the variable quality ofRCTs, what may be required are subgroup analysesof the highest quality studies. This is particularlypossible for the antiplatelet intervention wherethere are sufficient studies to be able to attemptIPD meta-analysis or meta-regression.190 An IPDanalysis of the antiplatelet trials has beencompleted and is due to be published shortly.

Conclusions of effectiveness reviewsSixteen systematic reviews of interventions werepresented in this report, of which 15 providedestimates of effectiveness in pre-eclampsia.However, the overall quality of studies was variableand few interventions have been shown to reducethe risk of pre-eclampsia. The largest systematicreview included 51 trials and investigated theeffectiveness of antiplatelet agents, principally


83


aspirin, to prevent pre-eclampsia. This was theonly review where the intervention was shown toreduce the RR of pre-eclampsia and itsconsequences for the baby. Calciumsupplementation also appears to reduce pre-

eclampsia but without any clear benefit to thebaby. Antioxidants, primarily the combination ofvitamin C and E and rest at home, also appear toreduce the risk of pre-eclampsia, but again thereare limitations with these results.


84

Methods for economic evaluationIntroductionThe objective of the economic evaluation in thisstudy was to collate the data from the reviews onthe accuracy of the tests with the data on theeffectiveness of the interventions and to explorethe relative cost-effectiveness of a range ofdifferent testing and treatment options. Whereasthe accuracy and effectiveness reviews consideredtests or interventions applied to both normalwomen at no predetermined risk of pre-eclampsiaand to women considered at risk or high risk, themain focus of the economic analysis was on testand interventions that are applied to normalwomen who have no prior history to suggest theyare at risk of pre-eclampsia. Although results from12 interventions were modelled, just the testsand/or interventions that are shown to be ofsignificant interest are presented in more detail.The final output of the modelling exercise is interms of the dominating strategies (thoseachieving greater effectiveness at reduced cost)and the relative incremental cost-effectivenessratios (ICERs) for the better test and treatmentoptions. The results are in terms of cost per caseof pre-eclampsia avoided. The perspectiveadopted for the economic evaluation was that ofthe NHS. Private out-of-pocket costs to women arenot included in the analysis.

Model structureThe appropriate model for this study was adecision tree. This was constructed in DATATreeage. Space constraints do not allow the fulldiagram of the model to be presented as itcomprises 538 alternative strategies combining all21 tests and 12 interventions and a branch with ano test, no treatment option [NB: the reason for538 branches rather than (21 × 12 × 4) +1branches is because where a branch looks at notest and treatment for all, only 12 branches arerequired rather than 21 × 12 branches and wherea branch is test all and no treatment, only 21branches are required rather than 21 × 12branches]. To illustrate the approach for eachtest/treatment pairing we present a subset of themodel for one test [Doppler: any unilateralnotching (AUN)] and one intervention (calcium).This is presented in Figure 92.

In this diagram, each branch to the right of thechance node (round symbol) indicates one way inwhich the test under consideration (Doppler AUN) and treatment (calcium) can be broughttogether. All the ways in which test and treatmentcould in theory be used together are consideredfor completeness, although not all of these may have direct clinical relevance (see below for further explanation). Thus the model considersfor each test and treatment combination thenumber of cases of pre-eclampsia and theassociated cost for:

1. No test and no intervention (“No test/notreatment”).

2. Intervention, calcium, given to all with nopreceding testing (“No test/calcium_all”).

3. Test, Doppler AUN, applied to all, but nosubsequent intervention [“Doppler (AUN)/notreatment”].

4. Test, Doppler AUN, applied to all, followed bythe intervention, calcium, being given just tothose testing positive (having the characteristicindicated, i.e. AUN or a test value above astated value) [“Doppler(AUN)/calcium_positive”].

5. Test, Doppler AUN, applied to all followed bythe intervention, calcium to all (regardless oftest result) [“Doppler (AUN)/calcium_all”].

Branch 1, the no test, no intervention option,represents the comparison group for all the otherbranches 2–5, and indeed is the commoncomparator for all modules of the model for each test and treatment pairing considered. Itindicates the number of cases of pre-eclampsiaand the associated costs in “normal practice”,assuming that there is currently no systematictesting and treatment of those deemed at high risk on the basis of the test. This assumption isunlikely to be true in the NHS, which is whynormal practice appears in parentheses. Despitethis, it still represents the most informative base-line against which to consider alternativestrategies.

Branches 2 and 4 represent the chief clinicallyrelevant alternative strategies for test andtreatment pairings. Branch 2 considers thebenefits and costs of treating all mothers, an


85


Chapter 5

Economic evaluation

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important scenario to investigate if there is doubtabout the accuracy of the available tests. Branch 4considers the approach which attempts to focusthe intervention on those indicated by the test tobe at highest risk, and so avoid any adverse effectsof the intervention in those thought unlikely togain benefit, because their risk of developing pre-eclampsia is so low.

Branches 3 and 5 represent theoreticalcombinations which have no direct clinicalrelevance, but are nonetheless important for acomplete understanding of the relationshipbetween benefits, disbenefits and costs. Branch 3provides an opportunity to scrutinise the costs and direct effects of testing independently of anyeffect of treatment. Branch 5 indicates the worst-case scenario with respect to cost, including bothtest and treatment costs applied to all. However, italso includes the highest level of benefit anddisbenefit that might conceivably be achieved too,as all mothers receive the treatment underconsideration.

In Figure 92, the right-hand side of the diagramindicates the outcomes considered in measuringwhich of branches 1–5 in this and other modulesis optimal. As already indicated, the main outcomeis cases of pre-eclampsia relative to cases withoutpre-eclampsia. In branches where a test result isobtained, the model considers separately thenumber of cases of pre-eclampsia occurring inthose testing positive and those testing negative.Although this is shown as being a feature of theway the model works in branches 3–5, it is onlystrictly necessary in branch 4, as this is the onlyoption where treatment is truly contingent on thetest result. The box beneath the population ofinterest, pregnant women, on the far left of thediagram, indicates the model parameters beingused. Thus “Calcium_cost=46.20” indicates thatthe cost of calcium supplementation over thecourse of pregnancy is £46.20 and“sensitivity_DopplerAUN=0.63” that thesensitivity estimate being used in this module ofthe model is 63%. These parameters will differdepending on the module. They will also vary if


87


TABLE 36 Diagnostic test sensitivity and specificity results for each test provided by the project’s systematic reviews of test accuracy– inputs to model

Accuracy Sensitivity 95% CI Specificity 95% CI PPVa NPVa

Maternal serum AFP 9 5 to 16 96 94 to 98 5 98Maternal serum HCG 24 16 to 35 89 86 to 92 5 98Serum unconjugated oestriol 26 9 to 56 82 61 to 93 4 98Cellular fibronectin 50 30 to 70 96 79 to 99 24 99Total fibronectin 65 42 to 83 94 86 to 98 22 99SUA 36 22 to 53 83 73 to 90 5 98fDNA 50 31 to 69 88 80 to 93 10 99Urinary calcium excretion 57 24 to 84 74 69 to 79 5 98Urinary calcium/creatinine ratio 50 36 to 64 80 66 to 89 6 98Total proteinurab 35 13 to 68 89 79 to 94 8 98Total albuminuria 70 45 to 87 89 79 to 94 14 99Microalbuminura 62 23 to 90 68 57 to 77 5 99Microalbumin/creatinine ratio 19 12 to 28 75 73 to 77 2 97Doppler uterine artery: pulsatility index 48 29 to 69 87 75 to 94 9 98Doppler uterine artery: any unilateral notching 63 51 to 74 82 74 to 87 8 99Doppler uterine artery: bilateral notching 48 34 to 62 92 87 to 95 13 99Doppler uterine artery: resistance index 66 54 to 76 80 74 to 85 8 99Doppler uterine artery: combination of 64 54 to 74 86 82 to 90 10 99

abnormal waveformsDoppler: other ratios 55 37 to 72 80 73 to 86 7 99BMI �34 18 15 to 21 93 87 to 97 6 98BMI >29 23 15 to 33 88 80 to 93 5 98

a Positive and negative predictive values (PPV and NPV), rounded to nearest integer, associated with given sensitivity andspecificity in population with prevalence of pre-eclampsia of 2.5%.

b Test accuracy of kallikreinuria also considered. Sensitivity and specificity were apparently good (83% and 99%,respectively, for thresholds of <100 or <200 inactive urinary kallikrein to creatinine ratio) but it was evaluated in a studywith only 12 cases of proteinuric pre-eclampsia. Hence although noting this to be a test worthy of further evaluation, theresults were not modelled, a reinforcing concern being clinical advice that the test is not routinely available. This concernalso applies to SDS-PAGE proteinuria.

the sensitivity of the model to variation in aparticular parameter is being tested.

Inputs to modelTest accuracy and effectiveness inputsThe results from the systematic reviews assessingthe accuracy of all the tests reviewed as part of thisproject, reported in Chapter 3, were the source ofthe sensitivity and specificity model parameters.The forms used for data collection are shown inAppendix 10. The actual values used weregenerally based on pooled sensitivities andspecificities using the bivariate method of meta-analysis described in the section ‘Methods for testaccuracy reviews’ (p. 13). These values and theirassociated 95% CIs are given in Table 36. Similarlythe results from the systematic reviews of theeffectiveness, reported in Chapter 4, were thesource of model parameters concerning the effectof various treatments on the number of cases ofpre-eclampsia. The values used, generally thesummary RR from the meta-analyses, along withtheir 95% CIs, are summarised in Table 37. Thereare two groups of treatments differentiatedbecause they are dealt with slightly differently bythe model (see below). In group 1, the 95% CIs forthe RR do not include values >1.0, indicating thata true value of the RR compatible with increasednumbers of pre-eclampsia cases (i.e. worsened

outcome) is unlikely. Conversely, in group 2, the95% CIs for RR do include values >1.0, that is, apossible worsened outcome. Table 37 also givesvalues for the RR values obtained from importantsubgroup analyses (for group 1 treatments only)which were used in sensitivity analyses (see below).Some of the Cochrane review update resultsbecame available too late to be incorporated intothe economic model. These have been reported inChapter 4 but are not referred to in this section.

Cost inputsA systematic review of the economic literature tosearch for costs was not undertaken as part of thisproject. A systematic review of the economicliterature on antenatal ultrasound screening191

and antenatal screening192 were carried out by oneof the present authors (TR) and were publishedduring the life of the current study. Any relevantinformation identified in the two systematicreviews mentioned above was used in the currentanalysis. The cost of each test and eachintervention was estimated from different sourcesdescribed in more detail below. All costs arepresented in UK£, 2005–06 prices.

Test accuracy costsCosts for the tests came from two main sources,the Birmingham Women’s Hospital (Table 38,

Economic evaluation

88

TABLE 37 Effectiveness RR of pre-eclampsia for each intervention provided by the project’s systematic reviews of effectiveness –inputs to model

Group Treatment RR 95% CI Revised RRa 95% CI

Group 1b Rest for normotensive women vs unrestricted activity 0.05 0.0 to 0.83 No subgroup analyses

Antioxidants vs placebo/no antioxidants 0.61 0.50 to 0.75 0.45d 0.31 to 0.66Calcium supplement vs placebo 0.48 0.33 to 0.69 0.62e 0.32 to 1.20Antiplatelets vs placebo/no intervention 0.81 0.75 to 0.88 0.85f 0.77 to 0.94

Group 2c Progesterone vs no progesterone 0.21 0.03 to 1.77 NADiuretics vs placebo/no diuretics 0.68 0.45 to 1.03 NAGarlic vs placebo 0.78 0.31 to 1.93 NANitric oxide donors or precursors vs placebo/no 0.83 0.49 to 1.41 NA

interventionMarine/fish oils vs placebo/no treatment 0.86 0.59 to 1.27 NAMagnesium vs placebo/no treatment 0.87 0.57 to 1.32 NAAntihypertensives vs placebo/no treatment 0.99 0.84 to 1.18 NAAdvice to reduce dietary salt vs advice to continue 1.11 0.46 to 2.66 NA

normal diet

a RRs based on subgroup analyses, defined in detail in the text, and used as parameters in sensitivity analyses.b Group 1 are those treatments with an RR whose upper 95% CI is <1.0.c Group 2 are those treatments with an RR whose 95% CI include a value compatible with worsened outcome.d Subgroup excluding the single large quasi-randomised trial.e Subgroup of trials carried out in populations with an adequate calcium diet.f Subgroup of trials carried out in populations with mothers at ‘moderate risk’ of pre-eclampsia rather than both ‘moderate-’

and ‘high-risk’ combined.

column 3) and the literature (Table 38, columns 4and 5). The costs for most of the tests, with theexception of Doppler, were available from theBirmingham Women’s Hospital (Coles N; personalcommunication, April 2006). The costs providedare the costs applied within the hospital for thenamed test. However, if the test was carried out onbehalf of another hospital, an additional cost(charge) would be applied.

An alternative set of literature-based test costs wasavailable from a previous study evaluatingantenatal tests that had been carried out by one of the members of the economic and modellingteam. The costs determined as part of that study are based on average estimates from aninclusive review of international literature that, atthe time, were considered the best availablepublished estimates. Consequently, the estimated


89


TABLE 38 Estimated costs of diagnostic tests

Test Nature of test Unit cost Costs from literature (UK£ 2005)from

Birmingham Unit cost SourceWomen’s (upper and lower

Hospital (£) estimates)

BMI measurements Measurement of 5.00 Estimate based on weight and height 5 minutes of nursing time

and an of estimate fixedcosts

Maternal serum AFP Venous blood test 16 44.41 Literature191

2.5 ml (38.25–50.56)

Cellular FN Venous blood test 5a 44.41 Proxy based on literature 5 ml (38.25–50.56) for AFP191

Total FN Venous blood test 5a 44.41 Proxy based on literature 5 ml (38.25–50.56) for AFP191

fDNA Venous blood test 5a 44.41 Proxy based on literature 5 ml (38.25 to 50.56) for AFP191

Maternal serum HCG Venous blood test 16 44.41 Proxy based on literature 2.5 ml (38.25 to 50.56) for AFP191

Serum unconjugated Venous blood test 16 44.41 Proxy based on literature oestriol 2.5 ml (38.25 to 50.56) for AFP191

SUA Venous blood test 5 44.41 Proxy based on literature5 ml (38.25 to 50.56) for AFP191

Urinary calcium excretion 24-hour urine collection 6.6 7.56 Proxy based on literature(home or hospital) for PCR tests195

Urinary calcium creatinine 24-hour urine collection 6.6 7.56 Proxy based on literature ratio (home or hospital) for PCR test195

Total proteinuria 24-hour urine collection 6.5 7.56 Proxy based on literature (home or hospital) for PCR test195

Albuminuria 24-hour urine collection 7.85 7.56 Proxy based on literature (home or hospital) for PCR test195

Microalbuminuria 24 hour urine collection 7.85 7.56 Proxy based on literature(home or hospital) for PCR test195

Albumin/creatinine ratio 24 hour urine collection 7.85 7.56 Proxy based on literature(home or hospital) for PCR test195

Doppler examinations Ultrasound scan lasting NA (used 20.86 Literature191

10 minutes literature (18.11–23.63)reference)

NA, not applicable; PCR, polymerase chain reaction.a These costs were not provided by the Birmingham Women’s Hospital and so cost of SUA was used as a proxy; chosen

because it was inexpensive and would not disadvantage the test. This will be discussed in case 4.

average costs are somewhat higher than localestimates.

A cost estimate for AFP was identified in a reviewof the economic antenatal literature carried out byone of the present authors some yearspreviously.191 This was inflated to 2005–6 pricesusing the hospital and community health servicespay and price inflation index193 and InternationalMonetary Fund website exchange rates.194 Aliterature estimate of cost was not identified for anyof the other blood tests and so in the absence ofmore accurate data, the cost of the AFP blood testwas used as a proxy for these other blood tests.

The accuracy reviews indicated that the sixultrasound scans all comprised Dopplerexaminations lasting approximately 10 minutesthat would cost the same. The cost of a Dopplerexamination had been estimated previously191 andwas inflated to current prices as described above.The Doppler scan, deemed most analogous to the10-minute scans reported by the accuracy reviews,was the second trimester anomaly scan. This costwas applied as a proxy for all six Dopplerexamination tests identified by the accuracyreviews.

The cost of the BMI tests, which comprisedmeasurement of weight and height, was assumedto take approximately 5 minutes, but costs wereestimated for 10 minutes of an antenatalappointment with midwife or nurse practitioner atthe general practice, the cost of which wasestimated from standard reference costs.193

Although the time taken to do the test would beonly a few minutes, extra time was included in thecost to allow for rapport building andadministration. The 24-hour urine tests were allassumed (based on expert advice from within thecurrent study) to be performed on a urinecollection carried out by the patients at home andnot as inpatients, with negligible costs for urinecollection receptacles provided by the hospital.Thus the required cost is for the test andadministration time of this only. No estimate ofthe costs of the alternative urine tests was found inany recently published reviews, so the cost of aurine test estimated as part of a different study,195

but carried out by some of this project’s healtheconomics and modelling team (TR and PB), wasused as a proxy for the cost of a urine test here.

Treatment costsThe systematic reviews on interventioneffectiveness indicated the dose and duration oftreatment used in the included RCTs. These are

summarised in Table 39. It was assumed that eachintervention therapy would be prescribed in anappointment with the clinician and the cost of thisappointment was not included in the analysis as itshould be approximately the same for allinterventions. However, in some cases theprescribed intervention has no direct cost to thehealth service, such as the advice to reduce salt inthe diet or advice to take rest. For otherinterventions, where a dose range was presented,the costs of the upper and the lower limit of thedose were used. The treatment dose (ifappropriate) and duration were applied to thetreatment unit costs to give the total cost. Fordrugs, the unit costs were taken from the BritishNational Formulary (BNF) (Volume 51, 2006).196

The unit costs for the vitamin or herbalsupplements such as fish oils and garlic wereobtained from the Holland and Barrett website (a commercial health food shop).197

Pre-eclampsia outcome costs We used the most recently available estimate forthe cost of pre-eclampsia198 (Table 39) In thatstudy, the cost of a case of pre-eclampsia, withouteclampsia occurring, was estimated to be$12760.32 (US$ 2001) in high-income countries.These costs were estimated in a regression analysisas part of the economic evaluation of the MagpieTrial198 [Simon J, University of Oxford HealthEconomics Research Centre (HERC): personalcommunication, March 2006]. The estimateincludes all hospital costs (even those not directlyrelated to pre-eclampsia, i.e. delivery costs, etc.)for both mother and baby. The cost translated to£10,074 in UK£ when converted and inflated asappropriate to the price year 2005–6.193,194 Thecost of a normal delivery was removed from thisestimate of pre-eclampsia for use in the model.The cost of normal delivery was estimated to bebetween £1227 and £903 with and withoutconcomitant complications, respectively.199

The resulting cost for pre-eclampsia of £9009 wasconsidered to be the best available estimatedespite including other costs. The reason forexcluding the cost of birth from the estimate wasthat the cost of birth was not being included inany of the comparator arms of the model.

Source of other model parameter The prevalence of pre-eclampsia that was used inthe model was estimated by using the CochraneReview on antiplatelet agents for preventing pre-eclampsia and its complications.74 We inspectedthe list of trials and their inclusion criteria to findtrials with low-, medium- and high-risk women

Economic evaluation

90


91


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Economic evaluation

92 TAB

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with pre-eclampsia. For studies with over 100participants there was one study that hadunselected pregnant women – low risk; there werefive studies with primiparous women only –medium risk; and six studies with high-riskwomen (e.g. previous pre-eclampsia, diabetes orhypertension). We then calculated the pre-testprevalence and 95% CIs of pre-eclampsia in thecontrol groups using MetaDisc software. Forunselected women the prevalence of pre-eclampsiain the control groups was 2.5% (95% CI 1.9 to3.4), for primiparous, medium-risk women it was4.7% (95% CI 4.3 to 5.3) and for high-risk womenit was 10% (95% CI 9.3 to 10.8).

AnalysisVarious alternative analyses were carried out.

In the base-case analyses, referred to as case 1, thepoint estimates of the key parameters for each testwere combined with the point estimates of the keyparameters for interventions where the 95% CIsfor the RR did not include 1.0 referred to asgroup 1 interventions in Table 2, p. 7. As alreadyindicated, this group of interventions is distinctbecause the true value of the RR is unlikely to becompatible with worsening of the outcome offrequency of pre-eclampsia, in contrast to otherinterventions where the 95% CI for the RRincludes values >1.0. The cost-effectivenessrelative to ‘no test/no treatment’ of each alternativecombination of test and treatment pairing wereestimated by the model in a deterministic analysis.The results, the ICERs, were expressed as theadditional cost for each additional case of pre-eclampsia avoided. In case 1, the average unit costwas applied to tests and interventions asappropriate. The costs of tests used in case 1 werethose provided by the Birmingham Women’sHospital. The prevalence of pre-eclampsia was setat 2.5%, a value compatible with a population ofmothers at low risk of developing pre-eclampsia.

In case 2, a probabilistic sensitivity analysis (PSA)of case 1 was carried out to explore the effects onthe ICERs of the uncertainty in the model inputdata, as implied by the 95% CI of RR ofdeveloping pre-eclampsia with any particularintervention. In PSA, each model parameter isassigned a distribution reflecting the amount andpattern of its variation and cost-effectivenessresults are calculated by simultaneously selectingrandom values from each distribution. The processis repeated many times in a Monte Carlosimulation of the model to give an indication ofhow variation in the model parameters leads tovariation in the ICERs for a given combination of

a test and treatment pairing. The appropriatedistribution for the data on test accuracy(sensitivity and specificity) is either a beta ornormal distribution depending on the statisticalcharacteristics of the parameters. The appropriatedistribution for data on intervention effectiveness(RR of developing pre-eclampsia) was a log-normal distribution.

Unit cost uncertainty is excluded from the PSAbecause any variations that might exist for unitcosts are of a different nature from the data-drivenuncertainty in the patient flow parameters. Furtheradditional analyses were conducted using differentcost estimates, and also more detailed analysis ofthe significant results (sensitivity analyses). Insummary, the complete set of analyses were:

● Case 1, base case (already detailed). Adeterministic analysis using data for all the testscombined with group 1 treatments/interventionswith costs from the Birmingham Women’sHospital in a low-risk population.

● Case 2 (already detailed). A PSA of case 1.● Sensitivity analyses were carried out for cases 1

and 2 in which the cost of pre-eclampsia isreduced.

● Case 3. A further PSA using alternative RRs forgroup 1 interventions suggested by subgroupanalyses undertaken as part of the effectivenessmeta-analyses – see Table 2, p. 7. However, theimpact of the subgroup RR for calcium was notactually examined because the 95% CI extendedbeyond 1.0 (rationale for exclusion, the same asfor separation of interventions into group 1 and2). The case 3 PSA was further repeated forprevalence estimates that applied to women atmoderate risk (4.5%) and high risk (10%) ofpre-eclampsia. The costs are the same as in case 1.

● Case 4. A threshold analysis to explore what testaccuracy and cost parameters would be requiredto optimise cost-effectiveness using the PSApresented in case 3 as the starting point. Thecosts are the same as in case 1.

Results from cases 1–4 are presented below in themain report. Two further sets of analyses were alsocarried out.

● Case 5. A deterministic analysis similar to case 1but using literature estimates for the costs oftests, rather than those provided by theBirmingham Women’s Hospital. Results notpresented.

● Case 6. A deterministic analysis similar to case 1but using data for the full range of the


93


interventions/treatments whether the RR 95%CI included 1.0 or not (i.e. both group 1 andgroup 2 interventions). The results of case 6 arepresented in Appendix 11

Results of economic evaluationMain resultThe results of the effectiveness reviews showedthat advice to take rest for women was the mosteffective option for reducing the risk of pre-eclampsia in normal women. The point estimatefor the RR was 0.05 (95% CI 0 to 0.83). This veryhigh level of effectiveness in reducing pre-eclampsia (although subject to uncertainty due tothe small sample size and other factors, theimplications of which are discussed later)associated with negligible cost to the health service(also subject to uncertainty, the implications ofwhich are also discussed later) combine to makeadvising rest for all women apparently the mostcost-effective option. When this intervention,applied to all women without preceding testing,was initially included in the case 1 deterministicmodel, it was shown to dominate (be moreeffective at reduced cost) all other combinations ofall other test and treatment pairings. It wasexcluded from the subsequent deterministicanalysis so that determination of the second bestintervention could be estimated. However, allfurther results need to be preceded by repetitionof the finding that a highly effective, near zerocost intervention, an example of which appears tobe advice to take rest, applied to all womenwithout preceding testing, has already beenindicated to be the most cost-effective option.

Case 1: base caseIn Table 40, the results of both a partial andcomplete analysis are presented for case 1 with‘rest for normotensive women’ excluded from themodel (see above for explanation). A partialanalysis was carried out first, which excluded thecosts of pre-eclampsia in the comparator arm ofthe model. In this partial analysis, the no test/notreatment option is shown to cost nothing inmonetary terms but has considerable cost in termsof effectiveness since doing nothing does not havea zero cost if it results in more cases of pre-eclampsia. Removing the cost of pre-eclampsia inthe partial analysis provides a comparator againstwhich additional costs of testing and treating canbe gauged, but overlooks the fact that substantialcost is associated with cases of pre-eclampsia andthat this cost can be reduced by reducing thenumber of cases of pre-eclampsia. This is the

additional factor which is captured in thecomplete analysis.

In the partial analysis only, the strategy ofproviding ‘no test/antiplatelets_all’ is the mostcost-effective strategy. The intervention ofantiplatelets is relatively cheap at an average costof £2.69 per woman treated and the strategy savesnearly five cases of pre-eclampsia per 1000women, a number-needed-to-treat (NNT) of 208.There is an additional cost of £566 per case ofpre-eclampsia averted compared with ‘no test/notreatment’. The next most effective option afterantiplatelets in this partial analysis is to use thetotal fibronectin test and provide calcium to allwho tested positive (‘total fibronectintest/calcium_positive’). The results are presentedincrementally compared with the previous bestoption. Therefore, ‘total fibronectintest/calcium_positive’ avoids nearly four morecases of pre-eclampsia in 1000 women than ‘notest/antiplatelet_all’, but costs £5.80 more, givingan ICER of £1557 of additional test and treatmentcost per additional case of pre-eclampsia averted.

When the model comparator arm included the fullcost of pre-eclampsia, it penalised the treatmentsthat missed the most cases of pre-eclampsia. Forinstance, the additional cost of providing calciumto all compared with the cost of antiplatelets wasoverwhelmed by the costs saved by avoiding morecases of pre-eclampsia. Hence, as calcium is moreeffective, ‘no test/calcium_all’ becomes thedominant strategy in terms of relative cost-effectiveness. Therefore, the complete analysisshows that the dominant strategy, out of thosestrategies included in the model, is to providecalcium treatment to all without any precedingtest. Alternatively stated, of the strategiesconsidered, ‘no test/calcium_all’ is the least costlyoption, because it is the option which avoids mostcases of pre-eclampsia. The next strategypresented in the complete analysis section ofTable 40 indicates that applying the Doppler(AUN) test to all before providing calcium to allleads to increased costs, without change in overalleffectiveness.

In Figure 93, the results shown for the completecase in Table 40 are presented diagrammaticallyalongside all the cost-effectiveness estimatesproduced by the case 1, base-case model. Eachpoint represents one of the options for eachtest/treatment pairing considered in the model.The nearer the bottom right corner of the graph apoint is, the greater is its effectiveness and the lessits cost. Most of the points represent dominated

Economic evaluation

94

options, where greater effectiveness can beachieved at lower cost by an alternative. Figure 93thus reaffirms that, when the costs of pre-eclampsia are included in the analysis the option‘no test/calcium_all’ dominates all other options,being nearest to the south-east extremity of thecost-effectiveness plane. However, it should againbe noted that the ‘no test/rest_all’ option wouldappear below and to the right of all the options onFigure 93 were it to have been included in themodel.

Case 2: probabilistic sensitivity analysisof case 1The results of case 2 are presented in Table 41.The results reaffirm that ‘no test/rest_all’ is thedominant option at all values of willingness to pay.

When ‘rest for normotensive women’ is removedfrom the model to explore the second most cost-effective option, the results show that ‘notest/calcium_all’ is the dominant option at allvalues of willingness to pay. For example, at a

given threshold of say £30,000, which means thata policy maker would be willing to pay £30,000per case of pre-eclampsia avoided, there is an 87%chance that ‘no test/calcium_all’ is the preferredoption with respect to its cost-effectiveness. At thesame threshold there is only a 10% chance that analternative option of ‘no test/antioxidant_all’ is thepreferred option and less than a 1% chance ofpreference for all other options such as ‘totalfibronenctin/antioxidants_positive’ and ‘totalfibronenctin/calcium_positive’. If the willingness topay threshold was increased to £100,000 per caseof pre-eclampsia avoided, then there is still an87% chance that ‘no test/calcium_all’ is thepreferred option whilst the chance of ‘notest/antioxidant_all’ being the preferred optionrises slightly to 11%. This shows that the results,particularly concerning the second preference forthe ‘no test/calcium_all’ option, are robust for allthresholds of willingness to pay. The results arepresented diagrammatically in Figure 94, a cost-effectiveness acceptability curve (CEAC). It shouldbe noted that the curves for most of the options


95


TABLE 40 Case 1, base-case results: costs, effects and ICERs for most cost-effective combinations of test and treatment pairs fromany test combined with a group 1 intervention

Test/treatment Mean Difference Effectivenessb Absolute ICERc NNTcombinationa cost per in costs risk

woman (UK£ 2005) reduction(UK£ 2005)

Partial analysis: excludes the cost of pre-eclampsia in the comparator arm of the modelNo test/no treatment 0 0.975No test/antiplatelets_all 2.7 2.7 0.980 0.005 566 208Total fibronectin test/calcium_positive 8.5 5.8 0.983 0.004 1557 270Albuminuria/calcium_positive 13.6 5.2 0.984 0.001 7938 1428No test/calcium_all 46.20 32.6 0.988 0.004 8355 256Doppler(AUN) test/calcium_alld 67.1 20.9 0.988 0 This (and the rest)

are dominated byno test/calcium_all

Complete analysis: includes the cost of pre-eclampsia in the comparator arm of modelNo test/calcium_all 154 0.988 DominantDoppler (AUN)/calcium_alld 174.8 20.9 0.988 0 These are all

dominated by no test/calcium_all

Doppler (RI)/calcium_alld 174.8 0 0.988 0Doppler (BN)/calcium_alld 174.8 0 0.988 0

The no test_rest option is the most effective option, achieved at zero additional cost, and is thus self-evidently the mostcost-effective approach. It was therefore not incorporated into the model whose results are reported in this table, whichprimarily explores the second most cost-effective option after the no test/rest_all option.a No test/rest_all dominates all options below.b Effectiveness is defined as the proportion of women remaining free of pre-eclampsia. Therefore, the difference in

effectiveness between two strategies is the absolute risk reduction.c ICER: incremental cost-effectiveness ratio expressed as the additional cost per additional case of pre-eclampsia prevented.d These “test all/treat all” strategies were included in the model for completeness (elaborated in more detail in the

economic methods section). Each is more costly and no more effective than a strategy of treating all women withouttesting.

examined are indistinguishable, because they arecoincident with the horizontal axis of the graph.Additional analyses were carried to examine theeffect of altering estimated eventual prevalence ofpre-eclampsia in the target populations from low-risk groups (2.5% as in the base case) to 4.7%representing moderate-risk groups and 10%representing high risk-groups. The results showthat the higher the prevalence, the higher is theprobability that an intervention of ‘notest/calcium_all’ was the preferred option at anywillingness to pay threshold.

Sensitivity analysis for case 1 and case 2The costs of pre-eclampsia used in the currentstudy were obtained from one published study andwere the only available estimate for this condition.Clearly there is some doubt about this estimate,but in the absence of any other information wesubjected this cost to sensitivity analysis. The highestimated cost for pre-eclampsia will severelypenalise any cases of pre-eclampsia missed by anyof the test and treat options.

Table 42 gives the results of the sensitivity analysisfor case 1, in which the costs of pre-eclampsia arereduced from the £9009 level used in the base-casedeterministic analysis. The partial analysis,presented in Table 40, which excluded the costs ofpre-eclampsia totally, highlighted which test andtreatment options could be considered more cost-effective than ‘no test/calcium all’ if the costs ofpre-eclampsia were reduced from the £9009 to zero.

The results in Table 42 show that if the cost of pre-eclampsia was £8300, the albuminuria test andtreating only the positives would be slightlycheaper and slightly more effective than ‘notest/calcium_all’ and would have been consideredmore cost-effective in the deterministic analysis. Ifthe cost of pre-eclampsia was reduced further to£7900, the ‘total fibronectin test/calcium_positive’becomes a more cost-effective option than ‘notest/calcium_all’ and would be considered cost-effective. When the cost is reduced to £1500, notest/antiplatelets_all becomes the most cost-effective option.

However, the deterministic analysis is based only on the point estimates of the sensitivity and specificity of the tests and RRs from thereviews. Table 43 shows that when the uncertaintyaround these point estimates is included in theanalysis, even if the cost of pre-eclampsia was aslow as £1000, ‘no test/calcium_all’ has the highest percentage of being the preferred option at all values of willingness to pay, thusshowing that despite the uncertainty surroundingthe costs of pre-eclampsia used in the currentstudy, the biggest driver in the results is the factthat the tests have very poor sensitivity andspecificity and the RRs of treatments such as ‘notest/rest_all’ (for which the result would alsoremain unchanged although not shown) and ‘notest/calcium_all’ remain the preferred optionbecause these are the tests shown to be mosteffective.

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0

50

100

150

200

250

300

350

400

450

500

0.94 0.95 0.96 0.97 0.98 0.99

Effectiveness (proportion free of pre-eclampsia)

Cos

t (U

K£

2005

)

‘No test/calcium _all’

FIGURE 93 Case 1, base-case results: costs, effects and ICERs on cost-effectiveness plane for all combinations of test and treatmentpairs from any test combined with a group 1 intervention (complete analysis)

Case 3: additional sensitivity analysesIn this version of the model, further PSAs werecarried out using revised data, based first onimportant subgroup analysis results emergingfrom the systematic reviews of effectiveness andassociated meta-analyses of the four group 1interventions. The revised results used for thisanalysis were presented in the last two columns ofTable 37, p. 88. There was no relevant subgroupanalysis for the intervention of advising rest, andthe subgroup result for calcium had a 95% CI

which exceeded 1.0, and so could not be includedin the model. The subgroup estimate (excluding aquasi-randomised trial) for the effectiveness ofantioxidants improved the estimate ofeffectiveness; the subgroup estimate forantiplatelets, restricting to trials which were in‘moderate’ as opposed to ‘moderate’ and ‘high’risk populations combined, slightly worsened the effectiveness. The results for case 3 arepresented in Table 44 and show that providingantioxidants to all with no preceding test (‘no


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TABLE 41 Case 2, PSA of case 1, results: probability that stated options are the most cost-effective option at different levels ofwillingness to pay for a case of pre-eclampsia avoided

Willingness to pay (UK£ 2005/6)a

0 10,000 30,000 50,000 80,000 100,000

Test/treatment optionNo test/rest_all 0.953 0.951 0.949 0.948 0.947 0.944

Secondary analysis excluding ‘no test/rest_all’ from the modelb (prevalence 2.5%)No test/calcium_all 0.268 0.815 0.871 0.870 0.869 0.868No test/antioxidants_all 0.003 0.060 0.098 0.107 0.110 0.110Total fibronectin/antioxidants_positive 0.041 0.009 0.001 0 0 0Total fibronectin /calcium_positive 0.232 0.017 0.001 0 0 0No test/no treatment 0 0 0 0 0 0

Sensitivity analysis for different prevalence ratesNo test/calcium_all (prevalence 4.7%) 0.818 0.885 0.882 0.880 0.879 0.879No test/calcium_all (prevalence 10%) 0.891 0.885 0.881 0.879 0.879 0.879

a Per case of pre-eclampsia avoided.b Explores the next most preferred option after ‘no test/rest_all’.

0

0.2

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Willingness to pay (UK£ 2005 per case of pre-eclampsia avoided)

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ost-

effe

ctiv

e

No test/no treatment

No test/aspirin_all

No test/anitoxid’s_all

No test/calcium_all

HCG/no treatment

SUO/no treatment

CF/no treatment

AFP/no treatment

tFN/no treatment

SUA/no treatment

fDNA/no treatment

UCE/no treatment

FIGURE 94 Case 2, PSA of case 1, results (‘no test/rest all’ option not included)

test/antioxidants_all’) becomes the preferredoption from a cost-effectiveness perspective at anywillingness to pay threshold. It should again beremembered that this does not overturn the mainresult concerning dominance of the option ‘notest/rest_all’. It indicates that in a best-casescenario for the effectiveness of antioxidants (butnonetheless still compatible with the results of thesystematic review), ‘no test/antioxidant_all’becomes the second most preferred option insteadof ‘no test/calcium_all’.

The second set of additional sensitivity analyses incase 3 examined the effect of altering theestimated eventual prevalence of pre-eclampsia inthe target populations from low risk (2.5%, as inthe base case) to 4.7%, representing moderate-riskgroups, and 10%, representing high-risk groups.The results show that the higher the prevalence,the higher was the probability that an intervention

of ‘no test/antioxidants_all’ was the preferredoption at any willingness to pay threshold.

Case 4: threshold analysis forpotentially cost-effective testparametersThe absence of any options involving prior testingfrom those indicated as preferred from a cost-effectiveness perspective in the prior analysesprompted this analysis. We used the modelpresented in case 3 to explore what the testcharacteristics would need to be for a test to beworth doing prior to providing an intervention.The intervention used in combination with thehypothetical test was antioxidants supplementation,hence the test whose cost-effectiveness was beingconsidered could be referred to as ‘hypotheticaltest/antioxidants_positive’. The majority of testswere shown to have relatively poor sensitivity butthe specificity was generally slightly better. The

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TABLE 42 Sensitivity analysis for case 1: deterministic analysis for case 1 when the cost of pre-eclampsia is reduced from the base-case level of £9009

Strategy Mean cost Difference Effectiveness Absolute ICER NNTper woman in costs risk (UK£ 2005) (UK£ 2005) reduction

Cost of pre-eclampsia £8300Albuminuria test/calcium_positive 145.6 0.9841No test/calcium_all 145.8 0.2 0.988 0.0039 55.53 256

Cost of pre-eclampsia £7900Total fibronectin test/calcium_positive 139.2 0.9834Albuminuria test/calcium_positive 139.2 0 0.9841 0.0007 38.46 1428No test/calcium_all 141 1.8 0.988 0.0039 455.53 256

Cost of pre-eclampsia £1500No test/antiplatelets 33.1 0.9797Total fibronectin test/calcium_positive 33.3 0.2 0.9834 0.0037 57.69 270Albuminuria test/calcium_positive 37.5 4.2 0.9841 0.0007 6438.46 1428No test/calcium_all 64.2 26.7 0.988 0.0039 6855.53 256

TABLE 43 Sensitivity analysis for case 2: PSA for case 1 when the cost of pre-eclampsia is reduced from the base-case level of £9009

Willingness to pay (UK£ 2005)

Strategy 0 10,000 30,000 50,000 80,000 100,000

Cost of pre-eclampsia = £2000Nothing/calcium_all 0 0.568 0.867 0.875 0.875 0.875Nothing/antioxidants_all 0 0.015 0.085 0.091 0.1 0.102Nothing/antiplatelets_all 0.282 0.004 0 0 0 0

Cost of pre-eclampsia = £1000Nothing/calcium_all 0 0.493 0.88 0.886 0.883 0.884Nothing/antioxidants_all 0 0.014 0.08 0.089 0.095 0.095Nothing/antiplatelets_all 0.773 0.006 0 0 0 0

starting characteristics for the hypothetical testwere therefore based, in part, on a test which hada relatively good specificity, such as Doppler(bilateral notching) with a specificity of 92% and acost of approximately £20 or either of the twofibronectin tests, cellular fibronectin, or totalfibronectin which have specificities of 96 and 94%,respectively.

In Tables 45 and 46, the results of the analysis arepresented. The model was first run with a

hypothetical test that was 99% sensitive andspecific. If this hypothetical test cost £20, thenthere was almost a 100% chance that the preferred option would be ‘hypotheticaltest/antioxidants_positive’ for all values ofwillingness to pay. Holding the costs at £20, as the sensitivity and specificity were adjusted,modest changes in these characteristics, such as a specificity of 96% and a sensitivity of 90%, resulted in a switch back in favour of ‘notest/antioxidants_all’ for thresholds above


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TABLE 44 Case 3, further PSA results based on important effectiveness subgroup analysis results from systematic reviews ofeffectiveness for group 1 interventions (especially antioxidants): probability that stated options are the most cost-effective option atdifferent levels of willingness to pay for a case of pre-eclampsia avoided

Willingness to pay UK£ (2005/6)a

0 10,000 30,000 50,000 80,000 100,000

Test/treatment optionNo test/antioxidants_allb

Prevalence 2.5% 0 0.811 0.964 0.974 0.977 0.978

Sensitivity analysis for different prevalence ratesNo test/antioxidants_allPrevalence 4.7% 0.813 0.982 0.986 0.988 0.989 0.989No test/antioxidants_allPrevalence 10% 0.991 0.996 0.977 0.997 0.997 0.997

a Per case of pre-eclampsia avoided.b This is equivalent to the secondary analysis in case 2, excluding ‘no test/rest_all’ from the model, and so explores the next

most preferred option after ‘no test/rest_all’.

TABLE 45 Case 4a, threshold analysis on characteristics of a test that would be cost-effective when combined with the interventionantioxidants (‘hypothetical test/antioxidants_positive’)

Necessary characteristics Test/treatment option Probability of being most cost-effective option at of test different levels of willingness to pay for a case

of pre-eclampsia averted (UK£ 2005/6)

0 10,000 30,000 50,000 100,000

Sensitivity = 0.99 Test and treat all positives 0.986 0.996 0.997 0.997 0.997Specificity = 0.99 with antioxidantsCost = £20.00



Sensitivity = 0.95a Test and treat all positives 0.873 0.992 0.629 0.125 0.0Specificity = 0.92 with antioxidantsCost = £20.00

a Level of sensitivity needing to be achieved in order to make ‘hypothetical test/antioxidants_positive’ the preferred cost-effective option in the majority of willingness to pay thresholds examined, assuming levels of cost and specificity actuallyobtained for Doppler (bilateral notching).

£10,000 (82% chance of being the preferredoption at the £20,000 threshold). Only at thelower thresholds did ‘hypotheticaltest/antioxidants_positive’ remain preferred (73%chance of being the preferred option at athreshold of £10,000).

When the model was run with two of thecharacteristics of the Doppler (bilateral notching)test, namely the cost of £20.00 and a specificity of 92%, the analysis showed that the test would be required to have a sensitivity of at least 95%, in order to have a 63% chance of ‘hypotheticaltest/antioxidants_positive’ being the preferredoption at the willingness to pay threshold of£30,000.

A similar analysis was carried out using thecharacteristic of a relatively cheaper test such ascellular FN. It must be emphasised that the cost of this test was a proxy based on the cost of theSUA test and the true costs of a cellular FN testmight be in excess of £5. However, if we assumethat the hypothetical test had the same specificityas cellular FN 96% (95% CI 79 to 99) and costapproximately £5, the analysis showed that thetest would be required to have a sensitivity of atleast 92% in order to have a 64% chance of‘hypothetical test/antioxidants_positive’ being thepreferred option at the willingness to paythreshold of £30,000. After that threshold, aswitch back in favour of ‘no test/antioxidants_all’occurred.

Case 5The results using the literature-based costs for thetests were no different to the results presented incase 1 and are therefore not presented.

Case 6The results are presented in Appendix 11 forcompleteness. However, they provide very limitedadditional insights into the cost-effectiveness ofalternative combinations of the test and treatmentpairings and are not considered further. The onlypossible exception is the predictable emergence ofprogesterone treatment (‘no test/progesterone_all’)as a potentially cost-effective additional option.The finding is in keeping with the generalobservation that effective, low-cost interventions,applied without prior testing, emerge as preferredfrom a cost-effectiveness perspective (RR = 0.21,95% CI 0.03 to 1.77; cost £54.10). However,progesterone needs to be approached with somecaution as a specific example of such anintervention for pre-eclampsia given the age andsize of the single RCT on which the effectivenessevidence is based (see the text on pp. 76–8 forfurther details).

Discussion of results of economicevaluationMain findingsThe key results, not already highlighted frompreceding parts of the project, emerging from the

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TABLE 46 Case 4b, threshold analysis on characteristics of a test that would be cost-effective when combined with the interventionantioxidants (‘hypothetical test/antioxidants_positive’): characteristics of hypothetical test based on cellular fibronectin

Necessary characteristics Test/treatment option Probability of being most cost-effective option at of test different levels of willingness to pay for a case

of pre-eclampsia averted (UK £ 2005/6)

0 10,000 30,000 50,000 100,000




a Level of sensitivity needing to be achieved in order to make ‘hypothetical test/antioxidants_positive’ the preferred cost-effective option in the majority of willingness to pay thresholds examined, assuming levels of cost and specificity actuallyobtained for cellular and total FN. Although the cost of the FN test at £5 was used in the model, this was a proxy estimatebased on another test as a more accurate estimate for the cost of an FN test was unavailable.

health economic and modelling evaluations wereas follows:

1. The cost of most of the tests examined in thisproject with potential to improveidentification of pre-eclampsia was modest. Itranged from £5 for blood tests such as SUA toapproximately £20 for Doppler examination.

2. Similarly, the cost of most interventionsexamined with potential to reduce thenumber of cases of pre-eclampsia was alsomodest. Treatment duration was generally for20 weeks and treatment costs to cover thisperiod ranged from:(a) virtually zero, but open to question as to

whether true cost would actually be zero,for example, advice to take rest in normalpregnancy and advice to reduce salt intake

(b) likely low cost, for example, antiplateletagents, particularly aspirin (£3) orantihypertensives (atenolol) (£5)

(c) upper range, but still modest, forexample, calcium supplementation (£46),antioxidants (£54) and progesteroneintramuscular injection (10 days) (£54).

3. In contrast, the best estimate of the additionalaverage cost associated with a case of pre-eclampsia is high at approximately £9000.This was reduced to £1000 in the PSA andstill did not change the result.

4. The main finding of the economic modellingis that advice to all women with a normalpregnancy (‘no test/rest_all’), without anyinitial testing is the most cost-effective‘test/treatment’ combination, delivering thegreatest reduction in number of cases of pre-eclampsia at virtually zero additional cost.

5. The economic modelling suggests that thesecond most cost-effective option is givingcalcium supplementation to all women,without any initial testing (‘notest/calcium_all’). The model indicates that forevery 1000 mothers treated there will beapproximately 13 fewer cases of pre-eclampsia. The costs averted as a result of thisreduction in cases of pre-eclampsia greatlyexceed the cost of the calciumsupplementation.

6. The third most cost-effective option suggestedby the economic modelling is antioxidantsupplementation to all women without initialtesting (‘no test/antioxidants_all’). Thesensitivity analysis suggested that with anoptimistic, yet plausible assumption abouteffectiveness, ‘no test/antioxidants all’ mightactually become the second most cost-effectiveoption ahead of ‘no test/calcium_all’.

7. All three main predictions of the economicmodel are affected by uncertainty, discussed indetail below.

8. However, within the constraints of the model,an important general finding is that effectivetreatments (RR < 0.7) with modest costs(<£50) applied to all women without priortesting are likely to be preferred from theperspective of cost-effectiveness.

9. Prior testing, particularly with the testaccuracy levels identified, appears to havelittle to offer as a way of improving cost-effectiveness. The threshold analysesconducted in the economic model suggestthat tests with costs in the upper range ofthose identified would need substantiallyimproved sensitivities (assuming that the bestlevel of specificity achieved in any test wasmaintained). Tests with costs in the lowerrange of those examined would need lessmarked improvements (again assuming thatthe best level of specificity achieved in any testwas maintained). However, such levels ofsensitivity have rarely been achieved. Therehave been particularly high hopes thatDoppler examinations might have usefulpredictive ability for pre-eclampsia. Theeconomic model provides little support thatany form of Doppler testing has sufficientlyhigh sensitivity and specificity to be cost-effective for the early identification of pre-eclampsia and in isolation from otherobjectives it might achieve.

10. The economic model also suggests that thepattern of cost-effectiveness is no different inhigher-risk mothers than the low-risk mothersconsidered in the base case. The cost-effectiveness of particular strategies isenhanced in high-risk populations (morecases of pre-eclampsia avoided for given cost).However, ‘no test/treat_all’ strategies remainthe most cost-effective options. It should benoted that the model assumes that the testaccuracy and RR of treatments remainsconstant with risk, there being no evidencethat these parameters differ depending onrisk level.

11. The economic model showed that the costsapplied to the tests and the treatments werelargely irrelevant to the overall final results.Key drivers in the analysis included the poorsensitivities and specificities of all the testswhich meant that none of them would berecommended as worth doing as part of a‘test/treat_positives’ strategy. For thetreatments, the key driver in the results wastheir RR, which led to the treatment which


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had the lowest RR being recommended. Thecost of pre-eclampsia used in the analysis washigh at approximately £9000. Thus thecombination of poor test accuracy andrelatively cheap effective interventions led to a‘no test/treat_all’ strategy dominating theresults because pre-eclampsia is a serious andcostly condition. Furthermore, even when thecost of pre-eclampsia was reduced to as low as£1000, the main results were unchanged.

Strengths of the economic evaluationThe economic analyses and model use data onaccuracy of tests and effectiveness of theinterventions from the most recently availablesystematic reviews and meta-analyses of theevidence. The model itself was developed by anexperienced health economic and modelling teamwith clinical and methodological input at allstages, from the original design of the model,through its execution, to the final interpretation ofits results. Although there are some importantlimitations, we believe that the model isstructurally sound, with key features such as PSAto help deal with the ever present challengesarising from uncertainty. As far as we are aware,there have been no previous attempts to modelcombined test-treatment options for theprevention of pre-eclampsia, particularly as part ofa project which simultaneously attempts tosummarise the best available evidence on allpotentially relevant tests and treatments. In thissituation, we cannot compare our approach withothers to judge relative merits.

Limitations of the economic evaluationThere are two main sources. The first arises fromconstraints arising from the way in which themodel itself was designed and structured, andinclude:

1. The model considers only single test results;combinations of tests or combinations oftreatments may offer opportunities which aremore cost-effective and these could not havebeen incorporated into the model as conceivedunless data were available for combined tests ortreatments (which they were not).

2. The existing model focuses on the outcomepre-eclampsia, and so may overlook the impactof test/treatment combinations on otheroutcomes, particularly to the infant such asintra-uterine growth retardation and perinataldeath. This is especially problematic if theeffect on these other outcomes is notexperienced to the same degree as the impacton the number of cases of pre-eclampsia.

Antioxidants provide a difficult example of thisproblem where although there is a reduction inrisk of pre-eclampsia, which is captured by themodel, there is an increase in risk of pretermbirth, which is not captured. However,fortunately, as can be seen in the results of thesystematic review of effectiveness, the directionof effect concerning pre-eclampsia usuallymirrors the effect on infant outcomes. Even so,there is a possibility that the modelsystematically underestimates the effect oftest/treatment combinations because benefitsattributable to reduction in outcomes likeperinatal death, preterm birth and small forgestational age are not fully accounted for.

3. Similarly, the existing model assumes that side-effects of tests and treatments are negligible.This seems a reasonable assumption given theavailable data for aspirin and calcium.200

However, it must be acknowledged that thisinformation is limited in many cases. This maybe particularly important where the universaluse of interventions without prior testing isbeing speculated on; confirmation of absenceof adverse events particularly to the baby mayrequire detailed investigation and high levels ofscrutiny. It should also be noted that apparentabsence of adverse events associated withtreatments is a contributor to the observedsuperiority of ‘no test/treat_all’ strategies; ifthere were associated adverse events therewould be added value from avoiding falsepositives such as would be achieved by apredictive test for pre-eclampsia with highspecificity.

4. The model assumes that the comparator for alltest/treatment pairings is ‘no test/no treatment’.Although the only practical choice for themodel, this may not be the best reflection ofcurrent practice in that some testing andtreatment may already occur. It therefore needsto be considered that the benefits and costs forall test/treatment combinations considered arelikely to overestimate those that can actually beachieved, to a degree which will varydepending on existing implementation. It alsoreminds us that there may be opportunities foravoiding costs associated with test/treatmentactivity is likely to be ineffective or inefficient.

5. Finally, care is required in the interpretation ofsome of the combinations of test/treatmentpairs examined in the model. Antihypertensivetherapy provides a good example. In applyingantihypertensive therapy to the reduction ofpre-eclampsia, blood pressure measurement isthe trigger for starting therapy and is thus ‘thetest’. There were, however, no data for the

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sensitivity and specificity for a given level ofblood pressure indicating need forantihypertensives. Further combiningantihypertensive treatment with any of theother tests is inappropriate as it is unlikely thattest positive results of, say, Dopplerexamination would be given antihypertensivesirrespective of actual blood pressure. In theevent, the inappropriateness of the model indealing with the actual options forantihypertensive therapy is mitigated by thefact that antihypertensives have very limitedeffectiveness in reducing cases of pre-eclampsia(RR 0.99, 95% CI 0.84 to 1.18), making itimplausible that it would be a potentially cost-effective option in any circumstances despitethe low cost of the drugs which might be used,such as atenolol (£5).

The restriction of the economic model to an NHSperspective could also be considered a potentiallimitation. The main counter argument is thatbecause most assessments of cost-effectiveness aredone from the perspective of the healthcare payer,doing the economic model from the NHSperspective remains most relevant in order tofacilitate comparison with other uses of healthcareresources. Ideally, cost-effectiveness taking intoaccount societal and individual costs would beworth exploring; however, experience suggeststhat data to do this accurately are rarely routinelyavailable and would require primary datacollection, which was outside the original agreedprotocol. It must be acknowledged that limitingthe analysis to the NHS perspective may lead tounderestimation of certain costs, particularly forinterventions such as advice to rest in normalpregnancy, where the onus is placed on theindividual, their family and society to achieveimplementation. In the absence of versions of themodel from an individual and societal perspective,such considerations can only be incorporated intothe conclusions qualitatively.

The second main source of limitations is the dataused to provide the model parameters. Again,there are a number of specific issues:

1. There is marked stochastic variation in many ofthe parameters, manifest in wide 95% CIs. Theeffect of this on conclusions of the economicmodelling is explored using the PSAs, and themain findings appear to be robust. However,the implications of the 95% CI do still need tobe considered, particularly where the 95% CIincludes values of RR > 1.0, implying that theintervention causing increased numbers of

cases of pre-eclampsia remains a possibilitybased on the available data. This was therationale for separating group 1 interventions,where ‘harm’ was unlikely to be a possibility,from group 2 interventions, where it was.Progesterone is an example of an interventionwhich, applied universally without prior testing,may be a relatively high preference from theperspective of cost-effectiveness. However,caution does need to be exercised through theobservation that the 95% CI for RR (0.03 to1.77) includes the possibility of increasing thenumber of cases of pre-eclampsia.

2. In addition to chance, there is uncertaintyarising from systematic variation, includingoperation of bias. Provisos therefore sometimesneed to be added concerning the fact thatthere may be threats to validity. Parametersbased on single, small studies with very smallnumbers of outcomes raise not just concernsabout effect of chance (reflected in the 95% CI)but also susceptibility to bias. This was animportant consideration in:(a) effectiveness of advice on rest in normal

pregnancy [RR 0.05 (95% CI 0.0 to 0.83)based on one small RCT (n = 32), withnine outcome events, with lack of clarityabout method of randomisation andcompleteness of follow-up]

(b) effectiveness of progesterone [RR 0.21(95% CI 0.03 to 1.77) based on a singleRCT published in 1962 (n = 122) with sixoutcome events, with limited reporting onmethod of randomisation]

(c) effectiveness of exercise [RR 0.31 (95% CI0.01 to 7.09) based on one outcome eventin two small RCTs (n = 29 and 16)].

In the last case, the concern was so great thatthe result was not actually included in themodelling exercise at all.

3. There is sometimes further uncertainty arisingwhere estimates of accuracy or effectiveness arebased on several primary studies and there isheterogeneity between the results (morevariation than can be accounted for by chancealone). If the cause of this heterogeneity cannotbe isolated, there may be concern about use ofa summary measure from a meta-analysis. Thisis a theoretically important issue for virtually allestimates of test accuracy, and for effectivenessestimates for interventions like calcium (RR0.48, �2 33.9, 11 degrees of freedom) andantiplatelets (RR 0.81, �2 85.6, 42 degrees offreedom). Sometimes plausible subgroup effectscan be identified and, where these occurred inthe group 1 interventions, the impact on theconclusions of the economic model were


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investigated with further sensitivity analyses. Ofparticular importance was that for antioxidants,where a subgroup estimate excluding theresults of a large quasi-randomised RCT led toan improved estimate of effectiveness [base-case RR 0.61 (95% CI 0.5 to 0.75); sensitivityanalysis, RR 0.45 (95% CI 0.31 to 0.66)].

4. There is general concern about the costestimates used for the tests and treatments andthis is common throughout economicevaluation. However, in the present study, thetests were not sensitive enough for their costs tobe worth investigating in any more detail thanpresented. If a test had been shown to be worthdoing in a ‘test/treatment_positives’ result, bythe economic model, and none were, then itwould be important to be sure that the costinformation leading to that recommendationwas accurate. But when the tests are shown tobe generally insensitive, accurate costs are lessrelevant. If the test was improved (i.e. moreeffort was made to make it of highersensitivity), the appropriate cost would alsochange. In the main analysis (cases 1–4) thecosts provided by the Birmingham Women’sHospital were applied. These were far lessexpensive than those suggested in the literature(which were used in case 5). There is somecertainty that test costs of £5 applied to thetotal FN test, for example, which appears toshow potential in the deterministic analysis, are probably lower than would be viable inpractice. We have, therefore, not disadvantagedthe tests with these low costs. This is confirmedin the PSA, in which it is shown that theuncertainty associated with the estimates ofsensitivity and specificity leads any potentialrecommendations in favour of these tests to beruled out, despite basing the evaluation on veryfavourable cost estimates. A similar argument holds for the cost oftreatments used in the model. The costs usedare considered reasonable estimates and basedon the BNF. There are only four treatments ingroup 1 that were used in the model. The orderof the results presented in case 2 is basedwholly on the order of the estimate for the RR,despite antiplatelets being estimated to cost just£2.69. The costs of these treatments would haveto be considerably and unrealistically higher fortheir cost to influence the results. This ishighlighted by case 3, when the priorities forcalcium and antioxidants switch in line withtheir RR in the subgroup analysis.

5. There was absence or effective absence ofinformation on certain key parameters. Hencethere may be new or established tests or

interventions which have not yet been fullyevaluated. Kallikreinuria is a test which fallsinto this category. Although the single smallevaluation identified in the systematic reviewsuggested potentially useful sensitivity andspecificity, the result was not modelled becauseof the limited number of evaluations and thereported rare use of the test in practice byclinical members of the project team.Interventions such as exercise, discussed above,could also fall into this category, in that initialevaluations indicate potential, but requirefurther confirmatory results. In addition, theremay well also be tests and treatments underdevelopment that do not appear in theliterature at all, of which we would be unaware.Finally, some systematic review results, orupdates thereof, arrived after the modellinghad been completed. There were also otherpre-eclampsia results that were notincorporated into the economic modelling fora variety of reasons. These are indicated inTable 47, which is a modified version of Table 37that gave the effectiveness parameters actuallyused in the modelling. As can be seen fromTable 47 the effectiveness results which were notincorporated into the model were extremelyunlikely to lead to changes in the mainfindings.

Recommendations for practiceThe findings of the health economic evaluationare insufficient on their own to dictate changes inpractice. However, the results do suggest thatuniversal application of a number of potentiallyeffective treatments requires consideration. Someinterventions such as exercise, advice to rest andprogesterone need further evaluation of theireffect on pre-eclampsia. For others, evidence oneffectiveness may already be sufficient to considerassessing feasibility, checking acceptability tomothers/healthcare staff and developing pilotschemes for further evaluation.

Recommendations for researchAs already indicated, the development andevaluation of pilot programmes applying effective,low-cost interventions, such as calciumsupplementation, without prior testing to mothersat low risk of pre-eclampsia would be the nextlogical step from the findings of the economicanalysis. Obtaining reassurance about adverseevents would be very important, as wouldconfirmation about costs.

RCTs providing further evidence about theeffectiveness of interventions such as rest, exercise

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and progesterone on pre-eclampsia are alsopriorities as they appear on preliminary RCTfindings to be sufficiently effective and low cost tobe cost-effective also. New effective, low-costinterventions may also continue to emerge, andthese too should be priorities for rigorousevaluation.

There are also opportunities for further researchthat may precede or accompany these mainrecommendations. The first might be to develop amore comprehensive economic model which dealssimultaneously with the multiple outcomes whichmay contribute to effectiveness and cost-effectiveness across the board. As a minimum thiswould need to consider the infant outcomesidentified, that is, preterm birth, and consider not

just tests and interventions thought to have animpact on pre-eclampsia, but those primarilytargeting these other outcomes also. Thecomplexity of such a model would be great,particularly if it attempted to explore whethercombinations of tests or combinations oftreatments might be more cost-effective. Any newmodelling should include the opportunity to doprimary data collection on costs, the absence ofwhich was a limitation in this analysis. Second,there should also be some continuing commitment to improving estimates of testaccuracy. Newly developed or emerging testspredicting development of pre-eclampsia withmodest costs that have very high levels of testaccuracy should continue to be sought andevaluated. Kallikreinuria is such a test, an initial


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TABLE 47 Data on all RR of pre-eclampsia estimates provided by the project’s systematic reviews of effectiveness

Treatment RR 95% CI Revised RRa 95% CI

Group 1b Rest for normotensive women vs unrestricted activity 0.05 0.0 to 0.83 No subgroup analyses

Antioxidants vs placebo/no antioxidants 0.61 0.50 to 0.75 0.45d 0.31 to 0.66Calcium supplement vs placebo 0.48 0.33 to 0.69 0.62e 0.32 to 1.20Antiplatelets vs placebo/no intervention 0.81 0.75 to 0.88 0.85f 0.77 to 0.94

Group 2c Progesterone vs no progesterone 0.21 0.03 to 1.77 NADiuretics vs placebo/no diuretics 0.68 0.45 to 1.03 NAGarlic vs placebo 0.78 0.31 to 1.93 NANitric oxide donors or precursors vs placebo/no 0.83 0.49 to 1.41 NA

interventionMarine/fish oils vs placebo/no treatment 0.86 0.59 to 1.27 NAAntihypertensives vs placebo/no treatment 0.99 0.84 to 1.18 NAAdvice to reduce dietary salt vs advice to continue 1.11 0.46 to 2.66 NA

normal dietComments

RRs not Updated reviewused in Antiplatelets vs placebo/no intervention 0.83 0.77 to 0.89 Results virtually identical the with older version of review models Updated review results used in the model

Antihypertensives vs placebo/no treatment 0.97 0.83 to 1.13

Exercise 0.31 0.01 to 7.09 Results based on oneoutcome in 2 small RCTs(n = 16 and 29)

Bed rest for hypertension during pregnancy 0.98 0.80 to 1.20 Inappropriate population

Nutritional advice during pregnancy 0.89 0.42 to 1.88 Results based on 1 RCT

Balanced energy/protein supplementation 1.20 0.77 to 1.89 Risk of harm

Isocaloric protein supplementation 1.00 0.57 to 1.75 Results based on 1 RCT

Energy/protein restriction 1.13 0.59 to 2.18 Risk of harm

a RRs based on subgroup analyses, defined in detail in the text, and used as parameters in sensitivity analyses.b Group 1 are those treatments with an RR whose upper 95% CI is <1.0.c Group 2 are those treatments with an RR whose 95% CI includes a value compatible with worsened outcome.d Subgroup excluding the single large quasi-randomised trial.e Subgroup of trials carried out in populations with an adequate calcium diet.f Subgroup of trials carried out in populations with mothers at ‘moderate risk’ of pre-eclampsia rather than both ‘moderate’and ‘high risk’ combined.

evaluation of which suggests that its sensitivity andspecificity may be at a level where it offers thepossibility of contributing to a cost-effectivetest/treatment pairing.

Conclusions from the economicevaluationThe observed limitations do impinge on theinitially stated main findings of the economicevaluation, particularly the specific interventionsemerging as potentially preferred from a cost-effectiveness perspective. Thus for the ‘no test/rest_all’ option there are concerns about therobustness of the estimate of effect and theassumption of near zero cost to the NHS; for ‘notest/calcium_all’ there may be concern that whenthe effectiveness results are restricted to just thoseRCTs in populations with an adequate calciumdiet, the 95% CI for the RR extends beyond 1.0and that there may be also uncertainty aboutadverse events associated with widespread use ofcalcium in a low-risk population; finally, for ‘notest/antioxidants all’ there may again be concernabout lack of data on adverse events and theobservation that there is a disadvantageous effecton preterm birth <37 weeks (RR 1.38, 95% CI1.04 to 1.82).

However, the general finding that the most cost-effective option is likely to be effective treatments(RR < 0.7) with modest costs (<£50) applied to allwomen without prior testing would seem to be

robust. The three interventions indicated wouldclearly be those of greatest potential, providedthat the uncertainties identified were resolved.However, other interventions such as progesteroneand exercise were also highlighted, which withfurther evaluation might emerge as equally cost-effective options. Similarly, the need to investigatecombinations of interventions should also not beoverlooked.

Concerning the pessimistic findings about the lackof contribution to predictive testing to a preferredoption from the point of view of cost-effectiveness,there seems little in the limitations to challengethis initial finding. As already stated, this situationprincipally arises because there are effective,relatively cheap interventions which appear to befree of adverse effects. Little would seem tothreaten this, with the exception that adverseevents might emerge when the interventions inquestion are widely used. The threshold analysisindicates the levels of accuracy that a test mightneed to achieve to become cost-effective.Generally, such levels of sensitivity and specificityhave not been achieved. However, there are somepreliminary results for kallikreinuria suggestingthat the there may be tests which can achieve thevery high levels of test accuracy demanded,provided that the cost remains modest. Hence thesearch for potentially useful tests should not becompletely abandoned, and kallikreinuriacertainly deserves further evaluation.

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IntroductionOverall this review hoped to identify combinationsof tests and treatments that would lead toreduction in pre-eclampsia, which is an importantthreat to public health in both developed anddeveloping countries. This project completed threedistinct pieces of work to contribute to this goal:

● series of systematic reviews of test accuracy ofthe prediction of pre-eclampsia

● series of systematic reviews of effectiveness ofinterventions with potential to reduce cases ofpre-eclampsia

● health economic evaluation, including aneconomic model, of the combined effect of testsand treatments on pre-eclampsia.

Each of these components has been described indetail, its main findings reported and theconclusions discussed in the light of anylimitations identified at the end of each of thethree preceding chapters. This chapter attempts tofocus on the key findings and limitations emergingfrom all the previous sections as a whole. It is nota comprehensive summary of all the issues raisedin each of the earlier chapters.

Main findings● The accuracy of virtually all tests purported to

be of value in prediction of pre-eclampsia wasdisappointing. Sensitivity, that is, the ability topredict all mothers who will develop pre-eclampsia, was particularly poor.

● The effectiveness of several interventions whichmight reduce the number of cases of pre-eclampsia was, in contrast, more promising. Inaddition to well-known interventions such asantiplatelet agents, the review has focusedattention on other less frequently citedinterventions, such as rest, exercise and calciumsupplementation.

● By the standard of many healthcareinterventions, those indicated to be potentiallyuseful in avoiding pre-eclampsia were noted tobe affordable (costs generally less than £50 forthe whole of pregnancy, often substantially so).

● From the perspective of cost-effectiveness,

providing effective treatment without priortesting is likely to be preferred to using a testfollowed by treating those who are positive. Theprovisos are that the true costs remain modest,that any effect on pre-eclampsia is not offset bycontrary effects on important infant outcomesand that there are no serious adverse eventsassociated with widespread use of theinterventions in low-risk mothers.

Strengths of the reportThere have been no previous attempts to assesssystematically the potential cost-effectiveness ofdifferent combinations of tests and treatments forpre-eclampsia as a whole. We believe that theparticular strength of this report is that itcombines the results from a wide range of testaccuracy systematic reviews with a wide range ofdifferent types of interventions in one economicmodel. The aim is to give clinicians andresearchers a much more comprehensive overviewof the current state of knowledge in this area than would be gained from single studies ondiagnostic tests and interventions to prevent pre-eclampsia.

Limitations of the project● It is acknowledged that not all possibly relevant

tests have been included in this report (possiblemissing candidates include sFlt1) and that notall possibly relevant interventions wereincluded.

● The systematic reviews of test accuracyencountered several challenges (see Chapter 3).However, none of these seriously threatened thevalidity of the main finding that the accuracy ofvirtually all tests was disappointing. Betterreviews and more primary research on thosetests examined are unlikely to change thispicture.

● It is possible that there are new tests which havenot been fully evaluated or have not reachedevaluation. Kallikreinuria is a possible exampleof a test which in early evaluation appears tocombine good sensitivity and specificity.

● One of the main limitations of the accuracy


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Chapter 6

Conclusions

reviews was that combinations of tests could notbe assessed. This will require new prospectiveprimary studies or IPD meta-analysis.

● The main limitation with the systematic reviewsof effectiveness (see Chapter 4) is the paucity ofdata for several promising interventions,particularly rest at home and exercise, and alsofor the lack of universal high-quality data forsome other interventions.

● Antiplatelet agents and calcium supplementationreduce the risk of pre-eclampsia. Forantiplatelet agents this is reflected in reductionsin perinatal outcomes of death, preterm birthand having a small for gestational age baby.However, for calcium supplementation there areno clear differences in baby outcomes. Also, forantioxidants, although the review presentedhere shows a reduction in the risk of pre-eclampsia, this is no longer statisticallysignificant in the updated review.

● Another limitation of the effectiveness reviewswas that combinations of interventions couldnot be assessed. This will require newprospective primary studies.

● One limitation of this project with respect toeffectiveness reviews is that results of Cochranereviews updated after the economic evaluationwas performed (particularly antioxidants, wheretwo new large trials were published late on inthis project) could not be included in the finalreport.

● Pre-eclampsia has limitations as an outcome. Itsfull impact needs to be assessed by looking at arange of other outcomes for the woman andbaby. It is the consequences of pre-eclampsiathat we really need to assess. Interventions mayinfluence the diagnosis of pre-eclampsia (byaltering blood pressure, for example, withoutactually influencing the underlying pathologicalprocess). The consequences of pre-eclampsia,rather than the diagnosis itself, that are mostimportant.

● There are some limitations to the economicmodel used, arising from the quality of the data(see above) and the availability of appropriatedata both on effectiveness and side-effects. Pre-eclampsia was the only outcome used and themodel did not assess side-effects. It is virtuallyself-evident that an effective, affordable andsafe intervention is unlikely to be improvedupon by applying a test with poor accuracy.Furthermore, with a condition as serious andcostly as pre-eclampsia, correct identification ofthose who will develop pre-eclampsia will bemore important than correct categorisation ofthose who will not develop pre-eclampsia. Inthis respect, it is important that the

compromised sensitivity is the aspect of testaccuracy where all the potential tests areparticularly deficient.

● The small amount of information on adverseevents associated with interventions, particularlyin the longer term and to the child, is animportant limitation, as is the lack ofinformation on side effects of the tests.

● Another limitation is the lack of qualityinformation concerning costs.

Overall conclusionThe main findings of this review appear largelyunaffected by the limitations identified. Of thesefindings, we believe that the main driver of futurepractice and research is the likelihood that aneffective intervention applied to all motherswithout preceding testing will be the most cost-effective approach to reducing pre-eclampsia. Wehave identified several candidates for anappropriate intervention. Some, such as rest andexercise, require further evidence on effectiveness;others, such as calcium supplementation, needconfirmation of absence of adverse events andreasonable cost.

Recommendations for practiceWith regard to effectiveness results, low-doseaspirin could be offered to women at risk of pre-eclampsia and calcium supplementation could beconsidered for those with low dietary calciumintake. With regard to the economic modelling,the most cost-effective approach to reducing pre-eclampsia is likely to be the provision of aneffective, affordable and safe intervention appliedto all mothers without prior testing to assess levelsof risk. However, we believe that it is probablypremature to suggest the implementation of atreat-all intervention strategy such as advice torest, low-dose aspirin or calcium supplementationon cost-effectiveness grounds at present. Someconsideration needs to be given as to whether weshould continue to do certain tests reviewed in thisreport whose main perceived value up to now hasbeen to help identify pre-eclampsia.

Recommendations for research● There is a need for systematic reviews to map

the aetiopathogenesis of pre-eclampsia in orderto better develop new tests and treatments.

● Similarly, there is a need for systematic reviews

Conclusions

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to evaluate prognostic/predictive features thatare associated with maternal and foetalcomplications once pre-eclampsia has started(see Figure 1, p. 6).

● Researchers may wish to consult more widely toensure that all relevant diagnostic tests andinterventions are considered for review in futureprojects. It is important to involve consumers inpriority setting for research. Consensusconferences and Delphic surveys may be usefulto define important questions and designs forthe future.

● There is a need for RCTs that investigatewhether lifestyle interventions such as rest athome and exercise are actually effective inreducing pre-eclampsia.

● Those who design future trials should do this ina way that facilitates meta-analysis and IPDanalysis, for example by using similar protocolswhenever possible, by collecting informationabout women’s risk status at trial entry andstandardising the definitions of outcomemeasures.

● Evaluation of pilot schemes for universaltreatment of mothers with effectivepharmacological interventions such as calciumsupplementation or aspirin should beconsidered. Such evaluation should includeinvestigation of adverse events and actual costs.

● There is a need for IPD meta-analysis ofeffectiveness literature where it has not alreadybeen done and where there is sufficient researchto warrant this approach in order to delineatesubgroup effects powerfully.

● Rigorous evaluation is required of tests withmodest cost whose initial assessments suggestthat they may have high levels of bothsensitivity and specificity. Kallikreinuria may fallinto this category, but there may be othercontenders in development which would needfurther investigation.

● Diagnostic IPD meta-analyses are required fordelineating the added value of tests and forstudying the value of test combinations in lightof the interdependence that exists between tests.

● Multiple (direct and indirect) comparisonsconsidering all the tests and interventions mayhelp delineate their rank. Methodologicalresearch is needed to assess if this couldproduce outputs suitable for decision analysis.

● There is a need for the development of aneconomic model which considers not just pre-eclampsia, but also other related outcomes,particularly those relevant to the infant such asperinatal death, preterm birth and small forgestational age. This would help to enable thedevelopment of comprehensive care pathways.Such a modelling project should make provisionfor primary data collection on costs.


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The authors wish to acknowledge DavidBraunholtz, Jos Kleijnen, Fiona Milne, Philip

Milner, Hans Reitsma and David Williams.

Contribution of authorsPelham Barton (Senior Lecturer) was modellingadvisor to the project. He advised on the modelstructure and provided advice throughout both theanalysis and interpretation of the results. Hecommented on the draft economic section of thereport. Jeltsje Cnossen (Research Fellow) didsystematic reviews of diagnostic tests (all exceptproteinuria), statistical analysis, projectmanagement of diagnostic accuracy work streamand drafting of methods and results of diagnosticaccuracy parts of the final report. Lelia Duley(Professor of Obstetric Epidemiology) was co-applicant on the grant application to obtainfunding, undertook project management ofeffectiveness systematic reviews and development ofthe generic protocol for effectiveness reviews,conducted new effectiveness reviews and updatedexisting reviews in collaboration with Cochranereview authors. She also contributed to thebackground, systematic reviews of effectivenessstudies and discussion sections of the final report.Janesh Gupta (Professor of Obstetrics andGynaecology) was co-applicant on the grantapplication to obtain funding and undertookproject management and editing and revisions ofmanuscript. Chris Hyde (Reader in EvidenceSynthesis in Health Care) was co-applicant on thegrant application to obtain funding and undertookdevelopment of protocol, assistance with testaccuracy review on proteinuria, assistance with theeconomic model, particularly interpretation andpresentation, and drafting and editing of the finalreport. Ariadna Juarez-Garcia (Research Fellow)helped to collate the data from the clinical reviews,constructed the model using Data TreeAge softwareand carried out the main analyses for the economicevaluation using the model and probabilisticsensitivity analysis. She helped to interpret theresults and commented on the draft economicsection of the report. Khalid Khan (Professor ofObstetrics-Gynaecology and Clinical Epidemiology)was the main applicant on the grant application toobtain funding and undertook development ofprotocol, project management and drafting andediting of the final report. Mariska Leeflang(Research Fellow) did systematic reviews ofdiagnostic accuracy studies. Catherine Meads

(Lecturer) did project management, organisedmeetings and took minutes, conducted one testaccuracy review, constructed abstracts of accuracyand effectiveness reviews, assisted with drafting ofthe background, methods section of accuracy andeffectiveness reviews and economics sections,drafted part of the effectiveness discussion andoverall discussion, finished the report and liaisedwith NCCHTA. Shireen Meher (Research Fellow)did systematic reviews of effectiveness, developedthe generic protocol for effectiveness reviews,coordinated input from Cochrane review authors,conducted new effectiveness reviews and updatedexisting reviews in collaboration with Cochranereview authors. She also contributed to drafting ofthe background and effectiveness sections of thefinal report. Ben Willem Mol (Consultant inObstetrics and Gynaecology) and Joris van der Post(Professor in Obstetrics) did systematic reviews ofdiagnostic accuracy studies. Gerben ter Riet(Associate Professor) developed the the protocoland undertook project management of diagnosticaccuracy systematic reviews, statistical analysis anddrafting of the diagnostic accuracy methods sectionin the final report. Tracy Roberts (Senior Lecturer)was co-applicant on the grant application to obtainfunding and was responsible for overseeing theeconomic evaluation component of the project. Shecollated data from the clinical reviews, collected thecost data used in the model, helped design themodel structure and co-analysed the results. Shewrote the main draft of the economics section ofthe report.

Papers published in other peer-reviewed journals relating to this research projectCnossen JS, de Ruyter-Hanhijärvi H, van der Post JAM,

Mol BWJ, Khan KS, ter Riet G. Accuracy of serumuric acid determination in predicting pre-eclampsia:a systematic review. Acta Obstet Gynecol Scand 2006;85:519–25.

Cnossen JS, van der Post JAM, Mol BWJ, Khan KS,Meads CA, ter Riet G. Prediction of preeclampsia: a protocol for systematic reviews of test accuracy.BMC Pregnancy Childbirth 2006;6:29.

Duley L, Meher S, Abalos E. Management of pre-eclampsia. BMJ 2006;332:463–8.

Leeflang MMG, Cnossen JS, van der Post JAM, MolBWJ, Khan KS, ter Riet G. Accuracy of fibronectintests for the prediction of preeclampsia: a systematicreview. Eur J Obstet Gynecol Reprod Biol 2007;133:12–19.


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200. Coomarasamy A, Braunholtz D, Song F, Taylor R,Khan KS. Individualising use of aspirin to preventpre-eclampsia: a framework for clinical decisionmaking. BJOG 2003;110:882–8.

201. Davey DA, MacGillivray I. The classification anddefinition of the hypertensive disorders ofpregnancy. Am J Obst Gynaecol 1988:158:892–8.

The effectiveness reviews were to be conductedin collaboration with the Cochrane Pregnancy

and Childbirth Group. The review process for thisproject therefore needed to be nested within theexisting framework of Cochrane reviews. It alsoneeded to comply with the editorial and peerreview processes of this review group. Key issues indeveloping a strategy for the effectiveness reviewswere to invite all existing Cochrane review authorsto collaborate, to ensure that their work wasproperly acknowledged and to agree a singlegeneric protocol within this collaborative groupfor these reviews.

Protocol development followed the followingsteps:

1. Identifying published reviews and protocols,and registered titles for reviews, that wererelevant to prevention of pre-eclampsia.

2. Inviting the contact review author for each ofthese reviews, protocols and titles to join acollaborative group to agree a generic protocollaying out a standard set of methods for theCochrane reviews of prevention of pre-eclampsia.

3. Requesting review authors of published reviewsand protocols, and of registered titles, to allowus to work with them to update as many reviewsas possible within the time frame of the project.

4. Dividing topics into ‘core reviews’ which had aprimary focus on prevention of pre-eclampsia

and would be completed or updated within thetime frame of this project, and ‘non-core’reviews which had a broader focus. Reviewauthors for both ‘core’ and ‘non-core’ reviewwere encouraged to use the generic protocol asthe basis for their reviews, and the searchstrategy included topics relevant to bothcategories.

5. Submitting the generic protocol, which hadbeen agreed by the Prevention of Pre-eclampsiaCochrane Review authors, to the editorial andpeer review process of the Cochrane Pregnancyand Childbirth Group.

The generic protocol is published within theCochrane Database of Systematic Reviews.79 It wasused for conducting all new reviews. Reviewauthors of reviews and protocols already publishedat the start of this project were also encouraged tocomply with these agreed standardised methodswhen updating their reviews or protocols.

Advantages of working within the Cochrane groupwere not only having access to the trial registermaintained by the group, but also that the generic protocol and each review were passedthrough the full editorial process. This processincluded peer review by an editor and a reviewauthor within the Cochrane Pregnancy andChildbirth Group, by the Group’s consumer panel,by the Group’s statistician and by an expertoutside the Group.


121


Appendix 1

Protocol for the effectiveness reviews

MEDLINE1. preeclamp* OR eclamp* OR pre-eclamp* OR

(pre AND eclamp*) OR (pregnan* ANDhypertens*)

2. ("Eclampsia"[MeSH] OR "Gestosis,EPH"[MeSH] OR ("Hypertension"[MeSH] AND"Pregnancy"[MeSH]))

3. "Sensitivity and Specificity"[MeSH] OR predict*OR diagnose* OR diagnosi* OR diagnost* ORaccura*

Diagnosis: (1 OR 2) AND 3

4. (((((("cohort studies"[mh] OR "case-controlstudies"[MeSH Terms]) OR "risk"[mh]) OR"epidemiologic factors"[MeSH Terms]) OR("odds"[tw] AND "ratio*"[tw])) OR ("relative"[tw]AND "risk"[tw])) OR ("case"[tw] AND"control*"[tw]))

Aetiology: (1 OR 2) AND 4

EMBASE1. exp "ECLAMPSIA AND PREECLAMPSIA"/2. exp PREGNANCY/3. exp hypertension/4. 2 and 35. 1 or 46. (preeclamp$ or eclamp$ or pre-eclamp$ or

(pre and eclamp$) or (pregnan$ andhypertens$)).mp.

7. (sensitiv$ or detect$ or accura$ or specific$ orreliab$ or positive or negative ordiagnos$).mp. or di.fs.

8. 5 or 69. 7 and 8 (diagnosis)10. cohort analysis/11. exp risk/12. (odds$ adj ratio$).mp.13. (relative adj risk).mp.14. case control study/15. (case$ adj control$).mp.16. (causa$ or predispos$).mp.17. or/10-1618. 5 or 619. 17 and 18 (aetiology)


123


Appendix 2

Test accuracy search strategy


125


Appendix 3

Data extraction form

Appendix 3

126

1. RefID Original Study: RefIDPP 1 Jeltsje Cnossen 5 Mariska LeeflangPP/ RL

2 Gerben ter Riet 6 ……………………….

3 Joris van der Post 7 ……………………….

2. Assessor:AssOr

4 Ben Willem Mol 8 Other, ……………….

3. ID of correspondingsystematic review: IdSR

State abbreviation of test under review 88

4. RefID within correspondingsystematic review: RefIDSR

5. First author: Author

88

6. Publication year: PubYear

7a. Setting: SetCare 1 primary careGP, midwifery

2 secondary/tertiary carehospital

3 mixedcare

55 other 66 not reported

7b. Number of participatingcenters: Centers 88

7c. Country of investigation:Country

88

8. Eligibility/ in-/ exclusion criteria NB: if “no”, state numbers if mentioned:e.g. # patients normotensive <20wk

8a. Were all patients normotensive before 20th

week of pregnancy (or 6 weeks after birth)?SelNormo

1 yes 2 no

……. /……..

66 not reported

8b. Were all patients non proteinuric before th20 week of gestation? SelProt

1 yes 2 no

……. /……..

66 not reported

8c. Did all patients have singleton pregnancies?SelSingl

1 yes 2 no

……. /……..

66 not reported

8d. Were all patients primigravid? SelPrimi 1 yes 2 no

……. /……..

66 not reported

8e. Were patients with pre-eclampsia in previous pregnancies excluded/not

included? SelPE

1 yes,or notapplicable

2 no 66 not reported

8f. Were patients with the following majorsystemic disorders excluded/not included?

8f1. Insulin dependent diabetes mellitus: SelIDDM 1 yes 2 no 66 not reported

8f2. Chronic renal disease: SelRenal 1 yes 2 no 66 not reported

8f3. Systemic lupus erythemathodes: SelSLE 1 yes 2 no 66 not reported


127


SevPE

66 not reported12b4.How was the controlgroup composed? ContrGrp

1 differential diagnosissample

2 conveniencesample

3 healthycontrols sample

77 not applicable

8f4. Antiphospholipid syndrome: SelAPLS 1 yes 2 no 66 not reported

8f5. Chronic hypertension: SelChrRR 1 yes 2 no 66 not reported

8f6. Foetal chromosomal or structuralabnormalities: SelFtGen

1 yes 2 no 66 not reported

8g. Other eligibility/in-/exclusion criteria: SelOth

`

88

66 not reported

9. Study population: describe age (mean ± SD or median (range)): PopAgeDescribe for whole group! If only data can be described for subgroups, describe for subgroups

88

66 not reported

10. Start inclusion patients (year): InclStrt 66 not reported

11. End inclusion patients (year): InclEnd 66 not reported

12a. Study design: StuDes 1 cohort 2 casecontrol

3 rct/ cct 4 crosssectional

55 other

66 not reported12b1. Case control design:CCDes

1 nested incohort

2 matched 3 both,nested andmatched

55 other

77 not applicable

66 not reported12b2. How was the casegroup composed? CaseGrp

1 incident casesoccurrence of pre-eclampsia ingroup of pregnant women

2 prevalent casespresence of pre-eclampsia in group ofwomen

3 both

77 not applicable

12b3. Severity of the diseasein pre-eclamptic patients:

1 representative sampleof population with thedisease

2 sample of moresevere cases

3 sample ofless severecases

66 not reported

Appendix 3

128

13a. Consecutive series ofpatients (selection): ConsPts

1 yes 2 no, randomsample

3 no, neither consecutive,nor random sample(e.g. matched cohort)

66 not reported

13b. If “no” at item 13a,number(s) of patients

missed: ConsMiss

66 not reported

14. Details of Index test measurementIndex test under review: IndDet

Fibronectin

88

14a. Fibronectin: FNmeas 1 total 2 cellular 3 both 66 not reported

14b. Manufacturer: Manuf

88

66 not reported

14c. Description Index test: DetMeth

88

15. Details of Reference test

15a. Blood pressure(Korotkoff): RefKor

1 K4 2 K5 3 both 66 not reported

15b. Blood pressuremeasurement (instrument):

RefInstr

1

mercurysphygmo-manometer

2

ambulatory3

automated55 other,

………………………………………

66 not reported

15c. Blood pressure (position):RefPos

1 seated 2 supine 3 lateral 66 not reported

15d1. Blood pressuremeasurement (mmHg diastolic,

repetitive, hours apart): RefDBP

1 �90mmHgtwice �4hrs apart

2 �110mmHg at leastonce

3 both (1+2) 55 other 66 not reported

15d2. If “other” at 15d1. report details (mmHg diastolic,repetitive, hours apart): RefBlood

88

15e1. Increase in bloodpressure (state quantity): RefIncr

1 yes

……… (Syst) /……… (Diast)

2 no 66 not reported

15f.Proteinuria (dipstick): RefDip 1 �1+ 2 �2+ 3 �3+ 55 other 66 not reported


129


15g. Proteinuria (state quantitythreshold): RefProt

1 g/ 24 hrs 2 g/ L 55 other,

……………

66 not reported

15h. Oedema (presence): RefOed 1 yes 2 no

15i. Other details of Referencetest (e.g. elevated serum uric

acid): RefOth

88

16. Flow, index test executedfirst: Indfirst

1 yes,or notapplicable

2 no,reference testfirst

3 no, atrandom

4 no, mixed 66 not reported

17. Prospective data collection:TimeData

1 yes 2 no, retrospective 3 no, ambispective 66 not reported

2 no18. Were pregnant womentreated before occurrence of

pre-eclampsia? Treat PE

1 yes treatment

88

66 not reported

19. Index test blind for reference test results: IndBlind 1 yes, or not applicable 2 no 66 not reported

20. Reference test blind for index test results:RefBlind

1 yes, or not applicable 2 no 66 not reported

21. Index test blind for clinical information: IndCli 1 yes 2 no 66 not reported

22. Reference test blind for clinical information:RefCli

1 yes 2 no 66 not reported

23. Training of assessors: TraiAss 1 yes 2 no 66 not reported

24. Number of assessors: NrAss 66 not reported

25a. Absence or existence of not interpretable,indeterminate, intermediate results reported: NonInt

1 yes 2 no

25b. Number of not interpretable, indeterminate,intermediate index test results: IndMes

index test

25c. Number of not interpretable, indeterminate,intermediate reference test results: RefMes

reference test

25d. Number of not interpretable, indeterminate,intermediate test results overall: TotMes

overall

Appendix 3

130

25f. Are drop-outs reported: DropoutDrop-outs should not have been scored at any previous

item!

1 yes 2 no

25g. If ‘yes’ at item 25f, state number of drop-out:NrDrop

66 not reported

25h. Total number of patients excluded: NrDrop 66 not reported

26. Prespecified cut-off for Index test positivity or variation () reported: CutRep

1 yes 2 no

27. Cut-off value(s) Index test: CutVal Threshold / 66 not reported

25e. Is reported, whether former results wereincluded or excluded when indexes of accuracy

were calculated: FormRes

1 yes 2 no 77 not applicable

28. Units of measurement for Index test(e.g. MoM, mg/dL): UnMeas

88

29a. Gestational age(s) of patients attime(s) of index test measurement(s):

GestAge

88

66 not reported

29b. Onset ofpre-eclampsia in study

population: OnsetPE

1

< 32 wks2

> 32 wks3

both (1+2)4

other:</> …………wks

66 not reported

30. Prevalence of pre-eclampsia instudy population (%): PrevPE

66 not reported

31. True Positives:TP

32. False Positives:FP

33. False Negatives:FN

34. True Negatives:TN

35a. Measures of statistical uncertaintypresented (e.g. confidence interval):

CIRep

1 yes 2 no


131


35b. State measures of statisticaluncertainty: CIMeas

88

36. If reported, describe data forreproducibility of 2x2 data table: ReprTab

(e.g. mean, median, SD, SE, CI, distribution)

88

37. Correlation coefficients betweentests (state coefficients and tests): CorrCo

88

38. Financial support of industry: Conflict 1 yes 2 no 66 not reported

CENTRAL (The Cochrane Library)1. pregnan2. *pregnancy*ME3. pregnancy-complications*ME4. hypertension*ME5. hypertens*6. blood press*7. ((#1 or #2 or #3) and (#4 or #5 or #6))8. PIH9. toxaemi* near pregnan*10. toxemi* near pregnan*11. pre-eclampsia*ME12. pre-eclamp*13. preeclamp*14. pre next eclamp*15. #7 or #8 or #9 or #1016. #15 or #11 or #12 or #13 or #14

EMBASE (2002 to current)1. randomization/ 2. double blind procedure/ 3. crossover procedure/ 4. intermethod comparison/ 5. single blind procedure/ 6. clinical study/ 7. controlled study/ 8. randomized controlled trial/

9. (clin$ adj2 trial$).tw. 10. ((singl$ or doubl$ or trebl$ or tripl$) adj2

(blind$ or mask$)).tw. 11. exp clinical trial/ 12. placebo/ 13. placebo$.tw. 14. random$.tw. 15. comparison/ 16. drug comparison/ 17. follow up/ 18. evaluation.mp. and follow up/ 19. "evaluation and follow up"/ 20. exp "drug control"/ 21. drug screening/ 22. prospective study/ 23. major clinical study/ 24. (control$ or prospectiv$ or volunteer$).tw. 25. or/1-17 26. or/19-24 27. 25 or 26 28. exp Eclampsia and Pre-eclampsia/29. (pre-eclamp$ or preeclamp$ or pre adj

eclamp$).tw.30. (toxemi$ or toxaemi$) adj3 pregnan$).tw.31. (hypertens$ adj3 pregnan$).tw.32. pih.ti,ab33. 28 or 29 or 30 or 31 or 3234. 33 and 2735. limit 34 to human


133


Appendix 4

Effectiveness reviews generic search strategy


135


Population subgroupsWhenever possible, and relevant, women weregrouped on the basis of their risk status at trialentry as follows.

For normotensive women● High risk: defined as having one or more of the

following: diabetes, renal disease, thrombophilia,autoimmune disease, previous severe or early-onset pre-eclampsia, or multiple pregnancy.

● Moderate risk: defined as none of the above,but having either previous pre-eclampsia thatwas not severe or early onset (or severityunspecified), or a first pregnancy and at leastone of the following: teenager or over 35 yearsage, family history of pre-eclampsia, obesity(BMI � 30), increased sensitivity to angiotensinII, positive roll-over test, abnormal uterineartery Doppler scan.

● Low risk: defined as pregnancy that did notqualify as either high or moderate risk.

● Undefined risk: when the risk was unclear ornot specified.

For hypertensive women, withoutproteinuriaThese women are all at high risk of developingpre-eclampsia. They were classified into twogroups:

● Gestational hypertension: hypertensiondetected for the first time after 20 weeks’gestation, in the absence of proteinuria.

● Chronic hypertension: essential or secondaryhypertension detected prior to pregnancy orbefore 20 weeks’ gestation. Some women withchronic hypertension may have long-standingproteinuria due to their underlying disease.These women were included, as theirproteinuria was not due to pre-eclampsia.

If a trial included women with pre-eclampsia inaddition to those with non-proteinurichypertension (gestational or chronic), wherepossible only the women with non-proteinurichypertension alone were included in the review.Trials that do not report results separately for the

two categories could be included in the review but,if so, were presented as a separate subgroup.

For women with undefined bloodpressureThis category was used for women for whom it wasunclear, or not specified, whether or not they hadhypertension at trial entry.

Cochrane review list of outcomesOutcomes for the woman

1. Pre-eclampsia: defined where possible ashypertension (blood pressure �140 mmHgsystolic or �90 mmHg diastolic) withproteinuria (�300 mg protein in a 24-hoururine collection or �30 mg/dl in a singlesample or �1+ on dipstick or �30 mg/mmolurine protein/creatinine ratio). For a womanwith chronic hypertension and proteinuria attrial entry, pre-eclampsia was defined assudden worsening of proteinuria and/orhypertension, or other signs and symptoms ofpre-eclampsia after 20 weeks’ gestation.

2. Severe hypertension was used as a mainoutcome for reviews which included womenwith hypertension during pregnancy definedwhere possible as blood pressure �160 mmHgsystolic or �110 mmHg diastolic.

3. Death: during pregnancy or up to 42 daysafter end of pregnancy.

4. Severe morbidity: including eclampsia, liveror renal failure, haemolysis, elevated liverenzymes and low platelets syndrome,disseminated intravascular coagulation, strokeand pulmonary oedema. These outcomes werereported individually, and as a compositemeasure where the information was available.

5. Severe pre-eclampsia: there is no widelyaccepted definition of severe pre-eclampsia.The following are generally regarded asfeatures of severe disease: severe hypertension(blood pressure �160 mmHg systolic or 110mmHg diastolic), severe proteinuria [usuallyat least 3 g (range 2–5 g) protein in 24 hours,or >3 on dipstick), reduced urinary volume(<400–500 in 24 hours), neurological

Appendix 5

Cochrane review subgroup categorisation and list of outcomes

disturbances such as headache, visualdisturbances and exaggerated tendon reflexes,upper abdominal pain, pulmonary oedema,impaired liver function tests, high serumcreatinine, low platelets, intrauterine growthrestriction or reduced liquor volume.

6. Early onset of pre-eclampsia: defined wherepossible as pre-eclampsia before 33 completedweeks.

7. Gestational hypertension: defined wherepossible as hypertension (blood pressure�140 mmHg systolic or �90 mmHg diastolic)after 20 weeks’ gestation.

8. Use of antihypertensive drugs or need foradditional antihypertensive drugs.

9. Abruption of the placenta or antepartumhaemorrhage.

10. Elective delivery: induction of labour orCaesarean section.

11. Caesarean section: emergency and elective.12. Postpartum haemorrhage: defined as blood

loss of 500 ml or more.13. Side-effects: any side-effects or adverse events

related to the intervention, interventionstopped due to side-effects.

14. Use of hospital resources: visit to day careunit, antenatal hospital admission, intensivecare (admission to intensive care unit, lengthof stay) ventilation, dialysis.

15. Women’s experiences and views of theinterventions: childbirth experience, physicaland psychological trauma, postnataldepression, breastfeeding, mother–infantinteraction and attachment.

Outcomes for the child1. Death: including all deaths before birth and

up to discharge from hospital.2. Preterm birth: defined as birth before 37

completed weeks’ gestation.3. Small for gestational age: defined as growth

below the third centile, or the lowest centilereported.

4. Death, classified by timing of death:miscarriage (foetal loss up to 19 completedweeks’ gestation or however defined in thestudy), stillbirth (death in utero at or after20 weeks’ gestation), perinatal death (stillbirthor death in the first 7 days of life), neonataldeath (death in the first 28 days after birth),infant death (death in the first year of life).

5. Severity of preterm birth: very preterm birth(before 33 completed weeks) and extremelypreterm birth (before 27 completed weeks).

6. Apgar score at 5 minutes: low (7) and verylow (4) or lowest reported.

7. Endotracheal intubation or use of mechanicalventilation.

8. Neonatal morbidity: respiratory distresssyndrome, chronic lung disease, sepsis,necrotising enterocolitis, retinopathy ofprematurity and intraventricularhaemorrhage.

9. Long-term growth and development:blindness, deafness, seizures, poor growth,neurodevelopmental delay and cerebral palsy.

10. Side-effects associated with the intervention.11. Use of hospital resources: admission to

neonatal intensive care unit, duration ofhospital stay after delivery.

Economic outcomes1. Costs to health service resources: short term

and long term for both mother and baby.2. Costs to the woman, her family, and society

associated with the intervention.

Subgroups investigated inCochrane reviewsThe following subgroup analyses are included inthe generic protocol:

1. By maternal risk of pre-eclampsia at trial entry:women at high risk, moderate risk, low risk orundefined risk. Women with gestationalhypertension and chronic hypertension wereeither analysed as a separate group tonormotensive women or within the high-riskgroup, depending on the focus of theindividual review.

2. By type of hypertension at trial entry:gestational hypertension or chronichypertension. Reviews with trials where resultsfor women with non-proteinuric hypertensionand pre-eclampsia had not been reportedseparately were presented as a separatesubgroup (as discussed above).

3. By gestation at trial entry: before 19 completedweeks, after 19 completed weeks or gestationunclear/not specified.

4. By baseline level of the intervention of interestat trial entry: adequate or inadequate (forexample, low or normal/high calcium intake) orunknown.

5. By type of intervention: type of drug orsupplement.

6. By dosage regimens of intervention: the cut-offfor each subgroup was explained andprespecified.

Appendix 5

136

As not all subgroup analyses were relevant to eachreview, and as multiple analyses increase the riskof being misled by the play of chance, reviewauthors prespecified which subgroups to includein their review. Thus the number of subgroups foreach review was minimised. Only the mainoutcomes listed above were included in thesubgroup analyses.

Details of which subgroup analyses wereconducted for each review are available in thepublished Cochrane reviews. Subgroup analysesprespecified for a review might not have beenconducted if there were insufficient data.

Sensitivity analyses were also conducted, wherenecessary, to explore the effects of trial quality onthe summary statistic as follows:

● excluding trials with clearly inadequateallocation concealment (rated C)

● excluding trials with no intervention for thecontrol group (no placebo)

● excluding quasi-randomised studies.

Details of which sensitivity analyses wereconducted for each review are available in thepublished Cochrane reviews.


137



139


Appendix 6

Comparison between proposed diagnostic and screening tests and treatments for pre-eclampsia to

be systematically reviewed and final systematicreviews completed

TABLE 48 Proposed and final diagnostic and screening tests for pre-eclampsia

Proposed list of diagnostic and Final list of diagnostic and screening tests screening tests systematically reviewed (see Table 3)

History Risk factors, e.g. nulliparity, new partner, (Review available78)hypertension on oral contraceptives, pre-existing diabetes, renal disease, chronic hypertension parity

Examination Blood pressure (systolic and diastolic and mean BMIarterial pressure), peripheral oedema, BMI, waist circumference, hip/waist ratio

InvestigationsBiochemical SUA, urinary calcium excretion, urinary albumin SUA, urinary calcium excretion, urinary

creatinine and calcium creatinine ratios, calcium creatinine ratio, plasma cellular microalbuminuria, FN, spot proteinuria, 24-hour FN, plasma total FN, 24-hour urinary protein, urinary protein levels urinary albumin creatinine ratio,

microalbuminuria, spot proteinuria

Haemodymanic Pressor response to various forms of stimuli, e.g., Uterine artery Dopplersupine ‘roll-over’, isometric exercise, passive tilting, uterine artery Doppler (update existing review)

Haematological Antithrombin III, platelet count, haemoglobin, Haemoglobin, haematocrithaematocrit, fibrinogen

Other tests Thrombomodulin, endothelin-1, plasminogen HCG, AFPactivator inhibitor, free fatty acids, atrial natriuretic peptide, angiotensin II infusion, platelet angiotensin II binding site density, HCG, AFP, fasting insulin levels

Additional tests Serum unconjugated oestriol (uE3)fDNA

Appendix 6

140

TABLE 49 Proposed and final list of treatments for pre-eclampsia

Proposed list of treatments Final list of treatments systematically reviewed (seeTable 4)

Antiplatelet agents for preventing and treating pre-eclampsia Antiplatelet agents for preventing pre-eclampsia

Abdominal decompression for suspected foetal compromise/ –pre-eclampsia

Abdominal decompression in normal pregnancy –

Balanced protein/energy supplementation in pregnancy –

Calcium supplementation during pregnancy for preventing Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems hypertensive disorders and related problems

Magnesium supplementation in pregnancy –

Reduced salt intake compared with normal dietary salt, or Reduced salt intake compared with normal dietary salt, or high intake, in pregnancy high intake, in pregnancy

Routine Doppler ultrasound in pregnancy –

Zinc supplementation in pregnancy –

Ambulatory versus conventional methods for monitoring Ambulatory versus conventional methods for monitoring blood pressure during pregnancy blood pressure during pregnancy

Antenatal oestrogens for preventing adverse foetal outcome –

Fish oil and other prostaglandin precursor supplementation Marine oil and other prostaglandin precursor during pregnancy for reducing pre-eclampsia supplementation during pregnancy for reducing pre-

eclampsia

Vitamins during pregnancy Antioxidants

Bed rest for prevention Bed rest for hypertension in pregnancyRest for preventing pre-eclampsia and its complications inwomen with normal blood pressure

Diet for prevention Energy and protein intake in pregnancy

Dietary advice for preventing pre-eclampsia –

Diuretics for preventing pre-eclampsia Diuretics for preventing pre-eclampsia

Self blood pressure monitoring versus conventional or –ambulatory blood pressure monitoring during pregnancy

Drugs for prevention – normotensive women at risk of Antihypertensiveshypertension/pre-eclampsia

Exercise for prevention of hypertension Exercise for prevention of hypertension

Additional treatments Nitric oxide Garlic Progesterone


141


Appendix 7

Test accuracy tables of methodological and reporting characteristics of included studies

TABLE 50 Methodological and reporting characteristics of studies on BMI

Study Population No. of Incidence Reference standard BMI Age women of PE cut-offCountry (study designa) analysed (%)

Sibai, 1997 IN: healthy nulliparae (CPEP trial). 4,310 7.6 DBP �90 mmHg twice 4–168 h �34EX: medical, obstetric or known apart, proteinuria �0.3 g/24 h �30foetal complications or + dipstick twice or protein/ �26Any age creatinine ratio �0.35 once or <20USA (RCT) ++ dipstick once

Baeten, 2001 IN: singleton pregnancies, nulliparae 96,384 6.8 NR �30Any age �25USA <20

Bianco, 1998 IN: singleton pregnancies, 11,926 3.7 NR �35 age 20–34 years, vs EX: BMI 27–34 19–27USA

Bowers, EX: <37 weeks of delivery, 281 5.0 Rise RR >30/15 mmHg or >291999 multiple pregnancies, pre-existing RR >140/90 mmHg twice 6 h >26

chronic maternal illness apart, proteinuria not specifiedAny age (mean 22.2 years)USA

Knuist, 1998 IN: nulliparae, singleton pregnancies, 2,080 1.4 DBP �90 mmHg twice 4 h apart, >26.0EX: pre-existing disease, obstetric proteinuria ++ dipstick twice <19.8abnormality 4 h apart, no UTIAny ageThe Netherlands

Lee, 2000 EX: chronic hypertension, 29,735 1.4 DBP �90 mmHg twice 4 h apart, >24.2foetal anomalies proteinuria >0.3 g/24 h or <19.829.9 ± 4.1 years >++ dipstick twice 4 h apartTaiwan

Ogunyemi, IN: black, low-income women, 582 7.9 New onset hypertension and >291998 singleton pregnancies, >37 weeks proteinuria >26

Any age <19.8USA

Ros, 1998 IN: nulliparae, age <34 years 2,418 5.4 RR �140/90 mmHg or rise >29Sweden 30/15 mmHg twice 6 h apart, >26

proteinuria + dipstick twice or <19.8�0.3 g/24 h

Sebire, 2001 Unselected population 28,7213 0.9 NR �3028.5 ± 5.2 years �25UK

Steinfeld, IN: singleton pregnancies 2,424 5.3 ACOG criteria �292000 Any age

USA

continued

Appendix 7

142

TABLE 50 Methodological and reporting characteristics of studies on BMI (cont’d)

Study Population No. of Incidence Reference standard BMI Age women of PE cut-offCountry (study designa) analysed (%)

Thadhani, EX: chronic hypertension 15,262 0.5 Baseline SBP <140 and rise of �301999 25–42 years 30 mmHg twice, baseline DBP �25

USA <90 and rise of 15 mmHg twice, <21proteinuria ++ dipstick or �0.3 g/24 h

ACOG, American College of Obstetricians and Gynecologists; CPEP, Calcium for Pre-eclampsia Prevention Trial; DBP,diastolic blood pressure; EX, excluded; IN, included; NR, not reported; PE, pre-eclampsia; SBP, systolic blood pressure;UTI, urinary tract infection.a Studies were cohort designs unless stated otherwise.Primary studies were extracted once and were derived from O’Brien TE, Ray JG, Chan WS. Maternal body mass index andthe risk of pre-eclampsia: a systematic overview. Epidemiology 2003;14:368–74.

TABLE 51 Methodological and reporting characteristics of studies on AFP

Study Population No. of Gestational Incidence Reference standard Index Age women age at test of PE test Country (study designa) analysed (weeks) (%) Cut-off

Morssink, IN: singleton pregnancies 2,008 15–20 2.0 Diastolic rise >15 mmHg; Method 1997 EX: diabetes, structural or Proteinuria �300 mg/24 h; NR

chromosomal anomalies Davey and MacGillivray, 2.5 MoM28 years 1988The Netherlands

Yaron, EX: structural or 60,040 14–22 3.2 SBP �140 mmHg or Competitive 1999 chromosomal anomalies DBP �90 mmHg; RIA (Sanofi

Age NR presence of proteinuria Diagnostics) USA 2.5 MoM

Wenstrom, EX: multiple pregnancies, 4,614 2nd 1.1 NR RIA (Sanofi 1996 foetal malformation or trimester Pasteur)

aneuploidy, AF blood 2.5 MoMcontamination, positive AF acetylcholinesteraseAge NRUSA

Jauniaux, IN: all singleton 41 20–24 26.8 RR �140/90 mmHg FEIA 1996 pregnancies with abnormal persistent; proteinuria (Hybritech)

uterine artery Doppler; �100 mg/l 2.5 MoMpast history of PE (n = 11) Age NRUK

Different cut-off valueLeung, IN: singleton pregnancies 1,015 18.1 ± 1.3 2.1 DBP �90 mmHg 2× 4 h MEIA (IMx 1999 30.8 ± 4.9 years or �110 mmHg 1×; Abbott)

China proteinuria �2+ 2× 4 h 2.0 MoMapart or 300 mg/24 h

Pouta, IN: nulliparas 637 15–19 5.3 RR �140/90 mmHg 2× 6 h Time-1998 EX: multiple pregnancies, apart or rise 30/15 mmHg; resolved FIA

foetal defects proteinuria �300 mg/24 h (Wallac)27.7 ± 4.5 years 2.0 MoMFinland

continued


143


TABLE 51 Methodological and reporting characteristics of studies on AFP (cont’d)

Study Population No. of Gestational Incidence Reference standard Index Age women age at test of PE test Country (study designa) analysed (weeks) (%) Cut-off

Milunsky, EX: multiple pregnancies 13,486 15–20 1.7 NR RIA (Clinical 1989 20–34 years (90%) Assays)

USA 2.0 MoM

Waller, IN: singleton pregnancies 51,008 15–19 1.3 NR EIA (Abbott) 1996 EX: foetal malformations 2.0 MoM

27 years (mean)USA

Capeless, Screening programme 358 16–20 2.0 NR Method NR1992 Age NR 2.0 MoM

USA

Simpson, EX: multiple pregnancies, 650 15–20 1.0 SBP �140 mmHg or EIA 1995 foetal malformations DBP �90 mmHg 2×; (Hybritech

Age NR proteinuria �1+ 2× or Tandem ERA, USA �300 mg/24 h Abbott)

2.0 MoM

Severe PERaty, 1999 Matching of delivery and 1,242 15.9 ± 1.2 0.8 Severe PE: Time

screening databases RR �160/110 mmHg; resolved 26.9 ± 3.6 years proteinuria �5.0 g/l; IFMA Finland oliguria; subjective (Wallac)

symptoms 2.0 MoM

Stamilio, IN: non-smoking, mild PE in 1,998 15–19 2.5 Severe PE: Method NR2000 control group SBP �160 mmHg or 2.0 MoM

EX: multiple pregnancies, DBP �110 mmHg; foetal anomalies proteinuria �3+ or 25.7 ± 0.3 years �5.0 g/24 h USA (oliguria/ symptoms)

AF, amniotic fluid; EIA, enzyme immunoassay; FEIA, fluoroenzyme immunoassay; FIA, fluoroimmunoassay; IFMA, immunofluorescence microassay enzyme immunoassay; MEIA, microenzyme immunoassay; RIA, radioimmunoassay.a All studies were cohort studies, often from foetal screening programmes. Most studies included singleton pregnancies only.

TABLE 52 Methodological and reporting characteristics of studies on cellular and total fibronectin

Study Population No. of Gestational Incidence Reference standard Index test Age women age at test of PE Cut-offCountry (study design) analyseda (trimester) (%) (�g/ml)

Chavarria, IN: normotensive and non- 78 2nd 33.3 RR �140/90 mmHg or ED-B 2002 proteinuric <20 weeks rise of SBP 30 and/or (EIA, Adeza

EX: IDDM, CTD, APLS, SLE, DBP 15 mmHg, 2× 6 h Biomedical)miscarriages, multiple apart; proteinuria 2.7; 3.6; 4.5pregnancies, essential >0.3 g/24 h or hypertension, aspirin therapy, >1+ dipstick and gest/transient hypertension, oedema >1+ after gest. DM, oligohydramnion, bedreststillbirth, preterm delivery28.2 ± 5.7 yearsMexico (nested matched case–control)

continued

Appendix 7

144

TABLE 52 Methodological and reporting characteristics of studies on cellular and total fibronectin (cont’d)

Study Population No. of Gestational Incidence Reference standard Index test Age women age at test of PE Cut-offCountry (study design) analyseda (trimester) (%) (�g/ml)

Lockwood, IN: singleton pregnancies, 14* 1st 45.6 RR 140/90 mmHg, ED 1+ 1990 normotensive <20 weeks rise of SBP 30 or (dual ELISA)

EX: IDDM, CH, abruptio DBP 15 mmHg; 2.8; 3.2; 4.0placentae and infections, proteinuria 1 g/l; history of previous PE 2× > 6 h apartMean 20.2 yearsUSA (nested matched case–control)

43** 2nd ED 1+3.2; 4.2; 5.8

Total FNLockwood, IN: singleton pregnancies, 14* 1st Total FN 1990 normotensive <20 weeks (dual ELISA)

EX: IDDM, CH, abruptio 347; 370; placentae and infections, 393; 415history of previous PEMean 20.2 yearsUSA (nested matched case–control)

43** 2nd Total FN230; 350;380; 400

Soltan, IN: normotensive and 88 14–24 weeks 19.3 Rise of SBP �30 mmHg Total FN 1996 non-proteinuric <20 weeks or DBP �15 mmHg (immuno-

gestation proteinuria �0.3 g/24 h diffusion EX: IDDM, CTD, history of (oedema) technique)cardiovascular or renal 293disease, aspirin therapy, antiprostaglandins, calcium, albuminuria, ‘any abnormality’ (e.g. congenital malformations).20.3 ± 2.6 yearsEgypt (cohort)

Paarlberg, IN: singleton pregnancies, 228* 1st 11.4 Rise of DBP �15 mmHg Total FN1998 nulliparous, normotensive and/or antenatal DBP (nephelo

<20 weeks �90 mmHg in previously metric assay, EX: GH, DM, CTD, normotensive woman; Beckman age <18 years; miscarriage proteinuria >0.3 g/24 h Array <16 weeks; treatment; Crohn; (ACOG) Immuno-idiopathic hyperglobulinuria; chemical myomata uteri; uterine System)anomaly; sickle cell anaemia; 240trisomy-21 infant; twin pregnancy; congenital abnormalities30.8 ± 0.4 yearsThe Netherlands (cohort)

228* 2nd Total FN 230

APLS, antiphospholipid syndrome; CH, chronic hypertension; CTD, connective tissue disease; DM, diabetes mellitus; ELISA,enzyme-linked immunosorbent assay; GH, gestational hypertension; IDDM, insulin-dependent diabetes mellitus; SLE, systemic lupus erythematosis.a * and ** indicate the same patients within individual study.


145


TABLE 53 Methodological and reporting characteristics of studies on fDNA

Study Population No. of Gestational Incidence Reference standard Index test Age women age at test of PE Cut-offCountry (study designa) analysed (weeks) (%)

Cotter, IN: normotensive non- 264 15.7 ± 3.6 NR RR �140/90 mmHg; fDNA2004 proteinuric women, proteinuria �0.3 g/24 h Real-time PCR

male foetuses or 1+/2+ dipstick TaqMan SRYEX: aneuploid foetuses26.1 ± 5.9 years (20/88 severe PE cases) <10,000 Ireland (nested and copies/mlmatched) <50,000

>50,000

Farina, IN: normotensive women 36 20.4 ± 2.1 18.7 SBP �140 mmHg 2× or Cell free fDNA2004 Median 32 (PE) vs 29.5 DBP �90 mmHg 2×; Real-time PCR

(controls) years proteinuria �0.3 g/24 h DYS14Japan (nested in cohort of 5; 10; 15; 209 controls and 48 PE) 20% FPR

Leung, IN: singleton pregnancies, 51 11–22 NR DBP �90 mmHg 2× fDNA2001 male foetuses �4 h apart or DBP Real-time PCR

Age NR �110 mmHg; TaqMan SRYHong Kong (nested and proteinuria �0.3 g/24 h �33.5 Geq/mlmatched) or 2+ dipstick 2× �4 h

apart

PCR, polymerase chain reaction.a Studies were case–control studies.

TABLE 54 Methodological and reporting characteristics of studies on haemoglobin/haematocrit


Goh, 1991 IN: singleton live 546 26 7.0 DBP �90 mmHg twice Haematocritdeliveries in nulliparas proteinuria �1+ dipstickAge NR >34%Australia �41%

Heilmann, EX: tocolysis, 707 14–30 5.4 Hypertension with Haemoglobin1993 haemodilution, multiple proteinuria, not

pregnancies quantified �13 g/dl28 ± 5.7 yearsGermany

a All studies are cohort studies.

Appendix 7

146

TABLE 55 Methodological and reporting characteristics of studies on HCG


Yaron, EX: structural or 45,565 14–22 3.0 SBP �140 mmHg or �-HCG 1999 chromosomal anomalies DBP �90 mmHg; IRMA

Age NR presence of proteinuria 2.5 MoMUSA

Morssink, IN: singleton pregnancies 2,008 15–20 2.0 Diastolic rise >15 mmHg; HCG1997 EX: diabetes, structural or proteinuria �300 mg/24 h; Method NR

chromosomal anomalies Davey and MacGillivray, 2.5 MoM28 years 1988The Netherlands

Lambert- IN: singleton pregnancies 359 15–21 16.7 RR >140/90 mmHg; Total HCG Messerlian, EX: chronic hypertension, proteinuria >300 mg/24 h (Serono MAIO 2000 diabetes or �2+ dipstick Clone)

26.9 ± 7.3 years 2.3 MoMUSA (case–control)

Heinonen, EX: multiple gestation, 5,290 15 4.6 NR Total �-HCG 1996 pregnancy loss <24 weeks, (IMx Abbott)

foetal chromosomal 2.0 MoMabnormalities, structural malformationsAge <18 years (n = 30), 18–35 years (n = 4698). >35 years (n = 562)Finland

Lee,b 2000 IN: singleton deliveries 1,052 15–20 9.0 RR �140/90 mmHg �-HCG MEIA >24 weeks’ gestation 2× 6 h apart; (Abbott) 28.7 ± 4.2 years proteinuria �1+ dipstick 2.0 MoMTaiwan (case–control)

Aquilina, EX: multiple pregnancy, 640 15–19 5.5 DBP �90 mmHg 2× 4 h Free �-HCG 2000 diabetic pregnancies, apart or DBP �110 mmHg; Sandwich

hypertension <20 weeks, proteinuria >300 mg/24 h magnetic chromosomal or structural or �2+ dipstick 2× 4 h ELISA abnormality apart 2.3 MoMAge NRUK

Muller, IN: normotensive, PIH, 5,776 15–18 0.6 SBP �140 mmHg or DBP HCG1996 SGA neonates �90 mmHg 2× 10 min EIA (SFRI)

Age NR rest; proteinuria >300 mg/l 2.0 MoMFrance

Ashour, IN: singleton pregnancies 6,138 15–22 3.2 SBP �140 mmHg or DBP �-HCG 1997 EX: foetal/chromosomal �90 mmHg 2× 6 h apart; (IMx Abbott)

abnormalities, diabetes, proteinuria >300 mg/24 h 2.0 MoMchronic hypertension or �1+ dipstick 2× 6 h 28.1 ± 5.3 years apartUSA

Luckas, IN: primigravidas 430 15–18 4.4 Gestational/chronic RIA 1998 EX: multiple pregnancies, hypertension; proteinuria (Amerlex-M)

essential hypertension, �300 mg/24 h or �2+ 2.0 MoMdiabetes, foetal abnormality dipstick or with HELLP;Age NR Davey and MacGillivray, UK 1988

continued


147


TABLE 55 Methodological and reporting characteristics of studies on HCG (cont’d)


Onderoglu, IN: non-diabetic, singleton 562 15–20 2.7 RR rise 30/15 mmHg over HCG1997 pregnancies 1st trimester values or (Kodak)

EX: MSAFP > 2.0 MoM persistent RR 2.0 MoM30.1 ± 5.2 years �140/90 mmHg; Turkey proteinuria �500 mg/l

Vaillant, EX: multiple pregnancies, 434 14–20 3.7 DBP �90 mmHg 2× 4 h �-HCG 1996 Down syndrome, IVF apart or DBP �110 mmHg EIA

29 ± 5 years > 22 weeks; proteinuria 41,000 IUFrance >300 mg/24 h or �2+

dipstick

Pouta, IN: nulliparas 637 15–19 4.7 RR �140/90 mmHg 2× 6 h �-HCG 1998 EX: multiple pregnancies, apart or rise 30/15 mmHg; FIA (Delfia

foetal defects proteinuria �300 mg/24 h Wallac)27.7 ± 4.5 years 2.0 MoMFinland

Jauniaux, IN: all singleton 41 20–24 26.8 �140/90 mmHg Free �-HCG1996 pregnancies with abnormal persistent; �100 mg/l IRMA

uterine artery Doppler; (BioMerieux)past history of PE 2.5 MoMAge NRUK

Early testHaddad, IN: singleton IVF 180 4–7 1.7 DBP >90 mmHg 2× 4 h HCG1999 pregnancies apart; proteinuria (Amerlite

33.6 ± 4.2 years �300 mg/24 h or �2+ HCG60)France dipstick 4 h apart 90th centile

Yaron, IN: singleton pregnancies 1,622 10–13 1.7 DBP �110 mmHg 1× or Free �-HCG 2002 EX: chromosome �90 mmHg 2× 4 h apart FIA (Delfia

aberrations, foetal anomalies (no history of pre-existing Wallac)30.4 ± 4.3 years hypertension or renal 2.0 MoMIsrael disease); proteinuria

>300 mg/24 h or >1+ dipstick

Severe PELee,b 2000 IN: singleton deliveries 1,052 15–20 5.3 Severe PE: �-HCG MEIA

>24 weeks’ gestation; SBP �160 mmHg or (Abbott) 28.7 ± 4.2 years DBP �110 mmHg 2× 6 h 2.0 MoMTaiwan (case–control) apart; proteinuria �3+

dipstick; oliguria <400 ml/24 h

Stamilio, IN: non-smoking, mild PE 1,998 15–19 2.5 Severe PE: HCG2000 in control group SBP �160 mmHg or Method NR

EX: multiple pregnancies, DBP �110 mmHg; 2.0 MoMfoetal anomalies proteinuria �3+ or 25.7 ± 0.3 years �5.0 g/24 h; USA (oliguria/symptoms)

IVF, in vitro fertilisation; MSAFP, maternal serum AFP; PIH, pregnancy-induced hypertension; SGA, small for gestational age.a Studies were cohort studies unless stated otherwise, mostly from foetal screening programmes. Most studies included

singleton pregnancies only. b One reference reporting on different outcomes.

Appendix 7

148

TABLE 56 Methodological and reporting characteristics of studies on oestriol


Yaron, 1999 Unselected 24,504 14–22 3.2 SBP �140 mmHg or RIA (Sanofi Age: NR DBP �90 mmHg; Diagnostics)USA presence of proteinuria 0.5 MoM

Kowalczyk, EX: patients with HCG or 309 15–21 4.2 SBP �140 mmHg or RIA 1998 AFP levels �2.0 MoM, DBP �90 mmHg; (Diagnostic

�35 years, multiple proteinuria �0.3 g/24 h Systems Lab.) pregnancies; or haemolysis, elevated 0.75 MoMAge: median 22 years liver enzymes, low (test-positives); 23 years platelets(test-negatives) USA

Severe PEStamilio, EX: multiple pregnancies 1,998 15–19 2.5 Severe PE: NR; 2000 and foetal anomalies; SBP �160 mmHg or 0.9 MoM

Age: 25.7 ± 0.3 years DBP �110 mmHg; USA proteinuria �3+ or

�5.0 g/24 h (and/or oliguria/subjective symptoms)

a All studies were cohort studies.

TABLE 57 Methodological and reporting characteristics of studies on serum uric acid


Jauniaux, IN: all singleton 41 20–24 26.8 SBP >140/90 mmHg; Enzymatic 1996 pregnancies with proteinuria �100 mg/l (uricase)

abnormal uterine artery 0.24 mmol/lDoppler; past history of PE (n = 11) Age NRUK

Salako, Source: normotensive 21 <20 23.8 SBP �140/90 mmHg; Alkaline 2003 primigravidae proteinuria >300 mg/l phosphotung

EX: history of chronic (1+ dipstick) state method hypertension, DM, (sodium renal disease, collagen carbonate)vascular disease 0.21 mmol/lAge 28.0 ± 3.6 yearsNigeria

Conde- Source: nulliparous women 387 20 3.4 SBP �140 mmHg or Enzymatic Agudelo, EX: DM; renal disease; DBP �90 mmHg; (uricase)1994 essential hypertension; proteinuria �300 mg/l 0.23 mmol/l

proteinuria <20 weeks; other chronic diseasesControl group in analysis: healthy (n = 335) + GH (n = 39)23.8 ± 5.7 yearsArgentina

continued


149


TABLE 57 Methodological and reporting characteristics of studies on serum uric acid (cont’d)


Winocour, Source: IDDM 22 2nd trimester 40.9 MAP >106 mmHg from Multichannel 1989 Median 25 years (range 3 recordings, confirmed analyser

18–44) on 3 separate occasions; 0.24 mmol/lUK proteinuria >300 mg/24 h;

oedema

Different type of cut-off valueJacobson, Source: essential 43 24 9.3 DBP �90 + rise of Method NR1990 hypertension; history of PE; 25 mmHg in previously Rise

DM; renal disease; history normotensive women or �0.05 mmol/l of IUGR/stillbirth/abruption; DBP rise of 15 mmHg above baselineother high-risk subjects in chronic hypertensive Control group in analysis: women; hyperuricaemia or healthy + GH (n = 7) + proteinuria �500 mg/24 hIUGR (n = 8) Age NRUK

GH, gestational hypertension; IUGR, intrauterine growth restriction; MAP, mean arterial pressure.a All studies were cohort studies.

TABLE 58 Methodological and reporting characteristics of studies on urinary calcium excretion


Sanchez- IN: normotensive nulliparas 99 10–24 8.1 RR �140/90 mmHg Colorimetric/Ramos, EX: diabetes mellitus, twice �6 h apart or colorimetric 1991 renal disease, chronic rise SBP �30 mmHg autoanalyser

hypertension, other chronic or DBP �15 mmHg; 195 mg/24 hmedical illnesses proteinuria �0.3 g/24 h 18.7 ± 0.5 years or �1+ dipstickUSA

Nisell, IN: hypertensive women 37 11–13 29.7 RR �140/90 mmHg NR1996 33.1 ± 1.7 years proteinuria �0.3 g/24 h 195 mg/24 h

Sweden37 19–21

Baker, IN: normotensive nulliparas 500 18–19 2.6 DBP �90 mmHg twice Perspective 1994 EX: renal disease, chronic �4 h apart; analyser

hypertension proteinuria �0.3 g/24 h (colorimetric)/Median 27 years Monarch (range 24–31) centrifugal UK analyser (kinetic)

NR

Suarez, IN: primigravidas <25 years 69 17–20 21.7 Presence of gestational Colorimetric 1996 EX: malnutrition, chronic hypertension; (cresolphthalein)/

hypertension, renal disease, proteinuria �0.3 g/24 h spectrophoDM or 0.03 g/dl on dipstick tometry19.6 ± 2.8 years and/or hyperuricaemia 192 mg/24 hPeru �5.5 mg/dl


Appendix 7

150

TABLE 59 Methodological and reporting characteristics of studies on urinary calcium/creatinine ratio

Study Population No. of Gestational Incidence Reference standard Index test Age women age at test of PE Cut-off (ratio)Country (study designa) analysed (weeks) (%)

Soltan, IN: healthy normotensive 88 14–24 19.3 Rise of SBP �30 mmHg NR1996 primigravidas or DBP �15 mmHg; NR

EX: cardiovascular or proteinuria �0.3 g/24 h renal diseases (oedema)20.3 ± 2.6 yearsEgypt

Rogers, IN: normotensive 199 18–26 4.0 RR �140/90 mmHg Cresolphthalein 1994 primigravidas, singleton � twice; proteinuria method

pregnancies �0.3 g/l (American EX: congenital Monitor)/malformations Beckman Astra-8 27.1 ± 3.8 years analyserHong Kong 0.3

Conde, IN: normotensive 387 20 3.4 SBP �140 or DBP Colorimetric 1994 nulliparas, singleton �90 mmHg twice (direct)/picrato

pregnancies �6 h apart; alcalino methodEX: DM, renal disease, proteinuria �0.3 g/l 0.07proteinuria, chronic hypertension, other chronic medical illnesses23.8 ± 5.7 yearsArgentina

Kazerooni, IN: nulliparas (18–35 years) 102 20–24 7.8 RR �140/90 mmHg or NR2003 EX: renal disease, DM, rise SBP �30 mmHg or 0.229

proteinuria, chronic DBP �15 mmHg twice (mg/dl:mg/dl)hypertension, other chronic �6 h apart; medical illnesses proteinuria �0.3 g/24 h 22.8 ± 4.5 years or �1+ dipstickIran

Suarez, IN: primigravidas <25 years 69 17–20 21.7 Presence of gestational Colorimetric 1996 EX: malnutrition, chronic hypertension; (cresolphthalein)/

hypertension, renal disease, proteinuria �0.3 g/24 h spectrophoDM or 0.03 g/dl on dipstick tometry19.6 ± 2.8 years and/or hyperuricaemia 0.24 mg/mgPeru �5.5 mg/dl

Baker, 1994 IN: normotensive nulliparas 500 18–19 2.6 DBP �90 mmHg twice Perspective EX: renal disease, chronic �4 h apart; analyser hypertension proteinuria �0.3 g/ 24 h (colorimetric)/Median 27 years Monarch (range 24–31) centrifugal UK analyser (kinetic)

NR



151


TABLE 60 Methodological and reporting characteristics of studies on proteinuria

Study Population No. of Gestational Incidence Reference standard Proteinuria Age women age at test of PE cut-off Country (study designa) analysed (weeks) (%)

Total proteinuriaSibai 2, IN: pregestational diabetes 462 9.6 ± 4.1 NA Development of �300 mg/24 h2000 and singleton pregnancy hypertension (either

25.9 years SBP �140 mmHg or (SD 6.0 years) DBP �90 mmHg on USA (RCT) �2 occasions �4 h

apart, mercury sphygmomanometer, seated 5th Korotkoff sound) plus one of proteinuria (300 mg/24 h or 2+ twice, recorded �4 h apart with no evidence of UTI), thrombocytopenia <100,000 cells/mm3) or pulmonary oedema

Combs, Case. Pregestational 311 <20 NA Either baseline MAP �300 mg/day 1993 diabetes, no UTI, creatinine (SBP + [2× DBP]/3)

excretion rate at least >105 mmHg on �2 10 mg/kg/day, pregnancy occasions or an increase beyond 20 weeks. in MAP of 20 mmHg Hypertension not excluded above baseline (BP taken Cont. no chronic in sitting or lateral hypertension decubitus position) plus 30.3 years (SD 5.4 years) proteinuria of for 113 participants, �300 mg/day 26.2 years (SD 5.0 years) for 198 participantsUSA (case–control)

Sibai 1, IN: singleton pregnancies 763 13–26 NA SBP �140 mmHg, DBP �300 mg/24 h1998 with chronic hypertension �90 mmHg, (mercury

EX: diabetes sphygmomanometer, 26.8% below 25 years, seated, 5th Korotkoff 27.9% between 26 and sound) on �2 occasions 30 years, 45.2% above �4 h apart plus proteinuria 30 years of �300 mg/24 h. Where USA (RCT) baseline proteinuria, PE

defined as either raised serum alanine aminotransferase (>70 U/l) or worsening hypertension (DBP �110 mmHg on �2 occasions �4 h apart no more than 1 week before delivery if hypertensive treatment, plus one of increasing proteinuria, persistent severe headaches or epigastric pain

continued

Appendix 7

152

TABLE 60 Methodological and reporting characteristics of studies on proteinuria (cont’d)


Delmis, IN: pregnant women with 692 1st trimester 27.9 SBP �140 mmHg, DBP �0.5 g/l1993 or without chronic �90 mmHg, or increase

hypertension. in SBP of 30 mmHg, DBP Hypertensives 29.2 years 15 mmHg, plus (SD 5.4). proteinuria �0.5 g/lControl 26.9 (SD 4.8)Croatia

Total albuminuriaEkbom 2, IN: pregestational diabetes 65 <14 12.3 SBP �140 mmHg, DBP >30 mg/24 h1999 (white ethnicity), before �90 mmHg and

17 weeks gestation proteinuria �0.3 g/24 hEX: hypertension, diabetic nephropathy, abortions 33 years (SD 5 years) for 8 PE participants30 years (SD 5 years) for 57 normal BP participantsDenmark

Winocour, IN: Diabetic pregnant 23 2nd trimester 39.1 Mean BP >106 mmHg 0.3 g/24 h1989 women. (supine, resting, left

25 years (range 18–44) lateral, mercury UK sphygmomanometer,

average of at least three recordings); proteinuria >0.3 g/24 h with oedema

Microalbuminuria Gonzalez, IN: singleton pregnancies 102 16–18 28.4 Diagnosis of PE according >20 mg/l2003 who all had risk factors for to criteria of ‘la Norma

PE Instritucional del IMSS’. EX: diabetes, renal disease, SBP �140 mmHg or rise collagenopathies, UTI, of 30 mmHg, DBP multiple pregnancy �90 mmHg or rise of 26 years 15 mmHg and proteinuria Spain >300 mg/l

Soltan, IN: primigravid women 88 14–24 19.3 SBP increased by 300 mg/24 h1996 EX: cardiovascular disease, 30 mmHg, DBP by

renal disease, gestational 15 mmHg, proteinuria age 14–24 years, >300 mg/24 h or BP >140/90 mmHg generalised oedema plus 19.8 years (SD 1.6) for 17 one or both BP increase with PE, 20.4 (SD 2.8) for or proteinuria71 non-PEEgypt

Microalbuminuria/creatinine ratioMasse, IN: nulliparous women. 1422 8–14 7.1 ACOG criteria (include 0.39 mmg/1993 EX: diabetes, cardiovascular 15–24 oedema) (BP seated, mmol

disease, chronic right arm, by Dinamap hypertension, renal disease, oscillometric more than 20 weeks sphygmomanometer); pregnant proteinuria >300 mg/24 h 25.5 years (SD 4.3) for 109 PE, 26.2 (SD 4.2) for 1116 non-PECanada

continued


153


TABLE 60 Methodological and reporting characteristics of studies on proteinuria (cont’d)


KallikreinMillar, 1996 IN: healthy, normotensive, 307 16–20 3.9 DBP >90 mmHg or IUK:Cr ratio of

normal renal function increase of 25 mmHg; 170EX: DM, taking drugs proteinuria >1+ on 25.6 years (SD 6.3) dipstickUK (cross-sectional)

SDS-PAGE proteinsWinkler, IN: asymptomatic 153 12–34 19.0 SBP >140 mmHg, DBP Cut-off not 1988 EX: hypertension, diabetes, >90 mmHg and specified

renal disease, SLE, proteinuria >0.3 g/24 hantiphospholipid syndromeAge not givenGermany

IUK, inactive urinary kallikrein; NA, not applicable.a All studies were cohort designs unless otherwise stated.

TABLE 61 Methodological and reporting characteristics of studies on Doppler any/unilateral notching

Study Population No. of Gestational Incidence Reference standard Cut-off Age women age at test of PE Index test Country (study designa) analysed (weeks) (%)

Geipel, IN: dichorionic twins 256 18–24 8.6 RR �140/90 mmHg Any notch 2002 EX: foetal malformation, repeated; (twin)

PPROM, unclear proteinuria �0.3 g/24 h CDchorionicity31.5 ± 4.2 yearsGermany

Geipel, IN: ICSI patients and 50 18–24 4.0 RR �140/90 mmHg CD2001 controls (low risk), twin repeated;

pregnancies proteinuria �0.5 g/24 h32.5 yearsGermany

IN: ICSI patients and 14 18–24 7.1controls (high risk), twin pregnancies: CH, DM, adiposity (BMI > 27), nulliparae �35 years; multiparae with history of IUGR, PE, placental abruption, IUD

Venkat- IN: recurrent miscarriage 164 16–18 9.8 RR �140/90 mmHg twice Any notch raman, and positive APL antibodies >4 h apart or DBP CD2001 (no SLE or thromboembolic 22–24 �110 mmHg once;

disease) proteinuria �0.3 g/24 h33 (21–43) yearsb

UK

continued

Appendix 7

154

TABLE 61 Methodological and reporting characteristics of studies on Doppler any/unilateral notching (cont’d)


Antsaklis, IN: all nulliparae 675 19–21 3.1 RR �140/90 mmHg twice Any notch 2000 EX: multiple pregnancies, 6 h apart; Unilateral

cardiovascular or renal 24 proteinuria �0.3 g/24 h notch disease, DM, foetal CD + PWabnormalitiesAge NR Greece

Aardema, IN: singleton pregnancies, 94 21–22 7.5 DBP �90 mmHg twice; Any notch2000 history of hypertensive proteinuria ++ dipstick CD + PW

disorders in previous pregnancy, no current pathology 31 (21–42) yearsb

The Netherlands

Ohkuchi, IN: unselected women 288 16–23.9 3.1 DBP �90 mmHg twice Any notch2000 with singleton pregnancies >4 h apart; proteinuria CD + PW

(healthy) �0.3 g/24 h or ++ dipstick28.7 ± 4.0 yearsJapan

Frusca, IN: chronic hypertension 78 24–25 3.9 Superimposed PE: Any notch1998 EX: multiple pregnancies, aggravated hypertension CD + PW

foetal anomalies (rise DBP >15 mmHg) Age NR and proteinuria >0.3 g/24 hItaly

Harrington, IN: singleton pregnancies, 626 12–16 4.8 SBP �140 or DBP Any notch1997 unselected �90 mmHg; proteinuria CD + PW

15–49 years >0.3 g/24 hUK

Harrington, EX: multiple pregnancies, 1204 18–21 3.7 Rise of RR �30/25 mmHg Unilateral 1996 foetal abnormalities, PE twice 4 h apart or DBP notch

and/or IUGR at 24 weeks �110 mmHg; proteinuria CD + PWAge NR >0.5 g/24 h UK

Konchak, IN: MSAFP >2.0 MoM 103 17–22 5.8 Not specified Unilateral 1995 twice or >2.5 MoM once, notch

singleton pregnancies, CD + PWno foetal anomaly, normal amniotic fluid volume27.1 ± 5.1 yearsUSA

Bower, Unselected 2058 18–22 2.2 Mild PE: rise RR Unilateral 1993 Age NR <30/25 mmHg; notch

UK proteinuria + CW + CDModerate PE: rise RR <30/25 mmHg; proteinuria ++ Severe PE: DBP �110 mmHg and rise �30/25 mmHg; proteinuria � ++ or �0.5 g/24 h

2026 24 2.2

continued


155




Phupong, IN: healthy nulli- and 322 22–28 5.9 RR >140/90 mmHg twice Any notch2003 multiparae 6 h apart; proteinuria CD + PW

EX: multiple pregnancies, �0.3 g/24 h or + dipstickrenal and cardiovascular (Severe PE: DBP disease, DM, foetal �110 mmHg, proteinuria anomalies 5.0 g/24 h or +++ dipstick)26.4 ± 4.8 yearsThailand

Marchesoni, Unselected women 900 20, 24 2.9 RR >140/90 mmHg; Any notch 2003 31.7 ± 5.3 years proteinuria >0.3 g/24 h CD

Italy

Frusca, IN: previous history of PE, 56 24 5.4 DBP �90 mmHg twice 4 h Any notch1996 normal blood pressure apart in 3rd trimester; CD + PW

after that pregnancy proteinuria >0.3 g/24 h; Age NR no UTIItaly

Coleman, IN: essential and secondary 116 22–24 27.6 RR �140/90 mmHg with Any notch1993 hypertension, renal disease, rise of DBP 15 mmHg twice CD

SLE, APL syndrome, >4 h apart; proteinuria previous PE or placental �0.3 g/24 h or ++ dipstick, abruption Superimposed PE: RR EX: multiple pregnancies, >140 mmHg with rise of foetal abnormalities �30/15 mmHg with new 31 (19-43) yearsb proteinuria or doubling of New Zealand existing proteinuria

Prefumo, IN: all singleton live births 4149 18–23 0.4 RR >140/90 mmHg; Any notch2004 from clinical database proteinuria �0.3 g/24 h or CD + PW

EX: foetal abnormalities + dipstick twice 29.4 ± 5.9 years UK

Carbillon, Routine ultrasound 243 12–14 4.9 RR �140/90 mmHg twice Any notch 2004 screening 4 h apart; proteinuria NR

29.6 ± 6.2 years �0.3 g/24 h or + dipstickFrance

Axt- IN: singleton pregnancies 52 19–26 7.7 RR >140/90 mmHg; Any notchFliedner, with history of PET, IUGR, proteinuria �0.3 g/24 h; CD2005 IUD, placental abruption no UTI

32.8 (23–46) yearsb

Germany

Audibert, IN: AFP + HCG testing at 2615 18–26 2.0 SBP �140 or DBP Unilateral 2005 14–18 weeks and �90 mmHg twice; notch

ultrasound screening proteinuria >0.3 g/24 h NR10–14 weeks or ++ dipstickEX: women with raised NT, delivery <24 weeks30.9 ± 4.5 years France

continued

Appendix 7

156



Schwarze, EX: essential hypertension, 215 19–22 4.7 RR >140/90 mmHg; Any notch2005 DM, autoimmune proteinuria �0.3 g/24 h; CD

disorders, history of PE, no UTIIUGR, IUD, placental abruption; multiple pregnancies, foetal anomalies31.4 (17–46) years Germany

131 23–26 4.6

APL, antiphospholipid syndrome; CD, colour Doppler; CW, continuous wave; ICSI, intracytoplasmic sperm injection; IUD, intra-uterine device; NT, nuchal translucency; PPROM, premature prelabour rupture of membranes; PW, pulsed wave. a All studies were cohort designs. b Median age.

TABLE 62 Methodological and reporting characteristics of studies on Doppler bilateral notching

Study Population No. of Gestational Incidence Reference standard Index test Age women age at test of PE Country (study designa) analysed (weeks) (%)

Zimmerman, IN: family or personal 55 22–24 10.9 RR �145/85 mmHg CD + PW1997 history of PE, CH, IUGR and dipstick testing Aloka SSD

or IUD not specified on �2 65028.1 ± 3.8 years occasions 24 h apartFinland

Geipel, 2002 IN: dichorionic twins 256 18–24 8.6 RR �140/90 mmHg ATL HDI EX: foetal malformation, repeated; proteinuria 5000, PPROM, unclear �0.3 g/24 h Acuson 128 chorionicity XP 1031.5 ± 4.2 yearsGermany

Yu, 2002 IN: twin pregnancies, 351 22–24 6.0 DBP �90 mmHg CD + PW2 live foetuses, no foetal twice >4 h apart; transvaginalabnormality, no TTS proteinuria �0.3 g/24 h 31.7 (18–46) yearsb or �2+ dipstick twice UK if no 24-h collection

available

Papageorghiou, IN: singleton pregnancies, 7851 22–24 1.4 DBP �90 mmHg twice CD + PW, 2001 routine antenatal care >4 h apart; proteinuria transvaginal

EX: foetal abnormalities �0.3 g/24 h or �2+ Acuson 29.7 (16–47) years dipstick twice if no 24-h SP-10, Aloka UK collection available 5000, Aloka

17000, ATLHDI 3000,ATL HDI3500,Hitachi,Toshiba,Siemens

continued


157


TABLE 62 Methodological and reporting characteristics of studies on Doppler bilateral notching (cont’d)


Venkat-Raman, IN: recurrent miscarriage 164 16–18 9.8 RR �140/90 mmHg CD2001 and positive APL twice >4 h apart or Acuson 128

antibodies (no SLE or single DBP XP 10thromboembolic disease) �110 mmHg; 33 (21–43) yearsb proteinuria �0.3 g/24 hUK

22–24

Antsaklis, 2000 IN: nulliparae 675 19–21 3.1 RR �140/90 mmHg CD + PWEX: multiple pregnancies, twice 6 h apart; Ultramark renal and cardiovascular proteinuria �0.3 g/24 h 9 HDIdisease, DM, foetal abnormalitiesAge NRGreece

24

Ohkuchi, 2000 IN: singleton pregnancies 288 16–23.9 3.1 DBP �90 mmHg twice CD + PW(healthy) >4 h apart; proteinuria EUB 165A28.7 ± 4.0 years �0.3 g/24 h or ++ Japan dipstick

Albaiges, 2000 IN: singleton pregnancies, 1757 22–25 3.7 RR �140/90 mmHg CD + PWroutine antenatal care twice >2 h apart; Acuson 30 (18–44) yearsb proteinuria �0.3 g/24 h Aspen or UK or dipstick 0.3 g/l Aloka SSD

1700

Mires, 1998 All women with singleton 6579 18–20 5.5 ICD 9 classification CDpregnancies eligible Acuson 15–49 years XP 10Scotland

18–20 and22–24

Kurdi, 1998 EX: multiple pregnancies, 946 19–21 2.2 Baseline DBP CDfoetal anomalies, women <90 mmHg and rise of Acuson 128 already on low-dose aspirin 25 mmHg, baseline Age NR DBP �90 mmHg and UK rise of 15 mmHg;

proteinuria �1+; no UTI

Frusca, 1998 IN: chronic hypertension 78 24–25 3.9 Superimposed PE: CD + PWEX: multiple pregnancies, aggravated hypertension Toshiba SSH foetal anomalies (rise DBP >15 mmHg) 140AAge NR and proteinuria Italy >0.3 g/24 h

Harrington, IN: singleton pregnancies, 626 12–16 4.8 SBP �140 or DBP CD + PW, 1997 unselected �90 mmHg; transvaginal

15–49 years proteinuria >0.3 g/24 h Acuson 128UK

Harrington, EX: multiple pregnancies, 1204 18–21 3.7 Rise RR �30/25 mmHg CD + PW1996 foetal abnormalities, PE or twice 4 h apart or DBP Acuson 128

IUGR <24 weeks �110 mmHg; Age NR proteinuria 0.5 g/24 hUK

Marchesoni, Unselected women 900 (20) 2.9 RR >140/90 mmHg; CD2003 31.7 ± 5.3 years 24 proteinuria >0.3 g/24 h Acuson

UK Sequoia

continued

Appendix 7

158

TABLE 62 Methodological and reporting characteristics of studies on Doppler bilateral notching (cont’d)


Uludag, 2002 IN: non-smokers 80 18–20 12.5 RR >140/90 mmHg CD + PWEX: DM, foetal anomalies, >24 weeks ± HDL 3000multiple pregnancies proteinuria >0.3 g/24 h30.8 ± 6.1 yearsTurkey

Coleman, 1993 IN: essential and secondary 116 22–24 27.6 RR �140/90 mmHg CDhypertension, renal disease, and rise of DBP Toshiba 270 SLE, APLS, previous PE or 15 mmHg twice >4 h or Diasonicsplacental abruption apart; proteinuria EX: multiple pregnancies, �0.3 g/24 h or ++ foetal abnormalities dipstick. 31 (19–43) yearsb Superimposed PE: RR New Zealand >140 mmHg and rise of

RR �30/15 mmHg with new proteinuria or doubling of existing proteinuria

Prefumo, 2004 IN: all singleton live births 4149 18–23 0.4 RR >140/90 mmHg; CD + PWfrom clinical database proteinuria �0.3 g/24 h EX: foetal abnormalities or + dipstick twice if 29.4 ± 5.9 years no 24 h collection UK available

Outcome: PE with delivery <32 weeks

Carbillon, 2004 Routine USS 243 (12–14) 4.9 RR �140/90 mmHg Toshiba 29.6 ± 6.2 years 22–24 twice 4 h apart; Powervision France proteinuria �0.3 g/24 h 6000

or + dipstick

Axt-Fliedner, IN: singleton pregnancies 52 19–26 7.7 RR >140/90 mmHg; CD2005 with history of PE, IUGR, proteinuria �0.3 g/24 h; Elegra,

IUD, abruption no UTI Acuson 128 32.8 (23–46) yearsb XP10Germany

Audibert, 2005 IN: AFP and HCG testing 2615 18–26 2.0 SBP �140 or DBP NRat 14–18 weeks and USS �90 mmHg twice; EX: women without USS proteinuria >0.3 g/24 h 10–14 weeks for dating, or ++ dipstick women with raised NT, delivery <24 weeks30.9 ± 4.5 yearsFrance

Schwarze, 2005 EX: essential hypertension, 215 19–22 4.9 RR >140/90 mmHg; CDDM, autoimmune disorders, proteinuria �0.3 g/24 h; Elegra history of PE, IUGR, IUD, no UTI (Siemens), placental abruption; Acuson 128 multiple pregnancies, XP10foetal abnormalities31.4 (17–46) yearsGermany

131 23–26

NT, Nuchal translucency; TTS, twin transfusion syndrome; USS, ultrasound screening.a All studies were cohort designs. b Median age.


159


TABLE 63 Methodological and reporting characteristics of studies on Doppler combinations of flow velocity waveforms


Resistance index and/or notchingAquilina, IN: unselected women 640 18–22 5.5 DBP �90 mmHg twice Mean RI 2001 with inhibin A measurement >4 h apart or DBP �0.55 and

EX: multiple pregnancies, �110 mmHg once; bilateral DM, CH, chromosome/ proteinuria �0.3 g/24 h notching; structural anomalies or ++ dipstick twice; or mean Age NR no UTI RI �0.65 UK and

unilateralnotching CD + PW

Bower, Unselected 2058 18–22 0.34 Mild PE: rise RR RI >95th 1993 EX: multiple pregnancies, <30/25 mmHg; proteinuria centile

foetal anomalies + dipstick. Moderate PE: and/or any Age NR rise RR <30/25 mmHg; notching UK proteinuria ++ dipstick. CW + CD

Severe PE: DBP �110 mmHg and rise RR �30/25 mmHg; proteinuria ++ dipstick or �0.5 g/24 h

Campbell, Age NR 264 19–21 4.9 RR �140/90 � twice 4 h RI >0.6 2000 UK apart; proteinuria and/or any

�0.3 g/24 h or + dipstick notchingCW + CD

24–26

Chan, 1995 IN: high risk due to age 334 20 6.9 RR �140/90 mmHg twice RI >90th >35 years, poor obstetric 6 h apart; proteinuria centile and history, medical >0.3 g/24 h or ++ dipstick bilateral complications of pregnancy, notchinglow pre-pregnancy weight, CWsingle mother, smoker >10/day Age NRHong Kong

Coleman, IN: essential and secondary 116 22–24 27.6 RR �140/90 mmHg and rise Any RI 1993 hypertension, renal disease, DBP >15 mmHg twice >0.58 and

SLE, APLS, previous PE or >4 h apart; proteinuria any notchingplacental abruption �0.3 g/24 h or ++ dipstick. EX: multiple pregnancies, Superimposed PE: RR foetal abnormalities >140 mmHg and rise of RR 31 (19–43) yearsb �30/15 mmHg with new New Zealand proteinuria or doubling of

existing proteinuriaAny RI �0.7and anynotchingBoth RI�0.7 andany notching

Driul, 2002 Age NR 840 24 1.2 Not specified RI >0.6 Italy and/or

monolateralnotchingCD

continued

Appendix 7

160

TABLE 63 Methodological and reporting characteristics of studies on Doppler combinations of flow velocity waveforms (cont’d)


Driul, 2005 IN: negative for lupus 103 20 37.9 ACOG guidelines RI >0.58 anticoagulant and and bilateral anticardiolipin antibodies, notchingall used folic acid, no family CD + PWor personal history of thrombo embolic disease31.5 ± 4.6 yearsItaly

Frusca, IN: history of PE 56 24 5.4 DBP �90 mmHg twice 4 h Mean RI 1996 Age NR apart in 3rd trimester; >0.58 and

Italy proteinuria >0.3 g/24 h; bilateral no UTI notching

CD + PW

Frusca, IN: nulliparae without risk 36 24 11.1 RR >140/90 mmHg twice RI >0.58 1997 factors >4 h apart; proteinuria and

EX: CH, DM, auto immune >0.3 g/24 h notchingdisorders CW + CDAge NRItaly

Geipel, IN: intracytoplasmic 170 18–24 3.5 RR �140/90 mmHg Bilateral 2001 sperm injection (ICSI) repeated; proteinuria notching

patients and controls �0.5 g/24 h and mean (low risk), singleton RI >0.55; pregnancies 32.5 years unilateral Germany notching IN: ICSI patients and 58 18–24 19.0 and mean controls (high risk), RI >0.65; singleton pregnancies: CH, no notch DM, adiposity (BMI >27), and RI >0.7nulliparae �35 years; CDmultiparae with history of IUGR, PE, placental abruption, IUD

Geipel, IN: dichorionic twins 256 18–24 8.6 RR �140/90 mmHg RI >95th 2002 EX: foetal malformation, repeated; proteinuria centile (twin

PPROM, unclear �0.3 g/24 h reference) chorionicity and 31.5 ± 4.2 years notchingGermany ATL HDI

5000,Acuson 128XP10

Harrington, Unselected 2437 20 2.0 Initial DBP <90 mmHg + RI >95th 1991 Age NR rise �25 mmHg twice 4 h centile

UK apart; proteinuria and/or >0.5 g/24 h notching

CW + CD

Harrington, EX: multiple pregnancies, 1204 18–21 3.7 Rise RR �30/25 mmHg RI >95th 1996 foetal anomalies, PE or twice 4 h apart or DBP centile or

IUGR <24 weeks �110 mmHg; proteinuria notchingAge NR 0.5 g/24 h CD + PWUK

continued


161



Study Population No. of Gestational Incidence Reference standard Cut-off Age women age at test of PE Index test Country (study analysed (weeks) (%)designa)

Harrington, IN: CH, previous PE, 170 19–21 11.8 DBP �90 mmHg twice 4 h RI �0.55 2004 GH, IUGR, preterm apart, or DBP �110 mmHg (50th

labour, placental once; proteinuria centile) and abruption, IUD, >0.3 g/24 h or ++ dipstick bilateral DM, renal or other twice 4 h apart; no UTI notching; medical disease or mean EX: foetal anomalies RI �0.65 Age NR (80th UK centile) and IN: unselected 458 19–21 0.44 unilateral multiparae with notchingsingleton pregnancies CD

Kurdi, 1998 IN: unselected women 946 19–21 2.2 Baseline DBP <90 mmHg Mean EX: multiple pregnancies, and rise of 25 mmHg, RI >0.55 foetal anomalies, women baseline DBP �90 mmHg (50th already on low-dose and rise of 15 mmHg; centile) and aspirin proteinuria + dipstick, bilateral Age NR no UTI notching; UK or mean RI

>0.65 (90thcentile) andunilateralnotching; or mean RI>0.7 (95thcentile)CD

North, IN: healthy nulliparae 446 19–24 3.4 RR �140/90 mmHg and RI or A/C 1994 EX: renal disease, DM rise DBP �15 mmHg >4 h >90th

Age NR apart; proteinuria centileAustralia >0.3 g/24 h or ++ dipstick CD + PW

Subtil, No contraindication to 1170 22–24 2.1 PIH, proteinuria ++ RI >0.61 2003 aspirin dipstick or �0.5 g/l or any

24.2 ± 4.4 years notchingCD

Valensise, IN: chronic hypertension 16 22, 24 43.8 Davey and MacGillivray201 RI >0.58 1994 Age NR and/or

Italy notchingCD

Pulsatility index and/or notchingAlbaiges, IN: singleton pregnancies, 1757 22–25 3.7 RR �140/90 mmHg twice Mean PI 2000 routine antenatal care >2 h apart; proteinuria >1.45 and

30 (18–44) yearsb �0.3 g/24 h or dipstick bilateral UK 0.3 g/l notching

CD + PWMean PI>1.45 orbilateralnotching

continued

Appendix 7

162


Study Population No. of Gestational Incidence Reference standard Cut-off Age women age at test of PE Index test Country (study analysed (weeks) (%)designa)

Papageorghiou, IN: singleton 7851 22–24 1.4 DBP �90 mmHg twice PI >1.63 or 2001 pregnancies attending >4 h apart; proteinuria bilateral

for routine antenatal �0.3 g/24 h or ++ dipstick notchingcare twice if no 24-h collection CD + PWEX: no foetal available abnormality29.7 (16–47) yearsb

UK

Yu, 2002 IN: twin pregnancies, 351 22–24 6.0 DBP �90 mmHg twice PI >95th 2 live foetuses, >4 h apart; proteinuria centile and no foetal abnormality, �0.3 g/24 h or ++ dipstick notchingno TTTS twice if no 24-h collection CD + PW31.7 (18–46) yearsb availableUK

S/D or D/S ratio and/or notchingBenifla, 1992 IN; SLE, APLS 28 20, 30 14.3 NR D/S <2 SD

30.4 ± 4.2 years both France arteries or

notchingpersistentafter24 weeksPW

Haddad, 1995 IN: aspirin treatment 48 23.8 ± 2.6 10.4 SBP �140 and/or DBP D/S <10th because of poor �90 mmHg; proteinuria centile previous outcome, PE, �0.5 g/24 h and/or eclampsia, HELLP, unilateral placental abruption, notchingIUGR, IUD CW31.3 ± 4.5 yearsFrance

Morris, 1996 IN: all nulliparae 768 18 4.7 RR >140/90 mmHg and rise S/D >3.3 23.9 ± 7.3 years of DBP �15 mmHg >twice (2 SD); or Australia 6 h apart; proteinuria + S/D >3.0

dipstick twice 6h apart or (90th hyperuricaemia centile) and

unilateralnotchingCD + PW

Soutif, 1996 EX: nephropathy, CH, 315 21, 24 1.3 SBP �150 and/or DBP S/D >2.6 on DM, systemic disorders, �90 mmHg twice, either side multiple pregnancies proteinuria �1.0 g/24 h and/or Age NR unilateral France notching

PW

A/B or S/D, peak systolic flow divided by late diastolic flow; A/C, peak systolic flow divided by early diastolic flow; APLS, antiphospholipid syndrome; D/S, late diastolic flow divided by peak systolic flow; PI, pulsatility index (peak systolicflow minus end diastolic flow) divided by mean flow [(A � B)/M]; RI, resistance index (peak systolic flow minus end diastolicflow) divided by peak systolic flow [(A � B)/A].a Studies were cohort designs unless stated otherwise. b Median age.


163


TABLE 64 Methodological and reporting characteristics of studies on Doppler pulsatility index

Study Population No. of Gestational Incidence Reference standard Cut- Index Age women age at test of PE off test Country (study analysed (weeks) (%) (PI)designa)

Yu, 2002 IN: twin pregnancies, 351 22–24 6.0 DBP �90 mmHg >95th CD + PW2 live foetuses, twice >4 h apart; centileno foetal abnormality, proteinuria no TTS �0.3 g/24 h or ++ 31.7 (18–46) yearsb dipstick twice UK

Martin, 2001 IN: routine antenatal 3045 11–14 2.1 DBP �90 mmHg >2.35 CD + PWcare twice >4 h apart; 95th 31.3 (16–47) yearsb proteinuria centileUK �0.3 g/24 h or ++

dipstick twice

Papageorghiou, IN: singleton 7851 22–24 1.4 DBP �90 mmHg >1.63 CD + PW2001 pregnancies, routine twice >4 h apart; Several

antenatal care proteinuria ultrasound EX: foetal abnormality �0.3 g/24 h or ++ machines29.7 (16–47) yearsb dipstickUK

Aardema, IN: healthy nulliparae, 531 21–22 0.9 DBP �90 mmHg >1.3 CD + PW2000 singleton pregnancies twice; proteinuria Acuson

Age NR ++ dipstick 128 XP 10The Netherlands

Aardema, IN: multiparae with 94 21–22 7.5 DBP �90 mmHg >1.3 CD + PW2000 history of hypertensive twice; proteinuria Acuson

disorders in previous ++ dipstick 128 XP 10pregnancy, no current pathology, singleton pregnancies

Albaiges, 2000 IN: singleton 1757 22–25 3.7 RR �140/90 mmHg >1.45 CD + PWpregnancies, routine twice >2 h apart; (mean) Acuson antenatal care proteinuria Aspen, 30 (18–44) yearsb �0.3 g/24 h or Aloka SSD UK dipstick testing 0.3 g/l 1700

Zeeman, 2003 IN: chronic 52 16–20 21.2 RR exceeding early >95th CD + PWhypertension requiring pregnancy values; centile Acuson medication proteinuria XP1032.0 ± 6.2 years �0.3 g/24 h or + USA dipstick (30 mg/dl)

Yu, 2004 IN: healthy singleton 683 22–24 8.8 DBP �90 mm/Hg >1.6 NRpregnancies twice 4 h apart or >95th EX: CH, cardiovascular DBP �120 mmHg centileand renal disease, DM, once; proteinuria bleeding disorders, SLE, �0.3 g 24 h or ++ foetal anomalies dipstick 30 (15–47) yearsb

UK

Sato,1995 31.7 (18–46) yearsb 333 16–23 4.8 Gestose index 2 �1.2 CD + PWJapan Aloka SSD

870

a All studies were cohort designs. b Median age.

Appendix 7

164

TABLE 65 Methodological and reporting characteristics of studies on Doppler resistance index

Study Population No. of Gestational Incidence Reference Cut- Index Age women age at test of PE standard off test Country (study analysed (weeks) (%) (RI)designa)

Geipel, IN: dichorionic twins 256 18–24 8.6 RR �140/90 mmHg >95th Colour NR2002 EX: foetal malformation, repeated; centile ATL HDI

PPROM, unclear proteinuria (singleton 5000, chorionicity �0.3 g/24 h reference) Acuson 31.5 ± 4.2 years >95th 128 XP 10Germany centile

(twin reference)

Tranquilli, EX: CH, foetal anomalies, 75 24 18.7 Hypertension and >0.58 CD2000 IUGR, primigravidae proteinuria, not Ansaldo

23–38 years quantified Hitachi AU Italy 590

Soregaroli, IN: history of GH, PE, 271 24 3.3 RR >140/90 mmHg >0.6 CD2001 SGA, IUD; CH, twice >4 h apart; Toshiba

autoimmune disorders, proteinuria SSH 140 Arenal diseases >0.3 g/24 hEX: multiple pregnancies, foetal or chromosomal anomalies, pregnancy complications <24 weeksAge NRItaly

Ohkuchi, IN: healthy singleton 288 16–23.9 3.1 DBP �90 mmHg >91st CD + PW2000 pregnancies twice >4 h apart; centile EUB 165A

28.7 ± 4.0 years proteinuria Japan �0.3 g/24 h or ++

dipstick

Aquilina, IN: unselected 550 18–22 7.3 DBP �90 mmHg NR CD + PW2000 primiparae, routine twice >4 h apart or Philips

antenatal care DBP �110 mmHg SD-800/Age NR once; proteinuria HP Sonos UK �0.3 g/24 h or ++ 550

dipstick twice; no UTI

Caforio, EX: congenital defects, 530 18–20 0.6 Davey and >90th CD + PW1999 chromosomal MacGillivray201 centile Esaoute

abnormalities, multiple AU570Apregnancies, infections, Rh isoimmunisation, non-immune hydrops, PPROM, IUD, delivery <26 weeks31 ± 4.8 yearsItaly

22–24 >90th centile

Caforio, IN: CH, DM, 335 18–20 12.5 Davey and >90th 1999 autoimmune disease, SLE, MacGillivray201 centile

renal disease; history of stillbirths, IUGR, PE, habitual abortionItaly

22–24 >90th centile

continued


165


TABLE 65 Methodological and reporting characteristics of studies on Doppler resistance index (cont’d)


Frusca, IN: CH 78 24–25 3.9 Superimposed PE: >2 SD CD + PW1998 EX: multiple pregnancies, aggravated Toshiba

foetal anomalies hypertension (rise SSH 140AAge NR DBP >15 mmHg); Italy proteinuria

>0.3 g/24 h

Frusca, IN: nulliparae without 419 24 1.9 RR >140/90 mmHg >0.58 CW + CD1997 risk factors twice >4 h apart; Doptek

EX: CH, DM, proteinuria autoimmune disorders >0.3 g/24 h Age NRItaly

Caruso, IN: CH, singleton 42 23–24 21.4 SBP �140 or DBP >90th CD1996 pregnancies �90 mmHg and centile Ansaldo

EXC: autoimmune exacerbation of Esacord diseases, foetal anomalies, hypertension; 81Rh isoimmunisation >0.3 g/l or + 32 (23–44) yearsb dipstick in 2 random Italy samples or �0.3 g/l

in 24 h urine collection; no UTI

Konchak, IN: increased MSAFP 103 17–22 5.8 Not specified >95th CD + PW1995 >2MoM twice or centile Acuson

>2.5MoM once, XP10singleton pregnancies, normal amniotic fluid volumeEX: foetal anomalies27.1 ± 5.1 yearsUSA

Chan, 1995 IN: high risk due to age 334 20 6.9 RR �140/90 mmHg >95th CW>35 years, poor twice 6 h apart; centile Doptekobstetric history, medical proteinuria complications of >0.3 g/24 h or ++ pregnancy, low dipstickprepregnancy weight, single mother, smoker >10 per dayAge NRHong Kong

Ferrier, IN: renal disease other 51 19–24 7.8 RR �140/90 mmHg >90th CD1994 than diabetic nephropathy and rise DBP centile Acuson

28 ± 6 years �15 mmHg >4 h Australia apart; proteinuria

>0.3 g/24 h or doubling of 24-h urinary protein excretion if already present <20 weeks

continued

Appendix 7

166



North, IN: healthy nulliparae 446 19–24 3.4 RR �140/90 mmHg >90th CD + PW1994 EX: renal disease, DM and rise DBP centile Acuson

Age NR �15 mmHg >4 h >0.57 128 XP10Australia apart; proteinuria

>0.3 g/24 h or ++ dipstick

Rizzo, 1993 IN: dichorionic twin 64 20–24 34.3 DBP �90 mmHg Mean RI CD + PWpregnancies twice >4 h apart or (twins) Ansaldo Age NR DBP �110 mmHg AU 560Italy once; proteinuria

�0.3 g/24 h

Caruso, IN: APLS 28 18–24 17.9 Davey and >90th CD + PW1993 19–42 years MacGillivray, 1988 centile NR

Italy

Pattinson, IN: women at high risk 53 16–28 Davey and >0.58 CW1991 for complications 13.2 MacGillivray, 1988 Doptek

28.5 ± 4.7 years 9000South Africa

Parretti, IN: normotensive, 144 24 25.0 RR >140/90 mmHg �0.58 AU5 Epi2003 white women with risk twice within 24 h (mean)

factors (previous PE, period; proteinuria stillbirth, placental >0.3 g/24 h; no UTIabruption, IUGR)EX: smokers, cardiovascular and renal disease, DM, multiple pregnancies, foetal chromosomal abnormalities, women on low-dose aspirin34.5 (27–41) yearsb

Italy

Valensise, IN: primiparae, 192 24 4.7 Gestational >0.58 CD1993 no current or previous hypertension (Davey Ansaldo

relevant medical history and MacGillivray;201 Hitachi (n = 104). History of PIH, proteinuria AU 590IUGR, IUD (n = 88) >0.3 g/24 hEX: IUGR, oligohydramnion30.0 ± 4.7 yearsItaly

Valensise, EX: history of 272 24 3.3 Davey and >0.58 CD1993 hypertension, DM, SLE, MacGillivray;201 Ansaldo

pharmacological proteinuria Hitachi induction of ovulation, >0.3 g/l/24 h AU 590foetal or chromosomal abnormalities26.4 ± 2.7 yearsItaly

continued


167




Arenas, Unselected women 319 20 3.5 RR �140/90 mmHg; �0.59 CD + PW2003 EX: multiple pregnancies, proteinuria Aloka SSD

congenital defects >0.3 g/24 h 200030.5 (16–43) yearsb

Spain

Frusca, IN: history of PE 56 24 5.4 DBP �90 mmHg >0.58 CD + PW1996 Age NR twice 4 h apart in Toshiba

Italy 3rd trimester; SSH 140aproteinuria >0.3 g/24 h; no UTI

Coleman, IN: essential and 116 22–24 27.6 RR �140/90 mmHg Any CD1993 secondary hypertension, and rise DBP >0.58 Toshiba

renal disease, SLE, APLS, >15 mmHg twice Both 270 or previous PE or placental >4 h apart; >0.58 Diasonicsabruption proteinuria Any EX: multiple pregnancies, �0.3 g/24 h or ++ �0.7foetal abnormalities dipstick. Both 31 (19–43) yearsb Superimposed PE: �0.7New Zealand RR >140 mmHg and

rise of RR �30/15 mmHg with new proteinuria or doubling of existing proteinuria

Axt- IN: singleton pregnancies 52 19–26 7.7 RR >140/90 mmHg; Any CDFliedner, with history of PE, IUGR, proteinuria >0.58 Elegra or 2005 IUD, placental abruption �0.3 g/24 h, no UTI Both Acuson

32.8 (23–46) years >0.58 128 XP1Germany Any >0.7

Both >0.7

Schwarze, EX: essential 346 19–26 4.9 RR >140/90 mmHg; Any CD Elegra 2005 hypertension, DM, proteinuria >0.58 (Siemens)

autoimmune disorders, �0.3 g/24 h; no UTI Both or Acuson history of PE, IUGR, IUD, >0.58 128 XP 10placental abruption, Any >0.7multiple pregnancies, Both >0.7foetal abnormalities31.4 (17–46) yearsGermany

Sato, 1995 31.7 (18–46) yearsb 341 16–23 4.7 Gestose Index (GI) 2 >0.60 CD + PWJapan Aloka SSD

870

a All studies were cohort designs. b Median age.

Appendix 7

168

TABLE 66 Methodological and reporting characteristics of studies on Doppler SD ratio


Schulman, IN: normal pregnancies 71 >20 26.8 Not specified S/D >2.61987 Age NR CW

USA

Saccini, EX: CH, other maternal 38 18 65.8 DBP �90 mmHg twice 4 h S/D >2.61995) medical diseases (e.g. DM, apart or DBP �110 mmHg, Duplex

cardiac or renal disease, proteinuria >0.3 g/24 h or DopplerSLE) 1 g/l in random urine 31.6 ± 5.0 years collectionItaly

Aquilina, IN: unselected primiparae, 550 18–22 7.3 DBP �90 mmHg twice A/B; 2000 routine antenatal care >4 h apart or DBP A/C

Age NR �110 mmHg once; CD + PWUK proteinuria �0.3 g/24 h or

++ dipstick twice; no UTI

North, IN: healthy nulliparae 446 19–24 3.4 RR �140/90 and rise DBP A/C >90th 1994 EX: renal disease, DM �15 mmHg >4 h apart; centile

Age NR proteinuria >0.3 g/24 h or CD + PWAustralia ++ dipstick

Ohkuchi, IN: healthy women, 288 16–23.9 3.1 DBP �90 mmHg twice A/C >91st 2000 singleton pregnancies >4 h apart; proteinuria centile

28.7 ± 4.0 years �0.3 g/24 h or ++ dipstick CD + PWJapan

Ferrier, IN: renal disease other 51 19–24 7.8 RR �140/90 and rise DBP A/C >90th 1994 than diabetic nephropathy �15 mmHg >4 h apart; centile

28 ± 6 years proteinuria >0.3 g/24 h or CDAustralia doubling of 24-h urinary

protein excretion if already present <20 weeks

Aardema, IN: multiparae with history 94 21–22 7.5 DBP �90 mmHg twice; NI >0.032000 of hypertensive disorders in proteinuria ++ dipstick CD + PW

previous pregnancy, but no current pathology, singleton pregnanciesThe Netherlands

Aardema, IN: healthy nulliparae, 531 21–22 0.94 DBP �90 mmHg twice; NI >0.032000 singleton pregnancies proteinuria ++ dipstick CD + PW

Age NRThe Netherlands

A/B or S/D, peak systolic flow divided by end diastolic flow; A/C, peak systolic flow divided by early diastolic flow; NI, notchindex (peak of notch minus nadir of notch) divided by mean flow [(D � C)/M].a Studies were cohort designs unless stated otherwise.


169


Appendix 8

Diagnostic test quality charts

TABLE 67 Body mass index quality characteristics

Study

Sibai, 1997 RCT ? – + – + + –Baeten, 2001 + ? – – – – + ?Bianco, 1998 + ? – + + – + ?Bowers, 1999 + ? – ? – – + ?Knuist, 1998 + + – + + + + –Lee, 2000 + + – – + – + –Ogunyemi, 1998 + + – + – + + ?Ros, 1998 + + – + – – + –Sebire, 2001 + ? – ? + – + ?Steinfeld, 2000 + + – + – – + ?Thadhani, 1999 + ? – + + + + –

Stud

y de

sign

(coh

ort)

Con

secu

tive

recr

uitm

ent

Blin

ding

of t

est

resu

lts

>90

% v

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on o

fdi

agno

sis

Inci

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<4%

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TABLE 68 AFP quality characteristics

Study

Morssink, 1997 + + – + + – – –Yaron, 1999 + + – + + ? + ?Wenstrom, 1996 + – – + + – + ?Jauniaux, 1996 + ? ? – – + + –Leung, 1999 + ? ? ? + ? + –Pouta, 1998 + + ? ? – ? + –Milunsky, 1994 + + – + + – + ?Waller, 1996 + – – + + – + ?Capeless, 1992 + ? ? ? + + – ?Simpson, 1995 + – ? – – – + +

Severe PERaty, 1999 + – – ? – – + –Stamilio, 2000 + + – + – – – –

Stud

y de

sign

(coh

ort)

Con

secu

tive

recr

uitm

ent

Blin

ding

of t

est

resu

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>90

% v

erifi

cati

on o

fdi

agno

sis

Inci

denc

e of

pr

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<4%

Pro

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dat

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Appendix 8

170

TABLE 69 Cellular and total fibronectin quality characteristics

Study

Chavarria, 2002 NMCC + ? + – + + –Lockwood, 1990 NMCC + ? + – + + –Soltan, 1996 + ? ? + – + ? –Paarlberg, 1998 + + ? + – + + –

NMCC, nested and matched case–control.

Stud

y de

sign

(coh

ort)

Con

secu

tive

recr

uitm

ent

Blin

ding

of t

est

resu

lts

>90

% v

erifi

cati

on o

fdi

agno

sis

Inci

denc

e of

pr

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psia

<4%

Pro

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dat

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nce

stan

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TABLE 70 Foetal DNA quality characteristics

Study

Cotter, 2004 NMCC ? + + ? – + +Farina, 2004 NCC – ? + – ? + +Leung, 2001 NMCC – + + ? + + –

NCC, nested case–control; NMCC, nested and matched case–control.

Stud

y de

sign

(coh

ort)

Con

secu

tive

recr

uitm

ent

Blin

ding

of t

est

resu

lts

>90

% v

erifi

cati

on o

fdi

agno

sis

Inci

denc

e of

pr

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lam

psia

<4%

Pro

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dat

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n

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nce

stan

dard

TABLE 71 Haemoglobin/haematocrit quality characteristics

Study

Goh, 1991 + + ? + – – – –Heilmann, 1993 + ? ? + – + – ?

Stud

y de

sign

(coh

ort)

Con

secu

tive

recr

uitm

ent

Blin

ding

of i

ndex

test

res

ults

>90

% v

erifi

cati

on o

fdi

agno

sis

Inci

denc

e of

pr

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lam

psia

<4%

Pro

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171


TABLE 72 HCG quality characteristics

Study

Yaron, 1999 + + ? + + ? ? ?Morssink, 1997 + + ? + + – – –Lambert–Messerlian, 2000 CC – ? + ? – ? –Heinonen, 1996 + + ? + – ? ? ?Lee, 2000 NCC ? ? ? + – + +Aquilina, 2000 + + ? + – – ? –Muller, 1996 + + ? + + – + –Ashour, 1997 + + ? – + – ? +Luckas, 1998 + + + + – + + ?Onderoglu, 1997 + – ? + + – ? –Vaillant, 1996 + + ? + + – ? –Pouta, 1998 + + ? ? – ? + –Jauniaux, 1996 + ? ? – – + + –

Early testHaddad, 1999 + + ? + + – ? –Yaron, 2002 + + ? + + ? + –

Severe PELee, 2000 NCC ? ? ? + – + +Stamilio, 2000 + + – + – – – –

CC, case–control; NCC, nested case–control.

Stud

y de

sign

(coh

ort)

Con

secu

tive

recr

uitm

ent

Blin

ding

of t

est

resu

lts

>90

% v

erifi

cati

on o

fdi

agno

sis

Inci

denc

e of

pr

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lam

psia

<4%

Pro

spec

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dat

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ion

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n

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nce

stan

dard

TABLE 73 Oestriol quality characteristics

Study

Yaron, 1999 + + ? + + ? + ?Kowalczyk, 1998 + ? ? – – – + +

Severe PEStamilio, 2000 + + – + – – – –

Stud

y de

sign

(coh

ort)

Con

secu

tive

recr

uitm

ent

Blin

ding

of t

est

resu

lts

>90

% v

erifi

cati

on o

fdi

agno

sis

Inci

denc

e of

pr

e-ec

lam

psia

<4%

Pro

spec

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dat

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Appendix 8

172

TABLE 74 Serum uric acid quality characteristics

Study

Jauniaux, 1996 + ? ? – – + ? –Salako, 2003 + + ? – – + ? –Conde–Agudelo, 1994 + ? + – + + ? –Winocour, 1989 + ? ? + – + ? –Jacobson, 1990 + ? ? + – – ? –

Stud

y de

sign

(coh

ort)

Con

secu

tive

recr

uitm

ent

Blin

ding

of t

est

resu

lts

>90

% v

erifi

cati

on o

fdi

agno

sis

Inci

denc

e of

pr

e-ec

lam

psia

<4%

Pro

spec

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dat

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ion

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stan

dard

TABLE 75 Urinary calcium excretion/urinary calcium/creatinine ratio quality characteristics

Study

Sanchez-Ramos, 1991a + + + – – + ? –Nisell, 1996a + ? ? ? – + – +Baker, 1994a,b + ? + ? + + – –Suarez, 1996a,b + – + – – + ? –Soltan, 1996b + ? ? – – + – –Rogers, 1994b + ? ? + – + + –Conde, 1994b + ? + – + + ? –Kazerooni, 2003b + + ? – – + – –

a Studies included for UCE.b Studies included for UCCR.

Stud

y de

sign

(coh

ort)

Con

secu

tive

recr

uitm

ent

Blin

ding

of t

est

resu

lts

>90

% v

erifi

cati

on o

fdi

agno

sis

Inci

denc

e of

pr

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lam

psia

<4%

Pro

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dat

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173


TABLE 76 Proteinuria quality characteristics

Study

Sibai, 2000 RCT – ? + ? + + –Combs, 1993 CC ? ? + ? ? + –Sibai, 1998 RCT – ? + ? + + –Delmis, 1993 + + ? ? – – – +Ekbom 2, 1999 + ? ? + – + + –Winocour, 1989 + ? ? + – ? + –Gonzalez, 2003 + ? ? + – + + –Soltan, 1996 + ? ? – – + – –Masse, 1993 + + ? – – + + –Millar, 1996 XSEC + ? + + + + –Winkler, 1988 + ? ? + – + – +

XSEC, cross-sectional study.

Stud

y de

sign

(coh

ort)

Con

secu

tive

recr

uitm

ent

Blin

ding

of t

est

resu

lts

>90

% v

erifi

cati

on o

fdi

agno

sis

Inci

denc

e of

pr

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lam

psia

<4%

Pro

spec

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dat

aco

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ion

Ade

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n

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nce

stan

dard

TABLE 77 Doppler any/unilateral notching of the main uterine arteries quality characteristics

Study

Geipel, 2002 + + ? + – – – +Venkat–raman, 2001 + + – + – + – +Antsaklis, 2000 + + + + + + – +Aardema, 2000 + + + + – + – –Ohkuchi, 2000 + + ? + + + – –Frusca, 1998 + + – + + + – –Harrington, 1997 + ? ? + – + – +Harrington, 1996 + ? ? + + ? – –Konchak, 1995 + ? ? + – ? – ?Bower, 1993 + + ? + + + + –Phupong, 2003 + + + + – + – +Marchesoni, 2003 + ? ? + + – – +Frusca, 1996 + ? ? + – ? – –Coleman, 1993 + ? – + – + – –Prefumo, 2004 + + ? + + – – +Carbillon, 2004 + + ? + – + – +Axt–Fliedner, 2005 + ? + + – + – +Audibert, 2005 + – ? + + – – –Schwarze, 2005 + + + + – + – +

Stud

y de

sign

(coh

ort)

Con

secu

tive

recr

uitm

ent

Blin

ding

of t

est

resu

lts

>90

% v

erifi

cati

on o

fdi

agno

sis

Inci

denc

e of

pr

e-ec

lam

psia

<4%

Pro

spec

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dat

aco

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Appendix 8

174

TABLE 78 Doppler bilateral notching of the main uterine arteries quality characteristics

Study

Zimmerman, 1997 RCT ? ? + – + – –Geipel, 2002 + + ? + – – – +Yu, 2002 + + ? + – + – –Papageorghiou, 2001 + + ? + + + – +Venkat–raman, 2001 + + – + – + – +Geipel (low risk), 2001 + + ? + – – – –Geipel (high risk), 2001 + + ? + – – – –Antsaklis, 2000 + + + + + + – –Ohkuchi, 2000 + + ? + + + – +Albaiges, 2000 + + ? + + + – +Mires, 1998 + + ? + – + – –Kurdi, 1998 + + + + + + – ?Frusca, 1998 + + – + + + – +Harrington, 1997 + ? ? + – + – –Harrington, 1996 + ? – + + – – –Marchesoni, 2003 + ? ? + + – – –Uludag, 2002 + – ? + – + – –Coleman, 1993 + ? – + – + – –Prefumo, 2004 + + ? + + – – –Carbillon, 2004 + + ? + – + – –Axt–Fliedner, 2005 + ? + + – + – –Audibert, 2005 + – ? + + – – –Schwarze, 2005 + + + + – + – –

Stud

y de

sign

(coh

ort)

Con

secu

tive

recr

uitm

ent

Blin

ding

of t

est

resu

lts

>90

% v

erifi

cati

on o

fdi

agno

sis

Inci

denc

e of

pr

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lam

psia

<4%

Pro

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dat

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TABLE 79 Doppler single ratios of the uterine artery quality characteristics

Study

Schulman, 1987 + – ? + – ? – ?Saccini, 1995 + ? ? + – ? – –Aquilina, 2000 + + ? – – + – –North, 1994 + ? + + + + + –Ohkuchi, 2000 + + ? + + + – –Ferrier, 1994 + ? ? + – + + –Aardema (high risk), 2000 + + ? + – + – –Aardema (low risk), 2000 + + ? + + + – –

Stud

y de

sign

(coh

ort)

Con

secu

tive

recr

uitm

ent

Blin

ding

of t

est

resu

lts

>90

% v

erifi

cati

on o

fdi

agno

sis

Inci

denc

e of

pr

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lam

psia

<4%

Pro

spec

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175


TABLE 80 Doppler pulsatility index of the main uterine artery quality characteristics

Study

Yu, 2002 + + ? + – + – –Martin, 2001 + + ? + + + – –Papageorghiou, 2001 + + ? + + + – –Aardema, 2000 + + ? + + + – –Aardema, 2000 + + ? + – + – –Albaiges, 2000 + + ? + + + – +Zeeman, 2003 + ? + + – + – ?Yu, 2004 + – ? + – – – –Sato, 1995 + ? ? ? – + – –

Stud

y de

sign

(coh

ort)

Con

secu

tive

recr

uitm

ent

Blin

ding

of t

est

resu

lts

>90

% v

erifi

cati

on o

fdi

agno

sis

Inci

denc

e of

pr

e-ec

lam

psia

<4%

Pro

spec

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dat

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ion

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TABLE 81 Doppler resistance index of the main uterine artery quality characteristics

Study

Geipel, 2002 + + ? + – – – +Tranquilli, 2000 + ? ? ? – + ? ?Soregaroli, 2001 + + ? + + + – +Ohkuchi, 2000 + + ? + + + – –Aquilina, 2000 + + ? – – + – –Caforio (low risk), 1999 + ? + ? + ? – –Caforio (high risk), 1999 + ? + ? – ? – –Frusca, 1998 + + – + + + – –Frusca, 1997 + ? + + + ? – +Caruso, 1996 + ? + + – ? – +Konchak, 1995 + ? ? + – ? – ?Chan, 1995 + ? ? + – ? – –Ferrier, 1994 + ? ? + – + + –North, 1994 + ? + + + + + –Rizzo, 1993 + ? ? + – – – –Caruso, 1993 + ? ? + – + – –Pattinson, 1991 + + ? ? – + – –Parretti, 2003 + + + + – + – +Valensise, 1993 + ? ? + – + + ?Valensise, 1993 + ? ? + + ? – ?Arenas, 2003 + – ? + + + + +Frusca, 1996 + ? ? + – ? – –Coleman, 1993 + ? – + – + – –Axt–Fliedner, 2005 + ? + + – + – +Schwarze, 2005 + + + + – + – +Sato, 1995 + ? ? ? – + – –

Stud

y de

sign

(coh

ort)

Con

secu

tive

recr

uitm

ent

Blin

ding

of t

est

resu

lts

>90

% v

erifi

cati

on o

fdi

agno

sis

Inci

denc

e of

pr

e-ec

lam

psia

<4%

Pro

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dat

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Appendix 8

176

TABLE 82 Doppler combinations of flow velocity waveforms of the main uterine artery quality characteristics

Study

Resistance index and/or notchingAquilina, 2001 + + ? – – + + –Bower, 1993 + + ? + + + – –Campbell, 2000 + + ? – – + – +Chan, 1995 + ? ? + – ? – –Coleman, 1993 + ? – + – + – –Driul, 2002 + ? ? – + + – ?Driul, 2005 CC ? ? + – – – ?Frusca, 1996 + ? ? + – ? – –Frusca, 1997 + ? + + – ? – +Geipel (low risk), 2001 + + ? + + – – –Geipel (high risk), 2001 + + ? + – – – –Geipel, 2002 + + ? + – – – +Harrington, 1991 + ? ? + + + – –Harrington, 1996 + ? – + + ? – –Harrington (high risk), 2004 + + ? + – + – –Harrington (low risk), 2004 + + ? + + + – –Kurdi, 1998 + + + + + + – –North, 1994 + ? + + + + + –Subtil, 2003 RCT ? ? + + + – ?Valensise, 1994 + ? ? + – ? – ?

Pulsatility index and/or notchingAlbaiges, 2000 + + ? + + + – +Papageorghiou, 2001 + + ? + + + – –Yu, 2002 + + ? + – + – –

S/D ratio and/or notchingBenifla, 1992 + ? ? + – + – ?Haddad, 1995 + + ? + – ? – –Morris, 1996 RCT + – – – + – –Soutif, 1996 + + ? + + + – –

CC, case control.

Stud

y de

sign

(coh

ort)

Con

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tive

recr

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ent

Blin

ding

of t

est

resu

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>90

% v

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on o

fdi

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sis

Inci

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<4%

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177


Appendix 9

Effectiveness reviews tables of methodological and reporting characteristics of included studies

TABLE 83 Trial details of bed rest with or without hospitalisation for hypertension during pregnancy

Study Methods Participants Interventions Outcomes Notes

Crowther,1986

R: random numbertables, variable blocksize AC: consecutivelynumbered opaque,sealed envelopes (A)FU: no losses (A)B: none

105 women withsingleton pregnancyat 28–38 weeks,proteinuric HT (DBP 90–109 mmHgand proteinuria�1+). No othercomplications ofpregnancy

Rest: strict bed restin hospital untildelivery. Ambulationonly to toilet.Control: allowed tomove around thehospital ward asdesired

Woman: severe HT(DBP >109 mmHg);increasedproteinuria;fulminating PE;eclampsia; placentalabruption; IOL Baby: NND;stillbirth; pretermbirth; low BW; verylow BW; meconium;Apgar; intubation;SCBU admission

Setting:Zimbabwe. One hospital

Crowther,1992

R: blocked, stratifiedby parity and type ofHT AC: consecutivelynumbered, opaque,sealed envelopes (A) FU: no losses (A)B: for babyoutcomes only

218 primigravid andmultigravid womenwith singletonpregnancy at28–38 weeks, non-proteinuric HT (BP�140/90 mmHg).Excluded: DBP�110 mmHg,symptomatic,Caesarean sectionscar or APH duringpregnancy

Rest: rest in hospital,voluntary movementin the ward. 4-hourlyBP + daily urinalysisControl: normalactivity at home, norestrictions. Dailyself analysis of urinefor protein. WeeklyBP, weight, bloods

Woman: severe HT(�160/110 mmHg);proteinuria;Caesarean section;IOL Baby: perinatal deathBW (mean); BW(<2500 g); SGA(<10%ile);admission to NICU;length of stay inhospital; Apgar

Setting:Zimbabwe. One hospitaland 13peripheralclinics

Leung, 1998

continued

R: “allocatedrandomly”. No otherinformation AC: consecutivelynumbered, opaque,sealed envelopes (A)FU: 26% excluded.Only 4% excludedfrom women’s viewsB: none

90 primigravid andmultigravid womenwith singletonpregnancy at28–38 weeks, non-proteinuric HT (DBP90–100 mmHg) after5 minutes’ rest Excluded:proteinuria �1+ orsymptoms of severePE

Rest: admission tohospital, advice torest in bed as muchas possible Control: normalactivity at home.Daily self analysis ofurine for protein.Reviewed weekly inday-care unit orclinic for BP, foetalmonitoring,urinalysis, bloods

Woman: HT (DBP>90 mmHg × 2),severe HT;proteinuria; mode ofdelivery; IOL;antihypertensivedrug; women’s viewsand preferences(questionnaire)Baby: stillbirth,neonatal death; BW(mean); SGA;admission NICU;length of stay inhospital; Apgar

Setting: HongKong. Onecentre.All dataexcluded exceptfor women’sviews, as datafor >20%women notavailable

Appendix 9

178

TABLE 83 Trial details of bed rest with or without hospitalisation for hypertension during pregnancy (cont’d)


Mathews,1982

R: “at random”. Noother information.AC: sealed envelopes(B)FU: 13% excluded(C)B: none

40 women withsingleton pregnancyat 26 to over36 weeks, withproteinuric HT (DBP90–109 mmHg +>trace proteinuria)and asymptomatic

Rest: admission forstrict bed restControl: allowed tomove around theward

Both groups:pedometer

Women: plasma ureaand urate; serumhuman placentallactogen andoestriol; imminenteclampsia; HT;proteinuria; mode ofdeliveryBaby: perinataldeath, gestation atbirth, BW, SGA

Setting: two UKhospitals. Datafor perinataldeath includedin review, otheroutcomes onlyfor 10 high-riskwomen

AC, allocation concealment; APH, antepartum haemorrhage; B, blinding; BP, blood pressure; BW, birthweight; DBP, diastolicblood pressure; Exp, experimental; FU, follow-up; HT, hypertension; IOL, induction of labour; NICU, neonatal intensive care;NND, neonatal death; PE, pre-eclampsia; R, randomisation; SCBU, special care baby unit; SGA, small for gestational age.

TABLE 84 Trial details of exercise or other physical activity for preventing pre-eclampsia and its complications


USA, 1997 R: random numbertable, blockedAC: opaque sealedenvelopes (A)FU: 4 (12%)excluded (C)B: for participantsnot possible, forcaregiver andoutcome assessor no

33 women<34 weeks’gestation withgestational diabetes.Excluded: any othermedical or obstetriccomplications (notspecified), unable toread/write English,current exerciseregimen for30 minutes>2×/week

Exercise:moderate/hardintensity (70% max.heart rate) for30 minutes×3–4/week untildelivery (5 minutes’warm up,20 minutes’ steadystate, 5 minutes’ cool down). Cycleergometer 2supervised sessions+ walking or cyclingunsupervised×1–2/week Control: usualphysical activity

Both groups: dietarycounselling

Woman: PIH,Caesarean section,blood glucose(mean), Hb A1Clevel, need forinsulin,cardiorespiratoryfitness, weightchange Baby: preterm birth,gestation at birth(mean), FHRpatterns duringexercise, birthweight(mean and >4 kg),Apgar (median)

144 womenscreened: 40 not eligible,68 declined, 3 exerciserecommendedby carer. Goodcompliance withexercise

USA, 2000 R: random numbertableAC: sealednumbered opaqueenvelopes (A) Follow-up: no losses(A)Blinding: forparticipants notpossible, forcaregiver notreported, foroutcome assessoryes

16 women�18 years, at18 weeks’ gestationwith either mild HT,or history or familyhistory ofhypertensivedisorders ofpregnancy.Excluded: renaldisease, diabetes,multiple pregnancy,and vigorousexercisers with RPE>14

Exercise: 45 minutes’moderate (RPE =13) intensity exercise×3/week for10 weeks (warm up5 minutes, steadystate 30 minutes,and cool down10 minutes). Atexercise laboratoryunder supervision,on bicycle andtreadmill Control: normal dailyphysical activity

Woman: PIH, pre-eclampsia, severehypertension, changein SBP and DBP over10 weeks, change inpercentage body fat(mean) Child: preterm birth,small for gestationalage, death

Goodcompliance withexerciseprogramme

DBP, diastolic blood pressure; FHR, foetal heart rate; Hb, haemoglobin; PIH, pregnancy-induced hypertension; RPE, rating ofperceived exertion; SBP, systolic blood pressure.


179


TABLE 85 Trial details of rest during pregnancy for women with normal blood pressure


Herrera,1993

R: computer-generatedAC: closedenvelopes, no otherinformation (B)FU: not reportedB: for participantsand caregivers yes,for outcomeassessor notreported

74 primigravidwomen at28–29 weeks’gestation, withnormal BP, positiveroll-over test andMAP �80 mmHg

Rest: advised rest athome in left lateralposition for15 minutes ×2/day,plus oral supplement×3/week (soyprotein 25 g, calcium300 mg, linoleic acid300 mg)Control: no adviceto rest, placebo×3/week (ferroussulfate 105 mg)

Both groups: untildelivery

Woman: gestationalHT (BP �140/90 ×2, 6 h apart), PE(gestational HT +>0.5 g/l proteinuria),Caesarean sectionBaby: gestation atbirth (mean),birthweight (mean)

Compliance: noinformation.

Conducted inColombia

Spinapolice,1983

R: computer-generated AC: closedenvelopes, no otherinformation (B)FU: not reportedB: of participants notpossible, ofcaregivers no, ofoutcome assessornot reported

32 nulliparouswomen at28–32 weeks’gestation withnormal BP andpositive roll-overtest

Rest: advised rest athome in left lateralrecumbent positionfor 4 h/day untildelivery. If MAPincreased�9 mmHg, restincreased to 6 h/dayControl: no adviceto rest

Both groups: seenevery 2 weeks

Woman: gestationalHT (BP �140/90 orincrease by30/15 mmHg ×2 atleast 6 h apart), PE(not defined),induction of labour,mode of deliveryBaby: gestation atbirth (mean),birthweight (mean),Apgar (mean)

Data for bothgroups onlyreported forgestationalhypertensionand PE

Compliance:rest grouphome visits bynurse ×3/week

Conducted inUSA

AC, allocation concealment; B, blinding; BP, blood pressure; Exp, experimental; FU, follow-up; HT, hypertension; MAP, meanarterial pressure; PE, pre-eclampsia; R, randomisation.

Appendix 9

180

TABLE 86 Trial details of altered dietary salt for preventing pre-eclampsia, and its complications


TheNetherlands,1997

R: method not statedAC: “closedenvelope system”,no other information(B)FU: 28 (10%)excluded (B)B: for participants no,for caregivers andoutcome assessornot reported

270 nulliparouswomen withsingleton pregnancyafter 12 weeks, bydates and ultrasound. Excluded: pre-existing HT, diabetes,renal disease,cardiovasculardisease

Low: diet with about20 mmol sodium perday. Oral and writteninstruction bydietician, no addedsalt and ready-madefoods only if no saltin preparation Normal: no dietaryrestriction

Woman: PIH, PE,severe HTBaby: death, SGA,preterm delivery

2 hospitalclinics. Mean urinarysodium afterrandomisation70 mmol/daylow-sodiumgroup,135 mmol/daynormal diet

TheNetherlands,1998

R: random numbersin blocks of 10.Stratified by centreAC: sealednumbered opaqueenvelopes (A)FU: no losses (A)B: for participants no,for caregiver only tourinary sodiumconcentration, foroutcome assessornot reported

361 women bookedfor midwifery care,nulliparous, DBP<90 mmHg atbooking visit<20 weeks.Randomised if dBP>85 ×2 insubsequent visit, orweight gain>1 kg/week 3consecutive weeks,or excess oedemaExcluded: planningto leave city, or riskfactors for PIH

Low: sodium-restricted diet,aimed at<50 mmol/dayWritten dietaryinstructions given bymidwife Normal: asked notto change eatinghabits

Woman: highest DBP,PE, eclampsia,hospital referrals andadmissions for HT,time to delivery,abruption, mode ofdeliveryBaby: death,gestation at birth(mean), birthweight,Apgar, NICUadmission

9 centres,midwiferypractices andhospital clinic. Mean urinarysodium afterrandomisation84 mmol/daylow-sodiumgroup,124 mmol/daynormal diet

AC, allocation concealment; B, blinding; DBP, diastolic blood pressure; HT, hypertension; NICU, neonatal intensive care unit;PE, pre-eclampsia; PIH, pregnancy-induced hypertension; SGA, small for gestational age.


181


TABLE 87 Trial details of antioxidants for preventing pre-eclampsia and its complications


Chappell,1999

R: computer-generated list, blocksof 10 AC: in hospitalpharmacy (A)FU: complete B: for caregivers andresearchers yes

283 womenbetween 16 and22 weeks’ gestationwith abnormalDoppler waveformat 18–22 weeks’gestation or pasthistory of PEnecessitating delivery<37 weeks’,eclampsia or HELLPsyndrome Excluded: heparin orwarfarin treatment,abnormal foetal-anomaly scan,multiple pregnancy

Antioxidant:1000 mg vitamin C+ 400 IU vitamin Edaily Control: identicalplacebo

Woman: PAI-1:PAI-2ratio, PE (definedaccording to ISSHP),abruption,spontaneouspreterm delivery(<37 weeks), SBPand DBP beforedelivery, biochemicalindices of oxidativestress and placentalfunctionBaby: stillbirth, SGA(10th centile),gestation at birth,birthweight

Location: UK1512 womenscreened, 273had abnormalDoppler, 242consented. 41with history ofPE alsoconsented. Of283randomised,160 completedprotocol

Han, 1994 R: “divided into twogroups randomly”,no other informationAC: unclear (B)FU: no reportedlosses B: for participantsyes, for carers oroutcome assessorsnot stated

100 women with“high risk factors ofPIH”. No otherinformation

Antioxidant:100 �g/day selenium,as a “natural dieteticliquid” for 6–8 weeks“during latepregnancy”Control: placebo,given in “the samemanner”

Women: change inmaternal andumbilical bloodselenium, change inSBP and DBP, PIH(not defined),oedema, proteinuria,side-effectsBaby: birthweight

Compliance:unclear, noinformation Location: China

People’sLeague, 1942

R: “divided into twogroups by placingthem alternatively onseparate lists” AC: (C)FU: 622 (11%)women excluded:494 evacuated, 39 twins and 89 miscarried B: no information

5021 women24 weeks’gestation, attendingantenatal clinics andin “good health” Excluded: anydisease or physicalabnormality

Antioxidant: 100 mgvitamin C inmultivitamin withferrous iron 0.26 g,calcium 0.26 g,minute quantities ofiodine, manganeseand copper,adsorbate of vitamin B1, halibutliver oil 0.36 gcontaining vitamin A(52,000 IU/g) andvitamin D(2500 IU/g) dailyControl: no placebo

Woman: “toxaemia”classified as HT only,proteinuria ± HT, orHT with proteinuria,sepsis.length of gestation,breastfeedingBaby: stillbirth, earlyneonatal death,birthweight

Compliance:unclear, noinformation Location: UK

continued

Beazley, 2002 R: “randomised”, noother information AC: no information(B)FU: 9 (8%) womenlost to follow-upB: “double blind”stated

109 womenbetween 14 and20 weeks’ gestationat “high risk of PE”,based on previousPE, chronic HT,diabetes mellitus andmultifoetal gestation

Antioxidant:1000 mg vitamin C+ 400 IU vitamin Edaily Control: placebo, noother details

Woman: PE (notdefined)Baby: gestation atbirth (mean),preterm birth(<37 weeks),birthweight(<10 centile)

Compliance: noinformation Location: USA

Appendix 9

182

TABLE 87 Trial details of antioxidants for preventing pre-eclampsia and its complications (cont’d)


Rivas, 2000 R: “randomly dividedinto two subgroups”AC: unclear (B)FU: no lossesreported B: stated “tripleblind”, but no otherdetails

127 women<29 weeks’gestation with “highrisk for PE”,including nulliparity,previous PE, obesity,HT, <20 years old,diabetes,nephropathy, meanarterial pressure>85 mmHg, positiveroll-over test, blackrace, family historyHT or PE, twinpregnancy and poorsocio-economicconditions

Antioxidant: 500 mgvitamin C and 400 IUvitamin E/day, plus1 g fish oil ×3/ dayand 100 mg aspirin×3/week Control: placebo,given “at the sameposology andpresentation”

Women: PE (notdefined)

Compliance: noinformation Location:Venezuela Published inabstract formatonly

Sharma, 2003 R: computergeneratedAC: numberedopaque envelopes(A)FU: no lossesreported B: for women,caregivers, researchstaff and outcomeassessors yes

251 primigravidasbetween 16 and20 weeks with nomedical complicationsuch as renal disease,primary HT,cardiovasculardisease, diabetes orconnective tissuedisease

Antioxidant: 2 mglycopene ×2/day untildelivery Control: placebo,similar tablets

Woman: PE (definedaccording to ISSHP),eclampsia, DBP(mean)Baby: IUGR (<10thcentile), birthweight

Compliance:assessed by pillcounts, but nootherinformation Location: India

Steyn, 2002 R: by drug companyAC: numberedcontainers, codeheld by drugcompany (A)FU: no lossesreported B: stated “doubleblind”

200 women<26 weeks’gestation withhistory of previouspreterm birthExcluded: previousiatrogenic pretermlabour, multiplepregnancy, provencervicalincompetence, otherreasons for pretermlabour

Antioxidant: 250 mgvitamin C ×2/dayuntil 34 weeks’gestation Control: “exactmatching” placebo

Women: PE, HT,APH (includingabruption), pretermlabour, gestation atdeliveryBaby: birthweight(median),miscarriage, stillbirth,neonatal death,length of stay inhospital

Trial stoppedearly byindependentpanel as“furtherrecruitment willnot haveresulted in asignificantdifference” Compliance:not reported Location: SouthAfrica

AC, allocation concealment; B, blinding; FU, follow-up; HELLP, haemolysis, elevated liver enzymes and low platelets; HT, hypertension; IP, isoprostane; IQR, interquartile range; ISSHP, International Society for the Study of Hypertension inPregnancy; PAI-1, plasminogen activator inhibitor-1; PAI-2, plasminogen activator inhibitor-2; PE, pre-eclampsia; PIH,pregnancy-induced hypertension; RDI, recommended daily intake; SGA, small for gestational age; TAS, total antioxidantstatus.


183


TABLE 88 Trial details of calcium supplementation during pregnancy for preventing hypertensive disorders and related problems


continued

Belizan, 1991 R: not statedAC: numbered,sealed opaqueenvelopes (A)FU: 29 (2%) lost,incomplete data for98 (8%)

1194 nulliparouswomen, <20 weeks;BP <140/90 mmHg(mean of 5measurements); nopresent or pastdisease; not takingmedication; normaloral glucosetolerance tests

Calcium: 2 g, as 500-mg calciumcarbonate tabletsControl: identicalplacebo

Women: gestationalHT (DBP �90, SBP�140 mmHg, ×2 6 hapart); PE(gestational HT +proteinuria >0.3 g/l)Baby: perinataldeath, BP >95thpercentile for sex,age and height at age5–9 years

Three hospitalsin Rosario,Argentina Compliance:85%Long-termfollow-up of

Crowther,1999

R: computergenerated, stratifiedby centre, variableblocksAC: telephone (A)B: double-blind

456 nulliparouswomen; singletonpregnancy;<24 weeks’gestation; BP<140/90 mmHgExcluded:antihypertensivetherapy;contraindication tocalciumsupplementation

Calcium: calciumcarbonate 1.8 g/dayuntil deliveryControl: placebo

Woman: PIH (DBP�90 mmHg ×2 4 hapart, or 110 mmHgonce); PE (as aboveplus proteinuria�0.3 g/24 h or �2+protein ×2); Baby: preterm birth(<37 weeks,<32 weeks;<28 weeks)

5 hospitals inAustralia. Trialstoppedprematurely forfinancial reasons Compliance:31% calciumgroup and 24%placebostopped takingthe tablets

Lopez-Jaramillo,1989

R: random numbersAC: not stated (B)FU: no losses

106 nulliparouswomen age25 years; certainmenstrual dates;<24 weeksgestation;normotensive; nomedical disorders;not takingmedication orvitamin/mineralpreparations

Calcium: 2 g ascalcium gluconate500 mg ×4/day untildeliveryControl: identicalplacebo

Women: gestationalHT (BP�140/90 mmHg, orrise 30 mmHgsystolic or 15 mmHgdiastolic, ×2 6 hapart); weeklyweight gainBaby: birthweight;length of gestation

Conducted inEcuador

CPEP, 1997 R: computer-generated AC: numberedtreatment packs (A)FU: 253 (6%) lost

4589 nulliparouswomen at13–21 weeks whopassed compliancetest; BP �134/84mmHg; proteindipstick negative ortrace Excluded: takingmedication;absorption ormetabolism ofcalcium; elevatedserum creatinine orcalcium; renaldisease; haematuria;history or familyhistory of urolithiasis

Calcium: 2 g/day ascalcium carbonateuntil delivery or PEControl: placebo. Both groups: 50 mgcalcium/day andasked to drink 6glasses of water/day

Woman: gestationalHT (DBP�90 mmHg ×2occasions 4 h–1 week apart);proteinuria(�300 mg/24 h,�2+ or more,protein/creatinineratio �0.35); PE(gestational HT +proteinuria); renalinsufficiency;urolithiasis Baby: prematurity(<37 weeks); smallfor gestational age;perinatal death

5 US universitycentres Compliance:64% calciumgroup, 67%placebo group

Appendix 9

184

TABLE 88 Trial details of calcium supplementation during pregnancy for preventing hypertensive disorders and related problems (cont’d)


continued


R: randomised, “eachpatient was assignedindependently insequence” AC: not stated (B)FU: no losses B: double-blind

56 nulliparous high-risk women withpositive roll-overtest at 28–30 weeks’gestation

Calcium: 2 gelementalcalcium/day untildeliveryControl: placebo

Women: gestationalHT (BP>140/90 mmHg ×26 h apart);proteinuria(300 mg/l) Baby: birthweight,gestation at birth

Conducted inEcuador.Discrepancy insize of groupsnot accountedfor


R: randomisedAC: (A)FU: 14 (5%) lostafter randomisationB: double-blind

274 nulliparouswomen with lowcalcium intake;<20 weeks’gestation; certainmenstrual dates; BP�120/80 mmHg; nounderlying medicaldisorders; no drug,mineral or vitamintherapy

Calcium: 2 g/day ascalcium carbonatePlacebo: placebo

Women: PE (BP>140/90 mmHg ×2 > 6 h apart +proteinuria>300 mg/L or >1+×2 4–24 h apart) Baby: gestation atbirth

Conducted inEcuador

Niromanesh,2001

R: “randomlyassigned”, no otherinformationAC: coded bypharmacy (A)FU: no lossesB: double-blind

30 high-risk womenwith positive roll-over test and at leastone risk factor forPE; 28–32 weeks’pregnant; BP<140/90 mmHg Excluded: chronicmedical conditions

Calcium: 2 g daily(500 mg 6-hourly)Control: placebo

Woman: PE:duration ofpregnancy; weeklymaternal weightincreaseBaby: birthweight

Sanchez-Ramos, 1994

R: computer-generated listAC: (A)FU: 4 (6%) lostB: double-blind

67 normotensivenulliparas; positiveroll-over test andpositive angiotensin IIinfusion test at20–24 weeks’gestationExcluded: renaldisease, collagenvascular disease,diabetes mellitus,chronic HT,multifoetal pregnancy

Calcium: 2 g/day as500 mg calciumcarbonate ×4Control: placebo

Women: gestationalHT (BP�140/90 mmHg ×24–6 h apart); PE(gestational HT +proteinuria: 1+ or 300 mg/24 h);severe PE Baby: birthweight;gestation at birth(mean) Apgar; cordarterial pH, foetalgrowth

Conducted inUS, universityhospital servinglow-incomepopulation.Compliance was 80%

Purwar, 1996 R: computer-generated listAC:, (A)FU: 11 (5.5%) lostto follow-upB: double-blind

201 nulliparouswomen; singletonpregnancy;<20 weeks; normalglucose tolerance test;no HT; no underlyingmedical disorder Excluded: renaldisease; collagenvascular disease;chronic HT;endocrinologicaldisease; takingmedication

Calcium: 2 g dailyControl: placebo

Woman: gestationalHT (SBP>140 mmHg andDBP >90 mmHg, ×2 6 h apart), PE(HT + proteinuria�0.3 g/24 h)

Conducted inIndia


185


TABLE 88 Trial details of calcium supplementation during pregnancy for preventing hypertensive disorders and related problems (cont’d)


BP, blood pressure; CI, confidence interval; DBP, diastolic blood pressure; SBP, systolic blood pressure; SEM, standard errorof the mean.

Villar, 1987 R: Random numbersAC: closedenvelopes (A)FU: no lossesB: double-blind

52 nulliparous orprimiparous;26 weeks’ gestation;age 18–30 years;singleton pregnancy;negative roll-overtest Excluded: underlyingmedical disorders

Calcium: calciumcarbonate 1.5 g(500-mg tablets) Control: placebo

Woman: weight gainin last trimester; BPincrease; gestationalHT

Conducted inUSA andArgentina Women in USalso receiveddaily vitamintabletscontaining200 mg calcium

Villar, 1990 R: computer-generated list AC: opaquenumbered envelopes(A)B: double-blind

178 women17 years; nounderlying medicaldisorder; singletonpregnancy

Calcium: 2 g as500 mg calciumcarbonate ×4Control: placebo

Woman: pretermdelivery(<37 weeks)Baby: birthweight<2500 g; postdates>42 weeks;impaired foetalgrowth; prematurerupture ofmembranes; Apgar

Conducted inUSA

All womenprescribedvitamin tabletscontaining200 mg calcium

WHO, 2006 R: stratified bycentre, computer-generated blocks of6–8AC: consecutivelynumbered treatmentpacks (A)FU: 13 (0.2%) lost.298 (4%) with somedata B: double blind

8325 primiparouswomen <20 weeks’gestation. Lowcalcium intake Excluded: renaldisease, urolithiasis;parathyroid disease;SBP >140 mmHg orDBP >90 mmHg;history of HT;antihypertensivetherapy; diuretic,digoxin, phenytoin ortetracyclinetreatment

Calcium: 1.5 g aschewable calciumcarbonate 500 mg×3/day until deliveryControl: identicalplacebo

Woman: PE (DBP�90 mmHg or SBP�140 mmHg, plusproteinuria 2+ or300 mg/day); severePE, PIH, eclampsia;abruptionBaby: preterm birth(<37 weeks).birthweight<2500 g; admissionNICU for >2 days;stillbirth, deathbefore dischargefrom hospital

Centres inArgentina,Egypt, India,Peru, SouthAfrica andVietnam. 14,362 womenscreened, 8325randomised.Treatmentcompliance84.5% and86.2%,respectively.Baselinecharacteristicswell matched

Appendix 9

186

TABLE 89 Trial details of garlic for the prevention of pre-eclampsia and its complications


AC, allocation concealment; B, blinding; FU, follow-up; R, randomisation sequence.

Iran, 2001 R: “randomlydivided”, no otherinformationAC: no information(B)FU: noneB: participants only

100 primigravidwomen between 28and 32 weeks’gestation with apositive roll-overtest

Garlic: 2 garlictablets/day, total800 mg/day (drypowder with1000 �g allicin ineach tablet) for8 weeksControl: 2 placebotablets for 8 weeks

Woman:hypertension, pre-eclampsia, weightgain (mean),Caesarean section,garlic odour, side-effects, plasma lipidlevels, plateletaggregation Baby: perinataldeath, gestation atbirth (mean),birthweight (mean),Apgar

300 womenscreened, 100recruited

Tablets statedto be odourcontrolled

Conducted inIran

TABLE 90 Trial details of energy and protein intake in pregnancy


Atton, 1990 Alternate allocation 148 non-obese Asianwomen with tricepsskinfold thickness<2 mm from 18 to28 weeks

Flavoured milksupplement withenergy and proteinControl: normal diet

Mean gestationalage, birth weight,length, headcircumference

25 non-compliersexcluded

Badrawi,1993

Allocation methodnot reported

100 obesemultiparous Egyptianwomen aged25–35 years

Balanced low-energydiet Control: normal diet

Gestational weightgain, birth weight,PIH

Criteria forobesity notreported

Blackwell,1973

Interventionsassigned “randomlyand blindly”,methods notspecified

Well nourishedTaiwanese with“marginal diets”

Chocolate-flavouredsupplement withprotein, energy andvitamins/mineralsControl:vitamins/mineralsonly, same time andduration

Gestational weightgain, preterm birth,SGA, length, headcircumference, IQ atage 5 years

High allegedenergysupplement notassociated withhighergestationalweight gain

Briley, 2002 R: not reported, noblinding

27 low-incomeAfrican-Americanwomen

Minimum 6 homenutrition assessmentand counsellingControl: two homevisits withoutcounselling

Energy intake,gestational weightgain, birthweight,preterm birth

7/27 droppedout and notincluded inanalyses

Campbell,1975


153 Scottish womenwith high gestationalweight gain between20 and 30 weeks

Low-energy dietstarting at 30 weeksControl: nointervention

Gestational weightgain, PIH, PE

No report oncompliance

continued


187


TABLE 90 Trial details of energy and protein intake in pregnancy (cont’d)


continued

Campbell,1983


182 obeseprimiparous Scottishwomen with normalIVGTT at 28 weeks

Low-energy dietControl: nointervention

Gestational weightgain, birth weight,birth length, pretermbirth, PE

Girija, 1984 Alternate allocation 20 poor Indianwomen in lasttrimester

Energy and proteincakeControl: normal diet

Gestational weightgain, birth weight,length, headcircumference,breast milk output

No informationon compliance

Hankin, 1962 Allocation by weekday

149 primi- andsecundigravidAustralian women, at first clinic visit<20 weeks

Advice to improveprotein in dietControl: no advice

Protein and energyintake, PE

13 lost tofollow-up

Iyengar, 1967 Allocation methodnot reported

25 low SES Indianwomen 25–40 years,low energy andprotein diet

Hospitalisation +energy, protein, iron,vitamin supplementControl: samewithout protein

Gestational weightgain, birthweight

No informationon total numberallocated totreatments andlosses to follow-up

Hunt, 1976 R: not reported 344 Spanish womenat <21 weeks

Nutrition classes,control no class

Protein and energyintake

65 lost tofollow-up

Elwood, 1981 R: random numbersin sealed envelopes

1251 Welsh womenin two towns at firstreporting ofpregnancy

Free tokens of 1/2pint milkControl: no tokens

Gestational age,preterm birth, lowbirth weight, length,head circumference

24% loss tofollow-up, highin controls

Campbell-Brown, 1983

Strict alternateallocation

180 (90 matchedpairs) Aberdeenprimipara at high riskfor low birth weightdelivery becauseshort, thin or lowweight gain

Milk or cheesesupplement startedat 29 weeksControl: normal diet

Gestational weightgain, preterm birth,birth weight, length,head circumference

Gestational agebiased byreplacement ofwomendelivering<37 weeks

Ceesay, 1997 Cluster randomisedby village usingstratified designaccording to villagesize. R not given

Rural Gambianwomen from 28villages with chronicmarginal nutrition

Energy, protein,calcium, ironsupplement biscuitseaten daily inpresence of birthattendants, from20 weeksControl: nosupplement

Gestational weightgain, gestational age,birth weight, headcircumference,stillbirth, neonataldeath

Effects reportedby individualbirth notcluster, resultsin reviewadjusted by1 + (n – 1)r,where r = 0.01

Appendix 9

188



continued

Kafatos, 1989 R: 20 clinics usingcomputer-generatedrandom numbers

568 rural Greekwomen, <27 weeks

Nutrition counsellingControl: nocounselling

Energy and proteinintake, gestationalweight gain,birthweight, birthlength, headcircumference,gestational age, LBW,SGA, preterm birth,stillbirth, neonataldeath

Analysis basedon individualwomen, resultsin reviewadjusted by1 + (n – 1)r,where r = 0.01

Kardjati, 1988 “Blind”randomisation basedon householdnumbers usingrandom numbertables

747 women in 3villages, Java, at 26–28 weeks,nutritionallyvulnerable

Energy and proteinsupplementControl: low-energysupplement

Gestational weightgain, birth weight,breast milk output

Mardones,1988

Alternate allocation Low-income Chileanwomen, <20 weekswith low weight forheight at first visit

High proteinsupplementControl: normalprotein supplementwith iron

Gestational weightgain, birth weight,head circumference,IUGR, LBW,gestational age,preterm birth,stillbirth, neonataldeath

Large losses tofollow-up

Mora, 1978 Allocation methodnot reported

456 poor first- orsecond-trimesterBogota slumresidents

Energy and proteinsupplement from 3rdtrimesterControl: normal diet

PE, gestational age,preterm birth, birthweight, LBW,stillbirth, perinatalmortality, neonatalmortality

Complianceassessed butresults notpresented,results odd

Ross, 1938 Alternate allocation,no blinding

56 young, poorprimipara, USwomen with‘marginal’ diets

Protein, energy andiron supplementControl: regular diet

PE, gestationalweight gain

Very high PErate, noinformation oncompliance

Ross, 1985 Allocation methodnot reported

127 black womenfrom South Africa,<20 weeks

Energy and proteinsupplementControl: placebo pills

Gestational weightgain, gestational age,birth weight

No informationon compliance,10% loss tofollow-up

Sweeney,1985

Stratifiedrandomisation using“biased coinmethodology”,probably not blinded

47 healthy women,<20 weeks

Advice on proteinand energy intakeControl: no advice

Protein and energyintake, gestationalweight gain, birthweight, gestationalage

Rush, 1980 Stratifiedrandomisation basedon random numbertable, sealedenvelope andblinding of allresearch staff

1051 low-incomeblack women, NewYork, USA,<30 weeks at riskfor low birth weight

1. Balanced energy,protein, vitamin andmineral supplement2. High-protein,vitamin and mineralsupplementControl: vitamin andmineral only

Gestational weightgain, gestational age,preterm birth, SGA,birth weight, LBW,stillbirth, neonatalmortality

25% loss tofollow-up


189




AC, allocation concealment; B, blinding; FU, follow-up; IVGTT, intravenous glucose tolerance test; LBW, low birth weight; R, randomisation sequence.

Viegas, 1982b Allocationmethod notreported

130 Asian UK women,<20 weeks?,nutritionally adequate

Protein, energy andvitamin supplementControl: iron andvitamin C

Gestational age,gestational weight gain,birth weight, length,head circumference

No informationon compliance

TABLE 91 Trial details of magnesium supplementation during pregnancy


AC, allocation concealment; B, blinding; FU, follow-up; Mg Asp HCI, magnesium aspartate hydrochloride; R, randomisationsequence.

Angola,1992

R: according to randomnumber table, placebo(olive oil)Non-blinded outcomeassessmentPost-randomisationexclusions not stated

100 primi- and multi-parous women aged14–40 years

500 mg magnesiumoxide daily from4 months gestation

PE, LBW Placebo group hadbetter diet thantwo treatmentgroups

Austria,1997

R: computer-generatedlist, no placebo, non-blinded outcomeassessment, 7.5% post-randomisationexclusions

530 women withnon-risk pregnancies

15 mmol magnesiumcitrate

Preterm labour,LBW

China,1997

R: not stated, separatefor high- and low-riskpregnancies, blindedoutcome assessment, no post-randomisationexclusions

52 women high-risk,50 low-riskpregnancies aged24–35 years

2 g/day magnesiumgluconate from28–30 weeks then3 g/day to delivery

Pregnancy-inducedhypertension

Hungary,1988

R: cluster 8 magnesium,7 placebo centres,blinded outcomeassessment, 13% post-randomisation exclusions

985 women withsingle pregnancies

15 mmol/daymagnesium aspartateat 6–21 weeks untildelivery

Preterm birth,IUGR, lowbirthweight

High non-compliance rate

Mississippi,1992

R: method not given,placebo, blindedoutcome assessment,13% post-randomisationexclusions

54 women with riskfactors for pretermdelivery

4 g magnesiumgluconate/day fromapprox. 23 weeks’gestation

Preterm labour

Zurich,1988

R: based on subjects’date of birth, placebo,blinded outcomeassessment, 1% post-randomisation exclusions

568 women at16 weeks’ gestationwith normal andhigh-risk pregnancies

15 mmol magnesiumaspartate HCl/dayfrom 16 weeks todelivery

PE, pretermlabour, gestationalage at delivery,LBW

Memphis,1989

R: computer-generated,placebo, allocation bypharmacy, blindedoutcome assessment,7% post-randomisationexclusions

400 normotensive,primigravid womenaged 13–25 years

365 mg elementalmagnesium as MgAsp HCl daily from13–24 weeks todelivery

BP, PE All women alsoreceived vitaminsupplements whichincluded 100 mgmagnesium and200 mg calcium/day

Appendix 9

190

TABLE 92 Trial details of marine oil and other prostaglandin supplementation during pregnancy


continued

Angola, 1992 R: random numbertableAC: no information(B)FU: not reportedB: Outcomeassessments partiallyblinded – olive oil andevening primrose oil+ fish oil capsulesidentical, but bothdifferent tomagnesium oxide

100 primiparous andmultiparous women,14–40 years and16 weeks’gestation

Marine oil: 8capsules/day eveningprimrose oil + fishoil (providing 296 mgGLA, 144 mg EPA,80 mg DHA/day) Control: 8 capsulesolive oil/day

Women: PIH,oedema, PE,eclampsia. Babies:birthweight(<2000 g and>2000 g)

No estimate ofsample size isgiven. Reporteddietary intake ofwomen at studyentry was poor. 3-arm study – 50women allocatedmagnesium oxideexcluded from thisreview

Europe, 2000 R: “packages orderedin a random way as tooil type”AC: “randomisationidentified a packagenumber at therelevant centre” (A)FU: 3% excluded (A)B: participants andoutcome assessmentsblinded, but aquestionnaire

Subset A–Drecruited 1477women at16 weeks’gestation. Subset Aincluded 232 womenwith a previouspreterm birth.Subset B included280 women withprevious IUGR.Subset C included

Marine oil: fish oil(1.3 g EPA and 0.9 gDHA/day), given as 4 capsules/day. Control: matchingolive oil capsules

Subset A:preterm birth,low birthweight.Subset B: small-for-gestationalage, lowbirthweight.Subset C: PIHand PESubset D:preterm birth,small for

Multicentre studywith 6 subsets(A–F). Each had astandard protocol,and were mutuallyexclusive. SubsetsA–D included inthis review

Sample sizeestimates weremodified during thecourse of the study

Denmark,1992

R: 3-arm trial in aratio of 2:1:1AC: sealed, opaqueenvelope containing arandomisationnumber (A)FU: complete (A)B: patients andoutcome assessmentwas blinded, but 85%of women in the fishoil group and 50% inthe olive oil groupcorrectly identifiedtheir group allocation

533 women,approximately30 weeks’ gestation,aged 18–44 years. Excluded: history ofplacental abruption,serious bleed incurrent pregnancy,use of prostaglandininhibitors, multiplepregnancy, fishallergy or regularintake of fish oil

Marine oil: fish oil(2.7 g n-3 fattyacids/day) given as 4 × 1-g capsules/day. Control: either 4 × 1-g capsulesolive oil/day or nosupplement

Women: SBP,DBP, PIH, PE.Babies: durationof gestation,birthweight, birthlength

Sample sizeestimates weredone but notreported in thepapers becausethey wereregarded as post-festum by authors(personalcommunication). Women completedbaselineinformationregarding fishintake

England,1995

R: computer-generated randomnumbersAC: sealed, opaque,numbered envelopesin hospital pharmacy.Pharmacy staffallocated the trialtreatments (A)FU: 0.4% excluded(A)B: for participants andoutcome assessorsyes, for carers notstated

232 women at19–26 weeks withhigh-risk singletonpregnancy: history of1 or more smallbabies (birthweight<3rd centile),pregnancyhypertension,unexplained stillbirth,or a primigravidawith abnormaluterine Doppler at24 weeks’ gestation

Marine oil: fish oil(2.7 g ofMaxEPA/day) givenas 9 capsules/day(provided 1.62 g EPAand 1.08 g DHA/day) Control: matchingair-filled capsules. Treatment stoppedat 38 weeks’gestation

Women: PIH, PEBabies:birthweight <3rdcentile

Sample sizeestimate is givenfor proteinurichypertension.All women wereasked to avoidNSAIDsCompliance: 50%of women in thefish oil group and57% of women inthe placebo grouptook <70% ofcapsules


191


TABLE 92 Trial details of marine oil and other prostaglandin supplementation during pregnancy (cont’d)


AC, allocation concealment; B, blinding; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; FU, follow-up; GLA, �-linolenic acid; IUGR, intrauterine growth restriction; PE, pre-eclampsia; PIH, pregnancy-induced hypertension; R, randomisation sequence.

indicated 80% ofwomen in fish oilgroup could guesstheir allocation

386 women withprevious PIH. SubsetD included 579women with twins.All subsets excludedwomen withdiabetes mellitus,severe foetalmalformation,previous placentalabruption, drug oralcohol abuse, use ofNSAIDs, use of fishoil or fish allergy

gestational age,low birthweight.For the combinedsubsets:prolongedgestation,maternalmorbidity andmortality, infantmorbidity

Subsets E–Fexcluded as“therapeutic” –women with PE (E)or suspected IUGR(F)

TheNetherlands,1994

R: randomisationperformed by hospitalpharmacy. No otherinformationAC: unclear (B)FU: 7.3% excluded(B) B: participants andoutcome assessorswere blinded

63 women at12–14 weeks’gestation with ahistory of IUGR,±PIH in the previous(index) pregnancy

Marine oil: 3 gEPA/day, given as 12capsules/day. Eachcapsule contained250 mg EPA. Noinformation aboutthe DHA content ofthe capsules.Control: 12 capsulescoconut oil/day

Women:pregnancyinducedhypertensionBabies:birthweight<10th percentile

Sample sizeestimate was basedon the firstrandomised studyof aspirin in high-risk pregnancies

USA, 2003 R: computer-generatedrandomisationscheduleAC: unclear (B)FU: 17% excluded(C)B: for women, andoutcome assessorsyes, for carers, notreported

350 women withsingletonpregnancies,16–36 years,between 24 and28 weeks’ gestationat enrolment.Excluded if diabetic.Majority of womenwere sociallydisadvantaged andblack (73%)

Marine oil: DHA-enriched eggs. Eachegg had 133 mgDHA. Women wereasked to eat 12 eggsper week butreported eating5.5 per week.Control: ordinaryeggs. Each egg had33 mg DHA. Womenwere asked to eat12 eggs per weekbut reported eating5.4 per week

Women: durationof gestation Babies:birthweight

Initial sample sizewas 285, butincreased to 350after a blindedreview of the datawas undertaken,after that first 100births to refinepower analysis

Appendix 9

192

TABLE 93 Trial details of antihypertensive drug therapy for mild to moderate hypertension during pregnancy (versus placebo only)


continued

CaribbeanIslands,1990

R: not statedAC: women givennumbercorresponding tosealed envelope andtreatment batch.Envelope withallocation kept byinvestigator, onlyopened if necessary.Envelopes collectedat end of study (A)FU: 1 woman lost

155 women withsingleton pregnancyat 20–36 weeksgestation, DBP<85 mmHg ×2before 20 weeks and>84 mmHg after20 weeks.Excluded: type 1diabetes, congestiveheart failure, cardiacblock, asthma,prepregnancy HT,antihypertensivedrug during currentpregnancy

Exp: oxprenolol160–320 mg ×2/day.Hydralazine50–100 mg added ifnecessary to keepDBP <86 mmHg Control: Placebo,identical appearance

Women: death,mean BP, severe HT,proteinuria (>1+ or0.25 g/l), additionalantihypertensive,eclampsia, side-effects, electivedelivery, Caesareansection, hospitaladmission, abruption Babies: perinataldeath, preterm birth(<37 weeks),birthweight (mean),SGA (undefined),Apgar, admission toSCBU, RDS

Two centres.For 23 women(15%),treatmentunblinded andother treatmentstarted.Additional dataprovided byauthors

Hong Kong,1990

R: “randomiseddouble-blind” AC: not stated (B)

41 nulliparouswomen admitted forPE (BP�140/90 mmHg ×2within 24 h)

Exp: labetalol200 mg ×3/day.Control: placebo(character notstated)

Women: BP, severeHT, additional drug.Babies: birthweight(mean), SGA (<10thcentile), gestation atbirth (mean)

Trial reported asin progress in1990. Missingdata for somebabies. Availableonly as anabstract

Ireland, 1991 R: cards with “test”or “control” sealed inenvelopes, shuffledand then numbered insequenceAC: consecutiveenvelopes opened (B)

36 women<38 weeks’gestation, BP�140/90 mmHg ontwo separate days,no proteinuriaExcluded: If lived toofar from the hospitalto attend frequently

Exp: choice betweenatenolol50–100 mg/day ormethyldopa750–2250 mg/day. If necessary, twodrugs combined.Bendrofluazide2.5–5.0 mg added asa third agent whennecessaryControl: noantihypertensive

Women: MAP,proteinuria Babies: perinataldeath, Apgar,gestation at delivery,birthweight

Additional dataprovided byauthors

Israel, 1992 R: blocks of 6AC: trial drugsupplied by pharmacyin packs with serialnumbers (A)

60 women<35 weeks’gestation with DBP85–99 mmHg ×212 h apart, and notreatment for HTduring this pregnancyExcluded: multiplepregnancy, insulin-dependent diabetes

Exp: pindolol 5 mg×2/day. Increased ifnecessary to 10 mg×2/dayControl: identicalplacebo

If necessary,hydralazine addedfor pindolol group. Inplacebo group,pindolol given first,then hydralazine

Women: additionaldrug, days inhospital, proteinuria>2+ or >0.5 g/l,side-effects,Caesarean sectionBabies: perinataldeath, gestation atdelivery (mean),birthweight, Apgar,SGA (<10th centile),hypoglycaemia,jaundice


193


TABLE 93 Trial details of antihypertensive drug therapy for mild to moderate hypertension during pregnancy (versus placebo only) (cont’d)


continued

Italy, 1997 R: “randomlyallocated”AC: not stated (B)

100 primigravidwomen at26–36 weeks’gestation with SBP140–160 mmHg andDBP 90–110 mmHgand proteinuria<300 mg/24 h Excluded: if othermedical maternal orfoetal pathology

Exp: nifedipine40–120 mg/dayorally and bed rest Control: bed restalone

Women: severe HT,proteinuria, days inhospital beforedelivery Babies: Stillbirth,neonatal death,gestation at delivery(mean), birthweight,placental weight,SGA (undefined)

Italy, 1998 R: stratified by centreand type ofhypertensionAC: central telephone(A)FU: 22 (8%) lost.Follow-up of childrenat 18 months:190/252 (77%)responded to postalsurvey

283 women at12–34 weeks’gestation, withmild–moderate HT(DBP 90–110 mmHg×2 4 h apart) Excluded: chronicdiseases (diabetes,renal disease), foetalmalformation,previousantihypertensivedrug

Exp: slow releasenifedipine 20–80 mg×2/day orally.Control: noantihypertensive

Women: Severe HT,proteinuria,Caesarean section,admission tointensive careBabies: perinataldeath, birthweight,SGA (<10th centile),preterm birth,admission to SCBU,hyperglycaemia,jaundice, RDS, otherserious neonatalproblems

Multicentre, 33 hospitals Data fromfollow-upexcluded as>20% lost

South Africa,1991

R: cards in a boxAC: cards labelled Rand Q picked blindlyfrom a box, theseidentified drugcontainer (B)

32 women at12–30 weeks’gestation withsingleton pregnancy,BP �140/90 mmHg×2 at least 6 h apart,no proteinuria, noantihypertensivedrug, no other drugtreatment

Exp: prazosin1–5 mg ×3/dayControl: identicalplacebo

Women: severe HT,proteinuria,abruption, CaesareansectionBabies: perinataldeath, gestation atdelivery (mean),birthweight, SGA(<10th centile)preterm birth

The trialstopped early

Sweden,1984

R: not statedAC: telephonerandomisation, nofurther details (B)

52 women in clinic,<37 weeksgestation, singletonpregnancy, BP�140/90 mmHg orincrease of�30 mmHg SBP or15 mmHg DBP ×2within 24 h Excluded: imminenteclampsia, seriousfoetal distress,severe HT, Rhesusdisease, diabetes,“social orpsychologicalhandicaps”

Exp: metoprolol100–200 mg ×2/day Control: identicalplacebo ×2/day

Women: proteinuria�2+, severe HT,side-effects, hospitaladmission, abruption,Caesarean sectionBabies: perinataldeath, gestation atdelivery (mean),Apgar (mean)


Appendix 9

194



continued

Sweden,1985

R: not statedAC: “enveloperandomisation”. Nofurther details (B)FU: 7 (4%) lost

168 women in ward,singleton pregnancy,<37 weeks, DBP�90 mmHg ×2, no proteinuriaExcluded: diabetes,asthma, heartdisease, psychiatricor psychologicaldisorders

Exp: metoprolol50–200 mg/day +hydralazine50–300 mg/day Control: noantihypertensive

Women: severe HT,proteinuria (>1+ or0.25 g/l), side-effects,abruption, CaesareansectionBabies: stillbirth,neonatal death,preterm birth, SGA(undefined),bradycardia,hypoglycaemia,Apgar, RDS

Multicentre, not stated howmany hospitals.Additional dataprovided byauthors

Sweden,1995

R: “randomised bynumbers totreatment withcapsules” in blocks of 6AC: details ofallocation in sealedenvelopes, opened ifsevere complicationsor side-effects (B) FU: 7 (6%) lost

118 women at26–37 weeks,singleton pregnancy,DBP 95–110 mmHgExcluded: if deliveryexpected within1 week, alcohol ordrug abuse

Exp: isradipine (slowrelease) 5 mg ×2/dayControl: placebo×2/day

Women: eclampsia,severe HT (DBP�110 mmHg),proteinuria �2+,additional drug, MAP,Caesarean section,induction of labour,side-effectsBabies: perinataldeath, gestation atdelivery (mean),admission to SCBU,birthweight (mean)

6 centres

UK, 1968 R: “allocated atrandom”AC: not stated (B)

100 women withDBP �90 mmHg ormore ×2, 48 h apart

Exp: methyldopa250–1000 mg ×2/day+ bendrofluazide5–10 mg/day Control: notreatment

Women: mean BP,proteinuria, HT,length of gestation Babies: birthweight(mean), perinataldeath

Women dividedinto two groups:“moderate”,DBP�90 mmHg(n = 42) and“severe”, DBP�100 mmHg(n = 58). Formain outcomesresultspresentedtogether

UK, 1976 R: “randomlyallocated”AC: not stated (B)FU: 5 (2%) lost.Follow-up of 202 live-born children: at4 years 34 (17%) lostto follow-up; at7 years 7 (3%) lost tofollow-up

247 women with BP�140/90 mmHg if<28 weeks’gestation, or�150/95 mmHg if>28 weeks’gestation ×2 24 hapart Excluded: diabetes,multiple pregnancy,Rh immunisation.Women >36 weeksexcluded during 1styear of trial,thereafter excludedif >32 weeks

Exp: methyldopa750–4000 mg/day Control: noantihypertensive. Hydralazine if severehypertension

Women: severe HT,proteinuria,Caesarean section,elective delivery,side-effects Babies: perinataldeath, birthweight(mean), gestation atdelivery (mean), SGA (<2 SD belowmean), nursed in anincubator,neurodevelopmentat 4 and 7 years


195




continued

UK, 1982 AC: enveloperandomisation, no furtherinformation (B)

126 women witheither chronic HT or PIH, and DBP>95 mmHg if<20 weeks or95–109 mmHg if>20 weeks

Exp: labetalol100 mg ×2/day,increased tomaximum of1200 mg/dayControl: noantihypertensive. If necessary,hydralazine

Women: severe HT,proteinuria(undefined),Caesarean section,abruptionBabies: perinataldeath, SGA (<10thcentile)


UK, 1983 AC: “allocated indouble-blind andrandomised manner”(B)FU: some datamissing for 35 (29%).Data for eachoutcome onlyavailable for >80%.110 children (92%)seen at 1 year

120 women withPIH in thirdtrimester admittedfor bedrest, SBP140–170 mmHg andDBP 90–110 mmHg×2, 24 h apart

Exp: atenolol100–200 mg/day Control: placebo

Women: proteinuria(>0.5 g/24 h),severe HT, additionaldrug, side-effects,admission tohospital, CaesareansectionBabies: perinataldeath, SGA (<10thcentile), bradycardia,hypoglycaemia,jaundice, RDS. At1 year: cerebralpalsy, IQ, weight

UK, 1989 R: random numbersAC: trial drugsdispensed inpharmacy (A) FU: 8 (5%) lost

152 women inhospital at20–38 weeksgestation, SBP140–160 mmHg andDBP 90–105 mmHg×2, 24 h apart, noproteinuriaExcluded: history ofHT, renal, metabolic,cardiovascular,respiratory orcollagen disease

Exp: labetalol100–200 mg ×3/day Control: identicalplacebo

Women: mean BP,severe HT,proteinuria(undefined),induction of labour,Caesarean section,days in hospital(mean), side-effectsBabies: perinataldeath, preterm birth,SGA (<5th centile),admission to SCBU,RDS

5 centres

UK, 1990 R: “randomised”, noother informationAC: not stated (B)FU: 4 (12%) lost

33 women12–24 weeks’gestation with SBP140–170 mmHg andDBP 90–110 mmHg×2, 24 h apart

Exp: atenolol50–200 mg/dayControl: placebo(character notstated)

Women: mean BP,severe HT, side-effectsBabies: stillbirth,birthweight, SGA(<5th centile),gestation at delivery(mean)

The trial wasstopped earlywhen theprincipalinvestigator leftGlasgow.Additional dataprovided byauthors

Appendix 9

196



continued

UK, 1992 R: Stratified by parityAC: numbered sealedopaque envelopes (A)

114 women withsingleton pregnancyat 24–39 weeksgestation, DBP>90 mmHg for>24 h and noproteinuria Excluded:psychoneurosis,cardiac abnormality,diabetes, asthma,antenatal drugtreatment

Exp: labetalol100 mg ×2/day,increased up to400 mg ×3/day Control: noantihypertensive

Women: proteinuria(>1+ or 0.25 g/l),stay in hospital, side-effects, electivedelivery, CaesareansectionBabies: perinataldeath, gestation atdelivery (mean),preterm birth(<37 weeks), SGA(<5th centile),admission to SCBU,stay in hospital(mean)


USA, 1979 R: “allocatedrandomly” AC: not stated (B)

58 women with HTbefore pregnancy orBP �140/90 mmHg×2 more than 24 hapart before20 weeks Excluded: DBP>100 mmHg,nulliparous, othermajor medical orobstetric problem

Exp: methyldopa750–2000 mg/day,hydrochlorothiazide50 mg/day,hydralazine75–250 mg/day Control: noantihypertensive

Women: severe HT,proteinuria (>1+ or>300 mg/l in 24 h),Caesarean section Babies: perinataldeath, gestation atdelivery, birthweight<2500 g, foetaldistress, SGA(undefined)

In exp group 11women hadmethyldopa +hydrochloroth-iazide, 10hydralazine +hydrochloroth-iazide, 8 allthree

USA, 1987 AC: physician drewsealed envelope withassignment (B)FU: 14 (7%) lost, butdata reported forperinatal death

200 primigravidwomen in hospital at26–35 weeksgestation, SBP140–160 mmHg,DBP 90–110 mmHg,proteinuria >0.3 g/l,uric acid >4.6 mg/dlExcluded: associatedmedical andobstetriccomplications, otherantihypertensivedrug

Exp: labetalol300 mg/day,increased to max.2400 mg/day +hospitalisation Control:hospitalisation alone

Women: severe HT,increasedproteinuria,eclampsia, abruption,Caesarean section,renal function Babies: perinataldeath, gestation atdelivery (mean),birthweight (mean),admission to SCBU,SGA (<10th centile)

USA, 1987a R: “randomlyallocated”AC: not stated (B)

25 women at<34 weeks’gestation, singletonpregnancy, BP140/90 mmHg ×2 at least 6 h apart, no proteinuria.Presumed chronicHT

Exp: methyldopa750 mg ×3/day to2000 mg ×4/dayControl: placeboIf severe PE,hydralazine orMgSO4 added

Women: MAP, newproteinuria (�2+),PE (defined assudden rise of30 mmHg SBP or15 mmHg DBP andweight gain>2 lb/week, orproteinuria >2+),elective delivery,side-effectsBabies: perinataldeath, gestation atdelivery (mean),birthweight (mean)


197




AC, allocation concealment; BP, blood pressure; DBP, diastolic blood pressure; Exp, experimental; FU, follow-up; HELLP,syndrome of haemolysis, elevated liver enzymes and low platelets; HT, hypertension; IUGR, intra uterine growth restriction;MAP, mean arterial pressure; PE, pre-eclampsia; PIH, pregnancy-induced hypertension; R, randomisation sequence; RDS,respiratory distress syndrome; SBP, systolic blood pressure; SCBU, special care baby unit; SGA, small for gestational age.

USA, 1990 R: computer-generated randomnumbersAC: “enveloperandomisation” (B)FU: 37 (12%) lost

300 women in wardwith chronic mild-moderate HT at6–13 weeks’gestation. All hadchronic HT beforepregnancy and noassociated medicalcomplications

Exp: (1) methyldopa750–4000 mg/day(no other details). (2) Labetalol300–2400 mg/day(no other details)Control: noantihypertensive

Women: PE (definedas HT, proteinuria,and hyperuricaemia),additional drug,hospital stay,abruption,congestive heartfailure Babies: perinataldeath, birthweight<2.5 kg, pretermbirth, SGA(undefined),admission to SCBU,hypoglycaemia,Apgar

36% of womenwere taking anantihypertensiveat the time oftrial entry

USA, 1992 R: computer-generated randomnumbersAC: physician drewsealed envelopecontaining assignment(B)FU: 3 (2%) lost

200 primigravidwomen at26–36 weeks’gestation, SBP140–160 mmHgand/or DBP90–110 mmHg 24 hafter hospitalisation,proteinuria>300 mg/24 h,and/or uric acid>6 mg/dlExcluded: medical orobstetriccomplications, foetalcompromise

Exp: nifedipine40–120 mg/day Control: bed restalone

Women: MAP, severeproteinuria(>5 g/24 h),antenatal hospitalstay (mean),Caesarean section,abruption, HELLPsyndromeBabies: stillbirth,neonatal death,birthweight, pretermbirth, SGA (<10thcentile), admission toSCBU

Method ofmeasuringblood pressurenot mentioned

Appendix 9

198

TABLE 94 Trial details of antiplatelet agents for preventing pre-eclampsia and its complications


continued

Australia,1988

R: random numbersequence linked to anidentification numbergiven to each womanat trial entryAC: in hospitalpharmacy (B)

46 women withsingleton pregnancyat 28–36 weeks andconcern about foetalwelfare, in whomumbilical arteryvelocity waveformsystolic/diastolic ratio>95th centile Excluded: if DBP>110 mmHg or>90 mmHg withproteinuria, and ifmaternal conditionlikely to lead todelivery

Antiplatelet: aspirin150 mg dailyControl: placebo

Women: Caesareansection; induction;placental weightBabies: stillbirth;neonatal death;ventilation; admissionto SCBU;cerebroventricularhaemorrhage;birthweight;gestation at delivery;head circumference;Apgar scores

2 groups: highumbilical arterysystolic/diastolicratio (>95thbut <99.5thcentile) andextremeumbilical arterysystolic/diastolicratio (>99.5thcentile). Dataincomplete forsecond group,so only includedif available forall women

Australia,1993

R: “randomised” AC: capsulesdispensed bypharmacy (B)

110 women at12–24 weeks witheither DBP �90 orSBP �140, or ahistory of PE

Antiplatelet: 100 mgaspirin.Control: placebo

Women: PE

Australia,1995

R: not reportedAC: Instructionsabout tablets innumbered sealedopaque envelopes.Women shown 5envelopes and askedto choose 1. (B)

51 women at28–36 weeks withultrasound diagnosisof restricted foetalgrowth, umbilicalartery. Dopplersystolic/diastolic ratio>95th centile. Noprevious aspirinduring pregnancy

Antiplatelet: 100 mgaspirinControl: starchtablets

Women: noneBabies: meangestation at birth;birthweight (<3 and10th centile); Apgar5 minutes; admissionSCBU; IVH

Australia,1995a

R: randomised by“envelope method”,no other informationAC: unclear (B)FU: 1 woman (5%)excluded asmiscarriage at20 weeks (B)

21 women withrenal disease. 20 hadprevious early onsetPE

Antiplatelet:dipyridamole75–100 mg × 4/day+ subcutaneousheparin 7500 u×2/dayControl: notreatment

Women: HT;proteinuria;‘complications’;Caesarean sectionBabies: neonataldeath; prematurebirth (<37 weeks);IUGR (<10th centile)

Trial stoppedearly on adviceof ad hoccommittee, dueto complicationsin control group

Australia,1996

R: “randomised trial”AC: unclear (B)B: “double blind”

52 primigravidwomen withabnormal uterineartery waveforms onDoppler examinationat 22–24 weeks

Antiplatelet: aspirin60 mg/day.Control: placebo

Women: PIH, PE,Caesarean section,abruptionBabies: death,preterm birth(<37 weeks), IUGR(<10th centile),admission to SCBU


199


TABLE 94 Trial details of antiplatelet agents for preventing pre-eclampsia and its complications (cont’d)


continued

Australia,1996a

R: not reportedAC: by taking thenext in a series ofnumber identicalblister packs (A) FU: 2 womenwithdrew (2%), onefrom each group (A)

104 primiparouswomen withabnormal uterineDoppler flow at18 weeks(systolic/diastolicratio >3.3 orSBP/DBP >3 andearly diastolic notch)

Antiplatelet: aspirin100 mg/day Control: placebo

Women: PIH; PE;eclampsia; APH Babies: pretermbirth; SGA

Selected from955 womenscreened, ofwhom 186 hadabnormalwaveforms

Australia,1997

R: series of randomnumbersAC: unclear (B)FU: 10% (12) ofwomen excluded asthey withdrew beforestarting treatment (C)

120 women at highrisk of PE because ofone of: pre-existingHT (BP�140/90 mmHgprior to pregnancy×2, orantihypertensivetherapy), renaldisease, previousearly severe PE Excluded: aspirinallergy, aspirin-sensitive asthma,pre-existing bleedingdiathesis or multiplepregnancy

Antiplatelet: aspirin100 mg modifiedrelease daily from17–19 weeks untildeliveryControl: placebo

Women: proteinuria;duration ofpregnancy;indications for andmode of delivery;maximum antenatalBP; “complications”Babies: perinataldeath; birthweight;Apgar scores

Austria, 1992 R: unclearAC: coded packagesof medication (A)B: participants andassessment ofprimary outcomeblinded

41 primigravidwomen with positiveroll-over test(increase of20 mmHg in DBP) at 28–32 weeks Exclusions: existingHT, renal gut, lung orheart disease, IUGR,impending pretermbirth

Antiplatelet: aspirin80 mg/day until37 weeks Control: placebo

Women: PIH; PE;Caesarean section;preterm birth(37 weeks) Babies: stillbirths;neonatal death; SGA(<10th centile);neonatal bleeding;admission to SCBU

Barbados,1998

R: computer-generated AC: randomlynumbered treatmentpacks dispensed bypharmacist (A)FU: 55/3697 women(1.5%) excluded: 42because of packlabelling errors, 8 notpregnant and 6 lost tofollow-up (A)

3697 women at12–32 weeks’gestation Excluded: ifincreased risk ofbleeding, aspirinallergy, highlikelihood ofimmediate deliveryor previous placentalabruption

Antiplatelet: aspirin75 mg controlledrelease daily untildeliveryControl: placebo

Women: PE; APH;PPH; Caesareansection; duration ofpregnancy; use ofantihypertensivesand anticonvulsantsBabies: stillbirth;death before hospitaldischarge; days inSCBU; bleedingproblems;birthweight

Appendix 9

200



continued

Brazil, 1996 R: central telephonerandomisationAC: (A)FU: 39/1009 women(4%) lost to followup (A)

1009 women at12–32 weeks’gestation (41%20 weeks) “whothe obstetricianthought were at risk”of PE – generallylow/moderate risk(primip 47%, chronichypertension 47%,diabetes 6%) Excluded: bleedingrisk, asthma, allergyto aspirin, gastriculcer, placenta praevia


Women: PE;Caesarean section;APHBabies: SGA;perinatal death;preterm birth;neonatal bleeding

Conducted in12 universityteachinghospitals and182 obstetricoffices

Brazil, 1992a R: randomly dividedinto 2 groups. Nofurther informationAC: unclear (B) FU: 4 womenexcluded (7%) (B)B: not reported

56 women in 2nd or3rd quarter ofpregnancy who wereyoung primigravidas,or had chronic HT,diabetes, previousPIH, twin pregnancy,or a family history ofHT

Antiplatelet:acetylsalicylic acid60 mg/day in asolution of 50% D-lysineControl: nointervention

Women: PIHBabies: death,birthweight (mean)

China, 1999 R: randomisation byoffering patient 5sealed envelopes (2 aspirin, 2 calcium,1 placebo)AC: sealed envelopes(B)FU: 22 women (6%)lost to follow-up (B)

215 primigravidwomen with MAP>80 and <106 earlyin 2nd trimester andMAP >60 at22–24 weeks

Antiplatelet: aspirin80 mg/day untildelivery Control: unclear, noplacebo mentioned

Women: PIH; PE;eclampsia; Caesareansection Babies: gestation atdelivery (mean);birthweight; Apgarscores

Authorsprovidedadditionalinformation. 132 womenallocated aspirin,154 calcium and83 control.Womenallocatedcalciumexcluded fromthis review

CLASP, 1994 R: centralisedcomputerrandomisationAC: by telephoning acentral randomisationservice. (A)FU: 0.6% (55) lost(A) Follow-up of survivingchildren with GPletter at 12 months inUK (4688 with 4675

9364 women at12–32 weeks’gestation at risk ofPE or IUGR, orwomen withestablished PE orIUGR

Antiplatelet: aspirin60 mg daily untildeliveryControl: placebo

Women: death;eclampsia; PE;bleedingcomplications;Caesarean section;induction; problemswith epiduralanalgesia; PPH;transfusion; use ofantihypertensives oranticonvulsants;compliance

Internationalstudy Compliance:96% startedtreatment, 88%took it for atleast 80% ofthe time fromentry-delivery.For someoutcomes datanot presented

China, 1996 R: “randomisedstudy”AC: unclear (B)B: “double-blind”

84 women with asingleton pregnancyat high risk of IUGR,and 28–34 weeks’gestation

Antiplatelet: 75 mgaspirin, from 28 to34 weeks for6–8 weeksControl: placebo

Women: PIH;Caesarean section;preterm deliveryBabies: neonataldeath; IUGR; IVH


201




continued

alive at 12 months)and parentalquestionnaire at18 months in UK andCanada (410 with 407alive at 18 months).For GP letter, 89%response rate, forparentalquestionnaire 86%responded

Babies: stillbirth;neonatal death;mortality at 1 year;birthweight (mean)and centile (< 3rd);gestation at delivery;admission to SCBU;IVH; other neonatalbleeding. Follow-upat 12–18 months:developmental delay;congenitalmalformations;respiratoryproblems; hospitaladmissions

separately forprophylaxis andtreatment.Follow-up dataonly for centresin the UK andOttawa, Canada

Colorado,1993

R: “randomised”, nofurther informationAC: unclear (B)FU: unclear

100 nulliparouswomen with multiplepregnancy in “earlypregnancy”


Women: PIH; PE.Babies: nonereported

Multicentretrial, stoppedearly due toslowrecruitment

EPREDA,1991

R: randomised bycentre withstratification for oneor two previous pooroutcomes AC: unclear (B)FU: 1 womanexcluded afterrandomisation (A)

323 women at15–18 weeks’gestation with pooroutcome duringprevious 2pregnancies, at leastone being IUGR, orIUGR in oneprevious pregnancy Excluded: twins,uterinemalformation, renaldisease, secondaryhypertension,diabetes, cardiacdisease

Study 1: antiplatelet: aspirin150 mg daily, oraspirin 150 mg plusdipyridamole 225 mgdailyControl: placeboStudy 2: Antiplatelet: aspirin150 mg anddypridamole 225 mgdailyControl: aspirin150 mg daily

Women: death; DBP >90 mmHg;proteinuria;abruption; Caesareansection <34 weeks;“poor outcome”Babies: stillbirth;neonatal death;ventilation; transferto intensive care;birthweight <10thcentile; duration ofhospital stay (mean)

Two separatecomparisonswithin the onestudy. Only datafor study 1included in thereview

ERASME,2003

R: computer-generatedrandomisation codes,stratified by centre inblocks of 8AC: via online 24-hour computer(A)

3294 primiparouswomen at14–20 weeks’gestation withsingleton or multiplepregnancy Excluded: knownHT, indication orcontraindication toaspirin

Antiplatelet: aspirin100 mg to 34 weeks Control: placebo

Women: PIH; PE;placental abruption;Caesarean section;induction; HELLP;PPH; hospitaladmission; side-effectsBabies: stillbirth;neonatal death; SGA(<10th and <3rdcentile); neonatalIVH; other bleeding;admission to SCBU

Multicentre, 28 centres inFrance and onein Belgium

Appendix 9

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continued

Finland, 1993 R: unclearAC: sealed envelopes,no further details (B) FU: 5% (11) womenexcluded (B) B: double-blind

208 women with pre-existing HT (BP>140/90 mmHgbefore pregnancy) orprevious severe PE(in immediatelyprecedingpregnancy), and12–18 weeksgestation Excluded: womenproteinuric beforepregnancy

Antiplatelet: aspirin50 mg daily Control: placebo

Women:exacerbation of HT± proteinuria;Caesarean section;blood loss at delivery(mean);hospitalisation duringpregnancy; bleedingtime, DBP at36 weeks (mean)Babies: perinataldeath; admissionSCBU; birthweight;SGA; gestation atdelivery

3 centres

Finland, 1997 R: “randomised”, noother informationAC: unclear (B)

26 high-risk womenwith uterine arterybilateral notches onDoppler, at22–24 weeks

Antiplatelet: aspirin50 mg Control: notreatment

Women: PIH; PE;placental abruption;delivery <37 weeks Babies: stillbirth;IUGR (<10thcentile); IVH onultrasound; gestationat delivery (mean);birthweight

Finland, 2002 R: randomisation inpharmacyAC: code brokenwhen last womandelivered (A)FU: 4 women lost (A)

90 women at risk ofPE or IUGR withabnormal uterineDoppler.12–14 weeks’gestation

Antiplatelet: aspirin0.5 mg/kg/dayControl: placebo

Women: PIH; PE;Caesarean section Babies: death;gestation at delivery(mean); birthweight<2500 g; admissionto SCBU; IVH

France, 1990 R: “randomisedstudy”, no otherinformationAC: unclear (B)

91 women at highrisk of PIH becauseof previous earlyonset PE, severeIUGR or foetal deathdue to placentalinsufficiency

Antiplatelet: aspirin100 mg anddipyridamole 300 mgdaily until deliveryControl: notreatment

Women: PIH ± PE;duration ofpregnancy (mean)Babies: foetal death;birthweight (mean)

Published inabstract formonly

France, 1985 R: “randomlyallocated to group Aor B”, no otherinformationAC: unclear (B)FU: 9% (9 women)excluded fromanalysis (2 lost to FU,7 had miscarriage<16 weeks) (B)

102 women at highrisk of PE or IUGR,i.e. several previouscomplicatedpregnancies orvascular risk factorssuch as essential HT(BP >160/95 mmHg) ora family history ofHTExcluded: womenwith secondary HTor known orsuspected renaldisease

Antiplatelet: aspirin150 mg anddipyridamole 300 mgdaily, from 3 monthsuntil deliveryControl: noantiplatelet agent

Women: PIH (BP�140/85 mmHg; PE;Caesarean section;abnormal bleedingduring delivery orCaesarean section;abruption; headacheBabies: stillbirth;neonatal death;foetal malformation;birthweight <10thand <3rd centile(livebirths only);haemorrhagiccomplication(undefined)


203




continued

Germany,2000

R: computer-generated AC: blister packs, and the code heldseparately fromperson doingrandomisation (A)

43 women withsingleton pregnancy,<20 weeks’gestation with earlyIUGR, impaireduteroplacental flow,chronic HT, orhistory of IUGR,stillbirth, or PEExcluded: diabetes,pre-existing HT orproteinuria, foetalmalformation


Women: PEBabies: gestation at birth(mean); birthweight(mean)

India, 1993 R: unclearAC: not reported (B)B: assessment ofoutcome not blinded

100 women withPIH at 24–36 weeks’gestation

Antiplatelet: aspirin60 mg/day Control: “standardtreatments only”

Women: severe PIH(proteinuria notspecified); eclampsia;preterm (gestation notspecified)Babies: stillbirths;neonatal deaths; SGA

Unclearwhetheraspirin groupalso had“standardtreatment”

India, 1994 R: “randomlyallocated”, no otherinformationAC: unclear (B)

94 nulliparouswomen with PIH inthe 3rd trimester(SBP �140 mmHg,and/or DBP�90 mmHg, on twooccasions more than6 h but less than24 h apart)

Antiplatelet: aspirin75 mg daily, until10 days beforeEDDControl: noantiplatelet agent

Women: developmentof PE; eclampsia orabruption; mean fall inBP; rise in BPBabies: neonatal death;admission to SCBU;gestational age atdelivery (mean);birthweight (mean);Apgar at 1 minute;macroscopic haematuria

Exclusioncriteria notdescribed

Israel, 1989 R: computer-generatedrandomisation list AC: coded packagesof 100 pills allocatedaccording to randomnumber list (A)

65 women witheither twinpregnancy, a historyof PE or in firstpregnancy, and apositive roll-over,test at 28–29 weeks’gestation


Women: PIH ±proteinuria (BP>140/90 mmHg on atleast two occasionswithin 24 h; proteinuria>1 g/24 h); Caesareansection; length ofhospitalisation (mean)Babies: stillbirth;neonatal death; gestationat birth (mean); born<37 weeks; birthweight<10th centile; Apgarscores; ventilation;admission to SCBU;IVH; haematuria;cephalhaematoma;sepsis workup

India, 1999 R: “randomised trial”,no further detailsAC: unclear (B)FU: 3 women (2%)lost to follow-up (A)

163 women withPIH at 20–32 weeks


Women: PE; eclampsia Babies: perinatal death;IUGR <10th centile

Available as anabstract only

Appendix 9

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continued

Israel, 1990 R: “divided randomlyinto two groups”, noother informationAC: unclear (B)

47 nulliparous at30–36 weeks withmild PIH (BP>140/90 but<165/110 mmHg),no signs of PE,normal platelets andproteinuria>500 mg/24 h Excluded: if aspirinsensitivity, chronichypertension, renaldisease orantihypertensivedrugs

Antiplatelet: aspirin100 mg until 5 daysbefore EDDControl: placebo

Women: PE (BP>165/110 mmHg withlow platelet countand/or proteinuria>500 mg/24 h);Caesarean sectionBabies: gestation atdelivery; birthweight(mean); Apgar score at5 minutes (mean)

Israel, 1994 R: randomisation listAC: allocated to acoded packageaccording torandomisation list (B)FU: 1 womanwithdrawn asthrombocytopaenia –data included wherepossible (A)

48 women with twinpregnancies at about18 weeks


Women: PIH; PE;Caesarean section;IUGRBabies: preterm birth;perinatal mortality;birthweight discordancy(15%)

Italy, 1993 R: telephonerandomisationAC: by telephone callto one of tworandomisationcentres. (A) FU: 6% (64) ofwomen lost tofollow-up (B)Follow-up of children:postal questionnaireto parents for 1083children at 18 months(excludes 41 bornbefore follow-upstarted). Onereminder and up to

1106 women at16–32 weeks’gestation.Prophylactic: age<18 or >40 year,mild-moderatechronic HT,nephropathy withnormal renalfunction and BP, PIHor IUGR in previouspregnancy, twinpregnancy) Therapeutic: PIH (DBP90–110 mmHg) orearly IUGR (foetal

Antiplatelet: aspirin50 mg dailyControl: notreatment

Women: PIH ±proteinuria; abruption;induced or spontaneousabortion; Caesareansection Babies: perinatalmortality; gestation atdelivery; birthweight <10th or <5th centile;admission to SCBU;IVH; gastric bleed. At 18 months: death;malformations heightand weight <10thcentile, and respiratory;motor; sight; hearing orlanguage problems

Data notpresentedseparately forprophylaxisandtreatment, so all womenincluded inprophylaxisfor this review

For follow-up,no differencebetweenrespondersand non-responders in

Italy, 1989 R: “randomlyassigned”, no otherinformationAC: unclear (B)

33 women at risk ofHT because ofessential HT or asignificant previousobstetric history(placentalinsufficiency causingfoetal death, severeIUGR or PE<32 weeks)Excluded: ifantiphospholipidantibodies

Antiplatelet: aspirin60 mg daily from12 weeks untildeliveryControl: placebo

Women: PIH (BP>140/90 mmHg and BPpreviously normal);gestation at delivery(mean) Babies: perinatal death;assisted ventilation;haemorrhagiccomplications;birthweight <10thcentile; born <37 weeks’gestation; Apgar scores,RDS


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continued

3 telephone calls fornon-responders. Datafor 427 aspirin (72%)and 361 no treatment(73%)

abdominalcircumference �2SD below mean forgestational age)Excluded: chronicdisease, allergy toaspirin, foetalmalformation

baselinecharacteristicsand outcomeat dischargefrom hospital.Also, nodifferences ininformationcollected bypost or bytelephone

Italy, 1999 R: “randomised”AC: unclear (B)FU: 9 women (4%)stopped treatmentearly, 4 aspirin and 5 control (A)

216 women aged18–36 years withpre-existing HT orhistory of severe PE,at 12–26 weeks

Antiplatelet: 50 mgaspirin/dayControl: placebo

Women: PE

Jamaica, 1998 R: women givensequential numberson admission whichidentified a bottlecontaining eitheraspirin or placeboAC: unclear (B)FU: 179 (3%) lost tofollow-up. 50 womenwith multiplepregnancy excluded.Some womenentered twice andgiven aspirin andplacebo excluded, butnumbers not given (A)

6275 primiparouswomen,12–32 weeks’ and nocontraindication toaspirin

Antiplatelet: aspirin60 mg daily untildelivery Control: placebo

Women: HT (DBP �90 mmHgor SBP �140 mmHg orrise of 25 mmHg DBPor 40 mmHg SBP); PE;eclampsia; Caesareansection; antenataladmission; PPHBaby: perinatal death;preterm birth;birthweight <2500 g;admission to SCBU;Apgar; IVH; otherneonatal bleeding

144 aspirin-treatedwomen and161 placeborandomisedafter32 weeks, but included in analysis

Japan, 1999 R: “enrolledrandomly”, no furtherinformationAC: unclear (B)

40 women withsevere PE inprevious pregnancy.Enrolled at6–18 weeks,treatment started at 20 weeks

Antiplatelet:ozagrelhydrochloride,400 mg/day from20 weeks todeliveryControl: placebo

Women: PEBabies: pretermdelivery; delivery<32 weeks; SGA

Ozagrel is athromboxanesynthetaseinhibitor

TheNetherlands,1986

R: randomisation list AC: coded packages,allocated according tolist (B)FU: 2 women intreatment groupexcluded because ofnon-compliance, butdata for some clinicaloutcomes reported(A)

46 angiotensin II-sensitive primigravidwomen at 28 weeks’gestation withuncomplicatedpregnancies, nohistory of HT,cardiovascular orrenal disease, DBP<80 mmHg andtaking no drugsexcept iron


Women: eclampsia; PIH(DBP at least 95 mmHgon two or moreoccasions 6 h apart); PE (HT as above plusproteinuria >0.5 g/l);preterm delivery(<37 weeks);Caesarean sectionBabies: stillbirth;neonatal death; RDS;birthweight forgestational age <10thor <3rd centile

Appendix 9

206



continued

TheNetherlands,1989

R: randomisation list AC: coded packages,allocated according tolist (B)

10 primigravidwomen with chronicHT and a positiveangiotensin IIsensitivity test at26 weeks’ gestation.No proteinuria, BP<90 mmHgdiastolic, serumcreatinine<70 �mol/l and anadequately grownfoetus

Antiplatelet: aspirin60 mg Control: placebo

Women: PIH (rise inDBP of 20 mmHg ormore); PE (HT asbefore + proteinuria�500 mg/l);Caesarean section Babies: birthweight<10th centile

All women hadmethyl dopa

TheNetherlands,1991a

R: randomisationsheet AC: coded packagesallocated according toa randomisationsheet. Code brokenat 34 weeks, somewomen then startedaspirin (B)

36 women with apositive angiotensinII sensitivity test at28 weeks

Antiplatelet: aspirin60 mg daily from 28to 32 weeksControl: placebo

Women: HT at34 weeksBabies: stillbirths

South Africa,1988

R: computer-generated randomnumbers, no otherinformationAC: unclear (B)FU: 1 woman (2%)lost (A)

44 women withelevated mid-trimester BP,12–28 weeks’gestation, DBP80–105 mmHg, andotherwise normal

Antiplatelet 1: aspirin81 mg daily Antiplatelet 2: aspirin81 mg +dipyridamole 200 mgdaily Control: noantiplatelet agent

Women: PEBabies: stillbirth

Published onlyas an abstract

Spain, 1997 R: computer-generated randomnumbers AC: tablets inidentical blister packs.Allocated to 6 groups,according totreatment and timingof administration (A)FU: 7 women (6%)excluded, becausepoor compliance orincomplete BPassessments (B)

107 women aged18–40 years at<16 weeks’gestation and atmoderate risk of PE.For example, familyor own history ofPIH, PE, chronic HT,cardiovascular orendocrine problem,bleeding orendocrine disease

Excluded: multiplepregnancy

Antiplatelet: 100 mgaspirin Control: placebo

Women: PIH; PE;Caesarean section;abruptionBaby: death; pretermbirth (<37 weeks);IUGR

Testing thehypothesis thataspirin effectsare timedependent,being greater inthe evening


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continued

Spain, 1999 R: randomised. AC: tablets inidentical blister packs.Allocated to 6 groups,according totreatment and timingof administration (A)FU: 15 womenexcluded (6%)because poorcompliance orincomplete BPassessment (B)

255 women aged18–40 years at<16 weeks’gestation atmoderate risk of PE.For example, familyor own history ofPIH, PE, chronic HT,cardiovascular orendocrine problem,bleeding orendocrine disease

Excluded: multiplepregnancy

Antiplatelet: 100 mgaspirin Control: placebo

Each treatmentgroup could also beallocated to 3different times of theday

Women: mean 24 hBPBaby: IUGR

Testing thehypothesis thataspirin effectsare timedependent,being greater inthe evening.Data enteredinto the reviewfrom the mainpublication.Data for 341women havebeen presented,but in abstractonly andincomplete

Tanzania,1995

R: unclearAC: packages codedA and B. No otherinformation (B)

127 women withpositive roll-overtest Excluded: HT orincreased BP beforescreening,proteinurea>300 mg

Antiplatelet: 80 mgaspirin dailyControl: placebo

Women: PIH; PEBaby: none

Thailand,1996

R: unclearAC: identicaltreatment andplacebo tablets inidentical containers(100 per box) –patient chose acontainer “atrandom” FU: 10% lost to FU(C)

1500 low-risknulliparous womenat 18–22 weeks,ultrasound toconfirm dates (meanage at randomisation20.7 weeks).Exclusions: renal orcardiovasculardisease, diabetes,twins, hypertension

Antiplatelet: aspirin60 mg/day, until birthControl: placebo

Women: death; PIH;PE; eclampsia;Caesarean section;APH Babies: stillbirth;preterm birth; SGA

Authorclarification ofrandomisationprovided

Compliancetesting – 86%aspirin, 81%placebo

UK, 1990 R: computer-generatedrandomisation list AC: seriallynumbered bottlesdispensed bypharmacist (A)FU: 6% (6) excluded(B)

106 primigravidwomen withpersistentlyabnormal Dopplerwaveform studies at24 weeks’ gestation Excluded: aspirinallergy, diabetes,bleeding disorders,peptic ulceration,systemic lupuserythematosus

Antiplatelet: aspirin75 mg daily Control: placebo

Women: PIH;proteinuria; HT<37 weeks’gestation; Caesareansection forcomplications of HTBabies: perinataldeath; birthweight<5th centile

Lancetcontacted toconfirm thisstudy has notbeen retracted

Appendix 9

208



continued

UK, 1992 R: “Simplyrandomised withblock size four”AC: unclear (B)

(a) 18 normalprimigravidae,16 weeks’ gestation,and (b) 16primigravidae withgestational HT butno proteinuria at>20 weeks

Antiplatelet: aspirin60 mg daily untildeliveryControl: placebo

Women: duration oflabour; blood loss atdeliveryBabies: <36 weeksat delivery;birthweight <10thcentile; minorbruising of newborn

Continuous dataonly presentedfor someoutcomes

UK, 1992b R: “randomlyallocated”, no otherinformation givenAC: unclear (B)

26 women withhistory of recurrentmiscarriage orconnective tissuedisorder, and positiveanticardiolipinantibodies

Antiplatelet: aspirin75 mg dailyControl: notreatment

Women: miscarriageBabies: neonataldeath

USA, 1993 R: unclearAC: “efforts weremade to concealrandomisation” (B) FU: <1% loss (A)B: participants andoutcome assessmentblinded

604 primiparouswomen at 24 weeks,in single antenatalclinicExcluded: renal orcollagen disease,diabetes, essentialHT, multiplepregnancy

Antiplatelet: aspirin60 mg/day, from22 weeks Control: placebo

Women: PIH; PE;eclampsia; APH;Caesarean section;preterm delivery(<37, <34,<32 weeks) Babies: perinataldeath; SGA

USA, 1993a R: “assignedrandomly”, no further detailsAC: unclear (B)FU:150 (5%) lost tofollow-up (A)

3135 nulliparouswomen at13–25 weeks withBP <135/85 mmHgand no proteinuria;out of the 4241entered into a run-incompliance phaseExcluded: chronicHT, diabetes, renaldisease, othermedical illness

Antiplatelet: aspirin60 mg/dayControl: placebo

Women: PIH; PE;eclampsia; Caesareansection; abruption;preterm delivery;PPHBabies: stillbirths;neonatal deaths; SGA <10th centile;bleeding

Mean gestationat trial entry19.8 weeks

UK, 1995 R: computer-generatedrandomisation listAC: sealed envelopes(B)FU: 4 women (3%)excluded (A)

122 women with noprevious pregnancyproceeding beyond12 weeks, Hb>13.2 g/dl at12–19 weeksgestation, DBP<90 mmHg and noproteinuria Excluded: multiplepregnancy, diabetes,recurrent miscarriageor contraindicationto aspirin

Antiplatelet: aspirin75 mg from18 weeks untildeliveryControl: placebo

Women: PIH; PE;eclampsia; abruption;Caesarean section;induction of labour;side-effectsBabies: perinatalmortality; delivery<34 weeks’gestation; admissionto SCBU; birthweight<5th centile

Trial conducted1989–92


209




AC, allocation concealment; APH, antepartum haemorrhage; AST, aspartate aminotransferase; B, blinding; DBP, diastolicblood pressure; DM, diabetes mellitus; EDD, estimated date of delivery; FU, follow-up; HT, hypertension; IUGR, intrauterinegrowth restriction; Hb, haemoglobin; IVH, intraventricular haemorrhage; MAP, mean arterial pressure; PE, pre-eclampsia;PIH, pregnancy-induced hypertension; PPH, postpartum haemorrhage; R, randomisation sequence; RDS, respiratory distresssyndrome; SBP, systolic blood pressure; SCBU, special care baby unit; SGA, small for gestational age.

USA, 1994 R: “randomised", no further detailsAC: unclear (B)FU: 5 (9%) womenlost to follow-up (B)

54 women withchronic HT orprevious severe PE,enrolled at13–15 weeks

Antiplatelet: aspirin100 mg sustainedrelease/day until37 weeksControl: placebo

Women: PE Babies: stillbirth;SGA

Published asabstract only

USA, 1998 R: computer-generated randomnumbers AC: packets withassigned numbersopened consecutivelyin each centre (A)FU: 36 women (1%)lost to follow-up (A)

2539 women at13–26 weeks’gestation withinsulin-treateddiabetes, chronic HT,multiple pregnancyor PE in a previouspregnancy. Womenwith multiplepregnancy excludedif also diabetes,chronic HT orproteinuria


Women: PIH; PE;abruption; pretermdelivery; PPHBaby: death; IUGR(<10th centile); IVH;other neonatalbleeding

Additional dataprovided by theauthors

Venezuela,2000

R: “randomised”, nofurther informationAC: unclear (B)

127 nulliparouswomen <29 weeks’gestation. At risk ofPE because previousPE, obesity, HT,diabetes,nephropathy, MAP>85, positive roll-over test, familyhistory of PE,multiple pregnancyor <20 years old

Antiplatelet: aspirin100 mg ×3/week +vitamin C500 mg/day +vitamin E 400 IU/day,fish oil ×3/day

Women: PE Abstract only

Zimbabwe,1998

R: randomisation list AC: list used todetermine sequenceof numberedcontainers. (B)FU: 20 (8%) womenlost to follow-up (B)

250 women at20–28 weeks with ahistory of PE in aprevious pregnancy,especially if at<32 weeks, orchronic HTExcluded:hypersensitivity toaspirin, PE thispregnancy, bleedingor peptic disorder

Antiplatelet: aspirin75 mg/dayControl: placebo

Woman: PE;antihypertensivedrug; pretermdelivery; PPH;Caesarean section.Baby: death; IUGR;admission SCBU

Appendix 9

210

TABLE 95 Trial details of diuretics for preventing pre-eclampsia


continued

Fallis, 1964 R: “randomlyassigned” to one oftwo groups, nofurther informationAC: not reported (B)FU: 6 women (8%)excluded, all from theactive group (B)B: “double blind”

80 primigravidwomen at<27 weeks’gestation with DBP<90 mmHg and noproteinuria oroedema

Diuretic:hydrochlorothiazide50 mg daily untildeliveryControl: placebotaken until delivery

Women: PE (SBP>140 or rise by>30 mmHg or DBP>90 or rise by>15 mmHg, with orwithout proteinuria,or oedema after24 weeks);medication stoppeddue to side-effects;biochemicaloutcome

Baby: stillbirth;neonatal death

Compliance:>80% for allpatients except 2who took >50%of pills

Diet: all newpatients giveninstruction on saltrestricted diet

Race: 97.5%womenrandomised wereblack. Foranalysis, 100%were black

Single centre,USA

Kraus, 1966 R: “randomisedinvestigation”, nofurther informationAC: not reported (B)FU: 109 women(10%) excluded dueto poor compliancewith treatment.Women deliveringbefore 28 weeks or

1139 nulliparous andmultiparous womenbetween 20 and24 weeks’ gestation Excluded: womenwith ITP, diabetes, orsickle cell disease

Diuretic:chlorothiazide 50 mgdailyControl: placebo.Treatment continueduntil delivery(average 17 weeks)

Women: PE (SBP>140 or rise by>30 mm Hg or DBP>90 or rise by>15 mmHg, with orwithout proteinuria,or oedema after24 weeks); HT;weight gain,eclampsia; severePE; use of additional

Compliance:patients withpoor complianceexcluded fromstudy. No furtherinformation

Diet: advice givenregarding saltintake (3–5 g) andcalories(1800 kcal)

Flowers,1962

R: treatment given “at random” to fourgroups, no furtherinformation AC: sealed envelopeswith a code knownonly to the hospitalpharmacist (B)FU: 74 women (14%)excluded due toexcess weightgain/oedema, poorcompliance,insufficient data, orintolerance to side-effects. (C)B: “double blind”

519 primiparous andmultiparous women,up to 30 weeks’gestation

Diuretic 1: 134patients receivedchlorothiazide250 mg dailyDiuretic 2: 141patients receivedchlorothiazide500 mg dailyDiuretic 3: 110patients receivedchlorothiazide750 mg dailyControl: 134 patientsreceived placeboAll medication takenuntil delivery

Women: toxaemia(defined as SBP�140 or DBP�90 mmHg ×2 inpreviouslynormotensivewomen orappreciable changein BP in women withchronic HT); changesin maternal weight(mean) and BP(mean); side-effects;biochemicaloutcomes

Baby: perinatal death(foetal deaths andneonatal deaths upto 28 days of life ininfants weighing>1 kg); prematurebirth (not defined);neonatal jaundice(60% participantsexcluded for thisoutcome, so notreported in review)

Compliance:>80% for60–69% womenin all 4 groups.Wide variation incompliance in theremaining30–40% ofpatients in eachgroup

Diet: all patientsadvised a low-sodium diet(1800 mgsodium)

For review, 3 diuretic armscombined andcompared withplacebo

Single centre,USA


211


TABLE 95 Trial details of diuretics for preventing pre-eclampsia (cont’d)


AC, allocation concealment; B, blinding; BP, blood pressure; DBP, diastolic blood pressure; FU, follow-up; HT, hypertension;ITP, idiopathic thrombocytopenic purpura; IUGR, intrauterine growth restriction; PE, pre-eclampsia; R, randomisationsequence; SBP, systolic blood pressure; SGA, small for gestational age.

at another hospitalalso excluded (B)B: “double blind”

thiazide diuretic;side-effects;biochemicaloutcomes Baby: perinatal death(stillbirth andneonatal death);birthweight

Race: 93%women non-white

Single centre,USA

Sibai, 1984 R: “randomlyassigned” to one oftwo groups, nofurther informationAC: not reported (B)FU: complete (A)B: not blinded

20 women in firsttrimester ofpregnancy, withlong-term mild tomoderate chronicHT (DBP90–110 mmHg),who were receivingthiazide diureticsprior to pregnancy.All women were ondiuretic therapy attrial entry

Diuretic: advised tocontinue thiazidediuretic throughoutpregnancy

Control: advised tostop diuretic therapyimmediately

Women:superimposed PE(not defined);Caesarean section;additionalantihypertensive;weight gain (mean);mean arterial BP;plasma volume;placental weight;biochemicaloutcomes Baby: gestational age(mean); birthweight;IUGR; SGA;prematurity(<37 weeks);perinatal death;Apgar; postmaturity

Compliance: notreported

Diet: advisedrestricted saltintake (2 g) andto avoid additionof salt to diet

Single centre,USA

Weseley,1962

R: “assignedrandomly” to twogroups, no furtherinformation AC: not reported (B)FU: complete (A)B: “double blind”

267 women insecond or thirdtrimester, withweight gain 5 lb ormore in 2 weeks orincreasing oedema ofextremitiesExcluded: HT orproteinuria orprenatal care in adifferent hospital

Diuretic: 2 groups,both receivedchlorothiazide500 mg ×2 tabletsdaily

Control: 2 groups,both receivedplacebo

Women: PE (SBP>140 or rise by>30 mm Hg or DBP>90 or rise by>15 mmHg, with orwithout proteinuria,or oedema after24 weeks); severePE (not defined)

Baby: perinatalmortality

Compliance: notreported

Diet: saltrestricted. No otherinformation

Single centre,USA

Appendix 9

212

TABLE 96 Trial details of nitric oxide donors and precursors for preventing pre-eclampsia and its complications


AC, allocation concealment; B, blinding; BP, blood pressure; DBP, diastolic blood pressure; FU, follow-up; HELLP, haemolysis,elevated liver enzymes, low platelets syndrome; HT, hypertension; IUGR, intrauterine growth restriction; IVH, intraventricularhaemorrhage; NICU, neonatal intensive care unit; NO, nitric oxide; PE, pre-eclampsia; RDS, respiratory distress syndrome;SBP, systolic blood pressure.

Davis, 2001 R: computer-generated randomnumbers AC: by telephone (A)FU: complete (A)B: caregiver only

16 women withgestationalhypertension

NO: glyceryltrinitrate skin patch(10 mg) 12 h/dayuntil delivery Control: no patch

Woman: PE; side-effects Study stoppedearly due tosevereheadaches inactive group

Picciolo,2000

R: random numberlistAC: no information(B)FU: not reportedB: not reported

68 women at<16 weeksgestation, with eitherchronic HT orprevious history ofPE before 34 weeksand/or IUGR

NO: glyceryltrinitrate skin patch5mg 14–16 h/day,to 38 weeks’gestationControl:observation only

Woman: PE; abruption;Doppler notch at24 weeksBaby: neonatal death;preterm birth; IUGR;Apgar; admission toNICU; RDS; IVH

Two centres inItaly

Facchinetti,2002

R: by pharmaceuticalcompany AC: investigatorsgiven list ofconsecutive numbersallocated A or B.Code not known totrialists (A) FU: 6/80 (7.5%)excluded fromanalysis (B) B: for participants and caregivers yes,for outcomeassessment no

74 women between24 and 36 weeks’gestation withgestational HT (BP>140/90 ×2 after20 weeks) or PE (asabove + proteinuria>300 g/24 h) Excluded: BP raised<20 weeks’gestation, severe HT,severe PE,antiphospholipidsyndrome, heartkidney or liverdisease, <2antenatal visitsbefore enrolment

NO: L-arginine20 g/500 ml i.v.daily for 5 days,then 4 g/day oralfor 2 weeksControl: placebo

Woman: BP; plateletaggregation; time todelivery; PE; severe PE(one of : BP>170/110 mmHg,proteinuria >5 g/24 h,HELLP, coagulationdisorders, arrestedfoetal growth) Baby: perinatal death;preterm birth;birthweight (mean);gestation at birth (mean)

Unpublisheddata forwomenwithoutproteinuria attrial entryused for thereview

Lees, 1998 R: by studypharmacist in onecentreAC: by pharmacist,code not available toclinicians until afterlast woman delivered(A)FU: complete (A)B: for participants andcaregivers yes, foroutcome assessmentno

40 women withsingleton pregnancy,normal BP andabnormal uterineDoppler at24–26 weeks(bilateral diastolicnotches andresistivity index>0.58)Excluded: pre-existing HT, diabetes,renal disease,antihypertensive orcardiovascular drug,IUGR, foetalabnormality

NO: glyceryltrinitrate skin patch5 mg 15 h/day untildelivery. Stopped if:BP>140/90 mmHg,antihypertensive,foetal growthrestriction orclinical indication tostop (includingside-effects)Control: placebopatches with sameinstructions

Woman: PE, gestation ofonset of PE, maternalBP changes; HELLP,side-effects (skin rashand headaches);abruption; Dopplerindices Baby: preterm birth;small for gestational age;birthweight (mean)

Two centres,UK and Italy


213


TABLE 97 Trial details of progesterone for preventing pre-eclampsia and its complications


AC, allocation concealment; B, blinding; BP, blood pressure; FU, follow-up; PE, pre-eclampsia; R, randomisation sequence.

Dalton, 1962 R: “at random”, noother informationAC: “numberedenvelope system”, noother information (B)FU: 22 (15%)excluded (C)B: for participant andcaregiver no, foroutcome assessmentnot reported

150 women at16–28 weeks’gestation with twoor more “toxaemicsymptoms” (nausea,vomiting, lethargy,backache, headache,vertigo, fainting,cramp orparaesthesia), bloodpressure<140/90 mmHg andno proteinuria

Progesterone: 100 mgi.m. daily or onalternate days for1 week. Then, doseand frequency ofinjection adjusteddepending onsymptoms (range300 mg daily to 50 mgon alternate days).Stopped if symptomsdisappeared, or whenlabour started Control: simplesymptomatic relief asrequired, such asalkalis, analgesics,sedatives,antihistamines

Woman: PE (BP>140/90 mmHg +either oedema orproteinuria after28 weeks); side-effects inprogesteronegroup only Baby: stillbirth,neonatal death

385interviewed,150 eligible andrecruited.Definition of PEincludedoedema, sodata forproteinuria usedfor review.Follow-up ofchildrenexcluded due tolarge losses(54% at 1 yearand 80% at16 years)


215


Data required from Accuracy ReviewsFOR ALL REVIEWS NEED TO HAVE A CONSENSUS VALUE FOR1. Pre-test Prevalence or risk factor for developing Pre-eclampsia

Essential Items from each individual accuracy review are:2. Sensitivity and Specificity of test in detecting target risk factor

OR

The +ve and –ve likelihood ratios

Desirable information (but not essential) from individual Accuracy Reviews3. Information on whether detection can avert early or late pre-eclampsia

Summary of info required from Accuracy Reviews

Accuracy Review Result required for: Value Comment

E.g. Doppler 1. Pre-test probability ? Need agreed value on this for of developing all Accuracy ReviewsPre-eclampsia

SEE Ducket Review

Essential 2. Sensitivity and This is all could get but enough specificity of test in to be usefuldetecting target risk factorOR

2. the +ve and –ve likelihood ratios

Desirable 3. Available data on N/awhether detection can avert early or late pre-eclampsia

Please describe procedure for carrying out the test E.g. Ultrasound scan lastingapprox. 10 minutes

Does the paper present any information regarding resource use: E.g. Trained ultrasonographer, if so please describe and include the relevant references Doppler machine, etc.

Appendix 10

Data extraction sheet for economics section

Appendix 10

216

Data Required from Effectiveness of Treatment ReviewsEssential Items from each Treatment/effectiveness Review are:1. Probability ratio of developing pre-eclampsia if treated compared to not

Desirable information (but not essential) from individual Accuracy Reviews2. Any variation according to risk factors or distinction between early and late pre-eclampsia

Summary of info required from Accuracy Reviews

Treatment/Effectiveness Result required for: Value CommentReview

E.g. Aspirin

Essential 1. Probability ratio of Enough info to be developing pre-eclampsia usefulif treated compared to not

Desirable 2. Any variation according to risk factors or distinction between early and late pre-eclampsia

Evidence of other outcomes avoided as a result of this review. If yes Explainplease specify and provide reference

Resource use involved E.g. An aspirin!


217


Appendix 11

Economic evaluation case 6 results

TABLE 98 Case 6: costs, effects and ICERs for most cost-effective combinations of test and treatment pairs from any test combinedwith any intervention, i.e. as case 1, base case, group 1 and group 2 interventions considered (No test/rest_all dominates all optionsbelowa)

Test/treatment combination Mean cost Difference Effectivenessb Absolute ICERc NNTper woman in costs risk (UK£ 2005) (UK£ 2005) reduction

Partial analysis: excludes the costs of pre-eclampsia in the comparator arm of the modelNo test/salt reduction_alld 0 0.972No test /no treatment 0 0 0.975 0.003 0 357No test/antiplatelets_alld 2.7 2.7 0.980 0.005 566.32 208Total fibronectin/progesterone_positive 9 6.4 0.988 0.008 785.65 123Total albuminuria/progesterone_positive 14.6 5.6 0.989 0.001 5625.32 1000No test/progesterone_all 54.1 39.5 0.995 0.006 6666.84 169Microalbumin_Creatinine/ 62 7.9 0.995 0

progesterone_alle

Microalbuminuria/progesterone_alle 62 0 0.995 Dominated

Complete analysis: includes the cost of pre-eclampsia in the comparator arm of modelNothing/progesterone_all 101.2 0.995 DominantMicroalbumin_Creatinine/ 109.1 7.9 0.995 0 These are

progesterone_alle all dominated

Total albuminuria/progesterone_alle 109.1 0 0.995 0

a The no test_rest option is the most effective option, achieved at zero additional cost, and is thus self-evidently the mostcost-effective approach. It was therefore not incorporated into the model whose results are reported in this table, whichprimarily explores the second most cost-effective option after the no test/rest_all option.

b Effectiveness is defined as the proportion of women remaining free of pre-eclampsia. Therefore, the difference ineffectiveness between two strategies is the absolute risk reduction.

c ICER: incremental cost-effectiveness ratio expressed as the additional cost per additional case of pre-eclampsia prevented.d Universal advice to reduce salt intake appears to be worse than no test_no treatment because it appears to increase the

number of cases of pre-eclampsia: RR 1.11, 95% CI 0.46 to 2.66.e These ‘test all/treat all’ strategies were included in the model for completeness (elaborated in more detail in the economic

evaluation section, p. 100). Each is more costly and no more effective than a strategy of treating all women withouttesting.


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Carbillon L, Uzan M, Largilliere C, Perrot N, Tigaizin A,Paries J, et al. Prospective evaluation of uterine arteryflow velocity waveforms at 12–14 and 22–24 weeks ofgestation in relation to pregnancy outcome and birthweight. Fetal Diagn Ther 2004;19:381–4.



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Harrington K, Cooper D, Lees C, Hecher K,Campbell S. Doppler ultrasound of the uterine arteries:the importance of bilateral notching in the prediction ofpre-eclampsia, placental abruption or delivery of asmall-for-gestational-age baby. Ultrasound Obstet Gynecol1996;7:182–8.

Kurdi W, Campbell S, Aquilina J, England P,Harrington K. The role of color Doppler imaging of theuterine arteries at 20 weeks’ gestation in stratifyingantenatal care. Ultrasound Obstet Gynecol 1998;12:339–45.

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Papageorghiou AT, Yu CK, Bindra R, Pandis G,Nicolaides KH. Multicenter screening for pre-eclampsiaand fetal growth restriction by transvaginal uterineartery Doppler at 23 weeks of gestation. UltrasoundObstet Gynecol 2001;18:441–9.

Prefumo F, Bhide A, Sairam S, Penna L, Hollis B,Thilaganathan B. Effect of parity on second-trimesteruterine artery Doppler flow velocity and waveforms.Ultrasound Obstet Gynecol 2004;23:46–9.


Uludag S, Madazli R, Benian A, Ocak V, Erez S. Therelationship between maternal serum a-fetoprotein anduterine artery Doppler findings at 20–24 weeks’

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gestation for prediction of preeclampsia andintrauterine growth retardation. Marmara Med J 2002;15:169–74.

Venkat-Raman N, Backos M, Teoh TG, Lo WT, Regan L.Uterine artery Doppler in predicting pregnancyoutcome in women with antiphospholipid syndrome.Obstet Gynecol 2001;98:235–42.

Yu CK, Papageorghiou AT, Boli A, Cacho AM,Nicolaides KH. Screening for pre-eclampsia and fetalgrowth restriction in twin pregnancies at 23 weeks ofgestation by transvaginal uterine artery Doppler.Ultrasound Obstet Gynecol 2002;20:535–40.

Zimmermann P, Eirio V, Koskinen J, Niemi K, Nyman R,Kujansuu E, et al. Effect of low-dose aspirin treatmenton vascular resistance in the uterine, uteroplacental,renal and umbilical arteries – a prospective longitudinalstudy on a high risk population with persistent notch inthe uterine arteries. Eur J Ultrasound 1997;5:17–30.

Combinations of waveformsAlbaiges G, Missfelder-Lobos H, Lees C, Parra M,Nicolaides KH. One-stage screening for pregnancycomplications by color Doppler assessment of theuterine arteries at 23 weeks’ gestation. Obstet Gynecol2000;96:559–64.

Aquilina J, Thompson O, Thilaganathan B,Harrington K. Improved early prediction of pre-eclampsia by combining second-trimester maternalserum inhibin-A and uterine artery Doppler. UltrasoundObstet Gynecol 2001;17:477–84.

Benifla JL, Tchobroutsky C, Uzan M, Sultan Y, Weill BJ,Laumond-Barny S. Predictive value of uterine arteryvelocity waveforms in pregnancies complicated bysystemic lupus erythematosus and the antiphospholipidsyndrome. Fetal Diagn Ther 1992;7:195–202.

Bower S, Schuchter K, Campbell S. Doppler ultrasoundscreening as part of routine antenatal scanning:prediction of pre-eclampsia and intrauterine growthretardation. Br J Obstet Gynaecol 1993;100:989–94.

Campbell S, Black RS, Lees CC, Armstrong V,Peacock JL. Doppler ultrasound of the maternal uterinearteries: disappearance of abnormal waveforms andrelation to birthweight and pregnancy outcome. ActaObstet Gynecol Scand 2000;79:631–4.


Chan FY, Pun TC, Lam C, Khoo J, Lee CP, Lam YH.Pregnancy screening by uterine artery Dopplervelocimetry – which criterion performs best? ObstetGynecol 1995;85:596–602.

Coleman MA, McCowan LM, North RA. Mid-trimesteruterine artery Doppler screening as a predictor of

adverse pregnancy outcome in high-risk women.Ultrasound Obstet Gynecol 2000;15:7–12.

Driul L, Damante G, D’Elia A, Ianni A, Springolo F,Marchesoni D. Genetic thrombophilias and uterineartery Doppler velocimetry and preeclampsia. Int JGynaecol Obstet 2005;88:265–70.

Driul L, Springolo F, Pezzani I, Casarsa S, Plaino L,Ianni A, et al. [Pathological monolateral Dopplervelocimetry of the uterine artery and materno-fetaloutcome]. Minerva Ginecol 2002;54:397–402.


Frusca T, Soregaroli M, Valcamonico A, Guandalini F,Danti L. Doppler velocimetry of the uterine arteries innulliparous women. Early Hum Dev 1997;48:177–85.


Geipel A, Ludwig M, Germer U, Katalinic A, Diedrich K,Gembruch U. Uterine artery Doppler velocimetry andthe outcome of pregnancies resulting from ICSI. HumReprod 2001;16:1397–402.

Haddad B, Uzan M, Breart G, Uzan S. Uterine Dopplerwave form and the prediction of the recurrence of pre-eclampsia and intra-uterine growth retardation inpatients treated with low-dose aspirin. Eur J ObstetGynecol Reprod Biol 1995;62:179–83.

Harrington K, Cooper D, Lees C, Hecher K, Campbell S.Doppler ultrasound of the uterine arteries: theimportance of bilateral notching in the prediction ofpre-eclampsia, placental abruption or delivery of asmall-for-gestational-age baby. Ultrasound Obstet Gynecol1996;7:182–8.

Harrington K, Fayyad A, Thakur V, Aquilina J. Thevalue of uterine artery Doppler in the prediction ofuteroplacental complications in multiparous women.Ultrasound Obstet Gynecol 2004;23:50–5.

Harrington KF, Campbell S, Bewley S, Bower S.Doppler velocimetry studies of the uterine artery in theearly prediction of pre-eclampsia and intra-uterinegrowth retardation. Eur J Obstet Gynecol Reprod Biol1991;42 Suppl:S14–20.

Kurdi W, Campbell S, Aquilina J, England P,Harrington K. The role of color Doppler imaging of theuterine arteries at 20 weeks’ gestation in stratifyingantenatal care. Ultrasound Obstet Gynecol 1998;12:339–45.

Morris JM, Fay RA, Ellwood DA, Cook C-M,Devonald KJ. A randomized controlled trial of aspirinin patients with abnormal uterine artery blood flow.Obstet Gynecol 1996;87:74–8.


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North RA, Ferrier C, Long D, Townend K, Kincaid-Smith P. Uterine artery Doppler flow velocitywaveforms in the second trimester for the prediction ofpreeclampsia and fetal growth retardation. Obstet Gynecol1994;83:378–86.


Soutif C, Prevost A, Andre M. [Value of the systematicuterine Doppler in the primiparous woman. A series of315 cases]. J Gynecol Obstet Biol Reprod (Paris) 1996;25:819–23.

Subtil D, Goeusse P, Houfflin-Debarge V, Puech F,Lequien P, Breart G, et al. Randomised comparison ofuterine artery Doppler and aspirin (100 mg) withplacebo in nulliparous women: the Essai RegionalAspirine Mere-Enfant study (Part 2). BJOG 2003;110:485–91.

Valensise H, Romanini C. Uterine Doppler in theidentification of patients at risk for hypertension andIUGR. J Perinat Med 1994;22 Suppl 1:69–72.


Pulsatility indexAardema MW, De Wolf BT, Saro MC, Oosterhof H,Fidler V, Aarnoudse JG. Quantification of the diastolicnotch in Doppler ultrasound screening of uterinearteries. Ultrasound Obstet Gynecol 2000;16:630–4.

Albaiges G, Missfelder-Lobos H, Lees C, Parra M,Nicolaides KH. One-stage screening for pregnancycomplications by color Doppler assessment of theuterine arteries at 23 weeks’ gestation. Obstet Gynecol2000;96:559–64.


Martin AM, Bindra R, Curcio P, Cicero S, Nicolaides KH.Screening for pre-eclampsia and fetal growth restrictionby uterine artery Doppler at 11–14 weeks of gestation.Ultrasound Obstet Gynecol 2001;18:583–6.


Sato H. [A study for predicting toxemia of pregnancy bythe diastolic notch in pulsed Doppler flow velocity

waveforms of the uterine arteries – quantitative analysisof the diastolic notch as uterine arterial index (UTAI)].Nippon Sanka Fujinka Gakkai Zasshi 1995;47:1055–62.


Yu CKH, Lakasing L, Papageorghiou AT, Spencer K,Nicolaides KH. Uterine artery Doppler and mid-trimester maternal plasma homocysteine in subsequentpre-eclampsia. J Matern Fetal Neonatal Med 2004;16:134–9.

Zeeman GG, McIntire DD, Twickler DM. Maternal andfetal artery Doppler findings in women with chronichypertension who subsequently develop superimposedpre-eclampsia. J Matern Fetal Neonatal Med 2003;14:318–23.

Resistance index Aquilina J, Barnett A, Thompson O, Harrington K.Comprehensive analysis of uterine artery flow velocitywaveforms for the prediction of pre-eclampsia.Ultrasound Obstet Gynecol 2000;16:163–70.

Arenas J, Fernandez I, Rodriguez-Mon C, Dupla B,Diez E, Gonzalez-Garcia A. [Doppler screening of theuterine arteries to predict complications duringpregnancy]. Clin Invest Ginecol Obstet 2003;30:178–84.


Bewley S, Cooper D, Campbell S. Doppler investigationof uteroplacental blood flow resistance in the secondtrimester: a screening study for pre-eclampsia andintrauterine growth retardation. Br J Obstet Gynaecol1991;98:871–9.

Caforio L, Testa AC, Mastromarino C, Carducci B,Ciampelli M, Mansueto D, et al. Predictive value ofuterine artery velocimetry at midgestation in low- andhigh-risk populations: a new perspective. Fetal DiagnTher 1999;14:201–5.


Caruso A, Caforio L, Testa AC, Ferrazzani S,Mastromarino C, Mancuso S. Chronic hypertension inpregnancy: color Doppler investigation of uterinearteries as a predictive test for superimposedpreeclampsia and adverse perinatal outcome. J PerinatMed 1996;24:141–53.

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Caruso A, De Carolis S, Ferrazzani S, Valesini G,Caforio L, Mancuso S. Pregnancy outcome in relation touterine artery flow velocity waveforms and clinicalcharacteristics in women with antiphospholipidsyndrome. Obstet Gynecol 1993;82:970–7.

Chan FY, Pun TC, Lam C, Khoo J, Lee CP, Lam YH.Pregnancy screening by uterine artery Dopplervelocimetry – which criterion performs best? ObstetGynecol 1995;85:596–602.


Ferrier C, North RA, Becker G, Cincotta R, Fairley K,Kincaid-Smith P. Uterine artery waveform as a predictorof pregnancy outcome in women with underlying renaldisease. Clin Nephrol 1994;42:362–8.


Frusca T, Soregaroli M, Valcamonico A, Guandalini F,Danti L. Doppler velocimetry of the uterine arteries innulliparous women. Early Hum Dev 1997;48:177–85.



Jacobson SL, Imhof R, Manning N, Mannion V, Little D,Rey E, et al. The value of Doppler assessment of theuteroplacental circulation in predicting preeclampsia orintrauterine growth retardation. Am J Obstet Gynecol1990;162:110–14.

Konchak PS, Bernstein IM, Capeless EL. Uterine arteryDoppler velocimetry in the detection of adverseobstetric outcomes in women with unexplained elevatedmaternal serum alpha-fetoprotein levels. Am J ObstetGynecol 1995;173:1115–19.



Parretti E, Mealli F, Magrini A, Cioni R, Mecacci F,La Torre P, et al. Cross-sectional and longitudinalevaluation of uterine artery Doppler velocimetry for theprediction of pre-eclampsia in normotensive womenwith specific risk factors. Ultrasound Obstet Gynecol2003;22:160–5.

Pattinson RC, Brink AL, De Wet PE, Odendaal HJ.Early detection of poor fetal prognosis by serial Dopplervelocimetry in high-risk pregnancies. S Afr Med J1991;80:428–31.

Rizzo G, Arduini D, Romanini C. Uterine arteryDoppler velocity waveforms in twin pregnancies. ObstetGynecol 1993;82:978–83.

Sato H. [A study for predicting toxemia of pregnancy bythe diastolic notch in pulsed Doppler flow velocitywaveforms of the uterine arteries – quantitative analysisof the diastolic notch as uterine arterial index (UTAI)].Nippon Sanka Fujinka Gakkai Zasshi 1995;47:1055–62.


Soregaroli M, Valcamonico A, Scalvi L, Danti L,Frusca T. Late normalisation of uterine arteryvelocimetry in high risk pregnancy. Eur J Obstet GynecolReprod Biol 2001;95:42–5.

Steel SA, Pearce JM, Chamberlain G. Dopplerultrasound of the uteroplacental circulation as ascreening test for severe pre-eclampsia with intra-uterine growth retardation. Eur J Obstet Gynecol ReprodBiol 1988;28:279–87.

Steel SA, Pearce JM, McParland P, Chamberlain GV.Early Doppler ultrasound screening in prediction ofhypertensive disorders of pregnancy. Lancet 1990;335:1548–51.

Tranquilli AL, Giannubilo SR, Bezzeccheri V, Garbati E.[The relative weight of Doppler of the uterine arteryand 24-h ambulatory blood pressure monitoring inpredicting hypertension in pregnancy andpreeclampsia]. Acta Biomed Ateneo Parmense 2000;71Suppl 1:351–5.

Valensise H, Bezzeccheri V, Rizzo G, Tranquilli AL,Garzetti GG, Romanini C. Doppler velocimetry of theuterine artery as a screening test for gestationalhypertension. Ultrasound Obstet Gynecol 1993;3:18–22.

Valensise H, Romanini C. Second-trimester uterineartery flow velocity waveform and oral glucose tolerancetest as a means of predicting intrauterine growthretardation. Ultrasound Obstet Gynecol 1993;3:412–16.

Other ratios

Aardema MW, De Wolf BT, Saro MC, Oosterhof H,Fidler V, Aarnoudse JG. Quantification of the diastolic


227


notch in Doppler ultrasound screening of uterinearteries. Ultrasound Obstet Gynecol 2000;16:630–4.

Aquilina J, Barnett A, Thompson O, Harrington K.Comprehensive analysis of uterine artery flow velocitywaveforms for the prediction of pre-eclampsia.Ultrasound Obstet Gynecol 2000;16:163–70.


Ferrier C, North RA, Becker G, Cincotta R, Fairley K,Kincaid-Smith P. Uterine artery waveform as a predictorof pregnancy outcome in women with underlying renaldisease. Clin Nephrol 1994;42:362–8.



Sacchini C, Ludovici G, Piantelli G, Amone F, Paita Y,Gramellini D. Clinical findings in gestationalhypertension categorized by doppler velocimetry.J Matern Fetal Invest 1995;5:230–5.

Schulman H, Ducey J, Farmakides G, Guzman E,Winter D, Penny B, et al. Uterine artery Dopplervelocimetry: The significance of divergentsystolic/diastolic ratios. Am J Obstet Gynecol 1987;157:1539–42.

Cochrane reviewsAmbulatory versus conventionalmethods for monitoring blood pressureNone.

Bed rest with or without hospitalisationfor hypertensionCrowther 1986 (published and unpublished data)

Crowther CA. Strict bed rest vs ambulation in themanagement of patients with proteinuric hypertensionin pregnancy. Personal communication 2004.

Crowther 1992 (published data only)

Crowther CA, Bouwmeester AM, Ashurst HM. Doesadmission to hospital for bed rest prevent diseaseprogression or improve fetal outcome in pregnancycomplicated by non-proteinuric hypertension? Br JObstet Gynaecol 1992;99:13–17.

Leung 1998 (published data only)

Leung KY, Sum TK, Tse CY, Law KM, Chan MYM. Is in-patient management of diastolic blood pressurebetween 90 and 100 mm Hg during pregnancynecessary? Hong Kong Med J 1998;4:211–17.

Mathews 1982 (published data only)

Mathews DD, Agarwal V, Shuttleworth TP. A randomizedcontrolled trial of complete bed rest vs ambulation in themanagement of proteinuric hypertension duringpregnancy. Br J Obstet Gynaecol 1982;89:128–31.

Mathews DD, Agarwal V, Shuttleworth TP. The effect ofrest and ambulation on plasma urea and urate levels inpregnant women with proteinuric hypertension. Br JObstet Gynaecol 1980;87:1095–8.

Exercise for prevention of hypertensionUSA 1997 (published and unpublished data)

Avery MD, Leon AS, Kopher RA. Effects for a partiallyhome-based exercise program for women withgestational diabetes. Obstet Gynecol 1997;89:10–15.

USA 2000 (published and unpublished data)

Yeo S, Steele N, Chang M-C, Leclaire S, Rovis D,Hayashi R. Effect of exercise on blood pressure inpregnant women with a high risk of gestationalhypertensive disorders. J Reprod Med 2000;45:293–8.

Rest in women with normal bloodpressureHerrera 1993 (published data only)

Herrera JA. Nutritional factors and rest reducepregnancy induced hypertension and pre-eclampsia inpositive roll-over test primigravidas. Int J Gynaecol Obstet1993;41:31–5.

Spinapolice 1983 (published data only)

Spinapolice RX, Feld S, Harrigan JT. Effectiveprevention of gestational hypertension in nulliparouswomen at high risk as identified by the rollover test. AmJ Obstet Gynecol 1983;146:166–8.

Altered dietary salt intakeNetherlands 1997 (published data only)

Delemarre FM, van Leest LA, Jongsma HW, Steegers EA.Effects of low-sodium diet on uteroplacental circulation.J Mat-Fet Med 2000;9:197–200.

Delemarre FMC, Thomas CMG, van den Berg RJ,Jongsma HW, Steegers EAP. Urinary prostaglandinexcretion in pregnancy: the effect of dietary sodiumrestriction. Prostaglandins, Leukot Essent Fat Acids2000;63:209–15.

Steegers EAP, van Buul EJA. Chronic dietary sodiumrestriction in the prevention of hypertension duringpregnancy: preliminary results of a Dutch multicenteredtrial. Proceedings of the 9th International Congress,International Society for the Study of Hypertension in

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Pregnancy; 1994 March 15–18; Sydney, Australia. 1994; 54.

Steegers EAP, Van Lakwijk HPJM, Jongsma HW, Fast JH,De Boo T, Eskes TKAB, et al. (Patho)physiologicalimplications of chronic dietary sodium restrictionduring pregnancy; a longitudinal prospectiverandomized study. Br J Obstet Gynaecol 1991;98:980–7.

van Buul BJA, Steegers EAP, Jongsma HW, Rijpkema AL,Eskes TKAB, Thomas CMG, et al. Dietary sodiumrestriction in the prophylaxis of hypertensive disordersof pregnancy: effects on the intake of other nutrients.Am J Clin Nutr 1995;62:49–57.

van Buul BJA, Steegers EAP, van der Maten GD,Delemarre FMC, Jongsma HW, Oosterbaan HP, et al.Dietary sodium restriction does not prevent gestationalhypertension: a Dutch two-center randomized trial.Hypertens Pregnancy 1997;16:335–46.

van Buul E, Rijpkema A, Steegers E, Jongsma T, Eskes P.Chronic dietary sodium restriction in pregnancy reducescalcium intake. J Perinat Med 1992;20(Suppl 1):216.

van Buul EJA, Steegers EAP, Jongsma HW,Thomas CMG, Hein PR. Chronic dietary sodiumrestriction in pregnancy: effects on urinaryprostaglandin excretion. Proceedings of 2nd EuropeanCongress on Prostaglandins in Reproduction; 1991; TheHague, The Netherlands. 1991:186.

Van der Maten GD. Low sodium diet in pregnancy:effects on maternal nutritional status. Eur J ObstetGynecol Reprod Biol 1995;61:63–4.

van der Maten GD, van der Hammen RM, Visman L,Oosterban HP, De Boer R, van der Heijden LJM, et al.Effect of sodium restricted diet during pregnancy onmaternal blood pressure and zinc status. J Perin Med1992;20(Suppl 1):49.

van der Maten GD, van Raaij JM, Visman L, van der Heijden LJ, Oosterbaan HP, de Boer R, et al.Low-sodium diet in pregnancy: effects on blood pressureand maternal nutritional status. Br J Nutr 1997;77:703–20.

van der Post JA, van Buul BJ, Hart AA, vanHeerikhuize JJ, Pesman G, Legros JJ, et al. Vasopressinand oxytocin levels during normal pregnancy: effects ofchronic dietary sodium restriction. J Endocrinol 1997;152:345–54.

Netherlands 1998 (published data only)

Knuist M, Bonsel GJ, Zondervan HA, Treffers PE. Lowsodium diet and pregnancy-induced hypertension: amulti-centre randomised controlled trial. Br J ObstetGynaecol 1998;105:430–4.

AntioxidantsBeazley 2002 (published data only)

Beazley D, Ahokas R, Livingston J, Griggs M, Scroggs M,Sibai B. Effects of vitamin c and e supplementation ontotal antioxidant status (tas) and 8-isoprostane (ip) levels

in women at high risk for preeclampsia [abstract]. Am JObstet Gynecol 2002;187(6 Pt 2):S76.

Beazley D, Ahokas R, Livingston J, Griggs M, Sibai BM.Vitamin C and E supplementation in women at highrisk for preeclampsia: a double-blind, placebocontrolled trial. Am J Obstet Gynecol 2005;192:520–1.

Beazley D, Livingston J, Kao L, Sibai B. Vitamin c and esupplementation in women at high risk forpreeclampsia: a double-blind placebo controlled trial[abstract]. Am J Obstet Gynecol 2002;187(6 Pt 2):S216.

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Chappell L, Seed P, Briley A, Kelly F, Lee R, Hunt B,et al. Effect of antioxidants on the occurrence of pre-eclampsia in women at increased risk: a randomisedcontrolled trial. Lancet 1999;354:810–6.

Chappell LC, Seed PT, Kelly FJ, Briley A, Hunt BJ,Charnock-Jones DS, et al. Vitamin c and esupplementation in women at risk of preeclampsia isassociated with changes in indices of oxidative stressand placental function. Am J Obstet Gynecol 2002;187(3):777–84.

Han 1994 (published data only)

Han L, Zhou SM. Selenium supplement in theprevention of pregnancy induced hypertension. ChinMed J 1994;107(11):870–1.

People’s League 1942 (published data only)

People’s League of Health. Nutrition of expectant andnursing mothers: interim report. Lancet 1942;2:10–12.

People’s League of Health. The nutrition of expectantand nursing mothers in relation to maternal and infantmortality and morbidity. J Obstet Gynaecol Br Emp 1946;53:498–509.

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Rivas-Echeverria CA, Echeverria Y, Molina L, Novoa D.Synergic use of aspirin, fish oil and vitamins C and E forthe prevention of preeclampsia [abstract]. HypertensPregnancy 2000;19(Suppl 1):30.

Sharma 2003 (published data only)

Sharma JB, Kumar A, Kumar M, Malhotra M, Arora R,Prasad S, et al. Effect of lycopene on pre-eclampsia andintra-uterine growth retardation in primigravidas. Int JGynaecol Obstet 2003;81(3):257–62.

Steyn 2002 (published data only)

Steyn P, Odendaal H, Schoeman J, Grove D. Vitamin c,pre-eclampsia and preterm labour: a randomized,placebo-controlled, double blind trial [abstract].Hypertens Pregnancy 2002;21(Suppl 1):43.

Steyn PS, Odendaal HJ, Schoeman J, Stander C, Fanie N,Grove D. A randomised, double-blind placebo-controlled trial of ascorbic acid supplementation for theprevention of preterm labour. J Obstet Gynaecol 2003;23(2):150–5.


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Calcium supplementation duringpregnancy for preventing hypertensivedisorders and related problemsBelizan 1991 (published and unpublished data)

Belizan JM. Prevention of hypertensive disorders ofpregnancy with calcium supplementation. 8th WorldCongress on Hypertension in Pregnancy; 1992 November8–12; Buenos Aires. 1992; 93.

Belizan JM, Villar J, Bergel E, del Pino A, Di Fulvio S,Galliano SV, et al. Long term effect of calciumsupplementation during pregnancy on the bloodpressure of offspring: follow up of a randomisedcontrolled trial. BMJ 1997;315:281–5.

Belizan JM, Villar J, Gonzalez L, Campodonico L,Bergel E. Calcium supplementation to preventhypertensive disorders of pregnancy. N Engl J Med1991;325:1399–405.

Stephens IF. Effect of calcium supplementation duringpregnancy on blood pressure of offspring. Authorscannot be sure of effect’s generalisability to all childrenaged 5–9 [letter; comment]. BMJ 1998;316:234.

Villar J, Belizan JM, Repke J. The effect of calciumsupplementation on the incidence of hypertensivedisorders of pregnancy and prematurity. 7th WorldCongress of Hypertension in Pregnancy; 1990; Perugia, Italy.1990; 54.

Villar J, Belizan JM, Repke JT. Does calciumsupplementation reduce pregnancy-inducedhypertension and prematurity? Proceedings of theInternational Symposium on advances in the prevention of lowbirthweight; 1988 May 8–11; Cape Cod, Massachusetts.1988; 187–95.

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Hatton DC, Harrison-Hohner J, Coste S, Reller M,McCarron D. Gestational calcium supplementation andblood pressure in the offspring. American J Hypertens2003;16:801–5.

Levine RJ, Esterlitz JR, Raymond EG, DerSimonian R,Hauth JC, Ben Curet L, et al. Trial of calcium forpreeclampsia prevention (CPEP): rationale, design, andmethods. Control Clin Trials 1996;17:442–69.

Levine RJ, Hauth JC, Curet LB, Sibai BM, Catalano PM,Morris CD, et al. Trial of calcium to preventpreeclampsia. N Engl J Med 1997;337:69–76.

Levine RJ for the CPEP Study Group. Calcium forpreeclampsia prevention (CPEP): a double-blind,placebo-controlled trial in healthy nulliparas. Am J ObstetGynecol 1997;176:S2.

Levine RJ for the CPEP Study Group. The trial ofcalcium for preeclampsia prevention (CPEP). 8th WorldCongress on Hypertension in Pregnancy – Protagonists andPresentations; 1992 November 8–12; Buenos Aires,Argentina. 1992; 94.

Crowther 1999 (published data only)

Crowther C, Hiller J, Pridmore B, Bryce R, Duggan P,Hague W, et al. Calcium supplementation in nulliparouswomen for the prevention of pregnancy inducedhypertension, pre-eclampsia and preterm birth: anAustralian randomized trial. 2nd Annual Congress of thePerinatal Society of Australia and New Zealand; 1998 March30–April 4, Alice Springs, Australia. 1998; 101.

Crowther CA, Hiller JE, Pridmore B, Bryce R, Duggan P,Hague WM, et al. Calcium supplementation innulliparous women for the prevention of pregnancy-induced hypertension, preeclampsia and preterm birth:an Australian randomized trial. Aust N Z J ObstetGynaecol 1999;39:12–18.

L-Jaramillo 1989 (published and unpublished data)

Lopez-Jaramillo P, Narvaez M, Weigel RM, Yepez R.Calcium supplementation reduces the risk of pregnancy-induced hypertension in an Andes population. Br JObstet Gynaecol 1989;96:648–55.

Lopez-Jaramillo P, Narvaez M, Yepez R. Effect ofcalcium supplementation on the vascular sensitivity toangiotensin II in pregnant women. Am J Obstet Gynecol1987;156:261–2.

Narvaez M, Lopez-Jaramillo P, Weigel M. Calcium(Ca++) supplementation reduces the risk for pregnancyinduced hypertension (PIH). World Congress of Gynecologyand Obstetrics; 1988 October 23–28; Brazil. 1988; 180–1.

L-Jaramillo 1990 (published data only)

Lopez-Jaramillo P, Narvaez M, Felix C, Lopez A. Dietarycalcium supplementation and prevention of pregnancyhypertension. Lancet 1990;335:293.

Narvaez M, Lopez-Jaramillo P, Weigel M. Calcium(Ca++) supplementation reduces the risk for pregnancyinduced hypertension (PIH). World Congress of Gynecologyand Obstetrics; 1988 October 23–28; Brazil. 1988; 180–1.

L-Jaramillo 1997 (published data only)

Lopez-Jaramillo P, Delgado F, Jacome P, Teran E,Ruano C, Rivera J. Calcium supplementation and therisk of preeclampsia in Ecuadorian pregnant teenagers.Obstet Gynecol 1997;90:162–7.

Niromanesh 2001 (published data only)

Niromanesh S, Laghaii S, Mosavi-Jarrahi A.Supplementary calcium in prevention of pre-eclampsia.Int J Gynaecol Obstet 2001;74:17–21.

Purwar 1996 (published data only)

Purwar M, Kulkarni H, Motghare V, Dhole S. Calciumsupplementation and prevention of pregnancy inducedhypertension. J Obstet Gynaecol Res 1996;22:425–30.

Purwar M, Motghare V, Kulkarni H. Calciumsupplementation and prevention of pregnancy inducedhypertension: randomized double blind controlled trial.J Clin Epidemiol 1996;49(Suppl 1):28S.

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S-Ramos 1994 (published data only)

Sanchez-Ramos L, Briones DK, Kaunitz AM,Delvalle GO, Gaudier FL, Walker KD. Prevention ofpregnancy-induced hypertension by calciumsupplementation in angiotensin II-sensitive patients.Obstet Gynecol 1994;84:349–53.

Sanchez-Ramos L, Delvalle GO, Briones D, Walker C,Delke I, Gaudier F. Prevention of preeclampsia bycalcium supplementation in angiotensin-sensitivepatients. Am J Obstet Gynecol 1994;170:408.

Villar 1987 (published and unpublished data)

Repke JT, Villar J, Anderson C, Pareja G, Dubin N,Belizan JM. Biochemical changes associated with bloodpressure reduction induced by calcium supplementationduring pregnancy. Am J Obstet Gynecol 1989;160:684–90.

Villar J, Repke J, Belizan JM, Pareja G. Calciumsupplementation reduces blood pressure duringpregnancy: results of a randomized controlled clinicaltrial. Obstet Gynecol 1987;70:317–22.

Villar 1990 (published and unpublished data)

Villar J, Belizan JM, Repke J. The effect of calciumsupplementation on the incidence of hypertensivedisorders of pregnancy and prematurity. 7th WorldCongress of Hypertension in Pregnancy; 1990; Perugia, Italy.1990; 54.

Villar J, Belizan JM, Repke JT. Does calciumsupplementation reduce pregnancy-inducedhypertension and prematurity? Advances in the preventionof low birthweight; 1988 May 8–11; Cape Cod,Massachusetts. 1998; 187–95.

Villar J, Repke JT. Calcium supplementation duringpregnancy may reduce preterm delivery in high-riskpopulations. Am J Obstet Gynecol 1990;163:1124–31.

WHO 2006 (unpublished data only)

Villar J, Abdel-Aleem H, Merialdi M, Mathai M, Ali M,Zavaleta N, et al. World Health Organisationrandomized trial of calcium supplementation amonglow calcium intake pregnant women. Am J Obstet Gynecol2006;194:639–49.

Villar J, Aleem HA, Merialdi M, Mathai M, Ali M,Zavaleta N, et al. WHO randomized trial of calciumsupplementation among low calcium intake pregnantwomen [abstract]. Am J Obstet Gynecol 2005;193(6 Suppl):S2.

Energy and protein intake in pregnancyAtton 1990 (published data only)

Atton C, Watney PJM. Selective supplementation inpregnancy: effect on birth weight. J Hum Nutr Dietetics1990;3:381–92.

Watney PJM, Atton C. Dietary supplementation inpregnancy. BMJ 1986;293:1102.

Badrawi 1993 (published and unpublished data)

Badrawi H, Hassanein MK, Badroui MHH, Wafa YA,Shawky HA, Badrawi N. Pregnancy outcome in obesepregnant mothers. J Perinat Med 1993;20(Suppl 1):203.

Badrawi H, Hassanein MK, Badroui MHH, Wafa YA,Shawky HA, Badrawi N. Pregnancy outcome in obesepregnant mothers. New Egypt J Med 1993;6:1717–26.

Blackwell 1973 (published data only)

Adair LS, Pollitt E. Outcome of maternal nutritionalsupplementation: a comprehensive review of the BaconChow Study. Am J Clin Nutr 1985;41:948–78.

Adair LS, Pollitt E, Mueller WH. The Bacon ChowStudy: effect of nutritional supplementation onmaternal weight and skinfold thickness duringpregnancy and lactation. Br J Nutr 1984;51:357–69.

Blackwell RQ, Chow BF, Chinn KSK, Blackwell BN,Hsu SC. Prospective maternal nutrition study in Taiwan:rationale, study design, feasibility and preliminaryfindings. Nutr Rep Int 1973;7:517–32.

Joos SK, Pollitt E, Mueller WH, Albright DL. The BaconChow Study: maternal nutritional supplementation andinfant behavioral development. Child Dev 1983;54:669–76.

McDonald EC, Pollitt E, Mueller W, Hsueh AM,Sherwin R. The Bacon Chow study: maternal nutritionalsupplementation and birth weight of offspring. Am JClin Nutr 1981;34:2133–44.

Mueller WH, Pollitt E. The Bacon Chow study: effects ofmaternal nutritional supplementation on birthmeasurements of children, accounting for the size of aprevious (unsupplemented) child. Early Hum Dev1984;10:127–36.

Mueller WH, Pollitt E. The Bacon Chow Study: effectsof nutrition supplementation on sibling-siblinganthropometric correlations. Hum Biol 1982;54:455–68.

Pollitt E, Mueller W. Maternal nutritionsupplementation during pregnancy interferes withphysical resemblance of siblings at birth according toinfant sex. Early Hum Dev 1982;7:251–6.

Wohlleb JC, Pollitt E, Mueller WH, Bigelow R. TheBacon Chow Study: maternal supplementation andinfant growth. Early Hum Dev 1983;9:79–91.

Briley 2002 (published data only)

Briley C, Flanagan NL, Lewis NM. In-home prenatalnutrition intervention increased dietary iron intakes andreduced low birthweight in low-income African-American women. J Am Diet Assoc 2002;102(7):984–7.

Campbell 1975 (published and unpublished data)

Blumenthal I. Diet and diuretics in pregnancy andsubsequent growth of offspring. BMJ 1976;2:733.

Campbell DM, MacGillivray I. The effect of a lowcalorie diet or a thiazide diuretic on the incidence ofpre-eclampsia and on birthweight. Br J Obstet Gynaecol1975;82:572–7.


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Campbell 1983 (published and unpublished data)

Campbell DM. Dietary restriction in obesity and itseffect on neonatal outcome. In: Campbell DM, GillmerMDG editor(s). Nutrition in pregnancy. Proceedings of 10thStudy Group of the RCOG. London: RCOG, 1983;243–50.

Campbell Brown 1983 (published data only)

Campbell Brown M. Protein energy supplements inprimigravid women at risk of low birthweight. In:Campbell DM, Gillmer MDG editor(s). Nutrition inpregnancy. Proceedings of the 10th Study Group of the RCOG.London: RCOG, 1983; 85–98.

Ceesay 1997 (published data only)

Ceesay SM, Saidykhan S, Prentice AM, Cole TJ, Day KC,Rowland MGM, et al. Effect on birth weight of acommunity-based supplementation programme forpregnant Gambian women: first year results. Proc NutrSoc 1992;51:77A.

Ceesay SN, Prentice AM, Cole TJ, Foord F, Weaver LT,Poskitt EME, et al. Effects on birth weight and perinatalmortality of maternal dietary supplements in ruralGambia: 5 year randomised controlled trial. BMJ 1997;315:786–90.

Moore SE, Collinson AC, Prentice AM. Immunefunction in rural Gambian children is not related toseason of birth, birth size, or maternal supplementationstatus. Am J Clin Nutr 2001;74:840–7.

Elwood 1981 (published and unpublished data)

Elwood PC, Haley TJL, Hughes SJ, Sweetnam PM,Gray OP, Davies DP. Child growth (0–5 years), and theeffect of entitlement to a milk supplement. Arch DisChild 1981;56:831–5.

Girija 1984 (published and unpublished data)

Girija A, Geervani P, Rao GN. Influence of dietarysupplementation during pregnancy on lactationperformance. J Trop Pediatr 1984;30:79–83.

Hankin 1962 (published data only)

Hankin ME, Symonds EM. Body weight, diet and pre-eclamptic toxaemia of pregnancy. Aust N Z J ObstetGynaecol 1962;4:156–60.

Hunt 1976 (published data only)

Hunt IF, Jacob M, Ostergard NJ, Masri G, Clark VA,Coulson AH. Effect of nutrition education on thenutritional status of low-income pregnant women ofMexican descent. Am J Clin Nutr 1976;29:675–84.

Iyengar 1967 (published data only)

Iyengar L. Effects of dietary supplements late inpregnancy on the expectant mother and her newborn.Indian J Med Res 1967;55:85–9.

Kafatos 1989 (published and unpublished data)

Kafatos AG, Vlachonikolis IG, Codrington CA. Nutritionduring pregnancy: the effects of an educationalintervention program in Greece. Am J Clin Nutr 1989;50:970–9.

Kardjati 1988 (published data only)

Kardjati S, Kusin JA, De With C. Energysupplementation in the last trimester of pregnancy inEast Java: I. Effect on birthweight. Br J Obstet Gynaecol1988;95:783–94.

Kardjati S, Kusin JA, Schofield WM, De With C. Energysupplementation in the last trimester of pregnancy inEast Java, Indonesia: effect on maternal anthropometry.Am J Clin Nutr 1990;52:987–94.

Kusin JA, Kardjati S, Houtkooper JM, Renqvist UH.Energy supplementation during pregnancy andpostnatal growth. Lancet 1992;340:623–6.

Van Steenbergen WM, Kusin JA, Kardjati S, De With C.Energy supplementation in the last trimester ofpregnancy in East Java, Indonesia: effect on breast-milkoutput. Am J Clin Nutr 1989;50:274–9.

Mardones 1988 (published and unpublished data)

Mardones-Santander F, Rosso P, Stekel A, Ahumada E,Llaguno S, Pizzaro F, et al. Effect of a milk-based foodsupplement on maternal nutritional status and fetalgrowth in underweight Chilean women. Am J Clin Nutr1988;47:413–19.

Mora 1978 (published data only)

Christiansen N, Mora JO, Navarro L, Herrera MG.Effects of nutritional supplementation during pregnancyupon birth weight: the influence of pre-supplementationon diet. Nutr Rep Int 1980;21:615–24.

Herrera MG, Mora JO, De Paredes B, Wagner M.Maternal weight/height and the effect of foodsupplementation during pregnancy and lactation.Maternal nutrition during pregnancy and lactation. A NestléFoundation workshop; 1979 April 26–27; Lausanne,Switzerland. Bern: Hans Huber, 1980; 252–63.

Mora JO, Clement J, Christiansen N, Suescun J,Wagner M, Herrera MG. Nutritional supplementationand the outcome of pregnancy. III. Perinatal andneonatal mortality. Nutr Rep Int 1978;18:167–75.

Mora JO, De Navarro L, Clement J, Wagner M,De Paredes B, Herrera MG. The effect of nutritionalsupplementation on calorie and protein intake ofpregnant women. Nutr Rep Int 1978;17:217–28.

Mora JO, De Paredes B, Wagner M, De Navarro L,Suescun J, Christiansen N, et al. Nutritionalsupplementation and the outcome of pregnancy. I. Birthweight. Am J Clin Nutr 1979;32:455–62.

Mora JO, Herrera MG, Suescun J, De Navarro L,Wagner M. The effects of nutritional supplementationon physical growth of children at risk of malnutrition.Am J Clin Nutr 1981;34:1885–92.

Appendix 12

232

Mora JO, Sanchez R, De Paredes B, Herrera MG. Sex related effects of nutritional supplementationduring pregnancy on fetal growth. Early Hum Dev1981;5:243–51.

Overholt C, Sellers SG, Mora JO, de Paredes B,Herrera MG. The effects of nutritional supplementationon the diets of low-income families at risk ofmalnutrition. Am J Clin Nutr 1982;36:1153–61.

Vuori L, Christiansen N, Clement J, Mora JO,Wagner M, Herrera MG. Nutritional supplementationand the outcome of pregnancy. II. Visual habituation at15 days. Am J Clin Nutr 1979;32:463–9.

Vuori L, De Navarro L, Christiansen N, Mora JO,Herrera MG. Food supplementation of pregnant womenat risk of malnutrition and their newborns’responsiveness to stimulation. Dev Med Child Neurol1980;22:61–71.

Waber DP, Vuori-Christiansen L, Ortiz N, Clement JR,Christiansen NE, Mora JO, et al. Nutritionalsupplementation, maternal education, and cognitivedevelopment of infants at risk of malnutrition. Am J ClinNutr 1981;34:807–13.

Ross 1938 (published data only)

Ross RA, Perlzweig WA, Taylor HM, McBryde A, Yates A,Kondritzer AA, et al. A study of certain dietary factors ofpossible etiologic significance in toxemias of pregnancy.Am J Obstet Gynecol 1938;35:426–40.

Ross 1985 (published data only)

Ross SM, Nel E, Naeye RL. Differing effects of low andhigh bulk maternal dietary supplements duringpregnancy. Early Hum Dev 1985;10:295–302.

Rush 1980 (published and unpublished data)

Jacobson HN. A randomized controlled trial of prenatalnutritional supplementation. Pediatrics 1980;65:835–6.

Pereira M, Rush D, Campbell-Brown M, Rosso P,Winick M, Brasel JA, et al. Effects of prenatal nutritionalsupplementation on the placenta: report of arandomized controlled trial. Am J Clin Nutr 1982;36:229–34.

Rush D, Kristal A, Blanc W, Navarro C, Chauham P,Campbell-Brown M, et al. The effects of maternalcigarette smoking on placental morphology,histomorphometry, and biochemistry. Am J Perinatology1986;3:263–72.

Rush D, Kristal A, Navarro C, Chauhan P, Blanc W,Naeye R, et al. The effects of dietary supplementationduring pregnancy on placental morphology, pathology,and histomorphometry. Am J Clin Nutr 1984;39:863–71.

Rush D, Stein Z, Susser, M. The rationale for, anddesign of, a randomized controlled trial of nutritionalsupplementation in pregnancy. Nutr Rep Int 1973;7:547–53.

Rush D, Stein Z, Susser M. A randomized controlledtrial of prenatal nutritional supplementation in NewYork City. Pediatrics 1980;65:683–97.

Rush D, Stein Z, Susser M. Controlled trial of prenatalnutrition supplementation defended. Pediatrics 1980;66:656–8.

Rush D, Stein Z, Susser M. Diet in pregnancy: arandomized controlled trial of nutritional supplements.Birth Defects 1980;16:1–187.

Stein Z, Susser M, Rush D. Prenatal nutrition and birthweight: experiments and quasi-experiments in the pastdecade. J Reprod Med 1978;21:287–97.

Sweeney 1985 (published data only)

Sweeney C, Smith H, Foster JC, Specht J, Kochenour NK,Prater BM. Effects of a nutrition intervention programduring pregnancy: maternal data phases 1 and 2. J Nurse Midwifery 1985;30:149–58.

Viegas 1982a (published data only)

Viegas OAC, Scott PH, Cole TJ, Mansfield HN,Wharton P, Wharton BA. Dietary protein energysupplementation of pregnant Asian mothers atSorrento, Birmingham. I. Unselective during secondand third trimesters. BMJ 1982;285:589–92.

Viegas 1982b (published data only)

Viegas OAC, Scott PH, Cole TJ, Eaton P, Needham PG,Wharton BA. Dietary protein energy supplementation ofpregnant Asian mothers at Sorrento, Birmingham. II.Selective during third trimester only. BMJ 1982;285:592–5.

GarlicIran 2001 (published data only)

Ziaei S, Hantoshzadeh S, Rezasoltani P, Lamyian M.The effect of garlic tablet on plasma lipids and plateletaggregation in nulliparous pregnants at high risk of pre-eclampsia. Eur J Obstet Gynecol Reprod Biol 2001;99:201–6.

Magnesium supplementation inpregnancyDenmark 2000 (published data only)

Rudnicki M, Frolich A, Pilsgaard K, Nyrnberg L,Moller M, Sanchez M, et al. Comparison of magnesiumand methyl dopa for the control of blood pressure inpregnancies complicated with hypertension. GynecolObstet Invest 2000;49:231–5.

Magpie Trial 2002 (published and unpublished data)

Bricker L, Magpie Trial Collaborative Group. TheMagpie Trial: magnesium sulphate versus placebo forwomen with pre-eclampsia. XVI FIGO World Congress ofObstetrics and Gynecology; 2000 Sept 3–8; Washington DC,USA 2000; Book 2; 47.

Duley L, Campbell L. The Magpie Trial: magnesiumsulphate for pre-eclampsia, evaluating the effects on


233


women and their babies. MIDIRS Midwifery Digest 1999;9:48–51.

Duley L, Magpie Trial Collaborative Group. TheMagpie Trial: magnesium sulphate versus placebo forwomen with pre-eclampsia. Hypertens Pregnancy 2000;19(Suppl 1):63.

Duley L, Neilson JP. Magnesium sulphate and pre-eclampsia. Trial needed to see whether it’s as valuable inpre-eclampsia as in eclampsia. BMJ 1999;319:3–4.

Duley L, Watkins K. Magnesium sulphate for treatmentof pre-eclampsia: a trial to evaluate the effects onwomen and their babies. Contemp Rev Obstet Gynaecol1998;10(4):267–74.

Magpie Trial Collaborative Group. Do women with pre-eclampsia, and their babies, benefit from magnesiumsulphate? The Magpie Trial: a randomised placebo-controlled trial. Lancet 2002;359:1877–90.

Moodley J, Magpie Trial Collaborative Group. TheMagpie Trial: magnesium sulphate versus placebo forwomen with pre-eclampsia. Women’s Health – into thenew millenium. Proceedings of the 4th InternationalScientific Meeting of the Royal College of Obstetricians andGynaecologists; 1999 October 3–6; Cape Town, SouthAfrica, 1999; 25.

Malaysia 1994 (published and unpublished data)

Adeeb N, Hatta AZ, Shariff J. Comparing magnesiumsulphate to diazepam in managing severe pre-eclampsiaand eclampsia. 10th World Congress of the InternationalSociety for the Study of Hypertension in Pregnancy; 1996August 4–8; Seattle, Washington, USA, 1996; 246.

Adeeb N, Ho CM. Comparing magnesium sulphateversus diazepam in the management of severe pre-eclampsia and eclampsia. 9th International Congress of the International Society for the Study of Hypertension inPregnancy; 1994 March 15–18; Sydney, Australia; 1994; 38.

Mexico 1992 (published data only)

Walss Rodriguez RJ, Levario AR. Anticonvulsanttreatment of severe pre-eclampsia: comparison ofdiazepam and magnesium sulfate. Ginecolog Obstet Mex1992;60:331–5.

Nimodipine SG 2003 (published data only)

Belfort M, Anthony J, Saade G, Nimodipine StudyGroup. Interim report of the nimodipine vs. magnesiumsulfate for seizure prophylaxis in severe preeclampsiastudy: an international randomized controlled trial. AmJ Obstet Gynecol 1998;178(1 Pt 2):S7.

Belfort M, Saade G, Yared M, Abedejos P, Dorman K.Change in estimated cerebral perfusion pressurefollowing nimodipine or magnesium sulfate in patientswith severe preeclampsia. Am J Obstet Gynecol 1998;178:S114.

Belfort MA, Anthony J, Saade GR, Allen JC, for theNimodipine Study Group. A comparison of magnesium

sulfate and nimodipine for the prevention of eclampsia.N Engl J Med 2003;348:304–11.

Belfort MA, Saade GR, Yared M, Grunewald C, Herd A,Varner MA, et al. Change in estimated cerebralperfusion pressure after treatment with nimodipine ormagnesium sulfate in patients with pre-eclampsia. Am JObstet Gynecol 1999;181:402–7.

South Africa 1994 (published data only)

Moodley J, Moodley VV. Prophylactic anticonvulsanttherapy in hypertensive crises of pregnancy – the needfor a large randomized trial. Hypertens Pregnancy1994;13:245–52.


Anthony J, Rush R. A randomised controlled trial ofintravenous magnesium sulphate versus placebo. Br JObstet Gynaecol 1998;105:809–10.

Coetzee E, Dommisse J, Anthony J. A randomisedcontrolled trial of intravenous magnesium sulphateversus placebo in the management of women withsevere pre-eclampsia. Br J Obstet Gynaecol 1998;105:300–3.

Coetzee E, Dommisse J, Anthony J. Are anticonvulsantsnecessary in the management of severe gestationalproteinuric hypertension. Int J Gynaecol Obstet 1994;46:121.

Coetzee E, Dommisse J, Anthony J. The prediction andprevention of seizures in 571 patients with severe pre-eclampsia. 10th World Congress of the International Societyfor the Study of Hypertension in Pregnancy; 1996 August4–8; Seattle, Washington, USA, 1996; 124.

Coetzee EJ, Anthony J, Dommisse AJ. Does magnesiumsulphate prevent eclampsia in severe gestationalproteinuria hypertension. Prenat Neonatal Med1996;1(Suppl 1):9.

Coetzee EJ, Dommisse AJ. Eclampsia: not a preventabledisease in the South African context. Proceedings of the13th Conference on Priorities in Perinatal Care; 1994; SouthAfrica, 1994; 3–5.

Moodley J, Pattinson RC, Hofmeyr GJ. A randomisedcontrolled trial of intravenous magnesium sulphateversus placebo in the management of women withsevere pre-eclampsia [letter; comment]. Br J ObstetGynaecol 1999;106:289–90.

Woods D, Anthony J, Dommisse J, Coetzee E. Canmagnesium sulphate before delivery reduce the risk ofhypoxic-ischaemic encephalopathy. Proceedings of the15th Conference on Priorities in Perinatal Care in SouthAfrica; March 5–8; Goudini Spa, South Africa, 1996.

Taiwan 1995 (published data only)

Chen FP, Chang SD, Chu KK. Expectant managementin severe preeclampsia: does magnesium sulfate preventthe development of eclampsia. Acta Obstet Gynecol Scand1995;74:181–5.

Appendix 12

234

USA – Alabama 1995 (published data only)

Atkinson MW, Guinn D, Owen J, Hauth JC. Doesmagnesium sulfate affect the length of labor inductionin women with pregnancy-associated hypertension? Am JObstet Gynecol 1995;173:1219–22.

Atkinson MW, Guinn D, Owen J, Hauth JC. Doesmagnesium sulfate prolong labor induction in womenwith gestational hypertension? Am J Obstet Gynecol1995;172:384.

USA – Maryland 1993 (published data only)

Friedman SA, Lim KH, Baker C, Repke JT. Phenytoin vsmagnesium sulfate in preeclampsia: a pilot study. Am JPerinatol 1993;10:233–8.

Friedman SA, Lim KH, Baker CA, Repke JT. Acomparison of phenytoin infusion versus magnesiumsulphate infusion in preeclampsia. Proceedings of the 10thAnnual Meeting of the Society of Perinatal Obstetricians;1990; Houston, Texas, USA, 1990; 16.

Repke JT, Friedman SA, Lim KH, Baker CA.Magnesium sulfate vs phenytoin in preeclampsia:preliminary results from a randomized clinical trial.Proceedings of 9th Annual Meeting of the Society of PerinatalObstetricians; 1989 February 1–4; New Orleans,Louisiana, USA, 1989; 123.

USA – Memphis 1997 (published data only)

Witlin A, Friedman S, Sibai B. The effect of magnesiumsulfate therapy on the duration of labor in women withmild preeclampsia at term: a randomized double-blind,placebo-controlled trial. Am J Obstet Gynecol 1997;176(1 Pt 2):S15.

Witlin AG, Friedman SA, Sibai BM. The effect ofmagnesium sulfate therapy on the duration of labor inwomen with mild preeclampsia at term: a randomized,double-blind, placebo-controlled trial. Am J ObstetGynecol 1997;76:623–7.

USA – Tennessee 2001 (published data only)

Livingston J, Livingston L, Mabie B, Sibai B. Theefficacy of magnesium sulfate in women with mildpreeclampsia: a double blinded placebo controlled trial.Hypertens Pregnancy 2002;20(Suppl 1):42.

Livingston J, Livingston L, Ramsey R, Kao L, Mabie B,Sibai B. Magnesium sulfate in women with mildpreeclampsia: a double blind placebo controlled trial.Am J Obstet Gynecol 2001;185(Suppl 6):S75.

Livingston JC, Livingston LW, Ramsey R, Mabie BC,Sibai BM. Magnesium sulfate in women with mildpreeclampsia: a randomised controlled trial. ObstetGynecol 2003;101(2):217–20.

USA – Texas 1995 (published data only)

Leveno KJ, Alexander JM, McIntire DD, Lucas MJ.Does magnesium sulfate given for the prevention ofeclampsia affect the outcome of labor? Am J ObstetGynecol 1998;178:707–12.

Lucas MJ, Leveno KJ, Cunningham MD. A comparisonof magnesium sulfate with phenytoin for the preventionof eclampsia. N Engl J Med 1995;333:201–5.

Marine oil and other prostaglandinprecursor supplementation duringpregnancy for reducing pre-eclampsiaAngola 1992 (published data only)

D’Almeida A, Carter JP, Anatol A, Prost C. Effects of acombination of evening primrose oil (gamma linolenicacid) and fish oil (eicosapentaenoic + docosahexaenoicacid) versus magnesium, and versus placebo inpreventing pre-eclampsia. Women Health 1992;19:117–31.

Denmark 1992 (published data only)

Dalby Sorensen J, Olsen SF, Pedersen AK, Boris J,Secher NJ, FitzGerald GA. Effect of fish oilsupplementation in the third trimester of pregnancy onprostacyclin and thromboxane production. Am J ObstetGynecol 1993;168:915–22.

Dalby Sorensen J, Secher NJ, Olsen SF. Effects of n-3fatty acids on blood pressure in the third trimester ofpregnancy. 7th World Congress of Hypertension inPregnancy; 1990; Perugia, Italy. 1990; 343.

Olsen SF, Dalby Sorensen J, Secher NJ, Hedegaard M,Brink Henriksen T, Hansen HS, et al. Randomisedcontrolled trial of effect of fish-oil supplementation onpregnancy duration. Lancet 1992;339:1003–7.

Olsen SF, Secher NJ. Fish oil and preeclampsia. 8thWorld Congress of the International Society for the Study ofHypertension in Pregnancy; 1992 November 8–12; BuenosAires, Argentina. 1992; 94.

Olsen SF, Secher NJ, Sorensen JD, Grant A. Gestationalage and fish oil supplementation in third trimester: apopulation-based randomized controlled trial.Proceedings of 13th World Congress of Gynaecology andObstetrics (FIGO); 1991 September; Singapore. 1991; 31.

Olsen SF, Sorensen JD, Secher NJ, Hedegaard M,Henriksen TB, Hansen HS, et al. Fish oilsupplementation and duration of pregnancy. Arandomized controlled trial. Ugeskrift for Laeger1994;156:1302–7.

Salvig JD, Olsen SF, Secher NJ. Effects of fish oilsupplementation in late pregnancy on blood pressure: arandomised controlled trial. Br J Obstet Gynaecol1996;103:529–33.

Sorensen JD, Olsen SF, Pedersen AK, Boris J, Secher NJ,FitzGerald GA. Effects of fish oil supplementation in thethird trimester of pregnancy on prostacyclin andthromboxane production. Int J Gynaecol Obstet 1993;43:229.

Sorensen JD, Olsen SF, Secher NJ. Effects of fish oilsupplementation in late pregnancy on blood pressure: arandomised controlled study. Acta Obstet Gynecol ScandSupple 1995;73:110.


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Sorensen JD, Olsen SF, Secher NJ, Jespersen J. Effectsof fish oil supplementation in late pregnancy on bloodlipids, serum urate, coagulation and fibrinolysis. Arandomised controlled study. Fibrinolysis 1994;8:54–60.

Van Houwelingen AC, Sorensen JD, Hornstra G,Simonis MMG, Boris J, Olsen SF, et al. Essential fattyacid status in neonates after fish-oil supplementationduring late pregnancy. Br J Nutr 1995;74:723–31.

England 1995 (published data only)

Onwude J, Hjartar H, Tuffnell D, Thornton JG,Lilford RJ. Fish oil in high risk pregnancy: arandomised, double blind, placebo-controlled trial.Proceedings of 26th British Congress of Obstetrics andGynaecology; 1992 July 7–10; Manchester, UK. 1992;430.

Onwude JL, Lilford RJ, Hjartardottir H, Staines A,Tuffnell D. A randomised double blind placebocontrolled trial of fish oil in high risk pregnancy. Br JObstet Gynaecol 1995;102:95–100.

Europe 2000 (published data only)

Olsen SF, Secher NJ, Tabor A, Weber T, Walker JJ,Gluud C. Randomised clinical trials of fish oilsupplementation in high risk pregnancies. Br J ObstetGynaecol 2000;107:382–95.


Bulstra-Ramakers MTEW, Huisjes HJ, Visser GHA. Theeffects of 3g eicosapentaenoic acid daily on recurrenceof intrauterine growth retardation and pregnancyinduced hypertension. Br J Obstet Gynaecol 1994;102:123–6.

USA 2003 (published data only)

Smuts CM, Huang M, Mundy D, Plasse T, Major S,Carlson SE. A randomized trial of docosahexaenoic acidsupplementation during the third trimester ofpregnancy. Obstet Gynecol 2003;101:469–79.

Antihypertensive drug therapy for mildto moderate hypertensionArgentina 1985 (published data only)

Voto L, Lapidus A, Neira J, Margulies M. Atenolol vsalpha methyldopa in the treatment of hypertension inpregnancy. 5th International Congress for the InternationalSociety for the Study of Hypertension in Pregnancy; 1986 July7–10; Nottingham, UK. 1986; 138.

Voto LS, Lapidus AM, Neira J, Margulies M. Treatmentof hypertension during pregnancy: Atenolol versusMethyldopa [Tratamiento de la hipertensión en elembarazo: Atenolol versus Alfa Metildopa]. ObstetGinecol Lat Am 1985;43:335–41.

Argentina 1987 (published data only)

Voto LS, Zin C, Neira J, Lapidus AM, Margulies M.Ketanserin versus alpha methyldopa in the treatment ofhypertension during pregnancy: a preliminary report. J Cardiovasc Pharmacol 1987;10(Suppl 3):S101–3.

Argentina 1988 (published data only)

Casavilla F, Vega HR. Prospective and randomized studyon mepindolol and alpha-methydopa efficacy in arterialhypertension (AH) treatment during pregnancy. WorldCongress of Gynecology and Obstetrics; 1988 October 23–28;Brazil. 1988; 182.

Australia 1983 (published data only)

Livingstone I, Craswell PW, Bevan EB, Smith MT,Eadie MJ. Propranolol in pregnancy – three-yearprospective study. Clin Exp Hypertens 1983;2:341–50.


Gallery EDM, Hunyor SN, Saunders DM, Gyory AZ. A randomized trial of oxyprenolol and a-methyl dopa intherapy of hypertension in pregnancy. 1st Congress of theInternational Society of Hypertens Pregnancy; 1978September 27–29; Dublin, Ireland. 1978; 88.

Gallery EDM, Ross MR, Gyory AZ. Antihypertensivetreatment in pregnancy: analysis of different responsesto oxprenolol and methyldopa. BMJ 1985;291:563–6.

Gallery EDM, Saunders DM, Hunyor SN, Gyory AZ.Randomised comparison of methyldopa and oxprenololfor treatment of hypertension in pregnancy. BMJ 1979;1:1591–4.

Australia 2001 (published and unpublished data)

Davis G, Brown M. Re: glyceryl trinitrate (GTN) patchesare unsuitable in hypertensive pregnancy. Aust J ObstetGynaecol 2001;41:474.

Brazil 1985 (published data only)

Kahhale S, Carrara W, Barros ACSD, Zugaib M, Neme B.A comparative study between treated (beta-blockerpindolol) and untreated chronic hypertension. 4th WorldCongress of the International Society for the Study ofHypertension in Pregnancy; 1984 June 18–21; Amsterdam,The Netherlands. 1984; 56.

Kahhale S, Zugaib M, Carrara W, Paula FJ, Sabbaga E,Neme B. Comparative study of chronic hypertensivepregnant women treated and non-treated with pindolol.Ginecologia e Obstetrícia Brasileiras 1985;8:85–9.

Brazil 1988 (published and unpublished data)

Freire S, de França LA, Rau de Almeida Callou M,Alves de Oliveira JE, Barbosa Filho J. Comparativestudy with pindolol and methyldopa in pregnant womenwith chronic hypertension. Jornal Brasileiro de Ginecologia1988;98:157–60.

Brazil 2000a (published and unpublished data)

Nascimento DJ. [Evaluation of the use of Verapamil withnon-serious form of chronic vascular hypertensiondisease during pregnancy]. Doctoral thesis. Brazil:Facultade Evangélica de Medicina do Paraná, 2000.

Caribbean Is.1990 (published and unpublished data)

Plouin PF, Breart G, Llado J, Dalle M, Keller ME,Goujon H, et al. A randomized comparison of early with

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conservative use of antihypertensive drugs in themanagement of pregnancy-induced hypertension. Br JObstet Gynaecol 1990;97:134–41.

France 1987 (published data only)

Plouin PF, Breart G, Maillard F, Papiernik E, Relier JP,Labetolol Methyldopa Study Group. Antihypertensiveefficacy and perinatal safety of labetalol in the treatmentof hypertension in pregnancy: a randomisedcomparison to methyldopa. Arch Mal Coeur Vaiss 1987;80:952–5.

Plouin PF, Breart G, Maillard F, Papiernik E, Relier JP,the Labetolol Methyldopa Study Group. Comparison ofantihypertensive efficacy and perinatal safety oflabetalol and methyldopa in the treatment ofhypertension in pregnancy: a randomized controlledtrial. Br J Obstet Gynaecol 1988;95:868–76.


Blazquez, Lardoux H, Leperlier E. Randomized andcomparative study of methyl dopa (MD), acebutolol(ACE) and labetalol for the treatment of moderatehypertension during pregnancy (HDP). 6th InternationalCongress, International Society for the Study of Hypertensionin Pregnancy; 1988 May 22–26; Montreal, Quebec,Canada. 1988; 100.

Lardoux H, Blazquez G, Leperlier E, Gerard J.[Randomized and comparative study of methyldopa(MD), acebutolol (ACE) and labetalol for the treatmentof moderate hypertension during pregnancy (HDP)].Arch Mal Coeur Vaiss 1988;91:137–40.


Jannet D, Carbonne B, Sebban E, Milliez J. Nicardipinevs metoprolol in the treatment of hypertension duringpregnancy: a randomized comparative trial. Int JGynaecol Obstet 1995;49:225.

Jannet D, Carbonne B, Sebban E, Milliez J. Nicardipinevs metoprolol in the treatment of hypertension duringpregnancy: a randomized comparative trial. ObstetGynecol 1994;84:354–9.

Hong Kong 1990 (published data only)

Li CY, Lao TT, Yu KM, Wong SP, Leung CF. The effectof labetalol on mild pre-eclampsia. Proceedings of the 7thWorld Congress of Hypertension in Pregnancy; 1990;Perugia, Italy. 1990; 191.

India 1992 (published data only)

Oumachigui A, Verghese M, Balachander J. Acomparative evaluation of metoprolol and methyldopain the management of pregnancy induced hypertension.Indian Heart J 1992;44:39–41.

Ireland 1991 (published and unpublished data)

Blake S, MacDonald D. The prevention of the maternalmanifestations of pre-eclampsia by intensiveantihypertensive treatment. Br J Obstet Gynaecol1991;98:244–8.

Israel 1986 (published data only)

Ellenbogen A, Jaschevatzky O, Davidson A, Anderman S,Grunstein S. Management of pregnancy-inducedhypertension with pindolol – comparative study withmethyldopa. Int J Gynaecol Obstet 1986;24:3–7.

Jaschevatzky OE, Davidson A, Ellenbogen A, AndermanS, Grunstein S. Comparative study of pindolol andmethyldopa and transplacental cross of pindolol in PIH.5th International Congress of the International Society for theStudy of Hypertension in Pregnancy; 1986 7–10 July;Nottingham, England. 1986; 137.

Israel 1986a (published data only)

Rosenfeld J, Bott-Kanner G, Boner G, Nissenkorn A,Friedman S, Ovadia, J, et al. Treatment of hypertensionduring pregnancy with hydralazine monotherapy orwith combined therapy with hydralazine and pindolol.Eur J Obstet Gynecol Reprod Biol 1986;22:197–204.


Bar J, Hirsch M, Friedman S, Fuchs J, Ovadia J, Bott-Kanner G. The effect of beta-adrenergic blockerpindolol on platelet function in chronic hypertensivepregnancies. Proceedings of 9th International Congress,International Society for the Study of Hypertension inPregnancy; 1994 March 15–18; Sydney, Australia. 1994;155.

Bott-Kanner G, Hirsch M, Boner G, Ovadia J, ModanM, Friedmann S, et al. Evaluation of antihypertensivetherapy (AHT) in the management of hypertension inpregnancy (HP). 6th International Congress of theInternational Society for the Study of Hypertension inPregnancy; 1988 May 22–26; Montreal, Quebec, Canada.1988; 11.

Bott-Kanner G, Hirsch M, Friedman S, Boner G,Ovadia J, Merlob P, et al. Antihypertensive therapy inthe management of hypertension in pregnancy – aclinical double-blind study of pindolol. Clin ExpHypertens 1992;B11:207–20.

Hirsch M, Bar J, Bott-Kanner G, Kaplan B, Fuchs J,Ovadia J. Effect of the beta-adrenergic blocker pindololon platelet function in chronic hypertensive pregnancy.Hypertens Pregnancy 1996;15:193–202.


Paran E, Baile Y, Holzberg G, Masor M, Zmora E, Insler V. Treatment of hypertension in pregnancy:different regime, different outcome. 6th InternationalCongress of the International Society for the Study ofHypertension in Pregnancy; 1988 May 22–26; Montreal,Quebec, Canada. 1988; 105.

Paran E, Holzberg G, Mazor M, Zmora E, Insler V. blocking agents in the treatment of pregnancy-induced

hypertension. Int J Clin Pharmacol Ther 1995;33:119–23.

Paran E, Maisner I, Holzberg G, Mazor M, Zmora E,Biale Y, et al. Beta-blocker treatment of PIH correlatedwith uteroplacental blood flow measurement. 6thInternational Congress, International Society for the Study of


237


Hypertension in Pregnancy; 1988 May 22–26; Montreal,Quebec, Canada. 1988; 109.

Italy 1997 (published data only)

Catalano D, Ercolano S, Pollio F, Ascione L, Russo C, De Santi B, et al. [Evaluation of nifedipine monotherapyin the management of pregnancy hypertension].Giornale Italiano Di Ostetricia e Ginecologia 1997;6:373–5.


Bortolus R, Ricci E, Chatenoud L, Parazzini F.Nifedipine administered in pregnancy: effect on thedevelopment of children at 18 months. BJOG2000;107:792–4.

Gruppo di Studio Ipertensione in Gravidanza.Nifedipine versus expectant management in mild tomoderate hypertension in pregnancy. Br J ObstetGynaecol 1998;105:718–22.

Luchini L, Bortolus R, Parazzini F. Multicentric,randomized, clinical trial on the efficacy of long-actingnifedipine in improving the prognosis of pregnancy inwomen with mild or moderate chronic or pregnancy-induced hypertension. J Nephrol 1991;6:51–4.

Italy 1999 (published and unpublished data)

Neri I, Ternelli G, Facchinetti F, Volpe A. Effectivenessof oral nifedipine and transdermal glyceryltrinitrate on24-hours blood pressure values in pregnancy-inducedhypertension. Hypertens Pregnancy 2000;19(Suppl 1):O65.

Neri I, Valensise H, Fachinetti F, Menghini S,Romanini C, Volpe A. 24-hour ambulatory bloodpressure monitoring: a comparison betweentransdermal glyceryl-trinitrate and oral nifedipine.Hypertens Pregnancy 1999;18:107–13.

Italy 2000 (published and unpublished data)

Borghi C, Degli Esposti D, Cassani A, Immordino V,Bovicelli L, Ambrosioni E. The treatment ofhypertension in pregnancy. J Hypertens 2002;20(Suppl 2):S52–6.

Borghi C, Immordino V, Degli Esposti D, Boschi S,Cassani A, Bentivenga C, et al. Comparison betweennifedipine-gits and methyldopa on blood pressurecontrol, utero-placental hemodynamic and fetaloutcome in patients with pre-eclampsia. HypertensPregnancy 2000;19(Suppl 1):P8.


Odendaal HJ, Schabort I, Pattinson RC. Prazosin forthe treatment of hypertension in pregnancy: arandomized control trial. In: Chalmers I ed. Oxforddatabase of perinatal trials, Version 1.2, disk issue 6,Autumn. Oxford: Oxford University Press, 1991.


Eloff WJ. The use of nifedipine vs methyldopa in mildto moderate pregnancy associated hypertension.

Proceedings of the 12th Conference on Priorities in PerinatalCare; 1993; South Africa. 1993; 30–3.

Sudan 2002 (published data only)

Elhassan EM, Mirghani OA, Habour AB, Adam I.Methyldopa versus no drug treatment in themanagement of mild pre-eclampsia. East Afr Med J2002;71:172–5.

Sweden 1984 (published and unpublished data)

Bjorksten B, Finnstrom O, Wichman K. Intrauterineexposure to the beta-adrenergic receptor-blocking agentmetoprolol and allergy. Int Arch Allergy Immunol 1988;87:59–62.

Finnstrom O, Ezitis J, Ryden G, Wichman K. Neonataleffects of beta-blocking drugs in pregnancy. Acta ObstetGynecol Scand Suppl 1984;118:91–3.

Ryden G, Karlberg BE, Wichman K. Metoprolol in thetreatment of hypertension in pregnancy – effect on themother and foetus. 4th World Congress of the InternationalSociety for the Study of Hypertension in Pregnancy; 1984June 18–21; Amsterdam, The Netherlands. 1984; 38.

Wichman K. Metoprolol in the treatment of mild tomoderate hypertension in pregnancy – effects on fetalheart activity. Clin Exp Hypertens 1986;5:195–202.

Wichman K, Ezitis J, Finnstrom O, Ryden G. Metoprololin the treatment of hypertension in pregnancy – effecton the newborn baby. Clin Exp Hypertens 1984;B3:153.

Wichman K, Ezitis J, Finnstrom O, Ryden G. Metoprololin the treatment of hypertension in pregnancy – effectson the newborn baby. 4th World Congress of theInternational Society for the Study of Hypertension inPregnancy; 1984 June 18–21; Amsterdam, TheNetherlands. 1984; 40.

Wichman K, Karlberg BE, Ryden G. Metoprolol in thetreatment of mild to moderate hypertension inpregnancy – effects on the mother. Clin Exp Hypertens1985;B4:141–56.

Wichman K, Ryden G, Karlberg BE. A placebocontrolled trial of metoprolol in the treatment ofhypertension in pregnancy. Scan J Clin Lab Invest1984;106:90–5.

Sweden 1985 (published and unpublished data)

Högstedt S, Lindberg B, Lindberg S, Ludviksson K,Sandström B. Effect of metoprolol on fetal heart ratepatterns during pregnancy and delivery. 4th WorldCongress of the International Society for the Study ofHypertension in Pregnancy; 1984 June 18–21; Amsterdam,The Netherlands. 1984; 39.

Hogstedt S, Lindberg B, Lindeberg S, Ludviksson K,Sandstrom B. Effect of metoprolol on fetal heart ratepatterns during pregnancy and delivery. Clin ExpHypertens 1984;B3:152.

Högstedt S, Lindeberg S, Axelsson O, Lindmark G,Rane A, Sandström B, et al. A prospective controlled

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trial of metoprolol-hydralazine treatment inhypertension during pregnancy. Acta Obstet Gynecol Scand1985;64:505–10.

Lindeberg S, Axelsson O, Lindeberg BS, Lindberg G,Ludviksson K, Sandstrom B. Effect of metoprolol incombination with hydralazine on fetal heart ratepatterns during hypertensive pregnancy and delivery.Clin Exp Hypertens 1985;4:87–94.

Sweden 1995 (published data only)

Wide-Swensson D, Ingemarsson I, Lunell NO,Lindberg B, Lindeberg S, Marsal K, et al. Calciumchannel blockade (isradipine) in treatment ofhypertension in pregnancy: a randomized placebo-controlled study. Int J Obstet Gynecol 1994;46:3.

Wide-Swensson DH, Ingemarsson I, Lunell NO,Forman A, Skajaa K, Lindberg B. Calcium channelblockade (isradipine) in treatment of hypertension inpregnancy: a randomized placebo-controlled study. Am JObstet Gynecol 1995;173:872–8.

UK 1968 (published data only)

Leather HM, Humphreys DM, Baker P, Chadd MA. A controlled trial of hypotensive agents in hypertensionin pregnancy. Lancet 1968;2:488–90.


Cockburn J, Moar VA, Ounsted MK, Redman CWG.Final report on study of hypertension during pregnancy:the effects of specific treatment on the growth anddevelopment of the children. Lancet 1982;1:647–9.

Moar VA, Jefferies MA, Mutch LMM, Ounsted MK,Redman CWG. Neonatal head circumference and thetreatment of maternal hypertension. Br J Obstet Gynaecol1978;85:933–7.

Mutch LMM, Moar VA, Ounsted MK, Redman CWG.Hypertension during pregnancy, with and withoutspecific hypotensive treatment. I. Perinatal factors andneonatal morbidity. Early Hum Dev 1977;1:47–57.

Mutch LMM, Moar VA, Ounsted MK, Redman CWG.Hypertension during pregnancy, with and withoutspecific hypotensive treatment. II The growth anddevelopment of the infant in the first year of life. EarlyHum Dev 1977;1:59–67.

Ounsted M. The children of women who hadhypertension during pregnancy. In: Rubin PC ed.Hypertens Pregnancy. Amsterdam: Elsevier, 1988; 341–62.

Ounsted MK, Moar VA, Good FJ, Redman CWG.Hypertension during pregnancy with and withoutspecific treatment: the development of the children atthe age of four years. Br J Obstet Gynaecol 1980;87:19–24.

Redman CWG, Beilin LJ, Bonnar J. Treatment ofhypertension in pregnancy with methyldopa: bloodpressure control and side effects. Br J Obstet Gynaecol1977;84:419–26.

Redman CWG, Beilin LJ, Bonnar J, Ounsted MK. Fetaloutcome in trial of antihypertensive treatment inpregnancy. Lancet 1976;2:753–6.


Lamming GD, Pipkin FB, Symonds EM. Comparison ofthe alpha and beta blocking drug, labetalol, and methyldopa in the treatment of moderate and severepregnancy-induced hypertension. Clin Exp Hypertens1980;2:865–95.

Lamming GD, Symonds EM. Comparison of the alphaand beta blocking drug labetalol and aldomet in thetreatment of pregnancy induced hypertension.Proceedings of the 2nd Congress of the International Societyfor the Study of Hypertension in Pregnancy; 1980 December1–4; Cairo, Egypt. 1980; 9.

Lamming GD, Symonds EM. Use of labetalol andmethyldopa in pregnancy-induced hypertension. Br JClin Pharmacol 1979;8:217S–222S.

UK 1982 (published and unpublished data)

Cameron AD, Walker JJ, Bonduelle M, Calder AA. Arandomised trial of the antihypertensive agent,labetalol, against bed rest in pregnancy hypertension.Archiv Gynecol 1985;237(Suppl 1):295.

Lang GD, Lowe GDO, Walker JJ, Forbes CD, Calder AA.Increased blood viscosity in pre-eclampsia: effect oftreatment with labetalol. Thromb Haemostas 1983;50:156.

Lang GD, Lowe GDO, Walker JJ, Forbes CD, Prentice CRM, Calder AA. Blood rheology in pre-eclampsia and intrauterine growth retardation: effects ofblood pressure reduction with labetalol. Br J ObstetGynaecol 1984;91:438–43.

Walker J. Intrauterine growth retardation and maternallabetalol treatment in a random allocation controlledstudy. MD thesis. Glasgow: University of Glasgow, 1992;141–55.

Walker JJ, Crooks A, Erwin L, Calder AA. Labetalol inpregnancy-induced hypertension: fetal and maternaleffects. In: Reilly A, Symonds EM eds. InternationalCongress Series 591. Amsterdam: Excerpta Medica, 1982;148–60.


Reynolds B, Butters L, Evans J, Adams T, Rubin PC.First year of life after the use of atenolol in pregnancyassociated hypertension. Arch Dis Child 1984;59:1061–3.

Rubin PC, Butters L, Clark D, Sumner D, Belfield A,Pledger D, et al. Obstetric aspects of the use inpregnancy-associated hypertension of the beta-adrenoceptor antagonist atenolol. Am J Obstet Gynecol1984;150:389–92.

Rubin PC, Butters L, Clark DM, Low RA, Reid JL.Atenolol in the management of hypertension duringpregnancy. Drugs 1983;25:212–14.


239


Rubin PC, Butters L, Clark DM, Reynolds B, Sumner DJ,Steedman D. Placebo-controlled trial of atenolol intreatment of pregnancy-associated hypertension. Lancet1983;1:431–4.

Rubin PC, Butters L, Reynolds B, Low RAL. Atenolol inthe management of pregnancy associated hypertension:obstetric and paediatric aspects. 4th World Congress of theInternational Society for the Study of Hypertension inPregnancy; 1984 June 18–21; Amsterdam, TheNetherlands. 1984; 41.

UK 1983a (published data only)

Fidler J, Smith V, Fayers P, de Swiet M. Randomisedcontrolled comparative study of methyldopa andoxprenolol in treatment of hypertension in pregnancy.BMJ 1983;286:1927–30.

Fidler J, Smith V, Fayers P, de Swiet M. Randomisedcontrolled comparative study of methyldopa andoxprenolol in treatment of hypertension in pregnancy.Obstet Gynecol Surv 1983;286:202–5.


Thorley KJ. Atenolol: side effects in the newborn infant.BMJ 1982;285:1116.

Thorley KJ. Randomised trial of atenolol and methyldopa in pregnancy related hypertension. 4th WorldCongress of the International Society for the Study ofHypertension in Pregnancy; 1984 June 18–21; Amsterdam,The Netherlands. 1984; 53.

Thorley KJ. Randomised trial of atenolol and methyldopa in pregnancy related hypertension. Clin ExpHypertens 1984;133:168.


Pickles C, Symonds E, Brinkman C. Effects of labetalol(L) vs placebo (P) on arterial pressure (AP) and forearmvenous distensibility (FVD) in women with pregnancyinduced hypertension (PIH). 5th International Congress ofthe International Society for the Study of Hypertension inPregnancy; 1986 7–10 July; Nottingham, England. 1986;92.

Pickles CJ, Broughton Pipkin F, Symonds EM. Arandomised placebo controlled trial of labetalol in thetreatment of mild to moderate pregnancy inducedhypertension. Br J Obstet Gynaecol 1992;99:964–8.

Pickles CJ, Symonds EM, Broughton Pipkin F. The fetaloutcome in a randomized double-blind controlled trialof labetalol vs placebo in pregnancy-inducedhypertension. Br J Obstet Gynaecol 1989;96:38–43.

Pickles CJ, Symonds EM, Broughton Pipkin F. The fetaloutcome of early intervention therapy in pregnancyinduced hypertension. A randomised, double-blindcontrolled trial of labetalol vs placebo. 6th InternationalCongress, International Society for the Study of Hypertensionin Pregnancy; 1988 May 22–26; Montreal, Quebec,Canada. 1988; 107.


Butters L, Kennedy S, Rubin PC. Atenolol in essentialhypertension during pregnancy. BMJ 1990;301:587–9.


Cruickshank DJ, Campbell D, Robertson AA,MacGillivray I. Intra-uterine growth retardation andmaternal labetalol treatment in a random allocationcontrolled study. J Obstet Gynaecol 1992;12:223–7.

Cruickshank DJ, Campbell DM. Atenolol in essentialhypertension during pregnancy. BMJ 1990;301:1103.

Cruickshank DJ, Robertson AA, Campbell DM,MacGillivray I. Does labetalol influence thedevelopment of proteinuria in pregnancy hypertension?A randomised controlled study. Eur J Obstet GynecolReprod Biol 1992;45:47–51.

Cruickshank DJ, Robertson AA, Campbell DM,MacGillivray I. Maternal obstetric outcome measures ina randomised controlled study of labetalol in thetreatment of hypertension in pregnancy. Clin ExpHypertens 1991;B10:333–4.


Arias F, Zamora J. Antihypertensive treatment andpregnancy outcome in patients with mild chronichypertension. Obstet Gynecol 1979;53:489–94.


Sibai BM, Gonzalez AR, Mabie WC, Moretti M. Acomparison of labetalol plus hospitalization vshospitalization alone in the management ofpreeclampsia remote from term. Obstet Gynecol1987;70:323–7.

USA 1987a (published data only)

Weitz C, Khouzami V, Maxwell K, Johnson JWC.Treatment of hypertension in pregnancy withmethyldopa: a randomized double blind study. Int JGynaecol Obstet 1987;25:35–40.


Sibai BM. The need of hypertensive drugs inmanagement of mild to moderate pregnanthypertension. Proceedings of the 7th World Congress ofHypertension in Pregnancy; 1990; Perugia, Italy. 1990; 133.

Sibai BM, Mabie WC, Shamsa F, Villar MA,Anderson GD. A comparison of no medication vsmethyldopa or labetalol in chronic hypertension duringpregnancy. Am J Obstet Gynecol 1990;162:960–7.


Barton JR, Mercer BM, Sibai BM. The effect ofnifedipine on urinary excretion of calcium inpreeclampsia. Am J Perinat 1997;14:609–12.

Sibai BM, Barton JR, Akl S, Sarinoglu C, Mercer BM. A randomized prospective comparison of nifedipine andbed rest vs bed rest alone in the management of

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preeclampsia remote from term. Am J Obstet Gynecol1992;167:879–84.

Sibai BM, Barton JR, Akl S, Sarinoglu C, Mercer BM. A randomized prospective comparison of nifedipine andbed rest vs bed rest alone in the management ofpreeclampsia remote from term. Am J Obstet Gynecol1992;166:280.

Venezuela 1988 (published data only)

Faneite PJ, Gonzalez X, Salazar G. [Evaluation ofantihypertensives in pregnancy: prospective randomizedstudy of mepindolol and alpha methyldopa]. Rev ObstetGinecol Venez 1988;48:139–43.

Antiplatelet agents for preventing pre-eclampsia and its complicationsAustralia 1988 (published data only)

Trudinger BJ, Cook CM, Connelly AJ, Giles WB,Thompson RS. Aspirin improves fetal weight inplacental insufficiency. Proceedings of 8th Annual Meetingof the Society of Perinatal Obstetricians; 1988 February 3–6;Las Vegas, Nevada, USA. 1988; 10.

Trudinger BJ, Cook CM, Thompson RS, Giles WB,Connelly AJ. Low-dose aspirin improves fetal weight inumbilical placental insufficiency. Lancet 1988;2:214–15.

Trudinger BJ, Cook CM, Thompson RS, Giles WB,Connelly AJ. Low-dose aspirin therapy improves fetalweight in umbilical placental insufficiency. Am J ObstetGynecol 1988;159:681–5.


Michael CA, Seville P, Wadeisha P, Walters BNJ.Randomised double blind placebo controlled trial ofaspirin in the prevention of pre-eclampsia. Proceedings of7th World Congress of Hypertension in Pregnancy; 1990October; Perugia, Italy. 1990; 73.

Michael CA, Walters BNJ. Low-dose aspirin in theprevention of pre-eclampsia: current evaluation. In:Teoh ES, Ratnam SS, Macnaughton MC eds. Maternalphysiology and pathology. The current status of gynaecologyand obstetrics series. Carnforth: Parthenon Publishing,1992; 183–9.


Newnham JP, Godfrey M, Walters BJN, Philips J,Evans SF. Low dose aspirin for the treatment of fetalgrowth restriction: a randomised controlled trial. Aust N Z J Obstet Gynaecol 1995;35:370–4.

Australia 1995a (published data only)

Kincaid Smith P, North RA, Fairley KF, Kloss M, Ihle BU.Prevention of pre-eclampsia in high risk women withrenal disease: a prospective randomized trial of heparinand dipyridamole. Nephrology 1995;1:297–300.

North RA, Fairley KF, Kloss M, Ihle B, Kincaid-Smith P.Prevention of pre-eclampsia in women with renaldisease. Proceedings of 7th World Congress of Hypertensionin Pregnancy; 1990 October; Perugia, Italy. 1990; 75.

North RA, Fairley KF, Kloss M, Ihle B, Kincaid-Smith P.Prevention of preeclampsia in women with renal disease[abstract]. 26th Annual Meeting of the Australasian Societyof Nephrology; 1990 March 14–16; Brisbane, Australia.1990; 9.

North RA, Fairley KF, Kloss M, Ihle B, Oats J, Kincaid-Smith P. Prevention of pre-eclampsia in womenwith renal disease. Proceedings of 6th International Congressof the International Society for the Study of Hypertension inPregnancy; 1988 May 22–26; Montreal, Quebec, Canada.1988; 193.


Ferrier C, North R, Kincaid-Smith P. Low dose aspirindelays the onset of pre-eclampsia in pregnancies withabnormal uteroplacental circulation. Proceedings of the10th World Congress of the International Society for the Studyof Hypertension in Pregnancy; 1996 August 4–8; Seattle,Washington, USA. 1996; 151.

Kincaid-Smith P. Trial to evaluate the role of aspirin(60mg) in the prevention of idiopathic intrauterinegrowth retardation and pregnancy inducedhypertension in primigravid women with abnormaluterine artery waveforms on Doppler examination at22–24 weeks gestation. Personal communication,October 30 1991.

Australia 1996a (published data only)

Morris JM, Fay RA, Ellwood DA, Cook C, Devonald KJ.A randomized controlled trial of aspirin in patients withabnormal uterine artery blood flow. Obstet Gynecol1996;87:74–8.


Gallery EDM, Hawkins M, Ross M, Gyory AZ, Leslie G.Low-dose aspirin in high risk pregnancy. Proceedings of9th International Congress of the International Society for theStudy of Hypertension in Pregnancy; 1994 March 15–18;Sydney, Australia. 1994; 71.

Gallery EDM, Ross MR, Hawkins M, Leslie GI, Gyory AZ. Low-dose aspirin in high-risk pregnancy.Hypertens Pregnancy 1997;16:229–38.

Leslie GI, Gallery ED, Arnold JD, Ross MR, Gyory AZ.Neonatal outcome in a randomized controlled trial oflow-dose aspirin in high-risk pregnancies. J PaediatrChild Health 1995;31:549–52.

Austria 1992 (published data only)

Schrocksnadel H, Sitte B, Alge A, Stechel-Berger G,Schwegel P, Pastner E, et al. Low-dose aspirin inprimigravidae with positive roll-over test. Gynecol ObstetInvest 1992;34:146–50.

Schrocksnadel H, Sitte B, Alge A, Steckel-Berger G,Daxenbichler G, Dapunt O. ]Low-dose aspirin inprevention and therapy of hypertension in pregnancy].Gynakologisch Geburtshilfliche Rundschau 1992;32:90–1.


241


Barbados 1998 (published data only)

Cruickshank J, Rotchell Y. The Barbados low-doseaspirin study in pregnancy (BLASP). 8th World Congresson Hypertension in Pregnancy; 1992 November 8–12;Buenos Aires, Argentina. 1992; 49.

Elder MG, de Swiet M, Sullivan M. A randomised trialof low dose aspirin for primiparae in pregnancy(Golding)/Barbados low dose aspirin study in pregnancy(BLASP) (Rotchell et al.) [Letter; comment]. Br J ObstetGynaecol 1999;106:180.

Griffiths J, Rotchell YE, Cruickshank JK, Philips-Gay M,Stewart A, Farrell B, et al. The Barbados Low-doseAspirin Study in Pregnancy (BLASP): a population-based trial in a developing country with excess pre-eclampsia and perinatal mortality [abstract]. West IndMed J 1996;45(2 Suppl):26–7.

Rotchell YE, Cruickshank JK, Griffiths J, Phillips G,Stuart A, Ayers S, et al. Results of the Barbados low doseaspirin study in pregnancy (BLASP): a population-basedtrial in a developing country with excess pre-eclampsia(PE) and perinatal mortality. 27th British Congress ofObstetrics & Gynaecology; 1995 July 4–7; Dublin, Ireland.1995; 31.

Rotchell YE, Cruickshank JK, Phillips Gay M, Griffiths J,Stuart A, Farrell B, et al. Barbados low dose aspirinstudy in pregnancy (BLASP): a randomized controlledtrial for the prevention of pre-eclampsia and itscomplications. Br J Obstet Gynaecol 1998;105:286–92.

Brazil 1996 (published data only)

Anonymous. ECPPA: randomised trial of low doseaspirin for the prevention of maternal and fetalcomplications in high risk pregnancies. Br J ObstetGynaecol 1996;103:39–47.

Atallah AN. ECPPA: randomized trial of low doseaspirin for the prevention of maternal and fetalcomplications in high risk pregnant women [abstract]. J Clin Epidemiol 1997;50 (Suppl 1):3S.

Atallah AN, Taborda WC. ECPPA: the Brazilian low-doseaspirin study in high risk pregnant women. HypertensPregnancy 1997;16:139.

Brazil 1992a (published data only)

Essinger S. [The use of low dose acetylsalicylic acid inprevention of pregnancy-induced hypertension]. Revistado Colegio Brasileiro de Cirurgioes 1992;19:58–62.

China 1996 (published data only)

Wang Z, Li W. A prospective randomized placebo-controlled trial of low dose aspirin for prevention ofintra uterine growth retardation. Chin Med J 1996;109:238–42.

Wang Z, Li W. Prevention of growth retardation by lowdose aspirin. Chung-Hua Fu Chan Ko Tsa Chih [Chin JObstet Gynecol] 1993;28:492–5.

China 1996a (published data only)

Wu J, Yang WW, Shen WH, He Y. Small dosage aspirinin the prevention of hypertension of pregnancy. ActaAcademiae Medicinae Suzhou 1996;16:551–3.

China 1999 (published and unpublished data)

Rogers MS, Fung HYM, Hung CY. Calcium and low-dose aspirin prophylaxis in women at high risk ofpregnancy-induced hypertension. Hypertens Pregnancy1999;18:165–72.

Rogers MS, Hung C, Arumanayagam M. Plateletangiotensin II receptor status during pregnancy inChinese women at high risk of developing pregnancy-induced hypertension. Gynecol Obstet Invest 1996;42:88–94.

CLASP 1994 (published data only)

Bar J, Hod M, Pardo J, Fisch B, Rabinerson D, Kaplan B,et al. Effect on fetal circulation of low-dose aspirin forprevention and treatment of pre-eclampsia andintrauterine growth restriction: Doppler flow study.Ultrasound Obstet Gynaecol 1997;9:262–5.

Bar J, Padoa A, Hod M, Sullivan MHF, Kaplan B,Kidron D. Decreased pathological placental findings inaspirin-treated pregnant women at risk of hypertensivecomplications. Hypertens Pregnancy 1997;16:435–44.

Bower SJ, Harrington KF, Schuchter K, McGirr C,Campbell S. Prediction of pre-eclampsia by abnormaluterine Doppler ultrasound and modification by aspirin.Br J Obstet Gynaecol 1996;103:625–9.

CLASP (Collaborative Low-dose Aspirin Study inPregnancy) Collaborative Group. CLASP: a randomisedtrial of low-dose aspirin for the prevention andtreatment of pre-eclampsia among 9364 pregnantwomen. Lancet 1994;343:619–29.

CLASP Collaborative Group. Low dose aspirin inpregnancy and early childhood development: follow upof the collaborative low dose aspirin study in pregnancy.Br J Obstet Gynaecol 1994;102:861–8.

Kyle PM, Buckley D, Kissane J, de Swiet M,Redman CWG. The angiotensin sensitivity test and low-dose aspirin are ineffective methods to predict andprevent hypertensive disorders in nulliparouspregnancy. Am J Obstet Gynecol 1995;173:865–72.

Mathai M. Aspirin for pre-eclampsia. Nat Med J India1995;8:23–4.

Vikhlyaeva K, Asymbekova GU, Zerdev VP. Aspirin inprofilaxis and treatment of placental insufficiency:lessons from Russian aspirin experience. HypertensPregnancy 2000;19(Suppl 1):68.

Colorado 1993 (published data only)

Porreco RP, Hickok DE, Williams MA, Krenning C. Low-dose aspirin and hypertension in pregnancy. Lancet1993;341:312.

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Egypt 2005 (published data only)

Ebrashy A, Ibrahim M, Marzook A, Yousef D. Usefulnessof aspirin therapy in high-risk pregnant women withabnormal uterine artery doppler ultrasound at 14–16weeks pregnancy: randomized controlled clinical trial.Croat Med J 2005;46(5):826–31.

EPREDA 1991 (published data only)

Beaufils M, Uzan S, Breart G, Bazin B, Paris J.Prevention of preeclampsia with low-dose aspirin: resultsof the epreda trial. XIth International Congress ofNephrology; 1990 July 15–20; Tokyo, Japan. 1990; 319A.

Sureau C. Prevention of perinatal consequences of pre-eclampsia with low-dose aspirin: results of the EPREDAtrial. Eur J Obstet Gynecol Rep Bio 1991;41:71–3.

Uzan M, Beaufils M, Breart G, Bazin B, Capitant C,Paris J, et al. Prevention of pre-eclampsia with low-doseaspirin: results of the EPREDA trial. J Perinat Med 1990;18(Suppl):116.

Uzan S, Beaufils M, Breart G, Bazin B, Capitant C,Paris J. Prevention of fetal growth retardation with low-dose aspirin: findings of the EPREDA trial. Lancet1991;337:1427–31.

Uzan S, Beaufils M, Breart G, Bazin B, Capitant C, Paris J. Prevention of pre-eclampsia with low-doseaspirin: results of the EPREDA trial. Eur J Obstet GynecolRep Bio 1992;44:12.

Uzan S, Beaufils M, Breart G, Bazin B, Paris J.Prevention of pre-eclampsia with low-dose aspirin:results of the EPREDA trial. Proceedings of 7th WorldCongress of Hypertension in Pregnancy; 1990 October;Perugia, Italy. 1990; 34.

Uzan S, Beaufils M, Breart G, Uzan M, Paris J.[Prevention of intrauterine growth retardation and pre-eclampsia by small doses of aspirin. Results of theFrench multicenter trial EPREDA and comparison withdata in the literature; value of uterine Doppler]. J Gynecol Obstet Biol Reprod (Paris) 1992;21(3):315–18.

ERASME 2003 (published data only)

ERASME collaborative group. Failure of systematic lowdose aspirin to prevent preeclampsia in primigravidae.Hypertens Pregnancy 2000;19(Suppl 1):34.

Subtil D, Goeusse P, Puech F, Lequien P, Biausque S,Breart G, et al. Aspirin (100 mg) used for prevention ofpre-eclampsia in nulliparous women: the Essai RegionalAspirine Mere-Enfant study (Part 1). BJOG2003;110:475–84.

Subtil D, Quandalle F, Houfflin-Debarge V, Malek Y,Truffert P, Breart G, et al. Low dose aspirin to preventpreeclampsia: what do we learn from a new "negative"trial? [abstract]. Eur J Obstet Gynecol Rep Bio 2002;104:179.

Finland 1993 (published data only)

Viinikka L, Hartikainen-Sorri AL, Lumme R,Hiilesmaa V, Ylikorkala O. Low dose aspirin inhypertensive pregnant women: effect on pregnancyoutcome and prostacyclin-thromboxane balance in

mother and newborn. Br J Obstet Gynaecol 1993;100:809–15.

Viinikka L, Hartikainen-Sorri AL, Lumme R,Hiilesmaa V, Ylikorkala O. The effect of 50mg of ASAdaily on pregnancy outcome and maternal and newbornprostacyclin and thromboxane. Proceedings of 2ndEuropean Congress on Prostaglandins in Reproduction; 1991April 30–May 3; The Hague, Netherlands. 1991; 93.


Zimmermann P, Eirio V, Koskinen J, Niemi K, Nyman R,Kujansuu E, et al. Effect of low dose aspirin treatmenton vascular resistance in the uterine, uteroplacental,renal and umbilical arteries – a prospective longitudinalstudy on a high risk population with persistent notch inthe uterine arteries. Eur J Ultrasound 1997;5:17–30.

Finland 1997a (published data only)

Tulppala M, Marttunen M, Soderstrom-Anttila V,Ailus K, Palosuo T, Ylikorkala O. Low dose aspirin inprevention of miscarriage in women with unexplainedor autoimmune related recurrent miscarriage: effect onprostacyclin and thromboxane A2. Hum Reprod 1997;12(1):191.

Tulppala M, Marttunen M, Soderstrom-Anttila V,Foudila T, Ailus K, Palosuo T, et al. Low-dose aspirin inprevention of miscarriage in women with unexplainedor autoimmune related recurrent miscarriage: effect onprostacyclin and thromboxane A2. Hum Reprod 1997;12:1567–72.


Vainio M, Kujansuu E, Iso-Mustajarvi M, Maenpaa J.Low dose acetylsalicylic acid in prevention of pregnancy-induced hypertension and intrauterine growthretardation in women with bilateral uterine arterynotches. BJOG 2002;109:161–7.

Vainio M, Kujansuu E, Riutta A, Maenpaa J. Effect ofASA on the risk of gestational hypertension andprostanoid synthesis in pregnant women screened byDoppler ultrasound. XXXIV Congress of Nordic Federationof Societies of Obstetrics and Gynecology; 2004 June 12–15;Helsinki, Finland. 2004; 21.

Vainio M, Riutta A, Koivisto AM, Maenpaa J. 9 alpha,11beta-prostaglandin f2 in pregnancies at high risk forhypertensive disorders of pregnancy, and the effect ofacetylsalicylic acid. Prostaglandins Leukot Essent Fat Acids2003;69:79–83.

Vainio M, Riutta A, Koivisto AM, Maenpaa J.Prostacyclin, thromboxane a2 and the effect of low-doseasa in pregnancies at high risk of hypertensivedisorders. Acta Obstet Gynecol Scand 2004;83:1119–23.


Beaufils M, Uzan S, Donsimoni R, Colau JC. Acontrolled trial of prophylactic treatment ofpreeclampsia: preliminary results. Arch Mal Coeur Vaiss1984;77:1226–8.


243


Beaufils M, Uzan S, Donsimoni R, Colau JC. Preventionof pre-eclampsia by early antiplatelet therapy. Lancet1985;1:840–2.


Azar R, Turpin D. Effect of antiplatelet therapy inwomen at high risk for pregnancy-inducedhypertension. Proceedings of 7th World Congress ofHypertension in Pregnancy; 1990 October; Perugia, Italy.1990; 257.

Germany 2000 (published data only)

Erdmann M, Paulus WE, Flock F, Herget I, Terinde R,Grab D. [Utero and fetoplacental hemodynamicmeasurements with low dose aspirin]. Z GeburtshilfeNeonatol 1999;203:18–23.

Grab D, Erdmann M, Paulus W, Oberhoffer R, Lang D.Effects of low dose aspirin on uterine and fetal bloodflow during pregnancy: a randomized placebocontrolled double blind trial. Acta Obstet Gynecol Scand1997;76:38.

Grab D, Paulus WE, Erdmann M, Terinde R,Oberhoffer R, Lang D, et al. Effects of low-dose aspirinon uterine and fetal blood flow during pregnancy:results of a randomized, placebo-controlled, double-blind trial. Ultrasound Obstet Gynecol 2000;15:19–27.


Rai U, Chakravorty M, Juneja Y. Role of low doseaspirin in PIH. J Obstet Gynaecol India 1993:883–6.


Roy UK, Pan S. A study of low dose aspirin inprevention of pregnancy induced hypertension. J IndianMed Assoc 1994;92:188–91.


Shenoy S, Chandrika D, Pisharody R. RCT of low doseaspirin to prevent the progression of pregnancy inducedhypertension grade A to B. J Clin Epidemiol 1999;52(Suppl 1):28S.


Schiff E, Peleg E, Goldenberg M, Rosenthal T, Ruppin E,Tamarkin M, et al. The use of aspirin to preventpregnancy-induced hypertension and lower the ratio ofthromboxane A2 to prostacyclin in relatively high riskpregnancies. N Engl J Med 1989;321:351–6.


Schiff E, Barkai G, Ben-Baruch G, Mashiach S. Low-dose aspirin does not influence the clinical course ofwomen with mild pregnancy-induced hypertension.Obstet Gynecol 1990;76:742–4.


Caspi E, Raziel A, Sherman D, Arieli S, Bukovski I,Weintraub Z. Prevention of pregnancy inducedhypertension in twins by early administration of low-

dose aspirin: a preliminary report. Am J Reprod Immunol1994;31:19–24.


Ballerini S, Valcamonico A, Greorini G, Frusca T,Benigni A, Orisio S, et al. Low dose aspirin (ASA) givento prevent preeclampsia only partially inhibits plateletcyclooxygenase activity. Proceedings of 6th World Congressof Hypertension in Pregnancy; 1988 May 22–26; Montreal,Quebec, Canada. 1988; 234.

Benigni A, Gregorini G, Frusca T, Chiabrando C,Ballerini S, Valcamonico A, et al. Effect of low-doseaspirin on fetal and maternal generation ofthromboxane by platelets in women at risk forpregnancy-induced hypertension. N Engl J Med1989;321:357–62.

Frusca T, Gregorini G, Ballerini S, Marchesi D, Bruni M.Low dose aspirin in preventing preeclampsia andIUGR. Proceedings of 6th World Congress of Hypertension inPregnancy; 1988 May 22–26; Montreal, Quebec, Canada.1988; 232.


Italian Study of Aspirin in Pregnancy. Low-dose aspirinin prevention and treatment of intrauterine growthretardation and pregnancy-induced hypertension. Lancet1993;341:396–400.

Parazzini DF. Low-dose aspirin in prevention andtreatment of intrauterine growth retardation andpregnancy-induced hypertension. Geburtshilfe undFrauenheilkunde 1993;53:822.

Parazzini F. Multicenter randomized Italian study oflow-dose aspirin for the prevention of pre-eclampsiaand intrauterine growth retardation. J Nephrol 1991;4:127–9.

Parazzini F, Benedetto C, Frusca T, Guaschino S,Romero M. The Italian study on low-dose aspirin for theprevention of pre-eclampsia and intrauterine growthretardation. Proceedings of 7th World Congress ofHypertension in Pregnancy; 1990 October; Perugia, Italy.1990; 32.

Parazzini F, Bortolus R, Chatenoud L, Restelli S,Benedetto C. Follow-up of children in the Italian Studyof Aspirin in Pregnancy. Lancet 1994;343:1235.

Parazzini F, Bortolus R, Chatenoud L, Restelli S, Ricci E,Marozio L, et al. Risk factors for pregnancy-inducedhypertension in women at high risk for the condition.Epidemiology 1996;7:306–8.


Volpicelli T, D’Anto V, Faticato A, Galante L, CivitilloRM, Rappa C, et al. Trial prospettico sull’uso profilatticodell’aspirina in donne gravide ad alto rischio dipreeclampsia. Gestosi ’99. 1999:159–60.

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Chiaffarino F, Parazzini F, Paladini D, Acaia B, OssolaW, Marozio L, et al. A small randomised trial of low-doseaspirin in women at high risk of pre-eclampsia. Eur JObstet Gynecol Reprod Biol 2004;112:142–4.

Jamaica 1998 (unpublished data only)

Elder MG, de Swiet M, Sullivan M. A randomised trialof low dose aspirin for primiparae in pregnancy(Golding)/Barbados low dose aspirin study in pregnancy(BLASP) (Rotchell et al.) [Letter; comment]. Br J ObstetGynaecol 1999;106:180

Forrester TE, Jones D, McCaw-Binns A, Palmer-Levy M,Wilks R, Bernard GW, et al. Low-dose aspirin inpregnancy – are there any benefits? [abstract]. West IndMed J 1996;45(2 Suppl):26.

Golding J. A randomised trial of low dose aspirin forprimiparae in pregnancy. Br J Obstet Gynaecol 1998;105:293–9.

McCaw-Binns A, Ashley D, Hawkins N, MacGillivray I,Golding J. International variation in the incidence ofhypertension in pregnancy among primiparae: theJamaican experience. 10th World Congress of theInternational Society for the Study of Hypertension inPregnancy; 1996 August 4–8; Seattle, Washington, USA.1996; 168.

McCaw-Binns A, Jamaica Low-Dose Aspirin Group. Lowdose aspirin in pregnancy – are there any benefits? 10thWorld Congress of the International Society for the Study ofHypertension in Pregnancy; 1996 August 4–8; Seattle,Washington, USA. 1996; 76.

Japan 1999 (published data only)

Seki H, Kuromaki K, Takeda S, Kinoshita K, Satoh K.Trial of prophylactic administration of TXA2 synthetaseinhibitor, ozagrel hydrochloride, for preeclampsia.Hypertens Pregnancy 1999;18:157–64.


Dekker GA. Low dose aspirin prevents pregnancy-induced hypertensive disease in angiotensin-sensitiveprimigravidae. Prediction and prevention of pregnancy-induced hypertensive disorders: a clinical andpathophysiologic study. MD thesis. Rotterdam:University Medical School, 1989; 91–102.

Wallenburg HCS, Dekker GA, Makovitz JW, Rotmans P.Low-dose aspirin prevents pregnancy-inducedhypertension and pre-eclampsia in angiotensin-sensitiveprimigravidae. Lancet 1986;1:1–3.


Dekker GA. Prediction and prevention of pregnancy-induced hypertensive disorders: a clinical andpathophysiologic study. MD thesis. Rotterdam:University Medical School, 1989.

Netherlands 1991a (published data only)

Wallenburg HCS, Dekker GA, Makovitz JW, Rotmans N.Effect of low-dose aspirin on vascular refractoriness inangiotensin-sensitive primigravid women. Am J ObstetGynecol 1991;164:1169–73.

Wallenburg HCS, Dekker GA, Makowitz JW. Reversal ofelevated vascular angiotensin II responsiveness inpregnancy by low-dose aspirin. Proceedings of 34th AnnualMeeting of the Society for Gynecologic Investigation; 1987March 18–21; Georgia, USA. 1987; 22.

Russia 1993 (published and unpublished data)

Rogov V, Tareeva I, Sidorova S, Androsova S. Preventionof pregnancy complications with acetylsalicylic acid(ASA) and dipyridamol (DP) in women with chronicglomerulonephritis (CGN) and essential hypertension(EH). Proceedings of 9th International Congress of theInternational Society for the Study of Hypertension inPregnancy; 1994 March 15–18; Sydney, Australia. 1994;280.

Rogov VA, Tareeva I, Sidorova S, Androsova SO,Katamadze KT, Nikiforova OV. Prevention of pregnancycomplications in glomerulonephritis and hypertensionwith acetylsalicylic acid and curantyl. TerapevticheskiiArkhiv 1993;65:65–8.

S Africa 1988 (published and unpublished data)

Railton A, Davey A. Aspirin and dipyridamole in theprevention of pre-eclampsia: effect on plasmaprostanoids 6 keto PG1a and TXB2 and clinicaloutcome of pregnancy. Proceedings of the 6th InternationalCongress of the International Society for the Study ofHypertension in Pregnancy; 1988 May 22–26; Montreal,Quebec, Canada. 1988; 60.

Railton A, Davey DA. Aspirin and dipyridamole in theprevention of pre-eclampsia: effect on plasma 6 ketoPGF1alpha and TxB2 and clinical outcome ofpregnancy. Proceedings of 1st European Congress onProstaglandins in Reproduction; 1988 July 6–9; Vienna,Austria. 1988; 48.

Spain 1997 (published data only)

Hermida RC, Ayala DE, Iglesias M, Mojon A, Silva I,Ucieda R, et al. Time-dependant effects of low doseaspirin administration on blood pressure in pregnantwomen. Hypertension 1997;30:589–95.

Spain 1999 (published data only)

Hermida R, Ayala D, Mojon A, Fernandez J, Alonso I,Silva I, et al. Time dependant effects of low dose aspirinadministration on blood pressure in high riskpregnancy. Hypertens Pregnancy 2000;19(Suppl 1):81.

Hermida RC, Ayala DE, Fernandez JR, Mojon A,Alonso I, Silva I, et al. Administration time-dependenteffects of aspirin in women at differing risk forpreeclampsia. Hypertension 1999;33:1079.

Hermida RC, Ayala DE, Fernandez JR, Mojon A,Alonso I, Silva I, et al. Administration time-dependenteffects of aspirin in women at differing risk forpreeclampsia. Hypertension 1999;34(4 Pt 2):1016–23.


245


Hermida RC, Ayala DE, Fernandez JR, Mojon A,Alonso I, Ucieda R, et al. Administration-timedependent effects of aspirin in women at high risk forpreeclampsia. Hypertens Pregnancy 2000;19(Suppl 1):35.

Hermida RC, Ayala DE, Iglesias M. Administrationtime-dependant influence of aspirin on blood pressurein pregnant women. Hypertension 2003;41:651–6.

Hermida RC, Ayala DE, Iglesias M. Administration-timedependent effects of low-dose aspirin on blood pressurein women at high risk for pre-eclampsia. HypertensPregnancy 2002;21(Suppl 1):47.

Hermida RC, Ayala DE, Iglesias M. Administration-timedependent effects of low dose aspirin on the incidenceof complications in women at high risk forpreeclampsia. Hypertens Pregnancy 2002;21(Suppl 1):20.

Tanzania 1995 (published data only)

Ramaiya C, Mgaya H. Low dose aspirin in prevention ofpregnancy-induced hypertension in primigravidae atthe Muhimbili Medical Centre, Dar Es Salaam. ActaObstet Gynecol Scand 1997;76(167):1.

Ramaiya C, Mgaya HN. Low dose aspirin in preventionof pregnancy-induced hypertension in primigravidae atthe Muhimbili Medical Centre, Dar es Salaam. East AfrMed J 1995;72:690–3.

Ramaiya CP. Low dosage of aspirin in prevention ofpregnancy induced hypertension (PIH) in primigravidaeat Muhimbili Medical Centre, Dar es Salaam. MD thesis.Dar es Salaam: University of Dar es Salaam, 1992.


McParland, Pearce JM, Chamberlain GVP. Dopplerultrasound and aspirin in recognition and prevention ofpregnancy-induced hypertension. Lancet 1990;335:1552–5.

McParland PJ, Pearce JMP. Low dose aspirin preventsproteinuric hypertension in women with abnormaluteroplacental waveforms. Proceedings of Silver JubileeCongress of Obstetrics and Gynaecology; 1989 July 4–7;London, UK. 1989; 8.


Louden KA, Broughton PF, Heptinsall S, Mitchell JRA,Symonds EM. Maternal low-dose aspirin spares theneonate. Proceedings of Silver Jubilee Congress of Obstetricsand Gynaecology; 1989 July 4–7; London, UK. 1989; 9.

Louden KA, Broughton PF, Symonds EM, Tuohy P,O’Callaghan C, Heptinstall S, et al. A randomizedplacebo-controlled study of the effect of low dose aspirinon platelet reactivity and serum thromboxane B2production in non-pregnant women, in normalpregnancy and in gestational hypertension. Int JGynaecol Obstet 1993;40:186.

Louden KA, Broughton-Pipkin F, Heptinstall S, Fox SC,Tuohy P, O’Callaghan C, et al. Neonatal plateletreactivity and serum thromboxane B2 production in

whole blood: the effect of maternal low dose aspirin. Br J Obstet Gynaecol 1994;101:203–8.

Louden KA, Broughton Pipkin F, Heptinstall S,Mitchell JRA, Symonds EM. Studies of the effect of low-dose aspirin on thromboxane production and plateletreactivity in normal pregnancy, pregnancy-inducedhypertension and neonates. Proceedings of 1st EuropeanCongress on Prostaglandins in Reproduction; 1988 July 6–9;Vienna, Austria. 1988; 30.

Louden KA, Broughton-Pipkin F, Heptinstall S,Mitchell RAM, Symonds EM. Maternal low-dose aspirinspares neonatal platelets. Br J Obstet Gynaecol 1990;97:1162.

Louden KA, Broughton Pipkin F, Symonds EM, Tuohy P,O’Callaghan C, Heptinstall S, et al. A randomizedplacebo-controlled study of the effect of low dose aspirinon platelet reactivity and serum thromboxane B2production in non-pregnant women, in normalpregnancy, and in gestational hypertension. Br J ObstetGynaecol 1992;99:371–6.

UK 1992b (published data only)

Quenby S, Farquharson R, Ramsden G. The obstetricoutcome of patients with positive anticardiolipinantibodies: aspirin vs no treatment. Proceedings of 26thBritish Congress of Obstetrics and Gynaecology; 1992 July7–10; Manchester, UK. 1992; 443.


Davies NJ. A study of low dose aspirin for theprevention of hypertensive disorders of pregnancy inprimiparous women. Proceedings of 2nd European Congresson Prostaglandins in Reproduction; 1991 April 30–May 3;The Hague, Netherlands. 1991; 183.

Davies NJ, Farquharson RG, Walkinshaw SA. Low-doseaspirin and nulliparae. Lancet 1991;338:324.

Davies NJ, Gazvani MR, Farquharson RG,Walkinshaw SA. Low-dose aspirin in the prevention ofhypertensive disorders of pregnancy in relatively low-risk nulliparous women. Hypertens Pregnancy 1995;14:49–55.

UK + others 2003 (published data only)

Yu CKH, Papageorghiou AT, Parra M, Palma Dias R,Nicolaides KH. Randomized controlled trial using low-dose aspirin in the prevention of pre-eclampsia inwomen with abnormal uterine Doppler at 23 weeksgestation. Ultrasound Obstet Gynecol 2003;22:233–9.


Copper R, Hauth J, Cutter G, DuBard M, Goldenberg R.Prerandomization compliance testing may predictpregnancy outcome in a randomized clinical trial. Am JObstet Gynecol 1993;168:414.

Goldenberg RL, Hauth JC, Copper RL, DuBard MB,Cutter GR. The effect of low dose aspirin on fetalgrowth in low risk primiparas. Am J Obstet Gynecol1993;168:383.

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Goldenberg RL, Hauth JC, DuBard MB, Copper RL,Cutter GR. Fetal growth in women using low-doseaspirin for the prevention of preeclampsia: effect ofmaternal size. J Mat Fet Med 1995;4:218–24.

Hauth J, Goldenberg R, Parker C, DuBard M, Copper R,Cutter G. Maternal serum thromboxane B2 reduction vspregnancy outcome in a low-dose aspirin trial. Am JObstet Gynecol 1993;168:316.

Hauth J, Goldenberg R, Philips J, Copper R, DuBard M,Cutter G. Low-dose aspirin therapy to preventpreeclampsia: safety considerations. Am J Obstet Gynecol1993;168:389.

Hauth JC, Goldenberg RL, DuBard MB, Copper RL,Parker CR. Low-dose aspirin does not alter longitudinalmaternal blood pressures. Am J Obstet Gynecol 1995;172:377.

Hauth JC, Goldenberg RL, Parker CR, Copper RL,Cutter GR. Maternal serum thromboxane B2 reductionvs pregnancy outcome in a low-dose aspirin trial. Am JObstet Gynecol 1995;173:578–84.

Hauth JC, Goldenberg RL, Parker CR Jr, Philips JB 3rd,Copper RL, DuBard MB, et al. Low-dose aspirin therapyto prevent preeclampsia. Am J Obstet Gynecol 1993;168:1083–93.

Hauth JC, Goldenberg RL, Parker R, Philips JB,Copper RL, DuBard MB, et al. Low-dose aspirin therapyto prevent preeclampsia. Int J Gynaecol Obstet1994;44:97.

Maher J, Owen J, Hauth J, Goldenberg R, Parker C.Low dose aspirin: effect on fetal urine output. Am JObstet Gynecol 1993;168:332.

Maher JE, Owen J, Hauth J, Goldenberg R, Parker CR Jr,Copper RL. The effect of low-dose aspirin on fetal urineoutput and amniotic fluid volume. Am J Obstet Gynecol1993;169:885–8.

Owen J, Maher J, Hauth J, Goldenberg R, Parker C.The effect of low dose aspirin on umbilical arteryDoppler measurements. Am J Obstet Gynecol 1993;168:357.

Owen J, Maher JE, Hauth JC, Goldenberg RL,Parker CR Jr. The effect of low-dose aspirin on umbilicalartery Doppler measurements [published erratumappears in Am J Obstet Gynecol 1994;170:1841]. Am JObstet Gynecol 1993;169:907–11.

Wenstrom KD, Hauth JC, Goldenberg RL, DuBard M,Lea C. The effect of low-dose aspirin on thedevelopment of preeclampsia in women with elevatedhCG. Am J Obstet Gynecol 1995;172:376.

Wenstrom KD, Hauth JC, Goldenberg RL, DuBard MB,Lea C. The effect of low-dose aspirin on pregnanciescomplicated by elevated human chorionic gonadotropinlevels. Am J Obstet Gynecol 1995;173:1292–6.

USA 1993a (published data only)

Caritis S, Sibai B, Thorn E, McLaughlin S, NICHD-MFM Network. Pregnancy effects of non-proteinuricgestational hypertension (GH). Am J Obstet Gynecol1995;172:376.

Di Sessa TG, Moretti ML, Khoury A, Pulliam DA,Arheart KL, Sibai BM. Cardiac function in fetuses andnewborns exposed to low-dose aspirin duringpregnancy. Am J Obstet Gynecol 1994;171:892–900.

Sibai B. Low-dose aspirin (60 mg/d) in pregnancy forthe prevention of preeclampsia. 8th World Congress onHypertension in Pregnancy; 1992 November 8–12; BuenosAires, Argentina 1992. 1992; 50.

Sibai B, Caritis S, Phillips E, Klebanoff M, McNellis D,Rocco L. Prevention of preeclampsia: low-dose aspirinin nulliparous women: a double-blind, placebocontrolled trial. Am J Obstet Gynecol 1993;168:286.

Sibai B, Caritis S, Phillips E, Klebanoff M, Paul R,Witter F, et al. Safety of low-dose aspirin in healthynulliparous women: a double-blind, placebo-controlledtrial. Proceedings of 40th Annual Meeting Society forGynecologic Investigation; 1993 March; Toronto, Canada.1993: S102.

Sibai B, Caritis S, Thom E, Shaw K, McNellis D,NICHD-MFM Network. Low-dose aspirin in nulliparouswomen: safety of epidural and correlation betweenbleeding time and maternal-neonatal bleedingcomplications. Am J Obstet Gynecol 1994;170:293.

Sibai B, Gordon T, Phillips E, McNellis D, Caritis S,Romero R, et al. Risk factors for preeclampsia in healthynulliparous women: a prospective multicenter study.Proceedings of 41st Annual Clinical Meeting of The AmericanCollege of Obstetricians and Gynecologists; 1993 May 3–6;Washington DC, USA. 1993; 2.

Sibai BM, Caritis SN, Thom E, Klebanoff M, McNellis D,Rocco L, et al. Prevention of preeclampsia with low-doseaspirin in healthy, nulliparous pregnant women. N EnglJ Med 1993;329:1213–18.

Sibai BM, Caritis SN, Thom E, Shaw K, McNellis D,NICHD-MFM Network. Low dose aspirin in nulliparouswomen: safety of continuous epidural block andcorrelation between bleeding time and maternal-neonatal bleeding complications. Am J Obstet Gynecol1995;172:1533–7.

Sibai BM, Gordon T, Thom E, Caritis SN, Klebanoff M,McNellis D, et al. Risk factors for preeclampsia inhealthy nulliparous women: a prospective multicenterstudy. Am J Obstet Gynecol 1995;172:642–8.

Witten FR. Double-blind, placebo-controlled trial of low-dose aspirin to prevent pre-eclampsia. Personalcommunication, 6 September 1991.

Yaffe S. Clinical trial of low dose aspirin (65mg) as apreventative of pre-eclampsia. Personal communication,3 December 1991.


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Cowchock S, Reece EA. Do low-risk pregnant womenwith antiphospholipid antibodies need to be treated?Organizing group of the antiphospholipid antibodytreatment trial. Am J Obstet Gynecol 1997;176:1099–100.


Caritis NS, NICHD-MFMU Network. Impact ofpreeclampsia on a subsequent pregnancy. Am J ObstetGynecol 1998;178(1 Pt 2):S120.

Caritis S. Low dose aspirin does not preventpreeclampsia in high risk women. Am J Obstet Gynecol1997;176(1 Pt 2):S3.

Caritis S, Sibai B, Hauth J, Lindheimer M, Klebanoff M,Thom E, et al. Low-dose aspirin to prevent preeclampsiain women at high risk. N Engl J Med 1998;338:701–5.

Hauth J, Sibai B, Caritis S, VanDorsten P, Lindheimer M,Klebanoff M, et al. Maternal serum thromboxane B2concentrations do not predict improved outcomes inhigh-risk pregnancies in a low-dose aspirin trial. Am JObstet Gynecol 1998;179:1193–9.

Hauth JC, NICHD MFMU Network. Adverse maternal,fetal and neonatal outcomes in a low dose aspirin trialwho developed pre-eclampsia. Am J Obstet Gynecol 1998;178(1 Pt 2):S110.

Hauth JC, NICHD MFMU Network. Maternal serumthromboxane B2 (TxB2) reduction did not predictimproved pregnancy outcome in high risk women in alow dose aspirin trial. Am J Obstet Gynecol 1998;178(1 Pt 2):S110.

Hauth JC, NICHD MFMU Network. Safety of low doseaspirin in high risk patients. Am J Obstet Gynecol1998;178(1 Pt 2):S111.

Sibai B. Low-dose aspirin (60 mg/d) in pregnancy forthe prevention of preeclampsia. 8th World Congress onHypertension in Pregnancy; 1992 November 8–12; BuenosAires, Argentina. 1992; 50.

Venezuela 2000 (published data only)

Rivas-Echeverria CA, Echeverria Y, Molina L, Novoa D.Synergic use of aspirin, fish oil and vitamins C and E forthe prevention of preeclampsia. Hypertens Pregnancy2000;19:30.

Zimbabwe 1998 (published data only)

Byaruhanga RN, Chipato T, Rusakaniko S. Arandomized controlled trial of low-dose aspirin inwomen at risk from pre-eclampsia. Int J Gynaecol Obstet1998;60:129–35.

Diuretics for preventing pre-eclampsiaFallis 1964 (published data only)

Fallis NE, Plauche WC, Mosey LM, Langford HG.Thiazide vs placebo in prophylaxis of toxemia ofpregnancy in primigravid patients. Am J Obstet Gynecol1964;88:502–4.

Flowers 1962 (published data only)

Crosland DM, Flowers CE. Chlorothiazide and itsrelationship to neonatal jaundice. Obstet Gynecol 1963;22:500–4.

Flowers CE, Grizzle JE, Easterling WE, Bonner OB.Chlorthiazide as a prophylaxis against toxemia ofpregnancy. Am J Obstet Gynecol 1962;84:919–29.

Kraus 1966 (published data only)

Kraus GW, Marchese JR, Yen SSC. Prophylactic use ofhydrochlorothiazide in pregnancy. JAMA 1966;198:128–32.

Sibai 1984 (published data only)

Sibai BM, Grossman RA, Grossman HG. Effects ofdiuretics on plasma volume in pregnancies with long-term hypertension. Am J Obstet Gynecol 1984;150:831–5.

Weseley 1962 (published data only)

Weseley AC, Douglas GW. Continuous use ofchlorothiazide for prevention of toxemia of pregnancy.Obstet Gynecol 1962;19:355–8.

Nitric oxide and precursorsDavis 2001 (published and unpublished data)

Davis G, Brown M. Glyceryl trinitrate patches areunsuitable in hypertensive pregnancy. Aust N Z J ObstetGynaecol 2001;41(4):474.

Facchinetti 2002 (published and unpublished data)

Facchinetti F, Piccinini F, Pizzi C, Bukowski R, Volpe A,Saade G. Effect of arginine supplementation in patientswith gestational hypertension. Am J Obstet Gynecol2002;187(6 Pt 2):S213.

Lees 1998 (published data only)

Lees C, Valensise H, Black R, Harrington K, Byiers S,Romanini C, et al. The efficacy and fetal-maternalcardiovascular effects of transdermal glyceryl trinitratein the prophylaxis of pre-eclampsia and itscomplications: a randomized double-blind placebo-controlled trial. Ultrasound Obstet Gynecol 1998;12(5):334–8.

Neri 1999 (published and unpublished data)

Neri I, Valensise H, Facchinetti F, Menghini S,Romanini C, Volpe A. 24-hour ambulatory bloodpressure monitoring: a comparison betweentransdermal glyceryl-trinitrate and oral nifedipine.Hypertens Pregnancy 1999;18:107–13.

Appendix 12

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Picciolo 2000 (published data only)

Picciolo C, Roncaglia N, Neri I, Pasta F, Arreghini A,Facchinetti F. Nitric oxide in the prevention of pre-eclampsia. Prenat Neonat Med 2000;5:212–15.

Zozulia 1997 (published data only)

Zozulia O, Rogov VA, Piatakova NV, Tareeva IE. Nitricoxide: its role in the development of pregnancycomplications and in their prevention in women withhypertension and chronic glomerulonephritis.Terapevticheskii Arkhiv 1997;69(6):17–20.

ProgesteroneDalton 1962 (published data only)

Dalton K. Ante-natal progesterone and intelligence. Br JPsychiatry 1968;114:1377–82.

Dalton K. Controlled trials in the prophylactic value ofprogesterone in the treatment of pre-eclamptictoxaemia. J Obstet Gynaecol Br Commonw 1969;3:463–8.

Lynch A, Mychalkiw W. Prenatal progesterone II. Its rolein the treatment of pre-eclamptic toxaemia and its effecton the offsprings’s intelligence: a reappraisal. Early HumDev 1978;2:323–39.

Lynch A, Mychalkiw W, Hutt SJ. Prenatal progesteroneI. Its effect on development and on intellectual andacademic achievement. Early Hum Dev 1978;2:305–22.

Hauth 1983 (published data only)

Hauth JC, Gilstrap LC, Brekken AL, Hauth JM. The effect of 17-alpha-hydroxyprogesterone caproate on pregnancy outcome in an active-duty militarypopulation. Am J Obstet Gynecol 1983;146:187–90.


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Volume 1, 1997

No. 1Home parenteral nutrition: a systematicreview.

By Richards DM, Deeks JJ, SheldonTA, Shaffer JL.

No. 2Diagnosis, management and screeningof early localised prostate cancer.

A review by Selley S, Donovan J,Faulkner A, Coast J, Gillatt D.

No. 3The diagnosis, management, treatmentand costs of prostate cancer in Englandand Wales.

A review by Chamberlain J, Melia J,Moss S, Brown J.

No. 4Screening for fragile X syndrome.

A review by Murray J, Cuckle H,Taylor G, Hewison J.

No. 5A review of near patient testing inprimary care.

By Hobbs FDR, Delaney BC,Fitzmaurice DA, Wilson S, Hyde CJ,Thorpe GH, et al.

No. 6Systematic review of outpatient servicesfor chronic pain control.

By McQuay HJ, Moore RA, EcclestonC, Morley S, de C Williams AC.

No. 7Neonatal screening for inborn errors ofmetabolism: cost, yield and outcome.

A review by Pollitt RJ, Green A,McCabe CJ, Booth A, Cooper NJ,Leonard JV, et al.

No. 8Preschool vision screening.

A review by Snowdon SK, Stewart-Brown SL.

No. 9Implications of socio-cultural contextsfor the ethics of clinical trials.

A review by Ashcroft RE, ChadwickDW, Clark SRL, Edwards RHT, Frith L,Hutton JL.

No. 10A critical review of the role of neonatalhearing screening in the detection ofcongenital hearing impairment.

By Davis A, Bamford J, Wilson I,Ramkalawan T, Forshaw M, Wright S.

No. 11Newborn screening for inborn errors ofmetabolism: a systematic review.

By Seymour CA, Thomason MJ,Chalmers RA, Addison GM, Bain MD,Cockburn F, et al.

No. 12Routine preoperative testing: a systematic review of the evidence.

By Munro J, Booth A, Nicholl J.

No. 13Systematic review of the effectiveness of laxatives in the elderly.

By Petticrew M, Watt I, Sheldon T.

No. 14When and how to assess fast-changingtechnologies: a comparative study ofmedical applications of four generictechnologies.

A review by Mowatt G, Bower DJ,Brebner JA, Cairns JA, Grant AM,McKee L.

Volume 2, 1998

No. 1Antenatal screening for Down’ssyndrome.

A review by Wald NJ, Kennard A,Hackshaw A, McGuire A.

No. 2Screening for ovarian cancer: a systematic review.

By Bell R, Petticrew M, Luengo S,Sheldon TA.

No. 3Consensus development methods, andtheir use in clinical guidelinedevelopment.

A review by Murphy MK, Black NA,Lamping DL, McKee CM, SandersonCFB, Askham J, et al.

No. 4A cost–utility analysis of interferon beta for multiple sclerosis.

By Parkin D, McNamee P, Jacoby A,Miller P, Thomas S, Bates D.

No. 5Effectiveness and efficiency of methodsof dialysis therapy for end-stage renaldisease: systematic reviews.

By MacLeod A, Grant A, Donaldson C, Khan I, Campbell M,Daly C, et al.

No. 6Effectiveness of hip prostheses inprimary total hip replacement: a criticalreview of evidence and an economicmodel.

By Faulkner A, Kennedy LG, Baxter K, Donovan J, Wilkinson M,Bevan G.

No. 7Antimicrobial prophylaxis in colorectalsurgery: a systematic review ofrandomised controlled trials.

By Song F, Glenny AM.

No. 8Bone marrow and peripheral bloodstem cell transplantation for malignancy.

A review by Johnson PWM, Simnett SJ,Sweetenham JW, Morgan GJ, Stewart LA.

No. 9Screening for speech and languagedelay: a systematic review of theliterature.

By Law J, Boyle J, Harris F, HarknessA, Nye C.

No. 10Resource allocation for chronic stableangina: a systematic review ofeffectiveness, costs and cost-effectiveness of alternativeinterventions.

By Sculpher MJ, Petticrew M, Kelland JL, Elliott RA, Holdright DR,Buxton MJ.

No. 11Detection, adherence and control ofhypertension for the prevention ofstroke: a systematic review.

By Ebrahim S.

No. 12Postoperative analgesia and vomiting,with special reference to day-casesurgery: a systematic review.

By McQuay HJ, Moore RA.

No. 13Choosing between randomised andnonrandomised studies: a systematicreview.

By Britton A, McKee M, Black N,McPherson K, Sanderson C, Bain C.

No. 14Evaluating patient-based outcomemeasures for use in clinical trials.

A review by Fitzpatrick R, Davey C,Buxton MJ, Jones DR.

Health Technology Assessment reports published to date

No. 15Ethical issues in the design and conductof randomised controlled trials.

A review by Edwards SJL, Lilford RJ,Braunholtz DA, Jackson JC, Hewison J,Thornton J.

No. 16Qualitative research methods in healthtechnology assessment: a review of theliterature.

By Murphy E, Dingwall R, GreatbatchD, Parker S, Watson P.

No. 17The costs and benefits of paramedicskills in pre-hospital trauma care.

By Nicholl J, Hughes S, Dixon S,Turner J, Yates D.

No. 18Systematic review of endoscopicultrasound in gastro-oesophagealcancer.

By Harris KM, Kelly S, Berry E,Hutton J, Roderick P, Cullingworth J, et al.

No. 19Systematic reviews of trials and otherstudies.

By Sutton AJ, Abrams KR, Jones DR,Sheldon TA, Song F.

No. 20Primary total hip replacement surgery: a systematic review of outcomes andmodelling of cost-effectivenessassociated with different prostheses.

A review by Fitzpatrick R, Shortall E,Sculpher M, Murray D, Morris R, LodgeM, et al.

Volume 3, 1999

No. 1Informed decision making: an annotatedbibliography and systematic review.

By Bekker H, Thornton JG, Airey CM, Connelly JB, Hewison J,Robinson MB, et al.

No. 2Handling uncertainty when performingeconomic evaluation of healthcareinterventions.

A review by Briggs AH, Gray AM.

No. 3The role of expectancies in the placeboeffect and their use in the delivery ofhealth care: a systematic review.

By Crow R, Gage H, Hampson S,Hart J, Kimber A, Thomas H.

No. 4A randomised controlled trial ofdifferent approaches to universalantenatal HIV testing: uptake andacceptability. Annex: Antenatal HIVtesting – assessment of a routinevoluntary approach.

By Simpson WM, Johnstone FD, BoydFM, Goldberg DJ, Hart GJ, GormleySM, et al.

No. 5Methods for evaluating area-wide andorganisation-based interventions inhealth and health care: a systematicreview.

By Ukoumunne OC, Gulliford MC,Chinn S, Sterne JAC, Burney PGJ.

No. 6Assessing the costs of healthcaretechnologies in clinical trials.

A review by Johnston K, Buxton MJ,Jones DR, Fitzpatrick R.

No. 7Cooperatives and their primary careemergency centres: organisation andimpact.

By Hallam L, Henthorne K.

No. 8Screening for cystic fibrosis.

A review by Murray J, Cuckle H,Taylor G, Littlewood J, Hewison J.

No. 9A review of the use of health statusmeasures in economic evaluation.

By Brazier J, Deverill M, Green C,Harper R, Booth A.

No. 10Methods for the analysis of quality-of-life and survival data in healthtechnology assessment.

A review by Billingham LJ, AbramsKR, Jones DR.

No. 11Antenatal and neonatalhaemoglobinopathy screening in theUK: review and economic analysis.

By Zeuner D, Ades AE, Karnon J,Brown J, Dezateux C, Anionwu EN.

No. 12Assessing the quality of reports ofrandomised trials: implications for theconduct of meta-analyses.

A review by Moher D, Cook DJ, JadadAR, Tugwell P, Moher M, Jones A, et al.

No. 13‘Early warning systems’ for identifyingnew healthcare technologies.

By Robert G, Stevens A, Gabbay J.

No. 14A systematic review of the role of humanpapillomavirus testing within a cervicalscreening programme.

By Cuzick J, Sasieni P, Davies P,Adams J, Normand C, Frater A, et al.

No. 15Near patient testing in diabetes clinics:appraising the costs and outcomes.

By Grieve R, Beech R, Vincent J,Mazurkiewicz J.

No. 16Positron emission tomography:establishing priorities for healthtechnology assessment.

A review by Robert G, Milne R.

No. 17 (Pt 1)The debridement of chronic wounds: a systematic review.

By Bradley M, Cullum N, Sheldon T.

No. 17 (Pt 2)Systematic reviews of wound caremanagement: (2) Dressings and topicalagents used in the healing of chronicwounds.

By Bradley M, Cullum N, Nelson EA,Petticrew M, Sheldon T, Torgerson D.

No. 18A systematic literature review of spiraland electron beam computedtomography: with particular reference toclinical applications in hepatic lesions,pulmonary embolus and coronary arterydisease.

By Berry E, Kelly S, Hutton J, Harris KM, Roderick P, Boyce JC, et al.

No. 19What role for statins? A review andeconomic model.

By Ebrahim S, Davey Smith G,McCabe C, Payne N, Pickin M, SheldonTA, et al.

No. 20Factors that limit the quality, numberand progress of randomised controlledtrials.

A review by Prescott RJ, Counsell CE,Gillespie WJ, Grant AM, Russell IT,Kiauka S, et al.

No. 21Antimicrobial prophylaxis in total hipreplacement: a systematic review.

By Glenny AM, Song F.

No. 22Health promoting schools and healthpromotion in schools: two systematicreviews.

By Lister-Sharp D, Chapman S,Stewart-Brown S, Sowden A.

No. 23Economic evaluation of a primary care-based education programme for patientswith osteoarthritis of the knee.

A review by Lord J, Victor C,Littlejohns P, Ross FM, Axford JS.

Volume 4, 2000

No. 1The estimation of marginal timepreference in a UK-wide sample(TEMPUS) project.

A review by Cairns JA, van der PolMM.

No. 2Geriatric rehabilitation followingfractures in older people: a systematicreview.

By Cameron I, Crotty M, Currie C,Finnegan T, Gillespie L, Gillespie W, et al.


252

No. 3Screening for sickle cell disease andthalassaemia: a systematic review withsupplementary research.

By Davies SC, Cronin E, Gill M,Greengross P, Hickman M, Normand C.

No. 4Community provision of hearing aidsand related audiology services.

A review by Reeves DJ, Alborz A,Hickson FS, Bamford JM.

No. 5False-negative results in screeningprogrammes: systematic review ofimpact and implications.

By Petticrew MP, Sowden AJ, Lister-Sharp D, Wright K.

No. 6Costs and benefits of communitypostnatal support workers: arandomised controlled trial.

By Morrell CJ, Spiby H, Stewart P,Walters S, Morgan A.

No. 7Implantable contraceptives (subdermalimplants and hormonally impregnatedintrauterine systems) versus other formsof reversible contraceptives: twosystematic reviews to assess relativeeffectiveness, acceptability, tolerabilityand cost-effectiveness.

By French RS, Cowan FM, MansourDJA, Morris S, Procter T, Hughes D, et al.

No. 8An introduction to statistical methodsfor health technology assessment.

A review by White SJ, Ashby D, Brown PJ.

No. 9Disease-modifying drugs for multiplesclerosis: a rapid and systematic review.

By Clegg A, Bryant J, Milne R.

No. 10Publication and related biases.

A review by Song F, Eastwood AJ,Gilbody S, Duley L, Sutton AJ.

No. 11Cost and outcome implications of theorganisation of vascular services.

By Michaels J, Brazier J, PalfreymanS, Shackley P, Slack R.

No. 12Monitoring blood glucose control indiabetes mellitus: a systematic review.

By Coster S, Gulliford MC, Seed PT,Powrie JK, Swaminathan R.

No. 13The effectiveness of domiciliary healthvisiting: a systematic review ofinternational studies and a selective review of the Britishliterature.

By Elkan R, Kendrick D, Hewitt M,Robinson JJA, Tolley K, Blair M, et al.

No. 14The determinants of screening uptakeand interventions for increasing uptake:a systematic review.

By Jepson R, Clegg A, Forbes C,Lewis R, Sowden A, Kleijnen J.

No. 15The effectiveness and cost-effectivenessof prophylactic removal of wisdomteeth.

A rapid review by Song F, O’Meara S,Wilson P, Golder S, Kleijnen J.

No. 16Ultrasound screening in pregnancy: asystematic review of the clinicaleffectiveness, cost-effectiveness andwomen’s views.

By Bricker L, Garcia J, Henderson J,Mugford M, Neilson J, Roberts T, et al.

No. 17A rapid and systematic review of theeffectiveness and cost-effectiveness ofthe taxanes used in the treatment ofadvanced breast and ovarian cancer.

By Lister-Sharp D, McDonagh MS,Khan KS, Kleijnen J.

No. 18Liquid-based cytology in cervicalscreening: a rapid and systematic review.

By Payne N, Chilcott J, McGoogan E.

No. 19Randomised controlled trial of non-directive counselling,cognitive–behaviour therapy and usualgeneral practitioner care in themanagement of depression as well asmixed anxiety and depression inprimary care.

By King M, Sibbald B, Ward E, BowerP, Lloyd M, Gabbay M, et al.

No. 20Routine referral for radiography ofpatients presenting with low back pain:is patients’ outcome influenced by GPs’referral for plain radiography?

By Kerry S, Hilton S, Patel S, DundasD, Rink E, Lord J.

No. 21Systematic reviews of wound caremanagement: (3) antimicrobial agentsfor chronic wounds; (4) diabetic footulceration.

By O’Meara S, Cullum N, Majid M,Sheldon T.

No. 22Using routine data to complement andenhance the results of randomisedcontrolled trials.

By Lewsey JD, Leyland AH, Murray GD, Boddy FA.

No. 23Coronary artery stents in the treatmentof ischaemic heart disease: a rapid andsystematic review.

By Meads C, Cummins C, Jolly K,Stevens A, Burls A, Hyde C.

No. 24Outcome measures for adult criticalcare: a systematic review.

By Hayes JA, Black NA, Jenkinson C, Young JD, Rowan KM,Daly K, et al.

No. 25A systematic review to evaluate theeffectiveness of interventions to promote the initiation of breastfeeding.

By Fairbank L, O’Meara S, RenfrewMJ, Woolridge M, Sowden AJ, Lister-Sharp D.

No. 26Implantable cardioverter defibrillators:arrhythmias. A rapid and systematicreview.

By Parkes J, Bryant J, Milne R.

No. 27Treatments for fatigue in multiplesclerosis: a rapid and systematic review.

By Brañas P, Jordan R, Fry-Smith A,Burls A, Hyde C.

No. 28Early asthma prophylaxis, naturalhistory, skeletal development andeconomy (EASE): a pilot randomisedcontrolled trial.

By Baxter-Jones ADG, Helms PJ,Russell G, Grant A, Ross S, Cairns JA, et al.

No. 29Screening for hypercholesterolaemiaversus case finding for familialhypercholesterolaemia: a systematicreview and cost-effectiveness analysis.

By Marks D, Wonderling D,Thorogood M, Lambert H, HumphriesSE, Neil HAW.

No. 30A rapid and systematic review of theclinical effectiveness and cost-effectiveness of glycoprotein IIb/IIIaantagonists in the medical managementof unstable angina.

By McDonagh MS, Bachmann LM,Golder S, Kleijnen J, ter Riet G.

No. 31A randomised controlled trial ofprehospital intravenous fluidreplacement therapy in serious trauma.

By Turner J, Nicholl J, Webber L,Cox H, Dixon S, Yates D.

No. 32Intrathecal pumps for giving opioids inchronic pain: a systematic review.

By Williams JE, Louw G, Towlerton G.

No. 33Combination therapy (interferon alfaand ribavirin) in the treatment ofchronic hepatitis C: a rapid andsystematic review.

By Shepherd J, Waugh N, Hewitson P.


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No. 34A systematic review of comparisons ofeffect sizes derived from randomisedand non-randomised studies.

By MacLehose RR, Reeves BC,Harvey IM, Sheldon TA, Russell IT,Black AMS.

No. 35Intravascular ultrasound-guidedinterventions in coronary artery disease:a systematic literature review, withdecision-analytic modelling, of outcomesand cost-effectiveness.

By Berry E, Kelly S, Hutton J,Lindsay HSJ, Blaxill JM, Evans JA, et al.

No. 36A randomised controlled trial toevaluate the effectiveness and cost-effectiveness of counselling patients withchronic depression.

By Simpson S, Corney R, Fitzgerald P,Beecham J.

No. 37Systematic review of treatments foratopic eczema.

By Hoare C, Li Wan Po A, Williams H.

No. 38Bayesian methods in health technologyassessment: a review.

By Spiegelhalter DJ, Myles JP, Jones DR, Abrams KR.

No. 39The management of dyspepsia: asystematic review.

By Delaney B, Moayyedi P, Deeks J,Innes M, Soo S, Barton P, et al.

No. 40A systematic review of treatments forsevere psoriasis.

By Griffiths CEM, Clark CM, ChalmersRJG, Li Wan Po A, Williams HC.

Volume 5, 2001

No. 1Clinical and cost-effectiveness ofdonepezil, rivastigmine andgalantamine for Alzheimer’s disease: arapid and systematic review.

By Clegg A, Bryant J, Nicholson T,McIntyre L, De Broe S, Gerard K, et al.

No. 2The clinical effectiveness and cost-effectiveness of riluzole for motorneurone disease: a rapid and systematicreview.

By Stewart A, Sandercock J, Bryan S,Hyde C, Barton PM, Fry-Smith A, et al.

No. 3Equity and the economic evaluation ofhealthcare.

By Sassi F, Archard L, Le Grand J.

No. 4Quality-of-life measures in chronicdiseases of childhood.

By Eiser C, Morse R.

No. 5Eliciting public preferences forhealthcare: a systematic review oftechniques.

By Ryan M, Scott DA, Reeves C, BateA, van Teijlingen ER, Russell EM, et al.

No. 6General health status measures forpeople with cognitive impairment:learning disability and acquired braininjury.

By Riemsma RP, Forbes CA, Glanville JM, Eastwood AJ, Kleijnen J.

No. 7An assessment of screening strategies forfragile X syndrome in the UK.

By Pembrey ME, Barnicoat AJ,Carmichael B, Bobrow M, Turner G.

No. 8Issues in methodological research:perspectives from researchers andcommissioners.

By Lilford RJ, Richardson A, StevensA, Fitzpatrick R, Edwards S, Rock F, et al.

No. 9Systematic reviews of wound caremanagement: (5) beds; (6) compression;(7) laser therapy, therapeuticultrasound, electrotherapy andelectromagnetic therapy.

By Cullum N, Nelson EA, FlemmingK, Sheldon T.

No. 10Effects of educational and psychosocialinterventions for adolescents withdiabetes mellitus: a systematic review.

By Hampson SE, Skinner TC, Hart J,Storey L, Gage H, Foxcroft D, et al.

No. 11Effectiveness of autologous chondrocytetransplantation for hyaline cartilagedefects in knees: a rapid and systematicreview.

By Jobanputra P, Parry D, Fry-SmithA, Burls A.

No. 12Statistical assessment of the learningcurves of health technologies.

By Ramsay CR, Grant AM, Wallace SA, Garthwaite PH, Monk AF,Russell IT.

No. 13The effectiveness and cost-effectivenessof temozolomide for the treatment ofrecurrent malignant glioma: a rapid andsystematic review.

By Dinnes J, Cave C, Huang S, Major K, Milne R.

No. 14A rapid and systematic review of theclinical effectiveness and cost-effectiveness of debriding agents intreating surgical wounds healing bysecondary intention.

By Lewis R, Whiting P, ter Riet G,O’Meara S, Glanville J.

No. 15Home treatment for mental healthproblems: a systematic review.

By Burns T, Knapp M, Catty J, Healey A, Henderson J, Watt H, et al.

No. 16How to develop cost-consciousguidelines.

By Eccles M, Mason J.

No. 17The role of specialist nurses in multiplesclerosis: a rapid and systematic review.

By De Broe S, Christopher F, Waugh N.

No. 18A rapid and systematic review of theclinical effectiveness and cost-effectiveness of orlistat in themanagement of obesity.

By O’Meara S, Riemsma R, Shirran L, Mather L, ter Riet G.

No. 19The clinical effectiveness and cost-effectiveness of pioglitazone for type 2diabetes mellitus: a rapid and systematicreview.

By Chilcott J, Wight J, Lloyd JonesM, Tappenden P.

No. 20Extended scope of nursing practice: amulticentre randomised controlled trialof appropriately trained nurses andpreregistration house officers in pre-operative assessment in elective generalsurgery.

By Kinley H, Czoski-Murray C,George S, McCabe C, Primrose J, Reilly C, et al.

No. 21Systematic reviews of the effectiveness ofday care for people with severe mentaldisorders: (1) Acute day hospital versusadmission; (2) Vocational rehabilitation;(3) Day hospital versus outpatient care.

By Marshall M, Crowther R, Almaraz-Serrano A, Creed F, Sledge W, Kluiter H, et al.

No. 22The measurement and monitoring ofsurgical adverse events.

By Bruce J, Russell EM, Mollison J,Krukowski ZH.

No. 23Action research: a systematic review andguidance for assessment.

By Waterman H, Tillen D, Dickson R,de Koning K.

No. 24A rapid and systematic review of theclinical effectiveness and cost-effectiveness of gemcitabine for thetreatment of pancreatic cancer.

By Ward S, Morris E, Bansback N,Calvert N, Crellin A, Forman D, et al.


254

No. 25A rapid and systematic review of theevidence for the clinical effectivenessand cost-effectiveness of irinotecan,oxaliplatin and raltitrexed for thetreatment of advanced colorectal cancer.

By Lloyd Jones M, Hummel S,Bansback N, Orr B, Seymour M.

No. 26Comparison of the effectiveness ofinhaler devices in asthma and chronicobstructive airways disease: a systematicreview of the literature.

By Brocklebank D, Ram F, Wright J,Barry P, Cates C, Davies L, et al.

No. 27The cost-effectiveness of magneticresonance imaging for investigation ofthe knee joint.

By Bryan S, Weatherburn G, BungayH, Hatrick C, Salas C, Parry D, et al.

No. 28A rapid and systematic review of theclinical effectiveness and cost-effectiveness of topotecan for ovariancancer.

By Forbes C, Shirran L, Bagnall A-M,Duffy S, ter Riet G.

No. 29Superseded by a report published in alater volume.

No. 30The role of radiography in primary carepatients with low back pain of at least 6weeks duration: a randomised(unblinded) controlled trial.

By Kendrick D, Fielding K, Bentley E,Miller P, Kerslake R, Pringle M.

No. 31Design and use of questionnaires: areview of best practice applicable tosurveys of health service staff andpatients.

By McColl E, Jacoby A, Thomas L,Soutter J, Bamford C, Steen N, et al.

No. 32A rapid and systematic review of theclinical effectiveness and cost-effectiveness of paclitaxel, docetaxel,gemcitabine and vinorelbine in non-small-cell lung cancer.

By Clegg A, Scott DA, Sidhu M,Hewitson P, Waugh N.

No. 33Subgroup analyses in randomisedcontrolled trials: quantifying the risks offalse-positives and false-negatives.

By Brookes ST, Whitley E, Peters TJ, Mulheran PA, Egger M,Davey Smith G.

No. 34Depot antipsychotic medication in thetreatment of patients with schizophrenia:(1) Meta-review; (2) Patient and nurseattitudes.

By David AS, Adams C.

No. 35A systematic review of controlled trialsof the effectiveness and cost-effectiveness of brief psychologicaltreatments for depression.

By Churchill R, Hunot V, Corney R,Knapp M, McGuire H, Tylee A, et al.

No. 36Cost analysis of child healthsurveillance.

By Sanderson D, Wright D, Acton C,Duree D.

Volume 6, 2002

No. 1A study of the methods used to selectreview criteria for clinical audit.

By Hearnshaw H, Harker R, CheaterF, Baker R, Grimshaw G.

No. 2Fludarabine as second-line therapy forB cell chronic lymphocytic leukaemia: a technology assessment.

By Hyde C, Wake B, Bryan S, BartonP, Fry-Smith A, Davenport C, et al.

No. 3Rituximab as third-line treatment forrefractory or recurrent Stage III or IVfollicular non-Hodgkin’s lymphoma: asystematic review and economicevaluation.

By Wake B, Hyde C, Bryan S, BartonP, Song F, Fry-Smith A, et al.

No. 4A systematic review of dischargearrangements for older people.

By Parker SG, Peet SM, McPherson A,Cannaby AM, Baker R, Wilson A, et al.

No. 5The clinical effectiveness and cost-effectiveness of inhaler devices used inthe routine management of chronicasthma in older children: a systematicreview and economic evaluation.

By Peters J, Stevenson M, Beverley C,Lim J, Smith S.

No. 6The clinical effectiveness and cost-effectiveness of sibutramine in themanagement of obesity: a technologyassessment.

By O’Meara S, Riemsma R, ShirranL, Mather L, ter Riet G.

No. 7The cost-effectiveness of magneticresonance angiography for carotidartery stenosis and peripheral vasculardisease: a systematic review.

By Berry E, Kelly S, Westwood ME,Davies LM, Gough MJ, Bamford JM,et al.

No. 8Promoting physical activity in SouthAsian Muslim women through ‘exerciseon prescription’.

By Carroll B, Ali N, Azam N.

No. 9Zanamivir for the treatment of influenzain adults: a systematic review andeconomic evaluation.

By Burls A, Clark W, Stewart T,Preston C, Bryan S, Jefferson T, et al.

No. 10A review of the natural history andepidemiology of multiple sclerosis:implications for resource allocation andhealth economic models.

By Richards RG, Sampson FC, Beard SM, Tappenden P.

No. 11Screening for gestational diabetes: asystematic review and economicevaluation.

By Scott DA, Loveman E, McIntyre L,Waugh N.

No. 12The clinical effectiveness and cost-effectiveness of surgery for people withmorbid obesity: a systematic review andeconomic evaluation.

By Clegg AJ, Colquitt J, Sidhu MK,Royle P, Loveman E, Walker A.

No. 13The clinical effectiveness of trastuzumabfor breast cancer: a systematic review.

By Lewis R, Bagnall A-M, Forbes C,Shirran E, Duffy S, Kleijnen J, et al.

No. 14The clinical effectiveness and cost-effectiveness of vinorelbine for breastcancer: a systematic review andeconomic evaluation.

By Lewis R, Bagnall A-M, King S,Woolacott N, Forbes C, Shirran L, et al.

No. 15A systematic review of the effectivenessand cost-effectiveness of metal-on-metalhip resurfacing arthroplasty fortreatment of hip disease.

By Vale L, Wyness L, McCormack K,McKenzie L, Brazzelli M, Stearns SC.

No. 16The clinical effectiveness and cost-effectiveness of bupropion and nicotinereplacement therapy for smokingcessation: a systematic review andeconomic evaluation.

By Woolacott NF, Jones L, Forbes CA,Mather LC, Sowden AJ, Song FJ, et al.

No. 17A systematic review of effectiveness andeconomic evaluation of new drugtreatments for juvenile idiopathicarthritis: etanercept.

By Cummins C, Connock M, Fry-Smith A, Burls A.

No. 18Clinical effectiveness and cost-effectiveness of growth hormone inchildren: a systematic review andeconomic evaluation.

By Bryant J, Cave C, Mihaylova B,Chase D, McIntyre L, Gerard K, et al.


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No. 19Clinical effectiveness and cost-effectiveness of growth hormone inadults in relation to impact on quality oflife: a systematic review and economicevaluation.

By Bryant J, Loveman E, Chase D,Mihaylova B, Cave C, Gerard K, et al.

No. 20Clinical medication review by apharmacist of patients on repeatprescriptions in general practice: arandomised controlled trial.

By Zermansky AG, Petty DR, RaynorDK, Lowe CJ, Freementle N, Vail A.

No. 21The effectiveness of infliximab andetanercept for the treatment ofrheumatoid arthritis: a systematic reviewand economic evaluation.

By Jobanputra P, Barton P, Bryan S,Burls A.

No. 22A systematic review and economicevaluation of computerised cognitivebehaviour therapy for depression andanxiety.

By Kaltenthaler E, Shackley P, StevensK, Beverley C, Parry G, Chilcott J.

No. 23A systematic review and economicevaluation of pegylated liposomaldoxorubicin hydrochloride for ovariancancer.

By Forbes C, Wilby J, Richardson G,Sculpher M, Mather L, Reimsma R.

No. 24A systematic review of the effectivenessof interventions based on a stages-of-change approach to promote individualbehaviour change.

By Riemsma RP, Pattenden J, Bridle C,Sowden AJ, Mather L, Watt IS, et al.

No. 25A systematic review update of theclinical effectiveness and cost-effectiveness of glycoprotein IIb/IIIaantagonists.

By Robinson M, Ginnelly L, SculpherM, Jones L, Riemsma R, Palmer S, et al.

No. 26A systematic review of the effectiveness,cost-effectiveness and barriers toimplementation of thrombolytic andneuroprotective therapy for acuteischaemic stroke in the NHS.

By Sandercock P, Berge E, Dennis M,Forbes J, Hand P, Kwan J, et al.

No. 27A randomised controlled crossover trial of nurse practitioner versus doctor-led outpatient care in abronchiectasis clinic.

By Caine N, Sharples LD,Hollingworth W, French J, Keogan M,Exley A, et al.

No. 28Clinical effectiveness and cost –consequences of selective serotoninreuptake inhibitors in the treatment ofsex offenders.

By Adi Y, Ashcroft D, Browne K,Beech A, Fry-Smith A, Hyde C.

No. 29Treatment of established osteoporosis: a systematic review and cost–utilityanalysis.

By Kanis JA, Brazier JE, Stevenson M,Calvert NW, Lloyd Jones M.

No. 30Which anaesthetic agents are cost-effective in day surgery? Literaturereview, national survey of practice andrandomised controlled trial.

By Elliott RA Payne K, Moore JK,Davies LM, Harper NJN, St Leger AS,et al.

No. 31Screening for hepatitis C amonginjecting drug users and ingenitourinary medicine clinics:systematic reviews of effectiveness,modelling study and national survey ofcurrent practice.

By Stein K, Dalziel K, Walker A,McIntyre L, Jenkins B, Horne J, et al.

No. 32The measurement of satisfaction withhealthcare: implications for practicefrom a systematic review of theliterature.

By Crow R, Gage H, Hampson S,Hart J, Kimber A, Storey L, et al.

No. 33The effectiveness and cost-effectivenessof imatinib in chronic myeloidleukaemia: a systematic review.

By Garside R, Round A, Dalziel K,Stein K, Royle R.

No. 34A comparative study of hypertonicsaline, daily and alternate-day rhDNase in children with cystic fibrosis.

By Suri R, Wallis C, Bush A,Thompson S, Normand C, Flather M, et al.

No. 35A systematic review of the costs andeffectiveness of different models ofpaediatric home care.

By Parker G, Bhakta P, Lovett CA,Paisley S, Olsen R, Turner D, et al.

Volume 7, 2003

No. 1How important are comprehensiveliterature searches and the assessment oftrial quality in systematic reviews?Empirical study.

By Egger M, Jüni P, Bartlett C,Holenstein F, Sterne J.

No. 2Systematic review of the effectivenessand cost-effectiveness, and economicevaluation, of home versus hospital orsatellite unit haemodialysis for peoplewith end-stage renal failure.

By Mowatt G, Vale L, Perez J, WynessL, Fraser C, MacLeod A, et al.

No. 3Systematic review and economicevaluation of the effectiveness ofinfliximab for the treatment of Crohn’sdisease.

By Clark W, Raftery J, Barton P, Song F, Fry-Smith A, Burls A.

No. 4A review of the clinical effectiveness andcost-effectiveness of routine anti-Dprophylaxis for pregnant women whoare rhesus negative.

By Chilcott J, Lloyd Jones M, WightJ, Forman K, Wray J, Beverley C, et al.

No. 5Systematic review and evaluation of theuse of tumour markers in paediatriconcology: Ewing’s sarcoma andneuroblastoma.

By Riley RD, Burchill SA, Abrams KR,Heney D, Lambert PC, Jones DR, et al.

No. 6The cost-effectiveness of screening forHelicobacter pylori to reduce mortalityand morbidity from gastric cancer andpeptic ulcer disease: a discrete-eventsimulation model.

By Roderick P, Davies R, Raftery J,Crabbe D, Pearce R, Bhandari P, et al.

No. 7The clinical effectiveness and cost-effectiveness of routine dental checks: asystematic review and economicevaluation.

By Davenport C, Elley K, Salas C,Taylor-Weetman CL, Fry-Smith A, Bryan S, et al.

No. 8A multicentre randomised controlledtrial assessing the costs and benefits ofusing structured information andanalysis of women’s preferences in themanagement of menorrhagia.

By Kennedy ADM, Sculpher MJ,Coulter A, Dwyer N, Rees M, Horsley S, et al.

No. 9Clinical effectiveness and cost–utility ofphotodynamic therapy for wet age-relatedmacular degeneration: a systematic reviewand economic evaluation.

By Meads C, Salas C, Roberts T,Moore D, Fry-Smith A, Hyde C.

No. 10Evaluation of molecular tests forprenatal diagnosis of chromosomeabnormalities.

By Grimshaw GM, Szczepura A,Hultén M, MacDonald F, Nevin NC,Sutton F, et al.


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No. 11First and second trimester antenatalscreening for Down’s syndrome: theresults of the Serum, Urine andUltrasound Screening Study (SURUSS).

By Wald NJ, Rodeck C, Hackshaw AK, Walters J, Chitty L,Mackinson AM.

No. 12The effectiveness and cost-effectivenessof ultrasound locating devices forcentral venous access: a systematicreview and economic evaluation.

By Calvert N, Hind D, McWilliamsRG, Thomas SM, Beverley C, Davidson A.

No. 13A systematic review of atypicalantipsychotics in schizophrenia.

By Bagnall A-M, Jones L, Lewis R,Ginnelly L, Glanville J, Torgerson D, et al.

No. 14Prostate Testing for Cancer andTreatment (ProtecT) feasibility study.

By Donovan J, Hamdy F, Neal D,Peters T, Oliver S, Brindle L, et al.

No. 15Early thrombolysis for the treatment of acute myocardial infarction: asystematic review and economicevaluation.

By Boland A, Dundar Y, Bagust A,Haycox A, Hill R, Mujica Mota R,et al.

No. 16Screening for fragile X syndrome: a literature review and modelling.

By Song FJ, Barton P, Sleightholme V,Yao GL, Fry-Smith A.

No. 17Systematic review of endoscopic sinussurgery for nasal polyps.

By Dalziel K, Stein K, Round A,Garside R, Royle P.

No. 18Towards efficient guidelines: how tomonitor guideline use in primary care.

By Hutchinson A, McIntosh A, Cox S,Gilbert C.

No. 19Effectiveness and cost-effectiveness ofacute hospital-based spinal cord injuriesservices: systematic review.

By Bagnall A-M, Jones L, Richardson G, Duffy S, Riemsma R.

No. 20Prioritisation of health technologyassessment. The PATHS model:methods and case studies.

By Townsend J, Buxton M, Harper G.

No. 21Systematic review of the clinicaleffectiveness and cost-effectiveness of tension-free vaginal tape fortreatment of urinary stress incontinence.

By Cody J, Wyness L, Wallace S,Glazener C, Kilonzo M, Stearns S,et al.

No. 22The clinical and cost-effectiveness ofpatient education models for diabetes: a systematic review and economicevaluation.

By Loveman E, Cave C, Green C,Royle P, Dunn N, Waugh N.

No. 23The role of modelling in prioritisingand planning clinical trials.

By Chilcott J, Brennan A, Booth A,Karnon J, Tappenden P.

No. 24Cost–benefit evaluation of routineinfluenza immunisation in people 65–74years of age.

By Allsup S, Gosney M, Haycox A,Regan M.

No. 25The clinical and cost-effectiveness ofpulsatile machine perfusion versus coldstorage of kidneys for transplantationretrieved from heart-beating and non-heart-beating donors.

By Wight J, Chilcott J, Holmes M,Brewer N.

No. 26Can randomised trials rely on existingelectronic data? A feasibility study toexplore the value of routine data inhealth technology assessment.

By Williams JG, Cheung WY, Cohen DR, Hutchings HA, Longo MF, Russell IT.

No. 27Evaluating non-randomised interventionstudies.

By Deeks JJ, Dinnes J, D’Amico R,Sowden AJ, Sakarovitch C, Song F, et al.

No. 28A randomised controlled trial to assessthe impact of a package comprising apatient-orientated, evidence-based self-help guidebook and patient-centredconsultations on disease managementand satisfaction in inflammatory boweldisease.

By Kennedy A, Nelson E, Reeves D,Richardson G, Roberts C, Robinson A,et al.

No. 29The effectiveness of diagnostic tests forthe assessment of shoulder pain due tosoft tissue disorders: a systematic review.

By Dinnes J, Loveman E, McIntyre L,Waugh N.

No. 30The value of digital imaging in diabeticretinopathy.

By Sharp PF, Olson J, Strachan F,Hipwell J, Ludbrook A, O’Donnell M, et al.

No. 31Lowering blood pressure to preventmyocardial infarction and stroke: a new preventive strategy.

By Law M, Wald N, Morris J.

No. 32Clinical and cost-effectiveness ofcapecitabine and tegafur with uracil forthe treatment of metastatic colorectalcancer: systematic review and economicevaluation.

By Ward S, Kaltenthaler E, Cowan J,Brewer N.

No. 33Clinical and cost-effectiveness of new and emerging technologies for earlylocalised prostate cancer: a systematicreview.

By Hummel S, Paisley S, Morgan A,Currie E, Brewer N.

No. 34Literature searching for clinical andcost-effectiveness studies used in healthtechnology assessment reports carriedout for the National Institute forClinical Excellence appraisal system.

By Royle P, Waugh N.

No. 35Systematic review and economicdecision modelling for the preventionand treatment of influenza A and B.

By Turner D, Wailoo A, Nicholson K,Cooper N, Sutton A, Abrams K.

No. 36A randomised controlled trial toevaluate the clinical and cost-effectiveness of Hickman line insertions in adult cancer patients bynurses.

By Boland A, Haycox A, Bagust A,Fitzsimmons L.

No. 37Redesigning postnatal care: arandomised controlled trial of protocol-based midwifery-led carefocused on individual women’s physical and psychological health needs.

By MacArthur C, Winter HR, Bick DE, Lilford RJ, Lancashire RJ,Knowles H, et al.

No. 38Estimating implied rates of discount inhealthcare decision-making.

By West RR, McNabb R, Thompson AGH, Sheldon TA, Grimley Evans J.


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No. 39Systematic review of isolation policies inthe hospital management of methicillin-resistant Staphylococcus aureus: a review ofthe literature with epidemiological andeconomic modelling.

By Cooper BS, Stone SP, Kibbler CC,Cookson BD, Roberts JA, Medley GF, et al.

No. 40Treatments for spasticity and pain inmultiple sclerosis: a systematic review.

By Beard S, Hunn A, Wight J.

No. 41The inclusion of reports of randomisedtrials published in languages other thanEnglish in systematic reviews.

By Moher D, Pham B, Lawson ML,Klassen TP.

No. 42The impact of screening on futurehealth-promoting behaviours and healthbeliefs: a systematic review.

By Bankhead CR, Brett J, Bukach C,Webster P, Stewart-Brown S, Munafo M,et al.

Volume 8, 2004

No. 1What is the best imaging strategy foracute stroke?

By Wardlaw JM, Keir SL, Seymour J,Lewis S, Sandercock PAG, Dennis MS, et al.

No. 2Systematic review and modelling of theinvestigation of acute and chronic chestpain presenting in primary care.

By Mant J, McManus RJ, Oakes RAL,Delaney BC, Barton PM, Deeks JJ, et al.

No. 3The effectiveness and cost-effectivenessof microwave and thermal balloonendometrial ablation for heavymenstrual bleeding: a systematic reviewand economic modelling.

By Garside R, Stein K, Wyatt K,Round A, Price A.

No. 4A systematic review of the role ofbisphosphonates in metastatic disease.

By Ross JR, Saunders Y, Edmonds PM,Patel S, Wonderling D, Normand C, et al.

No. 5Systematic review of the clinicaleffectiveness and cost-effectiveness ofcapecitabine (Xeloda®) for locallyadvanced and/or metastatic breast cancer.

By Jones L, Hawkins N, Westwood M,Wright K, Richardson G, Riemsma R.

No. 6Effectiveness and efficiency of guidelinedissemination and implementationstrategies.

By Grimshaw JM, Thomas RE,MacLennan G, Fraser C, Ramsay CR,Vale L, et al.

No. 7Clinical effectiveness and costs of theSugarbaker procedure for the treatmentof pseudomyxoma peritonei.

By Bryant J, Clegg AJ, Sidhu MK,Brodin H, Royle P, Davidson P.

No. 8Psychological treatment for insomnia inthe regulation of long-term hypnoticdrug use.

By Morgan K, Dixon S, Mathers N,Thompson J, Tomeny M.

No. 9Improving the evaluation of therapeuticinterventions in multiple sclerosis:development of a patient-based measureof outcome.

By Hobart JC, Riazi A, Lamping DL,Fitzpatrick R, Thompson AJ.

No. 10A systematic review and economicevaluation of magnetic resonancecholangiopancreatography comparedwith diagnostic endoscopic retrogradecholangiopancreatography.

By Kaltenthaler E, Bravo Vergel Y,Chilcott J, Thomas S, Blakeborough T,Walters SJ, et al.

No. 11The use of modelling to evaluate newdrugs for patients with a chroniccondition: the case of antibodies againsttumour necrosis factor in rheumatoidarthritis.

By Barton P, Jobanputra P, Wilson J,Bryan S, Burls A.

No. 12Clinical effectiveness and cost-effectiveness of neonatal screening forinborn errors of metabolism usingtandem mass spectrometry: a systematicreview.

By Pandor A, Eastham J, Beverley C,Chilcott J, Paisley S.

No. 13Clinical effectiveness and cost-effectiveness of pioglitazone androsiglitazone in the treatment of type 2 diabetes: a systematic review and economic evaluation.

By Czoski-Murray C, Warren E,Chilcott J, Beverley C, Psyllaki MA,Cowan J.

No. 14Routine examination of the newborn:the EMREN study. Evaluation of anextension of the midwife role including a randomised controlled trial of appropriately trained midwivesand paediatric senior house officers.

By Townsend J, Wolke D, Hayes J,Davé S, Rogers C, Bloomfield L, et al.

No. 15Involving consumers in research anddevelopment agenda setting for theNHS: developing an evidence-basedapproach.

By Oliver S, Clarke-Jones L, Rees R, Milne R, Buchanan P, Gabbay J, et al.

No. 16A multi-centre randomised controlledtrial of minimally invasive directcoronary bypass grafting versuspercutaneous transluminal coronaryangioplasty with stenting for proximalstenosis of the left anterior descendingcoronary artery.

By Reeves BC, Angelini GD, BryanAJ, Taylor FC, Cripps T, Spyt TJ, et al.

No. 17Does early magnetic resonance imaginginfluence management or improveoutcome in patients referred tosecondary care with low back pain? A pragmatic randomised controlledtrial.

By Gilbert FJ, Grant AM, GillanMGC, Vale L, Scott NW, Campbell MK,et al.

No. 18The clinical and cost-effectiveness ofanakinra for the treatment ofrheumatoid arthritis in adults: asystematic review and economic analysis.

By Clark W, Jobanputra P, Barton P,Burls A.

No. 19A rapid and systematic review andeconomic evaluation of the clinical andcost-effectiveness of newer drugs fortreatment of mania associated withbipolar affective disorder.

By Bridle C, Palmer S, Bagnall A-M,Darba J, Duffy S, Sculpher M, et al.

No. 20Liquid-based cytology in cervicalscreening: an updated rapid andsystematic review and economic analysis.

By Karnon J, Peters J, Platt J, Chilcott J, McGoogan E, Brewer N.

No. 21Systematic review of the long-termeffects and economic consequences oftreatments for obesity and implicationsfor health improvement.

By Avenell A, Broom J, Brown TJ,Poobalan A, Aucott L, Stearns SC, et al.

No. 22Autoantibody testing in children withnewly diagnosed type 1 diabetesmellitus.

By Dretzke J, Cummins C,Sandercock J, Fry-Smith A, Barrett T,Burls A.


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No. 23Clinical effectiveness and cost-effectiveness of prehospital intravenousfluids in trauma patients.

By Dretzke J, Sandercock J, Bayliss S,Burls A.

No. 24Newer hypnotic drugs for the short-term management of insomnia: asystematic review and economicevaluation.

By Dündar Y, Boland A, Strobl J,Dodd S, Haycox A, Bagust A, et al.

No. 25Development and validation of methodsfor assessing the quality of diagnosticaccuracy studies.

By Whiting P, Rutjes AWS, Dinnes J,Reitsma JB, Bossuyt PMM, Kleijnen J.

No. 26EVALUATE hysterectomy trial: amulticentre randomised trial comparingabdominal, vaginal and laparoscopicmethods of hysterectomy.

By Garry R, Fountain J, Brown J,Manca A, Mason S, Sculpher M, et al.

No. 27Methods for expected value ofinformation analysis in complex healtheconomic models: developments on thehealth economics of interferon-� andglatiramer acetate for multiple sclerosis.

By Tappenden P, Chilcott JB,Eggington S, Oakley J, McCabe C.

No. 28Effectiveness and cost-effectiveness ofimatinib for first-line treatment ofchronic myeloid leukaemia in chronicphase: a systematic review and economicanalysis.

By Dalziel K, Round A, Stein K,Garside R, Price A.

No. 29VenUS I: a randomised controlled trialof two types of bandage for treatingvenous leg ulcers.

By Iglesias C, Nelson EA, Cullum NA,Torgerson DJ on behalf of the VenUSTeam.

No. 30Systematic review of the effectivenessand cost-effectiveness, and economicevaluation, of myocardial perfusionscintigraphy for the diagnosis andmanagement of angina and myocardialinfarction.

By Mowatt G, Vale L, Brazzelli M,Hernandez R, Murray A, Scott N, et al.

No. 31A pilot study on the use of decisiontheory and value of information analysisas part of the NHS Health TechnologyAssessment programme.

By Claxton Kon K, Ginnelly L, SculpherM, Philips Z, Palmer S.

No. 32The Social Support and Family HealthStudy: a randomised controlled trial andeconomic evaluation of two alternativeforms of postnatal support for mothersliving in disadvantaged inner-city areas.

By Wiggins M, Oakley A, Roberts I,Turner H, Rajan L, Austerberry H, et al.

No. 33Psychosocial aspects of genetic screeningof pregnant women and newborns: a systematic review.

By Green JM, Hewison J, Bekker HL,Bryant, Cuckle HS.

No. 34Evaluation of abnormal uterinebleeding: comparison of threeoutpatient procedures within cohortsdefined by age and menopausal status.

By Critchley HOD, Warner P, Lee AJ, Brechin S, Guise J, Graham B.

No. 35Coronary artery stents: a rapid systematicreview and economic evaluation.

By Hill R, Bagust A, Bakhai A,Dickson R, Dündar Y, Haycox A, et al.

No. 36Review of guidelines for good practicein decision-analytic modelling in healthtechnology assessment.

By Philips Z, Ginnelly L, Sculpher M,Claxton K, Golder S, Riemsma R, et al.

No. 37Rituximab (MabThera®) for aggressivenon-Hodgkin’s lymphoma: systematicreview and economic evaluation.

By Knight C, Hind D, Brewer N,Abbott V.

No. 38Clinical effectiveness and cost-effectiveness of clopidogrel andmodified-release dipyridamole in thesecondary prevention of occlusivevascular events: a systematic review andeconomic evaluation.

By Jones L, Griffin S, Palmer S, MainC, Orton V, Sculpher M, et al.

No. 39Pegylated interferon �-2a and -2b incombination with ribavirin in thetreatment of chronic hepatitis C: asystematic review and economicevaluation.

By Shepherd J, Brodin H, Cave C,Waugh N, Price A, Gabbay J.

No. 40Clopidogrel used in combination withaspirin compared with aspirin alone inthe treatment of non-ST-segment-elevation acute coronary syndromes: asystematic review and economicevaluation.

By Main C, Palmer S, Griffin S, Jones L, Orton V, Sculpher M, et al.

No. 41Provision, uptake and cost of cardiacrehabilitation programmes: improvingservices to under-represented groups.

By Beswick AD, Rees K, Griebsch I,Taylor FC, Burke M, West RR, et al.

No. 42Involving South Asian patients inclinical trials.

By Hussain-Gambles M, Leese B,Atkin K, Brown J, Mason S, Tovey P.

No. 43Clinical and cost-effectiveness ofcontinuous subcutaneous insulininfusion for diabetes.

By Colquitt JL, Green C, Sidhu MK,Hartwell D, Waugh N.

No. 44Identification and assessment ofongoing trials in health technologyassessment reviews.

By Song FJ, Fry-Smith A, DavenportC, Bayliss S, Adi Y, Wilson JS, et al.

No. 45Systematic review and economicevaluation of a long-acting insulinanalogue, insulin glargine

By Warren E, Weatherley-Jones E,Chilcott J, Beverley C.

No. 46Supplementation of a home-basedexercise programme with a class-basedprogramme for people with osteoarthritisof the knees: a randomised controlledtrial and health economic analysis.

By McCarthy CJ, Mills PM, Pullen R, Richardson G, Hawkins N,Roberts CR, et al.

No. 47Clinical and cost-effectiveness of once-daily versus more frequent use of samepotency topical corticosteroids for atopiceczema: a systematic review andeconomic evaluation.

By Green C, Colquitt JL, Kirby J,Davidson P, Payne E.

No. 48Acupuncture of chronic headachedisorders in primary care: randomisedcontrolled trial and economic analysis.

By Vickers AJ, Rees RW, Zollman CE,McCarney R, Smith CM, Ellis N, et al.

No. 49Generalisability in economic evaluationstudies in healthcare: a review and casestudies.

By Sculpher MJ, Pang FS, Manca A,Drummond MF, Golder S, Urdahl H, et al.

No. 50Virtual outreach: a randomisedcontrolled trial and economic evaluationof joint teleconferenced medicalconsultations.

By Wallace P, Barber J, Clayton W,Currell R, Fleming K, Garner P, et al.


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Volume 9, 2005

No. 1Randomised controlled multipletreatment comparison to provide a cost-effectiveness rationale for theselection of antimicrobial therapy inacne.

By Ozolins M, Eady EA, Avery A,Cunliffe WJ, O’Neill C, Simpson NB, et al.

No. 2Do the findings of case series studiesvary significantly according tomethodological characteristics?

By Dalziel K, Round A, Stein K,Garside R, Castelnuovo E, Payne L.

No. 3Improving the referral process forfamilial breast cancer geneticcounselling: findings of threerandomised controlled trials of twointerventions.

By Wilson BJ, Torrance N, Mollison J,Wordsworth S, Gray JR, Haites NE, et al.

No. 4Randomised evaluation of alternativeelectrosurgical modalities to treatbladder outflow obstruction in men withbenign prostatic hyperplasia.

By Fowler C, McAllister W, Plail R,Karim O, Yang Q.

No. 5A pragmatic randomised controlled trialof the cost-effectiveness of palliativetherapies for patients with inoperableoesophageal cancer.

By Shenfine J, McNamee P, Steen N,Bond J, Griffin SM.

No. 6Impact of computer-aided detectionprompts on the sensitivity and specificityof screening mammography.

By Taylor P, Champness J, Given-Wilson R, Johnston K, Potts H.

No. 7Issues in data monitoring and interimanalysis of trials.

By Grant AM, Altman DG, BabikerAB, Campbell MK, Clemens FJ,Darbyshire JH, et al.

No. 8Lay public’s understanding of equipoiseand randomisation in randomisedcontrolled trials.

By Robinson EJ, Kerr CEP, StevensAJ, Lilford RJ, Braunholtz DA, EdwardsSJ, et al.

No. 9Clinical and cost-effectiveness ofelectroconvulsive therapy for depressiveillness, schizophrenia, catatonia andmania: systematic reviews and economicmodelling studies.

By Greenhalgh J, Knight C, Hind D,Beverley C, Walters S.

No. 10Measurement of health-related qualityof life for people with dementia:development of a new instrument(DEMQOL) and an evaluation ofcurrent methodology.

By Smith SC, Lamping DL, Banerjee S, Harwood R, Foley B, Smith P, et al.

No. 11Clinical effectiveness and cost-effectiveness of drotrecogin alfa(activated) (Xigris®) for the treatment ofsevere sepsis in adults: a systematicreview and economic evaluation.

By Green C, Dinnes J, Takeda A,Shepherd J, Hartwell D, Cave C, et al.

No. 12A methodological review of howheterogeneity has been examined insystematic reviews of diagnostic testaccuracy.

By Dinnes J, Deeks J, Kirby J,Roderick P.

No. 13Cervical screening programmes: canautomation help? Evidence fromsystematic reviews, an economic analysisand a simulation modelling exerciseapplied to the UK.

By Willis BH, Barton P, Pearmain P,Bryan S, Hyde C.

No. 14Laparoscopic surgery for inguinalhernia repair: systematic review ofeffectiveness and economic evaluation.

By McCormack K, Wake B, Perez J,Fraser C, Cook J, McIntosh E, et al.

No. 15Clinical effectiveness, tolerability andcost-effectiveness of newer drugs forepilepsy in adults: a systematic reviewand economic evaluation.

By Wilby J, Kainth A, Hawkins N,Epstein D, McIntosh H, McDaid C, et al.

No. 16A randomised controlled trial tocompare the cost-effectiveness oftricyclic antidepressants, selectiveserotonin reuptake inhibitors andlofepramine.

By Peveler R, Kendrick T, Buxton M,Longworth L, Baldwin D, Moore M, et al.

No. 17Clinical effectiveness and cost-effectiveness of immediate angioplastyfor acute myocardial infarction:systematic review and economicevaluation.

By Hartwell D, Colquitt J, LovemanE, Clegg AJ, Brodin H, Waugh N, et al.

No. 18A randomised controlled comparison ofalternative strategies in stroke care.

By Kalra L, Evans A, Perez I, Knapp M, Swift C, Donaldson N.

No. 19The investigation and analysis of criticalincidents and adverse events inhealthcare.

By Woloshynowych M, Rogers S,Taylor-Adams S, Vincent C.

No. 20Potential use of routine databases inhealth technology assessment.

By Raftery J, Roderick P, Stevens A.

No. 21Clinical and cost-effectiveness of newerimmunosuppressive regimens in renaltransplantation: a systematic review andmodelling study.

By Woodroffe R, Yao GL, Meads C,Bayliss S, Ready A, Raftery J, et al.

No. 22A systematic review and economicevaluation of alendronate, etidronate,risedronate, raloxifene and teriparatidefor the prevention and treatment ofpostmenopausal osteoporosis.

By Stevenson M, Lloyd Jones M, De Nigris E, Brewer N, Davis S, Oakley J.

No. 23A systematic review to examine theimpact of psycho-educationalinterventions on health outcomes andcosts in adults and children with difficultasthma.

By Smith JR, Mugford M, Holland R,Candy B, Noble MJ, Harrison BDW, et al.

No. 24An evaluation of the costs, effectivenessand quality of renal replacementtherapy provision in renal satellite unitsin England and Wales.

By Roderick P, Nicholson T, ArmitageA, Mehta R, Mullee M, Gerard K, et al.

No. 25Imatinib for the treatment of patientswith unresectable and/or metastaticgastrointestinal stromal tumours:systematic review and economicevaluation.

By Wilson J, Connock M, Song F, YaoG, Fry-Smith A, Raftery J, et al.

No. 26Indirect comparisons of competinginterventions.

By Glenny AM, Altman DG, Song F,Sakarovitch C, Deeks JJ, D’Amico R, et al.

No. 27Cost-effectiveness of alternativestrategies for the initial medicalmanagement of non-ST elevation acutecoronary syndrome: systematic reviewand decision-analytical modelling.

By Robinson M, Palmer S, SculpherM, Philips Z, Ginnelly L, Bowens A, et al.


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No. 28Outcomes of electrically stimulatedgracilis neosphincter surgery.

By Tillin T, Chambers M, Feldman R.

No. 29The effectiveness and cost-effectivenessof pimecrolimus and tacrolimus foratopic eczema: a systematic review andeconomic evaluation.

By Garside R, Stein K, Castelnuovo E,Pitt M, Ashcroft D, Dimmock P, et al.

No. 30Systematic review on urine albumintesting for early detection of diabeticcomplications.

By Newman DJ, Mattock MB, DawnayABS, Kerry S, McGuire A, Yaqoob M, et al.

No. 31Randomised controlled trial of the cost-effectiveness of water-based therapy forlower limb osteoarthritis.

By Cochrane T, Davey RC, Matthes Edwards SM.

No. 32Longer term clinical and economicbenefits of offering acupuncture care topatients with chronic low back pain.

By Thomas KJ, MacPherson H,Ratcliffe J, Thorpe L, Brazier J,Campbell M, et al.

No. 33Cost-effectiveness and safety of epiduralsteroids in the management of sciatica.

By Price C, Arden N, Coglan L,Rogers P.

No. 34The British Rheumatoid Outcome StudyGroup (BROSG) randomised controlledtrial to compare the effectiveness andcost-effectiveness of aggressive versussymptomatic therapy in establishedrheumatoid arthritis.

By Symmons D, Tricker K, Roberts C,Davies L, Dawes P, Scott DL.

No. 35Conceptual framework and systematicreview of the effects of participants’ andprofessionals’ preferences in randomisedcontrolled trials.

By King M, Nazareth I, Lampe F,Bower P, Chandler M, Morou M, et al.

No. 36The clinical and cost-effectiveness ofimplantable cardioverter defibrillators: a systematic review.

By Bryant J, Brodin H, Loveman E,Payne E, Clegg A.

No. 37A trial of problem-solving by communitymental health nurses for anxiety,depression and life difficulties amonggeneral practice patients. The CPN-GPstudy.

By Kendrick T, Simons L, Mynors-Wallis L, Gray A, Lathlean J,Pickering R, et al.

No. 38The causes and effects of socio-demographic exclusions from clinicaltrials.

By Bartlett C, Doyal L, Ebrahim S,Davey P, Bachmann M, Egger M, et al.

No. 39Is hydrotherapy cost-effective? Arandomised controlled trial of combinedhydrotherapy programmes comparedwith physiotherapy land techniques inchildren with juvenile idiopathicarthritis.

By Epps H, Ginnelly L, Utley M,Southwood T, Gallivan S, Sculpher M, et al.

No. 40A randomised controlled trial and cost-effectiveness study of systematicscreening (targeted and total populationscreening) versus routine practice forthe detection of atrial fibrillation inpeople aged 65 and over. The SAFEstudy.

By Hobbs FDR, Fitzmaurice DA,Mant J, Murray E, Jowett S, Bryan S, et al.

No. 41Displaced intracapsular hip fractures in fit, older people: a randomisedcomparison of reduction and fixation,bipolar hemiarthroplasty and total hiparthroplasty.

By Keating JF, Grant A, Masson M,Scott NW, Forbes JF.

No. 42Long-term outcome of cognitivebehaviour therapy clinical trials incentral Scotland.

By Durham RC, Chambers JA, Power KG, Sharp DM, Macdonald RR,Major KA, et al.

No. 43The effectiveness and cost-effectivenessof dual-chamber pacemakers comparedwith single-chamber pacemakers forbradycardia due to atrioventricularblock or sick sinus syndrome: systematic review and economicevaluation.

By Castelnuovo E, Stein K, Pitt M,Garside R, Payne E.

No. 44Newborn screening for congenital heartdefects: a systematic review and cost-effectiveness analysis.

By Knowles R, Griebsch I, DezateuxC, Brown J, Bull C, Wren C.

No. 45The clinical and cost-effectiveness of leftventricular assist devices for end-stageheart failure: a systematic review andeconomic evaluation.

By Clegg AJ, Scott DA, Loveman E,Colquitt J, Hutchinson J, Royle P, et al.

No. 46The effectiveness of the HeidelbergRetina Tomograph and laser diagnosticglaucoma scanning system (GDx) indetecting and monitoring glaucoma.

By Kwartz AJ, Henson DB, Harper RA, Spencer AF, McLeod D.

No. 47Clinical and cost-effectiveness ofautologous chondrocyte implantationfor cartilage defects in knee joints:systematic review and economicevaluation.

By Clar C, Cummins E, McIntyre L,Thomas S, Lamb J, Bain L, et al.

No. 48Systematic review of effectiveness ofdifferent treatments for childhoodretinoblastoma.

By McDaid C, Hartley S, Bagnall A-M, Ritchie G, Light K,Riemsma R.

No. 49Towards evidence-based guidelines for the prevention of venousthromboembolism: systematic reviews of mechanical methods, oralanticoagulation, dextran and regionalanaesthesia as thromboprophylaxis.

By Roderick P, Ferris G, Wilson K,Halls H, Jackson D, Collins R,et al.

No. 50The effectiveness and cost-effectivenessof parent training/educationprogrammes for the treatment ofconduct disorder, including oppositionaldefiant disorder, in children.

By Dretzke J, Frew E, Davenport C,Barlow J, Stewart-Brown S, Sandercock J, et al.

Volume 10, 2006

No. 1The clinical and cost-effectiveness ofdonepezil, rivastigmine, galantamineand memantine for Alzheimer’s disease.

By Loveman E, Green C, Kirby J,Takeda A, Picot J, Payne E, et al.

No. 2FOOD: a multicentre randomised trialevaluating feeding policies in patientsadmitted to hospital with a recentstroke.

By Dennis M, Lewis S, Cranswick G,Forbes J.

No. 3The clinical effectiveness and cost-effectiveness of computed tomographyscreening for lung cancer: systematicreviews.

By Black C, Bagust A, Boland A,Walker S, McLeod C, De Verteuil R, et al.


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No. 4A systematic review of the effectivenessand cost-effectiveness of neuroimagingassessments used to visualise the seizure focus in people with refractoryepilepsy being considered for surgery.

By Whiting P, Gupta R, Burch J,Mujica Mota RE, Wright K, Marson A, et al.

No. 5Comparison of conference abstracts and presentations with full-text articles in the health technologyassessments of rapidly evolvingtechnologies.

By Dundar Y, Dodd S, Dickson R,Walley T, Haycox A, Williamson PR.

No. 6Systematic review and evaluation ofmethods of assessing urinaryincontinence.

By Martin JL, Williams KS, AbramsKR, Turner DA, Sutton AJ, Chapple C,et al.

No. 7The clinical effectiveness and cost-effectiveness of newer drugs for childrenwith epilepsy. A systematic review.

By Connock M, Frew E, Evans B-W, Bryan S, Cummins C, Fry-Smith A, et al.

No. 8Surveillance of Barrett’s oesophagus:exploring the uncertainty throughsystematic review, expert workshop andeconomic modelling.

By Garside R, Pitt M, Somerville M,Stein K, Price A, Gilbert N.

No. 9Topotecan, pegylated liposomaldoxorubicin hydrochloride andpaclitaxel for second-line or subsequenttreatment of advanced ovarian cancer: asystematic review and economicevaluation.

By Main C, Bojke L, Griffin S,Norman G, Barbieri M, Mather L, et al.

No. 10Evaluation of molecular techniques in prediction and diagnosis ofcytomegalovirus disease inimmunocompromised patients.

By Szczepura A, Westmoreland D,Vinogradova Y, Fox J, Clark M.

No. 11Screening for thrombophilia in high-risksituations: systematic review and cost-effectiveness analysis. The Thrombosis:Risk and Economic Assessment ofThrombophilia Screening (TREATS)study.

By Wu O, Robertson L, Twaddle S,Lowe GDO, Clark P, Greaves M, et al.

No. 12A series of systematic reviews to informa decision analysis for sampling andtreating infected diabetic foot ulcers.

By Nelson EA, O’Meara S, Craig D,Iglesias C, Golder S, Dalton J, et al.

No. 13Randomised clinical trial, observationalstudy and assessment of cost-effectiveness of the treatment of varicoseveins (REACTIV trial).

By Michaels JA, Campbell WB,Brazier JE, MacIntyre JB, PalfreymanSJ, Ratcliffe J, et al.

No. 14The cost-effectiveness of screening fororal cancer in primary care.

By Speight PM, Palmer S, Moles DR,Downer MC, Smith DH, Henriksson Met al.

No. 15Measurement of the clinical and cost-effectiveness of non-invasive diagnostictesting strategies for deep veinthrombosis.

By Goodacre S, Sampson F, StevensonM, Wailoo A, Sutton A, Thomas S, et al.

No. 16Systematic review of the effectivenessand cost-effectiveness of HealOzone®

for the treatment of occlusal pit/fissurecaries and root caries.

By Brazzelli M, McKenzie L, FieldingS, Fraser C, Clarkson J, Kilonzo M, et al.

No. 17Randomised controlled trials ofconventional antipsychotic versus newatypical drugs, and new atypical drugsversus clozapine, in people withschizophrenia responding poorly to, or intolerant of, current drugtreatment.

By Lewis SW, Davies L, Jones PB,Barnes TRE, Murray RM, Kerwin R, et al.

No. 18Diagnostic tests and algorithms used inthe investigation of haematuria:systematic reviews and economicevaluation.

By Rodgers M, Nixon J, Hempel S,Aho T, Kelly J, Neal D, et al.

No. 19Cognitive behavioural therapy inaddition to antispasmodic therapy forirritable bowel syndrome in primarycare: randomised controlled trial.

By Kennedy TM, Chalder T, McCrone P, Darnley S, Knapp M, Jones RH, et al.

No. 20A systematic review of the clinicaleffectiveness and cost-effectiveness ofenzyme replacement therapies forFabry’s disease andmucopolysaccharidosis type 1.

By Connock M, Juarez-Garcia A, FrewE, Mans A, Dretzke J, Fry-Smith A, et al.

No. 21Health benefits of antiviral therapy formild chronic hepatitis C: randomisedcontrolled trial and economicevaluation.

By Wright M, Grieve R, Roberts J,Main J, Thomas HC on behalf of theUK Mild Hepatitis C Trial Investigators.

No. 22Pressure relieving support surfaces: arandomised evaluation.

By Nixon J, Nelson EA, Cranny G,Iglesias CP, Hawkins K, Cullum NA, et al.

No. 23A systematic review and economicmodel of the effectiveness and cost-effectiveness of methylphenidate,dexamfetamine and atomoxetine for thetreatment of attention deficithyperactivity disorder in children andadolescents.

By King S, Griffin S, Hodges Z,Weatherly H, Asseburg C, Richardson G,et al.

No. 24The clinical effectiveness and cost-effectiveness of enzyme replacementtherapy for Gaucher’s disease: a systematic review.

By Connock M, Burls A, Frew E, Fry-Smith A, Juarez-Garcia A, McCabe C, et al.

No. 25Effectiveness and cost-effectiveness ofsalicylic acid and cryotherapy forcutaneous warts. An economic decisionmodel.

By Thomas KS, Keogh-Brown MR,Chalmers JR, Fordham RJ, Holland RC,Armstrong SJ, et al.

No. 26A systematic literature review of theeffectiveness of non-pharmacologicalinterventions to prevent wandering indementia and evaluation of the ethicalimplications and acceptability of theiruse.

By Robinson L, Hutchings D, CornerL, Beyer F, Dickinson H, Vanoli A, et al.

No. 27A review of the evidence on the effectsand costs of implantable cardioverterdefibrillator therapy in different patientgroups, and modelling of cost-effectiveness and cost–utility for thesegroups in a UK context.

By Buxton M, Caine N, Chase D,Connelly D, Grace A, Jackson C, et al.


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No. 28Adefovir dipivoxil and pegylatedinterferon alfa-2a for the treatment ofchronic hepatitis B: a systematic reviewand economic evaluation.

By Shepherd J, Jones J, Takeda A,Davidson P, Price A.

No. 29An evaluation of the clinical and cost-effectiveness of pulmonary arterycatheters in patient management inintensive care: a systematic review and arandomised controlled trial.

By Harvey S, Stevens K, Harrison D,Young D, Brampton W, McCabe C, et al.

No. 30Accurate, practical and cost-effectiveassessment of carotid stenosis in the UK.

By Wardlaw JM, Chappell FM,Stevenson M, De Nigris E, Thomas S,Gillard J, et al.

No. 31Etanercept and infliximab for thetreatment of psoriatic arthritis: a systematic review and economicevaluation.

By Woolacott N, Bravo Vergel Y,Hawkins N, Kainth A, Khadjesari Z,Misso K, et al.

No. 32The cost-effectiveness of testing forhepatitis C in former injecting drugusers.

By Castelnuovo E, Thompson-Coon J,Pitt M, Cramp M, Siebert U, Price A, et al.

No. 33Computerised cognitive behaviourtherapy for depression and anxietyupdate: a systematic review andeconomic evaluation.

By Kaltenthaler E, Brazier J, De Nigris E, Tumur I, Ferriter M,Beverley C, et al.

No. 34Cost-effectiveness of using prognosticinformation to select women with breast cancer for adjuvant systemic therapy.

By Williams C, Brunskill S, Altman D,Briggs A, Campbell H, Clarke M, et al.

No. 35Psychological therapies includingdialectical behaviour therapy forborderline personality disorder: a systematic review and preliminaryeconomic evaluation.

By Brazier J, Tumur I, Holmes M,Ferriter M, Parry G, Dent-Brown K, et al.

No. 36Clinical effectiveness and cost-effectiveness of tests for the diagnosisand investigation of urinary tractinfection in children: a systematic reviewand economic model.

By Whiting P, Westwood M, Bojke L,Palmer S, Richardson G, Cooper J, et al.

No. 37Cognitive behavioural therapy inchronic fatigue syndrome: a randomisedcontrolled trial of an outpatient groupprogramme.

By O’Dowd H, Gladwell P, Rogers CA,Hollinghurst S, Gregory A.

No. 38A comparison of the cost-effectiveness offive strategies for the prevention of non-steroidal anti-inflammatory drug-inducedgastrointestinal toxicity: a systematicreview with economic modelling.

By Brown TJ, Hooper L, Elliott RA,Payne K, Webb R, Roberts C, et al.

No. 39The effectiveness and cost-effectivenessof computed tomography screening forcoronary artery disease: systematicreview.

By Waugh N, Black C, Walker S,McIntyre L, Cummins E, Hillis G.

No. 40What are the clinical outcome and cost-effectiveness of endoscopy undertakenby nurses when compared with doctors?A Multi-Institution Nurse EndoscopyTrial (MINuET).

By Williams J, Russell I, Durai D,Cheung W-Y, Farrin A, Bloor K, et al.

No. 41The clinical and cost-effectiveness ofoxaliplatin and capecitabine for theadjuvant treatment of colon cancer:systematic review and economicevaluation.

By Pandor A, Eggington S, Paisley S,Tappenden P, Sutcliffe P.

No. 42A systematic review of the effectivenessof adalimumab, etanercept andinfliximab for the treatment ofrheumatoid arthritis in adults and aneconomic evaluation of their cost-effectiveness.

By Chen Y-F, Jobanputra P, Barton P,Jowett S, Bryan S, Clark W, et al.

No. 43Telemedicine in dermatology: a randomised controlled trial.

By Bowns IR, Collins K, Walters SJ,McDonagh AJG.

No. 44Cost-effectiveness of cell salvage andalternative methods of minimisingperioperative allogeneic bloodtransfusion: a systematic review andeconomic model.

By Davies L, Brown TJ, Haynes S,Payne K, Elliott RA, McCollum C.

No. 45Clinical effectiveness and cost-effectiveness of laparoscopic surgery forcolorectal cancer: systematic reviews andeconomic evaluation.

By Murray A, Lourenco T, de Verteuil R, Hernandez R, Fraser C,McKinley A, et al.

No. 46Etanercept and efalizumab for thetreatment of psoriasis: a systematicreview.

By Woolacott N, Hawkins N, Mason A, Kainth A, Khadjesari Z, Bravo Vergel Y, et al.

No. 47Systematic reviews of clinical decisiontools for acute abdominal pain.

By Liu JLY, Wyatt JC, Deeks JJ,Clamp S, Keen J, Verde P, et al.

No. 48Evaluation of the ventricular assistdevice programme in the UK.

By Sharples L, Buxton M, Caine N,Cafferty F, Demiris N, Dyer M, et al.

No. 49A systematic review and economicmodel of the clinical and cost-effectiveness of immunosuppressivetherapy for renal transplantation inchildren.

By Yao G, Albon E, Adi Y, Milford D,Bayliss S, Ready A, et al.

No. 50Amniocentesis results: investigation ofanxiety. The ARIA trial.

By Hewison J, Nixon J, Fountain J,Cocks K, Jones C, Mason G, et al.

Volume 11, 2007

No. 1Pemetrexed disodium for the treatmentof malignant pleural mesothelioma: a systematic review and economicevaluation.

By Dundar Y, Bagust A, Dickson R,Dodd S, Green J, Haycox A, et al.

No. 2A systematic review and economicmodel of the clinical effectiveness andcost-effectiveness of docetaxel incombination with prednisone orprednisolone for the treatment ofhormone-refractory metastatic prostatecancer.

By Collins R, Fenwick E, Trowman R,Perard R, Norman G, Light K, et al.

No. 3A systematic review of rapid diagnostictests for the detection of tuberculosisinfection.

By Dinnes J, Deeks J, Kunst H,Gibson A, Cummins E, Waugh N, et al.

No. 4The clinical effectiveness and cost-effectiveness of strontium ranelate forthe prevention of osteoporotic fragility fractures in postmenopausalwomen.

By Stevenson M, Davis S, Lloyd-Jones M, Beverley C.


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No. 5A systematic review of quantitative andqualitative research on the role andeffectiveness of written informationavailable to patients about individualmedicines.

By Raynor DK, Blenkinsopp A,Knapp P, Grime J, Nicolson DJ, Pollock K, et al.

No. 6Oral naltrexone as a treatment forrelapse prevention in formerly opioid-dependent drug users: a systematic review and economicevaluation.

By Adi Y, Juarez-Garcia A, Wang D,Jowett S, Frew E, Day E, et al.

No. 7Glucocorticoid-induced osteoporosis: a systematic review and cost–utility analysis.

By Kanis JA, Stevenson M, McCloskey EV, Davis S, Lloyd-Jones M.

No. 8Epidemiological, social, diagnostic andeconomic evaluation of populationscreening for genital chlamydial infection.

By Low N, McCarthy A, Macleod J,Salisbury C, Campbell R, Roberts TE, et al.

No. 9Methadone and buprenorphine for themanagement of opioid dependence: a systematic review and economicevaluation.

By Connock M, Juarez-Garcia A,Jowett S, Frew E, Liu Z, Taylor RJ, et al.

No. 10Exercise Evaluation Randomised Trial(EXERT): a randomised trial comparingGP referral for leisure centre-basedexercise, community-based walking andadvice only.

By Isaacs AJ, Critchley JA, See Tai S, Buckingham K, Westley D,Harridge SDR, et al.

No. 11Interferon alfa (pegylated and non-pegylated) and ribavirin for thetreatment of mild chronic hepatitis C: a systematic review and economicevaluation.

By Shepherd J, Jones J, Hartwell D,Davidson P, Price A, Waugh N.

No. 12Systematic review and economicevaluation of bevacizumab andcetuximab for the treatment ofmetastatic colorectal cancer.

By Tappenden P, Jones R, Paisley S,Carroll C.

No. 13A systematic review and economicevaluation of epoetin alfa, epoetin betaand darbepoetin alfa in anaemiaassociated with cancer, especially thatattributable to cancer treatment.

By Wilson J, Yao GL, Raftery J,Bohlius J, Brunskill S, Sandercock J, et al.

No. 14A systematic review and economicevaluation of statins for the preventionof coronary events.

By Ward S, Lloyd Jones M, Pandor A,Holmes M, Ara R, Ryan A, et al.

No. 15A systematic review of the effectivenessand cost-effectiveness of differentmodels of community-based respite care for frail older people and theircarers.

By Mason A, Weatherly H, SpilsburyK, Arksey H, Golder S, Adamson J, et al.

No. 16Additional therapy for young childrenwith spastic cerebral palsy: a randomised controlled trial.

By Weindling AM, Cunningham CC,Glenn SM, Edwards RT, Reeves DJ.

No. 17Screening for type 2 diabetes: literaturereview and economic modelling.

By Waugh N, Scotland G, McNamee P, Gillett M, Brennan A,Goyder E, et al.

No. 18The effectiveness and cost-effectivenessof cinacalcet for secondaryhyperparathyroidism in end-stage renal disease patients on dialysis: asystematic review and economicevaluation.

By Garside R, Pitt M, Anderson R,Mealing S, Roome C, Snaith A, et al.

No. 19The clinical effectiveness and cost-effectiveness of gemcitabine formetastatic breast cancer: a systematicreview and economic evaluation.

By Takeda AL, Jones J, Loveman E,Tan SC, Clegg AJ.

No. 20A systematic review of duplexultrasound, magnetic resonanceangiography and computed tomographyangiography for the diagnosis and assessment of symptomatic, lowerlimb peripheral arterial disease.

By Collins R, Cranny G, Burch J,Aguiar-Ibáñez R, Craig D, Wright K, et al.

No. 21The clinical effectiveness and cost-effectiveness of treatments for childrenwith idiopathic steroid-resistantnephrotic syndrome: a systematic review.

By Colquitt JL, Kirby J, Green C,Cooper K, Trompeter RS.

No. 22A systematic review of the routinemonitoring of growth in children ofprimary school age to identify growth-related conditions.

By Fayter D, Nixon J, Hartley S,Rithalia A, Butler G, Rudolf M, et al.

No. 23Systematic review of the effectiveness ofpreventing and treating Staphylococcusaureus carriage in reducing peritonealcatheter-related infections.

By McCormack K, Rabindranath K,Kilonzo M, Vale L, Fraser C, McIntyre L,et al.

No. 24The clinical effectiveness and cost ofrepetitive transcranial magneticstimulation versus electroconvulsivetherapy in severe depression: a multicentre pragmatic randomisedcontrolled trial and economic analysis.

By McLoughlin DM, Mogg A, Eranti S, Pluck G, Purvis R, Edwards D,et al.

No. 25A randomised controlled trial andeconomic evaluation of direct versusindirect and individual versus groupmodes of speech and language therapyfor children with primary languageimpairment.

By Boyle J, McCartney E, Forbes J,O’Hare A.

No. 26Hormonal therapies for early breastcancer: systematic review and economicevaluation.

By Hind D, Ward S, De Nigris E,Simpson E, Carroll C, Wyld L.

No. 27Cardioprotection against the toxic effects of anthracyclines given tochildren with cancer: a systematic review.

By Bryant J, Picot J, Levitt G, Sullivan I, Baxter L, Clegg A.

No. 28Adalimumab, etanercept and infliximabfor the treatment of ankylosingspondylitis: a systematic review andeconomic evaluation.

By McLeod C, Bagust A, Boland A,Dagenais P, Dickson R, Dundar Y, et al.


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No. 29Prenatal screening and treatmentstrategies to prevent group Bstreptococcal and other bacterialinfections in early infancy: cost-effectiveness and expected value ofinformation analyses.

By Colbourn T, Asseburg C, Bojke L,Philips Z, Claxton K, Ades AE, et al.

No. 30Clinical effectiveness and cost-effectiveness of bone morphogeneticproteins in the non-healing of fracturesand spinal fusion: a systematic review.

By Garrison KR, Donell S, Ryder J,Shemilt I, Mugford M, Harvey I, et al.

No. 31A randomised controlled trial ofpostoperative radiotherapy followingbreast-conserving surgery in aminimum-risk older population. ThePRIME trial.

By Prescott RJ, Kunkler IH, WilliamsLJ, King CC, Jack W, van der Pol M, et al.

No. 32Current practice, accuracy, effectivenessand cost-effectiveness of the schoolentry hearing screen.

By Bamford J, Fortnum H, Bristow K,Smith J, Vamvakas G, Davies L, et al.

No. 33The clinical effectiveness and cost-effectiveness of inhaled insulin in diabetes mellitus: a systematic review and economic evaluation.

By Black C, Cummins E, Royle P,Philip S, Waugh N.

No. 34Surveillance of cirrhosis forhepatocellular carcinoma: systematicreview and economic analysis.

By Thompson Coon J, Rogers G,Hewson P, Wright D, Anderson R,Cramp M, et al.

No. 35The Birmingham Rehabilitation UptakeMaximisation Study (BRUM). Home-based compared with hospital-basedcardiac rehabilitation in a multi-ethnicpopulation: cost-effectiveness andpatient adherence.

By Jolly K, Taylor R, Lip GYH,Greenfield S, Raftery J, Mant J, et al.

No. 36A systematic review of the clinical,public health and cost-effectiveness of rapid diagnostic tests for thedetection and identification of bacterial intestinal pathogens in faeces and food.

By Abubakar I, Irvine L, Aldus CF, Wyatt GM, Fordham R, Schelenz S, et al.

No. 37A randomised controlled trialexamining the longer-term outcomes ofstandard versus new antiepileptic drugs. The SANAD trial.

By Marson AG, Appleton R, Baker GA,Chadwick DW, Doughty J, Eaton B, et al.

No. 38Clinical effectiveness and cost-effectiveness of different models of managing long-term oralanticoagulation therapy: a systematicreview and economic modelling.

By Connock M, Stevens C, Fry-Smith A,Jowett S, Fitzmaurice D, Moore D, et al.

No. 39A systematic review and economicmodel of the clinical effectiveness andcost-effectiveness of interventions forpreventing relapse in people withbipolar disorder.

By Soares-Weiser K, Bravo Vergel Y,Beynon S, Dunn G, Barbieri M, Duffy S,et al.

No. 40Taxanes for the adjuvant treatment ofearly breast cancer: systematic reviewand economic evaluation.

By Ward S, Simpson E, Davis S, Hind D, Rees A, Wilkinson A.

No. 41The clinical effectiveness and cost-effectiveness of screening for open angleglaucoma: a systematic review andeconomic evaluation.

By Burr JM, Mowatt G, Hernández R,Siddiqui MAR, Cook J, Lourenco T, et al.

No. 42Acceptability, benefit and costs of earlyscreening for hearing disability: a studyof potential screening tests and models.

By Davis A, Smith P, Ferguson M,Stephens D, Gianopoulos I.

No. 43Contamination in trials of educationalinterventions.

By Keogh-Brown MR, BachmannMO, Shepstone L, Hewitt C, Howe A,Ramsay CR, et al.

No. 44Overview of the clinical effectiveness ofpositron emission tomography imagingin selected cancers.

By Facey K, Bradbury I, Laking G,Payne E.

No. 45The effectiveness and cost-effectiveness ofcarmustine implants and temozolomidefor the treatment of newly diagnosedhigh-grade glioma: a systematic reviewand economic evaluation.

By Garside R, Pitt M, Anderson R,Rogers G, Dyer M, Mealing S, et al.

No. 46Drug-eluting stents: a systematic reviewand economic evaluation.

By Hill RA, Boland A, Dickson R, Dündar Y, Haycox A, McLeod C, et al.

No. 47The clinical effectiveness and cost-effectiveness of cardiac resynchronisation(biventricular pacing) for heart failure:systematic review and economic model.

By Fox M, Mealing S, Anderson R,Dean J, Stein K, Price A, et al.

No. 48Recruitment to randomised trials:strategies for trial enrolment andparticipation study. The STEPS study.

By Campbell MK, Snowdon C,Francis D, Elbourne D, McDonald AM,Knight R, et al.

No. 49Cost-effectiveness of functional cardiac testing in the diagnosis andmanagement of coronary artery disease: a randomised controlled trial. The CECaT trial.

By Sharples L, Hughes V, Crean A,Dyer M, Buxton M, Goldsmith K, et al.

No. 50Evaluation of diagnostic tests whenthere is no gold standard. A review ofmethods.

By Rutjes AWS, Reitsma JB,Coomarasamy A, Khan KS, Bossuyt PMM.

No. 51Systematic reviews of the clinicaleffectiveness and cost-effectiveness ofproton pump inhibitors in acute uppergastrointestinal bleeding.

By Leontiadis GI, Sreedharan A,Dorward S, Barton P, Delaney B,Howden CW, et al.

No. 52A review and critique of modelling inprioritising and designing screeningprogrammes.

By Karnon J, Goyder E, Tappenden P,McPhie S, Towers I, Brazier J, et al.

No. 53An assessment of the impact of the NHS Health Technology AssessmentProgramme.

By Hanney S, Buxton M, Green C,Coulson D, Raftery J.

Volume 12, 2008

No. 1A systematic review and economicmodel of switching from non-glycopeptide to glycopeptide antibioticprophylaxis for surgery.

By Cranny G, Elliott R, Weatherly H,Chambers D, Hawkins N, Myers L, et al.


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No. 2‘Cut down to quit’ with nicotinereplacement therapies in smokingcessation: a systematic review ofeffectiveness and economic analysis.

By Wang D, Connock M, Barton P,Fry-Smith A, Aveyard P, Moore D.

No. 3A systematic review of the effectivenessof strategies for reducing fracture risk inchildren with juvenile idiopathicarthritis with additional data on long-term risk of fracture and cost of diseasemanagement.

By Thornton J, Ashcroft D, O’Neill T,Elliott R, Adams J, Roberts C, et al.

No. 4Does befriending by trained lay workers improve psychological well-being and quality of life for carers ofpeople with dementia, and at what cost?A randomised controlled trial.

By Charlesworth G, Shepstone L,Wilson E, Thalanany M, Mugford M,Poland F.

No. 5A multi-centre retrospective cohort studycomparing the efficacy, safety and cost-effectiveness of hysterectomy anduterine artery embolisation for thetreatment of symptomatic uterinefibroids. The HOPEFUL study.

By Hirst A, Dutton S, Wu O, Briggs A,Edwards C, Waldenmaier L, et al.

No. 6Methods of prediction and preventionof pre-eclampsia: systematic reviews ofaccuracy and effectiveness literature witheconomic modelling.

By Meads CA, Cnossen JS, Meher S,Juarez-Garcia A, ter Riet G, Duley L, et al.


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267

Health Technology AssessmentProgramme

Prioritisation Strategy GroupMembers

Chair,Professor Tom Walley, Director, NHS HTA Programme,Department of Pharmacology &Therapeutics,University of Liverpool

Professor Bruce Campbell,Consultant Vascular & GeneralSurgeon, Royal Devon & ExeterHospital

Professor Robin E Ferner,Consultant Physician andDirector, West Midlands Centrefor Adverse Drug Reactions,City Hospital NHS Trust,Birmingham

Dr Edmund Jessop, MedicalAdviser, National Specialist,Commissioning Advisory Group(NSCAG), Department ofHealth, London

Professor Jon Nicholl, Director,Medical Care Research Unit,University of Sheffield, School of Health and Related Research

Dr Ron Zimmern, Director,Public Health Genetics Unit,Strangeways ResearchLaboratories, Cambridge

Director, Professor Tom Walley, Director, NHS HTA Programme,Department of Pharmacology &Therapeutics,University of Liverpool

Deputy Director, Professor Jon Nicholl,Director, Medical Care ResearchUnit, University of Sheffield,School of Health and RelatedResearch

HTA Commissioning BoardMembers

Programme Director, Professor Tom Walley, Director, NHS HTA Programme,Department of Pharmacology &Therapeutics,University of Liverpool

Chair,Professor Jon Nicholl,Director, Medical Care ResearchUnit, University of Sheffield,School of Health and RelatedResearch

Deputy Chair, Dr Andrew Farmer, University Lecturer in GeneralPractice, Department of Primary Health Care, University of Oxford

Dr Jeffrey Aronson,Reader in ClinicalPharmacology, Department ofClinical Pharmacology,Radcliffe Infirmary, Oxford

Professor Deborah Ashby,Professor of Medical Statistics,Department of Environmentaland Preventative Medicine,Queen Mary University ofLondon

Professor Ann Bowling,Professor of Health ServicesResearch, Primary Care andPopulation Studies,University College London

Professor John Cairns, Professor of Health Economics,Public Health Policy, London School of Hygiene and Tropical Medicine, London

Professor Nicky Cullum,Director of Centre for EvidenceBased Nursing, Department ofHealth Sciences, University ofYork

Professor Jon Deeks, Professor of Health Statistics,University of Birmingham

Professor Jenny Donovan,Professor of Social Medicine,Department of Social Medicine,University of Bristol

Professor Freddie Hamdy,Professor of Urology, University of Sheffield

Professor Allan House, Professor of Liaison Psychiatry,University of Leeds

Professor Sallie Lamb, Director,Warwick Clinical Trials Unit,University of Warwick

Professor Stuart Logan,Director of Health & SocialCare Research, The PeninsulaMedical School, Universities ofExeter & Plymouth

Professor Miranda Mugford,Professor of Health Economics,University of East Anglia

Dr Linda Patterson, Consultant Physician,Department of Medicine,Burnley General Hospital

Professor Ian Roberts, Professor of Epidemiology &Public Health, InterventionResearch Unit, London Schoolof Hygiene and TropicalMedicine

Professor Mark Sculpher,Professor of Health Economics,Centre for Health Economics,Institute for Research in theSocial Services, University of York

Professor Kate Thomas,Professor of Complementaryand Alternative Medicine,University of Leeds

Professor David John Torgerson,Director of York Trial Unit,Department of Health Sciences,University of York

Professor Hywel Williams,Professor of Dermato-Epidemiology,University of Nottingham

Current and past membership details of all HTA ‘committees’ are available from the HTA website (www.hta.ac.uk)


Health Technology Assessment Programme

268

Diagnostic Technologies & Screening PanelMembers

Chair,Dr Ron Zimmern, Director ofthe Public Health Genetics Unit,Strangeways ResearchLaboratories, Cambridge

Ms Norma Armston,Freelance Consumer Advocate,Bolton

Professor Max Bachmann,Professor of Health CareInterfaces, Department ofHealth Policy and Practice,University of East Anglia

Professor Rudy BilousProfessor of Clinical Medicine &Consultant Physician,The Academic Centre,South Tees Hospitals NHS Trust

Ms Dea Birkett, Service UserRepresentative, London

Dr Paul Cockcroft, ConsultantMedical Microbiologist andClinical Director of Pathology,Department of ClinicalMicrobiology, St Mary'sHospital, Portsmouth

Professor Adrian K Dixon,Professor of Radiology,University Department ofRadiology, University ofCambridge Clinical School

Dr David Elliman, Consultant inCommunity Child Health,Islington PCT & Great OrmondStreet Hospital, London

Professor Glyn Elwyn, Research Chair, Centre forHealth Sciences Research,Cardiff University, Departmentof General Practice, Cardiff

Professor Paul Glasziou,Director, Centre for Evidence-Based Practice,University of Oxford

Dr Jennifer J Kurinczuk,Consultant ClinicalEpidemiologist, NationalPerinatal Epidemiology Unit,Oxford

Dr Susanne M Ludgate, Clinical Director, Medicines &Healthcare Products RegulatoryAgency, London

Mr Stephen Pilling, Director,Centre for Outcomes, Research & Effectiveness, Joint Director, NationalCollaborating Centre for MentalHealth, University CollegeLondon

Mrs Una Rennard, Service User Representative,Oxford

Dr Phil Shackley, SeniorLecturer in Health Economics,Academic Vascular Unit,University of Sheffield

Dr Margaret Somerville,Director of Public HealthLearning, Peninsula MedicalSchool, University of Plymouth

Dr Graham Taylor, ScientificDirector & Senior Lecturer,Regional DNA Laboratory, TheLeeds Teaching Hospitals

Professor Lindsay WilsonTurnbull, Scientific Director,Centre for MR Investigations &YCR Professor of Radiology,University of Hull

Professor Martin J Whittle,Clinical Co-director, NationalCo-ordinating Centre forWomen’s and Childhealth

Dr Dennis Wright, Consultant Biochemist &Clinical Director, The North West LondonHospitals NHS Trust, Middlesex

Pharmaceuticals PanelMembers

Chair,Professor Robin Ferner,Consultant Physician andDirector, West Midlands Centrefor Adverse Drug Reactions, City Hospital NHS Trust,Birmingham

Ms Anne Baileff, ConsultantNurse in First Contact Care,Southampton City Primary CareTrust, University ofSouthampton

Professor Imti Choonara,Professor in Child Health,Academic Division of ChildHealth, University ofNottingham

Professor John Geddes,Professor of EpidemiologicalPsychiatry, University of Oxford

Mrs Barbara Greggains, Non-Executive Director,Greggains Management Ltd

Dr Bill Gutteridge, MedicalAdviser, National SpecialistCommissioning Advisory Group(NSCAG), London

Mrs Sharon Hart, Consultant PharmaceuticalAdviser, Reading

Dr Jonathan Karnon, SeniorResearch Fellow, HealthEconomics and DecisionScience, University of Sheffield

Dr Yoon Loke, Senior Lecturerin Clinical Pharmacology,University of East Anglia

Ms Barbara Meredith,Lay Member, Epsom

Dr Andrew Prentice, SeniorLecturer and ConsultantObstetrician & Gynaecologist,Department of Obstetrics &Gynaecology, University ofCambridge

Dr Frances Rotblat, CPMPDelegate, Medicines &Healthcare Products RegulatoryAgency, London

Dr Martin Shelly, General Practitioner, Leeds

Mrs Katrina Simister, AssistantDirector New Medicines,National Prescribing Centre,Liverpool

Dr Richard Tiner, MedicalDirector, Medical Department,Association of the BritishPharmaceutical Industry,London

Current and past membership details of all HTA ‘committees’ are available from the HTA website (www.hta.ac.uk)

Therapeutic Procedures PanelMembers

Chair, Professor Bruce Campbell,Consultant Vascular andGeneral Surgeon, Departmentof Surgery, Royal Devon &Exeter Hospital

Dr Mahmood Adil, DeputyRegional Director of PublicHealth, Department of Health,Manchester

Dr Aileen Clarke,Consultant in Public Health,Public Health Resource Unit,Oxford

Professor Matthew Cooke,Professor of EmergencyMedicine, Warwick EmergencyCare and Rehabilitation,University of Warwick

Mr Mark Emberton, SeniorLecturer in OncologicalUrology, Institute of Urology,University College Hospital

Professor Paul Gregg,Professor of OrthopaedicSurgical Science, Department ofGeneral Practice and PrimaryCare, South Tees Hospital NHSTrust, Middlesbrough

Ms Maryann L Hardy, Lecturer, Division ofRadiography, University ofBradford

Dr Simon de Lusignan,Senior Lecturer, Primary CareInformatics, Department ofCommunity Health Sciences,St George’s Hospital MedicalSchool, London

Dr Peter Martin, ConsultantNeurologist, Addenbrooke’sHospital, Cambridge

Professor Neil McIntosh,Edward Clark Professor of ChildLife & Health, Department ofChild Life & Health, Universityof Edinburgh

Professor Jim Neilson,Professor of Obstetrics andGynaecology, Department ofObstetrics and Gynaecology,University of Liverpool

Dr John C Pounsford,Consultant Physician,Directorate of Medical Services,North Bristol NHS Trust

Dr Karen Roberts, NurseConsultant, Queen ElizabethHospital, Gateshead

Dr Vimal Sharma, ConsultantPsychiatrist/Hon. Senior Lecturer, Mental HealthResource Centre, Cheshire andWirral Partnership NHS Trust,Wallasey

Professor Scott Weich, Professor of Psychiatry, Division of Health in theCommunity, University ofWarwick

Disease Prevention PanelMembers

Chair, Dr Edmund Jessop, MedicalAdviser, National SpecialistCommissioning Advisory Group(NSCAG), London

Mrs Sheila Clark, ChiefExecutive, St James’s Hospital,Portsmouth

Mr Richard Copeland, Lead Pharmacist: ClinicalEconomy/Interface, Wansbeck General Hospital,Northumberland

Dr Elizabeth Fellow-Smith,Medical Director, West London Mental HealthTrust, Middlesex

Mr Ian Flack, Director PPIForum Support, Council ofEthnic Minority VoluntarySector Organisations, Stratford

Dr John Jackson, General Practitioner, Newcastle upon Tyne

Mrs Veronica James, ChiefOfficer, Horsham District AgeConcern, Horsham

Professor Mike Kelly, Director, Centre for PublicHealth Excellence, National Institute for Healthand Clinical Excellence, London

Professor Yi Mien Koh, Director of Public Health andMedical Director, London NHS (North West LondonStrategic Health Authority),London

Ms Jeanett Martin, Director of Clinical Leadership& Quality, Lewisham PCT,London

Dr Chris McCall, GeneralPractitioner, Dorset

Dr David Pencheon, Director,Eastern Region Public HealthObservatory, Cambridge

Dr Ken Stein, Senior ClinicalLecturer in Public Health,Director, Peninsula TechnologyAssessment Group, University of Exeter, Exeter

Dr Carol Tannahill, Director,Glasgow Centre for PopulationHealth, Glasgow

Professor Margaret Thorogood,Professor of Epidemiology,University of Warwick, Coventry

Dr Ewan Wilkinson, Consultant in Public Health,Royal Liverpool UniversityHospital, Liverpool


269Current and past membership details of all HTA ‘committees’ are available from the HTA website (www.hta.ac.uk)

Health Technology Assessment Programme

270Current and past membership details of all HTA ‘committees’ are available from the HTA website (www.hta.ac.uk)

Expert Advisory NetworkMembers

Professor Douglas Altman,Professor of Statistics inMedicine, Centre for Statisticsin Medicine, University ofOxford

Professor John Bond,Director, Centre for HealthServices Research, University ofNewcastle upon Tyne, School ofPopulation & Health Sciences,Newcastle upon Tyne

Professor Andrew Bradbury,Professor of Vascular Surgery,Solihull Hospital, Birmingham

Mr Shaun Brogan, Chief Executive, RidgewayPrimary Care Group, Aylesbury

Mrs Stella Burnside OBE,Chief Executive, Regulation and ImprovementAuthority, Belfast

Ms Tracy Bury, Project Manager, WorldConfederation for PhysicalTherapy, London

Professor Iain T Cameron,Professor of Obstetrics andGynaecology and Head of theSchool of Medicine,University of Southampton

Dr Christine Clark,Medical Writer & ConsultantPharmacist, Rossendale

Professor Collette Clifford,Professor of Nursing & Head ofResearch, School of HealthSciences, University ofBirmingham, Edgbaston,Birmingham

Professor Barry Cookson,Director, Laboratory ofHealthcare Associated Infection,Health Protection Agency,London

Dr Carl Counsell, ClinicalSenior Lecturer in Neurology,Department of Medicine &Therapeutics, University ofAberdeen

Professor Howard Cuckle,Professor of ReproductiveEpidemiology, Department ofPaediatrics, Obstetrics &Gynaecology, University ofLeeds

Dr Katherine Darton, Information Unit, MIND – The Mental Health Charity,London

Professor Carol Dezateux, Professor of PaediatricEpidemiology, London

Dr Keith Dodd, ConsultantPaediatrician, Derby

Mr John Dunning,Consultant CardiothoracicSurgeon, CardiothoracicSurgical Unit, PapworthHospital NHS Trust, Cambridge

Mr Jonothan Earnshaw,Consultant Vascular Surgeon,Gloucestershire Royal Hospital,Gloucester

Professor Martin Eccles, Professor of ClinicalEffectiveness, Centre for HealthServices Research, University ofNewcastle upon Tyne

Professor Pam Enderby,Professor of CommunityRehabilitation, Institute ofGeneral Practice and PrimaryCare, University of Sheffield

Professor Gene Feder, Professorof Primary Care Research &Development, Centre for HealthSciences, Barts & The LondonQueen Mary’s School ofMedicine & Dentistry, London

Mr Leonard R Fenwick, Chief Executive, Newcastleupon Tyne Hospitals NHS Trust

Mrs Gillian Fletcher, Antenatal Teacher & Tutor andPresident, National ChildbirthTrust, Henfield

Professor Jayne Franklyn,Professor of Medicine,Department of Medicine,University of Birmingham,Queen Elizabeth Hospital,Edgbaston, Birmingham

Dr Neville Goodman, Consultant Anaesthetist,Southmead Hospital, Bristol

Professor Robert E Hawkins, CRC Professor and Director ofMedical Oncology, Christie CRCResearch Centre, ChristieHospital NHS Trust, Manchester

Professor Allen Hutchinson, Director of Public Health &Deputy Dean of ScHARR,Department of Public Health,University of Sheffield

Professor Peter Jones, Professorof Psychiatry, University ofCambridge, Cambridge

Professor Stan Kaye, CancerResearch UK Professor ofMedical Oncology, Section ofMedicine, Royal MarsdenHospital & Institute of CancerResearch, Surrey

Dr Duncan Keeley,General Practitioner (Dr Burch& Ptnrs), The Health Centre,Thame

Dr Donna Lamping,Research Degrees ProgrammeDirector & Reader in Psychology,Health Services Research Unit,London School of Hygiene andTropical Medicine, London

Mr George Levvy,Chief Executive, Motor Neurone Disease Association,Northampton

Professor James Lindesay,Professor of Psychiatry for theElderly, University of Leicester,Leicester General Hospital

Professor Julian Little,Professor of Human GenomeEpidemiology, Department ofEpidemiology & CommunityMedicine, University of Ottawa

Professor Rajan Madhok, Consultant in Public Health,South Manchester Primary Care Trust, Manchester

Professor Alexander Markham, Director, Molecular MedicineUnit, St James’s UniversityHospital, Leeds

Professor Alistaire McGuire,Professor of Health Economics,London School of Economics

Dr Peter Moore, Freelance Science Writer, Ashtead

Dr Andrew Mortimore, PublicHealth Director, SouthamptonCity Primary Care Trust,Southampton

Dr Sue Moss, Associate Director,Cancer Screening EvaluationUnit, Institute of CancerResearch, Sutton

Mrs Julietta Patnick, Director, NHS Cancer ScreeningProgrammes, Sheffield

Professor Robert Peveler,Professor of Liaison Psychiatry,Royal South Hants Hospital,Southampton

Professor Chris Price, Visiting Professor in ClinicalBiochemistry, University ofOxford

Professor William Rosenberg,Professor of Hepatology andConsultant Physician, Universityof Southampton, Southampton

Professor Peter Sandercock,Professor of Medical Neurology,Department of ClinicalNeurosciences, University ofEdinburgh

Dr Susan Schonfield, Consultantin Public Health, HillingdonPCT, Middlesex

Dr Eamonn Sheridan,Consultant in Clinical Genetics,Genetics Department,St James’s University Hospital,Leeds

Professor Sarah Stewart-Brown, Professor of Public Health,University of Warwick, Division of Health in theCommunity Warwick MedicalSchool, LWMS, Coventry

Professor Ala Szczepura, Professor of Health ServiceResearch, Centre for HealthServices Studies, University ofWarwick

Dr Ross Taylor, Senior Lecturer, Department ofGeneral Practice and PrimaryCare, University of Aberdeen

Mrs Joan Webster, Consumer member, HTA –Expert Advisory Network

The National Coordinating Centre for Health Technology Assessment,Mailpoint 728, Boldrewood,University of Southampton,Southampton, SO16 7PX, UK.Fax: +44 (0) 23 8059 5639 Email: [email protected]://www.hta.ac.uk ISSN 1366-5278

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