ORIGINAL ARTICLE - i-med.sk

ORIGINAL ARTICLE

Economic assessment of screening for pre-eclampsia†

Amir Shmueli1, Hamutal Meiri2,4* and Ron Gonen3

1Department of Health Management and Economics, Braun School of Public Health, The Hebrew University-Hadassah2Diagnostic Technologies, Yokneam, Israel3Bnai Zion Medical Center and Rapaport Faculty of Medicine, Technion, Haifa, Israel4TeleMarpeh Ltd. Tel Aviv, Israel*Correspondence to: Hamutal Meiri. E-mail: [email protected]†AS developed the model and the overall analysis. The database, clinical definitions and medical relevancies were contributed by RG. HM contributed to costinformation and partial analysis. All authors participated in writing the manuscript and final analysis.

ABSTRACTBackground Pre-eclampsia is a major contributor to maternal and neonatal morbidity andmortality. Our objectives inthis study are to economically assess, from the payer perspective, routine screening for pre-eclampsia using placentalmarkers -placental protein 13 and placental growth factor - and uterine artery Doppler compared with standard care.

Methods A decision model was developed, which progresses through three sequential endpoints, and comparesscreening with no screening: (1) Pre-eclampsia yes/no: calculation of the incremental cost of pre-eclampsia-caseaverted; (2) Hospital discharge: calculation of the mean accumulated costs until discharge after delivery; and (3)Offspring death: calculation of the incremental cost per quality of life-adjusted life-year gained by screening. Dataused includes: (1) Obstetrical data of 14 500 births; (2) cost data from the Israeli Ministry of Health and the literature;and (3) screening performance and outcome from the literature.

Results (1) The incremental cost of pre-eclampsia-case averted is $66 949 and $24 723 when the prevalence is 1.7 and5% respectively. (2) With test cost of $112, the total cost until discharge with/without screening is equal. With pre-eclampsia prevalence of 3%, screening is cheaper. (3) The cost per quality of life-adjusted life-year with screening is$18 919 and< $10 000 with pre-eclampsia prevalence of 1.7 and 3%, respectively.

Conclusions Screening for pre-eclampsia is cost-effective under various scenarios. © 2012 John Wiley & Sons, Ltd.

Funding sources: This study was funded in part by the European Union FP6 grant Pregenesys #037244 (HM) and the Canada-Israel industrial R&D Fund(CIIRDF) # 39 (HM)Conflicts of interest: None declared

Supporting information may be found in the online version of this article.

INTRODUCTIONEvery year 59000 pregnant women die of pre-eclampsia andeclampsia, and 2 to 7% of pregnant women suffer from thedisorder.1 Although its etiology remains unknown, the centralpathologic events are placental hypoperfusion and diffuseendothelial cell injury.2,3 Current management of women at riskfor pre-eclampsia entails close surveillance and frequentmeasurements of blood pressure and urine protein. Once thedisease develops around term (‘late pre-eclampsia’), promptinduction of labor is usually the rule.4 When pre-eclampsiadevelops remote from term – before 34weeks (‘early pre-eclampsia’) – early delivery is usually required and often steroidsare used to enhance fetal lung maturation while treatment

with magnesium sulfate and antihypertensives often allows alimited prolongation of pregnancy, for the sake of reducingthe risk for neonatal morbidity and mortality.4–6

During 1992, $18bn to $22bn of direct healthcare costs wereallocated in the United States to treat women with pre-eclampsiaand their neonates.7,8 Moreover, pre-eclampsia is associated withlong-term maternal and neonatal increased risk of cardiovasculardiseases,9 diabetes, and metabolic syndrome.10,11

Diverse strategies have been suggested for pre-eclampsiaprevention: vitamin C and E,12,13 low-dose aspirin,14 calciumsupplementation,15 folic acid,16 dark chocolate,17 vitamin D18

and fibers.19 Recent meta-analyses showed that low-doseaspirin, particularly when given before gestational week 16, and

Prenatal Diagnosis 2012, 32, 29–38 © 2012 John Wiley & Sons, Ltd.

DOI: 10.1002/pd.2871

calcium supplementation are beneficial, although more studiesare still required.15,20

During the last two decades numerous maternal-serummarkers have been evaluated as possible candidates forpredicting pre-eclampsia.21–23 Decreased first trimesterplacental protein 13,24,25 placental growth factor (PIGF) andpregnancy-associated plasma protein A (PAPP-A,26 were shownto predict the development of pre-eclampsia at sensitivity levelsof 70 to 80% for an individual marker at a 5 to 20% false positiverate (FPR). Marker combination alone,27 or in conjunction withuterine arteries Doppler28,29 and with maternal risk factors29,30

increased the sensitivity to approximately 94 to 95% for a 5 to10% FPR for early pre-eclampsia, and is a little less for late pre-eclampsia.29–31 This degree of accuracy meets the World HealthOrganization’s requirements for introducing anew screening test.21

The aim of the present study was to build a model for theeconomic assessment of a universal first-trimester screening forpre-eclampsia from the payer’s perspective. The model is basedon the use of two serummarkers – PP13 and PIGF – together withuterine artery Doppler pulsatility index (PI), and is based on themarker performance accuracy reported in contemporary literature(Table 1). The basic model assumes that early screening identifiespatients at risk and enables referrals to appropriate surveillance. Inthis way the risk for developing the disease is identified early inpregnancy and prevention might be offered during pregnancymanagement. In our model, the high-risk group is also offeredpreventivemedication such as daily intake of calcium supplementand low-dose aspirin, among others. The modified managementwhen coupledwith the use ofmedicationsmay reduce the burdenof pre-eclampsia8 by lowering the incidence and severity ofthe disease and its associated maternal complications, as wellas by reducing the proportion and magnitude of pretermbirths and their associated short-term and long-term morbidityand mortality.32,33

METHODS

The modelFigure 1 presents the sequence of events and the decision treealongwith the study assumptions. Themodel includes two arms:

(1) No screening for pre-eclampsia followed by routineprenatal care for women without risk factors for pre-eclampsia.The assumptions are that: (a) women without known prior riskfactors will see a physician five times during pregnancy(‘no surveillance’ or ‘normal’ management). Women withobstetrical or medical risk factors are directed to ‘full’ (ten visits)or ‘partial’ (seven visits) surveillance at the doctor’s clinic or at ahigh risk clinic, and weekly or biweekly nurse appointments forblood pressure and urinary protein determination. The payerallots a price for each frequency of visits. (b) The proportionof women referred to the ‘no’, ‘partial’ and ‘full’ surveillancegroup was taken from the pregnancy database of major healthmaintenance organizations (HMOs) in Israel.34 (c) The partialand full surveillance is accompanied with daily use of any of

low-dose aspirin, calcium and vitamin D supplement, folicacid and prenatal multivitamins (or their combinations) takendaily between week 16 and 35. Treatment cost is based on thesupplement list price (Table 3). Accordingly, the cost of fullsurveillance represents the combined cost of visit frequency andmedication/food additives. A modest treatment benefits is takeninto consideration according to the lowest values of publishedmeta-analysis for each drug/supplement individually and furtheranalyzed in Table 5. In this approach, the cost of the respectiveprenatal management in the no-screen arm thus took intoconsideration the frequency of prior risk and the estimatedeffectiveness and costs of the treatment strategies withoutscreening (although we bear in mind the nagging doubt abouttreatment benefit).

(2) Screening for pre-eclampsia with PP13, PlGF, and uterinearteries Doppler PI. Screen-positive cases are managed in thesamemanner as women with risk factors, including the highestfrequency of doctor visits and the administration of preventivemeasures (same as ‘full surveillance’ in the no-screen arm),while ‘screen-negative’ subjects are directed to routineprenatal care (five visits, no medications). The effectivenessof screening in identifying patients at risk along with falsepositive results are detailed in Table 1 and further sensitivityanalysis is also presented in Table 5. The cost of introducingthe screening program is based on prices currently chargedfor testing Pp13, PIGF and Doppler in Israel and Austria today.Different prices obtained from the ‘Israeli New TechnologyCommittee’ of the Ministry of Health are evaluated in Table 5.In this approach, the cost of the respective prenatalmanagementin the plus screen arm thus took into consideration the cost andaccuracy of the screening tests and the estimated effectivenessand costs of the treatment strategies.

While pregnancy management with or without screening is thefirst branch of themodel, the next event (second bifurcation of thetree) is the disease of pre-eclampsia (healthy or affected), and themode of delivery. Pre-eclampsia cases (especially early pre-eclampsia) are more likely than unaffected pregnancies to beassociated with preterm births, more maternal hospitalizationdays prior to delivery, a higher rate of cesarean deliveries, andhigher utilization of the neonatal intensive-care unit (NICU).The impact of prevention on this branch is included in thisbranch. The basic model assumes a very low impact ofprevention because of the use of aspirin, calcium, folate, andvitamins (Table 3). In the sensitivity analysis we furtherexamined the impact of more effective medications if such willbecome available (Table 5).

The next branch of the tree (third bifurcation) is offspringfollow-up from discharge until death, calculating the numberof quality-of-life adjusted life-years (QALYs). We consideredthe risks of stillbirths, of the offspring’s survival by the end ofthe first year of life, and the risk of diabetes at age 32. Wechoose these risks because of the relatively solid evidence ontheir relation to pre-eclampsia.35–37 We did not consider themother’s increased risk of cardiovascular diseases and

A. Shmueli et al.30


mortality because of the yet unclear relations with pre-eclampsia and its prevention.9

Accordingly, three analyses were performed corresponding tothe three main events described above: (1) screening andthe subsequent management as described above; (2) thedevelopment of pre-eclampsia and its consequences for themother and neonate; and (3) the follow up of the offspring afterhospital discharge and the calculation of the number of QALYSgained.

The endpoint of the first analysis is the presence of pre-eclampsia upon admission to the maternity ward. Wecalculated the incremental cost per pre-eclampsia caseprevented, namely, the additional cost per patient that wouldbe needed to switch a cohort of pregnant women from a‘pre-eclampsia pregnancy regime’ with its adverse healthand economic impact to a ‘normal pregnancy regime’. Thiscost was compared with the incremental cost of a pre-eclampsia case. In the second analysis, we extended theoutcomes and the costs to cover the hospitalization perioduntil discharge of the mother and child, and compared thetotal cost of prenatal care and inpatient care in the screeningand in the no-screening arms. The third analysis covered thepost-natal morbidity costs and quantity and quality of life(QALYs) of the offspring, and we calculated the incremental

cost per QALY gained by screening. A 3% discount rate wasapplied to both later costs and outcomes.

The analysis took the perspective of the payer and was firstperformed for the base-case values of the parameters, thenfollowed by a sensitivity analysis in which the main parameterswere varied to check the robustness of the economicevaluation’s conclusions.

The dataThe 2005 to 2008 obstetrical data of 14500 births was obtainedfrom the electronic database at the Bnai-Zion Medical Centerand was supplemented by the Central Bureau of Statistics’ reportsfor 2005 to 2008. Pre-eclampsia was defined according to theWorldCongress of Hypertension in Pregnancy as recently updated.38

Data for the screening tests’ cost was derived from thecurrent cost of PP13 clinical testing in Israel, Austria andGermany, the PIGF test charge in several European countries,and the results of a questionnaire distributed in 2010 amongseveral leading sonographers in Israel regarding theanticipated charge for uterine artery Doppler PI when addedto first-trimester routine nuchal translucency screening(Table 1). Test accuracy was derived from contemporaryliterature.24,25,27,29,30 Data for the cost of prenatal care,predelivery hospitalization, and maternal and neonatal hospital

Figure 1 The decision tree and sequence of events. The final subtree should be added to all previous branches (Note that this subtree appearsin Figure 1 only for one branch for brevity, but should appear in all other branches as well). PE, pre-eclampsia; CS, casarean section; BW,birth weight; NICU, neonatal intensive care unit

Economic evaluation of pre-eclampsia screening 31


costs were obtained from the Israeli Ministry of Health’s pricelist, the mean cost of the services obtained from a major IsraeliHMO’s information database,34 and from the Israel CentralBureau of Statistics’ reports for 2005 to 2008.39 Data on theoffspring’s lifetime outcomes and costs were retrieved from a30-year follow-up of women after pregnancy,35,40 and from amajor Israeli HMO’s database34 along with recent further analysisof the data,36,37,41 which was further supported by internationalstudies.10,11,33

RESULTS

Base-caseTables 1–3 present the basic parameters of the economicevaluation at base-case. The prevalence of pre-eclampsia inour cohort was 1.7 %, which is lower than the 3 to 5% generallyreported in the literature.1 Under current practice (no-screening) 82% of pregnant women are referred to standardcare, 15% to ‘partial surveillance’, and 3% to ‘full surveillance’.On the basis of contemporary literature, as described above,the following assumptions were made for this model: (1) Theaccuracy of the screening program – for a 10% FPR, a detectionrate of 90% for early pre-eclampsia and 70% for late pre-eclampsia.29,31 The referrals to full and no surveillance will beaccordingly. (2) The efficacy of applying preventive measuresfor reducing the frequency and morbidity of early pre-eclampsia – 10% for late pre-eclampsia and 30% for early pre-eclampsia.14 The impact of higher disease frequency, differentscreening accuracy and treatment effectiveness are all furtheranalyzed in Table 5 (see below).

Table 2 displays the probabilities – taken as the base-case – ofthe birth outcomes in women with pre-eclampsia comparedwith unaffected women. Among women who developed pre-eclampsia, 18.4% had early pre-eclampsia (before 34weeks,Table 2), and among these, there were 93% cesarean deliveriesand 93% of the newborns required NICU, compared with 44%

cesarean deliveries and 2.6% NICU utilization among womenwho developed late pre-eclampsia. Women with early pre-eclampsia were hospitalized for conservative managementbefore delivery for an average of 7 days, compared with 2dayson average for late pre-eclampsia.

The offspring’s lifetime outcomes were obtained from theJerusalem Prenatal Study.40 In that study women with andwithout pre-eclampsia and their offspring were followed-upfor 32 years. The results showed that the probability of stillbirthwas ninefold higher and the probability of infant death duringthe first year of life was twofold higher among women withpre-eclampsia compared with mothers without the disease.35

Similarly, the risk for diabetes at age 32 was sevenfold higheramong the offspring of mothers with pre-eclampsia.36,37

Table 3 presents the base-case’s costs of care. The screening-test cost (PP13, PIGF, and Doppler) was set to US $112 adjustedfor purchasing power parity ($112 PPP). The PPP exchange rateis somewhat lower than the regular exchange rate, and is 3.2New Israeli Shekels for 1 PPP$. The cost of standard prenatalcare was estimated at $469, and ‘partial’ and ‘full surveillance’at 1.5 and double that cost, respectively. The Israeligovernmental price list provides a flat rate ($2981) for deliveryand does not differentiate between vaginal and caesareandeliveries. The prospective reimbursement for hospitalizationin NICU (for newborns below 1750 g) is $45 055.

Table 4 presents the base-case results of the three criteria ofthe economic assessment discussed above. The mean cost ofcare for the prenatal period until admission for delivery is $633with screening and $511 without screening, resulting in anincremental cost of $122 per pregnant woman. Withoutscreening, the expected rate of pre-eclampsia is the actualprevalence (0.017), and with screening – and the subsequenttreatment – this rate is expected to decrease to 0. 015. Thus, theincremental cost per pre-eclampsia case prevented is $66 949.This cost includes screening and pregnancy management only,

Table 1 Basic probabilities at base-case

Parameter Pre-eclampsia Source

All Early(<34weeks)

Late(>34weeks)

Preeclampsia prevalence 1.7% BZMC

Preeclampsia subgroups 100% 18.4% 81.6% BZMC

Concurrent multiple markers detection rate 77% 90% 70% Cuckle, 201131; Akolekar et al., 201129

False positive rate 10% 10% 10% Cuckle, 201131; Akolekar et al., 201129;Khalil et al., 201030

Effectiveness of preventive management and fullsurveillance (reduction of preeclampsia cases)

18% 30% 10% Aspirin – Askie et al., 200714 (Paris study), Bujold et al., 201020a,

calcium –

Hofmeyr et al., 201015, folic acid – Nilsen et al., 200816b

The information is derived from the medical records of Bnai-Zion Medical Center (BZMC). Screening effectiveness is according to the list of references.In this study, we used the term Doppler PI for uterine arteries Doppler Pulsatility Index.aData on early Aspirin benefit of Bujold et al., 201020 showing higher effectiveness were taken for sensitivity analysis.bNo studies have shown the benefit of the early combined use of aspirin, calcium and folic acid supplementation. Thus, values presented according to the lower benefit of eachsupplement individually.

A. Shmueli et al.32


and not the hospital cost associated with the delivery. When thecost of screening is $112 and when all costs are included – fromprenatal care until discharge from the hospital after delivery –

according to the base-case parameters, the costs for screeningand nonscreening are equal ($4693). The third and most

comprehensive criteria considers the lifetime of the offspring:here, the incremental cost of screening is $105, and theincremental QALYs of screening is 0.006, resulting in anincremental cost per QALY gained by screening of $18919.

Sensitivity analysisTable 5 reports the sensitivity analysis results. We focused onvariations in five basic parameters of the evaluation: the testcost, the FPR, pre-eclampsia prevalence, the test’s detectionrate, and the effectiveness of the preventive measures(measured as the proportion of women whose pre-eclampsiawas not averted by the preventive measures). The first rowsummarizes the base-case scenario.

The results are quite sensitive to the test cost (scenarios 1–2).If the test cost increases from $112 to $300, the cost per caseaverted increases to $170 664, screening becomes moreexpensive by $188 than the no-screening option, and the costper QALY gained increases to $52 865. The sensitivity of theresults of the FPR is smaller (scenarios 1–4): if the test cost is$300, halving the FPR from 10 to 5%, leads to a small changein the results. However, there is a certain tradeoff betweenthe test cost and the FPR in the evaluation. This is reflectedin the similar results for a combination of a test cost of $112

Table 2 Basic outcome according to the base-case model

Parameter Pre-eclampsia No pre-eclampsia Source

Early(<34weeks)

Late(>34weeks)

Early(<34weeks)

Late(>34weeks)

Delivery outcome and bed rest prior to delivery

Delivery 18.4% 81.6% 2.6% 97.4% BZMC, CBS

Bed rest prior to delivery 90% 18.8% 1% 0% BZMC, CBS

Cesarean Section 93.2% 43.8% 53.7% 17.9% BZMC, CBS

Birth weight below 1750 g 93.2% 2.6% 80.6% 0.2% BZMC, CBS

Offspring lifetime outcome

Stillbirth 8.5% 8.5% 0.9% 0.9% Calderon-Margalit et al., 200735

Newborn death age 0–1 year 4% 4% 2% 2% Calderon-Margalit et al., 200735, 201036

DM2 at age 32 6.5% 6.5% 0.8% 0.8% Calderon-Margalit et al., 200735, 201036;Tsadok et al., 200837

Expected utility of health state after age 32a 0.987 0.987 0.998 0.998 Matusevich, 201041; Chodick et al., 201034;

Expected annual burden of DM2 afterage 32 (PPP$)b

65 65 8 8 Chodick et al., 201034

Life expectancy at age 32c 52.480 52.480 52.936 52.936 Calderon-Margalit et al., 200735, 201036;Matusevich, 201041; Chodick et al., 201034;Tsadok et al., 200837 and CBS

The disease information is based on the hospital medical records when applied to pregnancy outcome and to national statistics records presented from the payer’s perspectivefrom official publications (CBS) and a major HMO.34 Matusevich, 2010 is a Ph.D. thesis that can be obtained from the medical library of the Hebrew University – HadassahMedical School. Calderon-Margalit et al. (2010)36 published in the national conference available on-line from Hebrew University Medical Library. Initial publication alsoavailable in Tsadok et al. (2008)37.BZMC, Bnai-Zion Medical Center, Haifa; CBS, Central Bureau of Statistics, Jerusalem, Israel; PC, personal communication; DM2, type 2 diabetes mellitus.aOn a scale where 0= death, 1= full health. Utility of DM2=0.834,41 utility without DM2=1.bAnnual burden of DM2=$1000.34cLife expectancy with DM2 at age 34=45 years34,41 life expectancy at age 32=52 years (CBS) .

Table 3 Cost at base case (PPP$; $1 =3.2NISa)

Subject Mean cost Source

Screening test 112 DTL, HVD, MOHb

Standard care 469 MOH

Partial surveillance 652 MOH

Full surveillance 938 MOH

Hospitalization before delivery 3125 MOH

Vaginal delivery 2.981 MOH

Cesarean section 2.981 MOH

Neonatal intensive care unit 45 055 MOH

Cost is presented from the payer’s perspective.MOH, Israel Ministry of Health Price list; NIS, New Israeli Shekel.aNote that the PPP exchange rate of $1=3.2 NIS is lower than the officialexchange rate.bEstimated Cost of screening derived from average current market prices in Israel(Diagnostic Technologies Ltd (DTL) and MOH) and Austria (HVD Vertriebs Ges.m.b.H.(HVD)).



and an FPR of 10%, and alternatively, a test cost of $140 and anFPR of 5% (scenarios 1 vs 3, and 2 vs 4).

The prevalence of pre-eclampsia is an important determinantof the evaluation. Our sensitivity analysis shows that higherprevalence is related to more favorable results of the screeningoption. If the prevalence of pre-eclampsia is 3%, the cost of caseaverted drops to $39343, screening is less expensive by $88, andthe cost per QALY gained drops to $9884 (scenario 5). If theprevalence is elevated to 5% or 7% (scenarios 6 and 7), the costof case averted drops further to $24 723 and $18 374, respectively,screening is less expensive by $221 and $353, respectively, andthe cost per QALY gained drops to $5099 and $3021, respectively.

The results are also sensitive to the effectiveness of theprevention and to the screening’s detection rates. When theproportion of prevention increases to 50% among subjectsdestined to present with early pre-eclampsia (instead of 30%in the base-case scenario), and to 30% among those destinedto develop late pre-eclampsia (instead of the base-case value

of 10%; scenario 8), the incremental cost of pre-eclampsia caseaverted drops to $28142 and the cost per QALY gained dropsto $6218. When the effectiveness of screening is reduced(scenario 9), theses costs increase markedly. If the detection ratefalls from 90% to 65% among the early pre-eclampsia subjects,and from 70% to 40% among the late pre-eclampsia cases(scenario 10), the outcome of the economic performance ofthe screening is worse. If the detection rate improves from90% to 95% and from 70% to 80% (scenario 11), the costs slightlydecrease. Finally, the base-case results assume a flat rate fordelivery regardless of its type, as is the case in Israel. Enteringa differential cost, which was evaluated internally in the hospitalas $1562.5 PPP for a vaginal delivery and $3125 PPP for acaesarian delivery, did not lead to a significant difference inthe base-case results (not shown).

Scenario 12 presents the ‘worst case’ in terms of the screening’sdetection and the surveillance’s effectiveness, in which theincremental cost per pre-eclampsia case averted increases to

Table 4 The Results of the Economic Evaluation of Screening for Preeclampsia at Base-Case

End point Criteria

Admission to maternity ward Cost per case averted (PPP$1a )

Expected cost under

No screening 511

screening 633

Incremental cost 122 122

Expected preeclampsia cases under

No screening 0.017000000

screening 0.015183125

Incremental number of cases 0.001816875 0.001816875

Incremental cost per preeclampsia case averted 66,949

Incremental cost of preeclampsia case until discharge 8,631

Discharge of mother and newborn after delivery Total cost minimization (PPP$1)

No screening 4693

screening 4693

Screening is more costly by 0

Death of offspringb Cost per QALY gained by screening (PPP$)3

Expected cost under

No screening 4888

screening 4783

Increment cost �105

Expected number of QALYs No screening 30.426286

screening 30.420735

Incremental number of QALYS 0.005551

Incremental cost per QALY gained by screening 18,919

PPP - Purchasing Power Parity; NIS – New Israeli Shekel QALY – Quality of life Adjusted Life YearsThe model calculations are based on cost values provided from the payer’s perspective.aNote that the PPP exchange rate of $1=3.2NIS is lower than the official exchange rate.b Incremental cost and QALYs accounting for offspring’s risk of death by age 1 and diabetes mellitus type 2 at age 32.11,34–36c3Cost and QALY are discounted by 3% as is common in the field.

A. Shmueli et al.34


$292833 and the cost per QALY to $92850. In the ‘best case’(scenario 12), these costs drop to $25404 and $5322 respectively.

Finally, scenarios 13 to 14 repeat the ‘worst case’ and the‘best case’ scenarios, but with a prevalence of 3%. The resultsare clearly better.

DISCUSSIONPre-eclampsia places a considerable burden on societies interms of costs, fetal loss and morbidity, years-of-life, andquality-of-life lost.1,21,42 The present paper presents an attemptto economically assess the impact of introducing a screening

program for pre-eclampsia based on two serum markers –

PP13 and PIGF – and on uterine arteries Doppler PI. Thebase-case incremental cost per QALY gained by screening isabout $19 000, representing a good investment in health. Thecommonly used thresholds in health technology assessments,namely, how much society is willing to pay for a QALY gained,are all above $50 000;43 therefore, from the payer’s perspectivescreening seems to provide good value for money. In fact, theresults show that for each scenario, the longer the horizonconsidered the better the results. For the base-case, the costper pre-eclampsia case averted ($66 949) far exceeds the cost of

Table 5 Sensitivity analysis of the results of the economic evaluation of screening for pre-eclampsia

scenarioTest Cost(PPP$) FPR Prevalence

DR(<34)

DR(>34)

Fraction Notcured by fullsurveillance

(<34)

Fraction Notcured by fullsurveillance

(>34)

Incremental costper preeclampsiacase averted

(PPP$)a

Screeningis morecostly by(PPP$)

Cost per QALYgained by screening(Offspring’s life time)

(PPP$)b

b1 (BC) 112(BC) 0.1(BC) 0.017(BC) 0.9(BC) 0.7(BC) 0.7(BC) 0.9(BC) 66,949(BC) 0(BC) 18.919(BC)

2 300 0.1 0.017 0.9 0.7 0.7 0.9 170,664 188 52,865

3 140 0.05 0.017 0.9 0.7 0.7 0.9 69,232 0 19,667

4 300 0.05 0.017 0.9 0.7 0.7 0.9 157,983 162 48,714

5 112 0.1 0.03 0.9 0.7 0.7 0.9 39,343 �88 9,888

6 112 0.1 0.05 0.9 0.7 0.7 0.9 24,723 �221 5,099

7 112 0.1 0.07 0.9 0.7 0.7 0.9 18,374 �353 3,021

8 112 0.1 0.017 0.9 0.7 0.5 0.7 28,142 �3 6,218

9 112 0.1 0.017 0.9 0.7 0.8 1.0 215,698 1 67,571

10 112 0.1 0.017 0.65 0.4 0.7 0.9 102,348 28 30,505

11 112 0.1 0.017 0.95 0.8 0.7 0.9 61,103 �6 17,006

12 112 0.1 0.017 0.65 0.4 0.8 1.0 292,833 29 92,850

13 112 0.1 0.017 0.95 0.8 0.5 0.7 25,404 �9 5,322

14 112 0.1 0.03 0.65 0.4 0.8 1.0 166,862 �38 52,278

15 112 0.1 0.03 0.95 0.8 0.5 0.7 14,917 �103 1,890

Data in boldface emphasizes the parameter modified from the base-case. Upward or downward arrows indicate significant deviation from base-case. BC, base-caseaTotal incremental cost of preeclampsia case – 8,631 PPP$.bCommon thresholds are not below 50,000 PPP$.



a pre-eclampsia case ($8631). However, when the costcalculation includes the time until discharge of the mother andnewborn, the base-case cost of screening equals that of the no-screening, and the comprehensive cost per QALY gained is aslow as $18 919. As long as the frequency of pre-eclampsiaremained very low (1.7%), the cost per pre-eclampsia caseaverted is significantly higher than the cost of a pre-eclampsiacase in all the scenarios considered. Once the prevalence ofpre-eclampsia is above 3%, with a good detection rate and aneffective treatment, the cost per pre-eclampsia case preventedmight be below the actual cost of a pre-eclampsia case.

The results are naturally sensitive to the screeningcharacteristics – the test cost, the FPR, and the detection rates.There is some trade-off between these three characteristics. Anadditional trade-off exists between the test accuracy and cost,and the effectiveness of the treatment. The analysis wasperformed in front of some doubts regarding treatmentbenefit, thus using low prevention effectiveness. In our study,screening for pre-eclampsia was performed in conjunction withthe current practice of screening for Down syndrome.31,44

Because the biochemical tests and sonography required for bothscreening programs can be performed at the same time, theanticipated additional cost is small and is likely to be reduced.Because the model shows high sensitivity to the cost ofscreening, this approach provides potential cost savings.

Our base-case prevalence of 1.7% is relatively low. It isencouraging that at the more common (3–5%) prevalence rate theresults are better, and that at the frequency of 7% such as in manydeveloping countries1,42 the benefits of introducing screening arebetter, and the screening might prove even more cost-effective.The good economic performance of the screening is robust bothwhen evaluating the cost until hospital discharge after the delivery,as well as when it is combined with the differences in the first-year-of-life survival of newborns to mothers with and without pre-eclampsia. Even when the survival ratio is reduced from 4 to 2,36

the cost per QALY (in dollars) is still highly acceptable.Hadker et al. (2010)45 have published a model evaluating the

introduction of a later diagnosis of pre-eclampsia using the ratioof soluble fms-like tyrosine kinase-1 (sFlit-1) and PIGF.46 Inreviewing their data and our sensitivity analysis, it appears thattheir base model was calculated assuming a cheaper test priceof approximately £31 (compared to $112 in our base-case), ahigher pre-eclampsia frequency of 5% (compared to 1.7% inour base-case), and extremely effective prevention throughprophylactic treatment with magnesium sulphate (comparedto the Magpie results.)47 As such, and although they utilized UKNational Health Service figures for their calculations as well asa very different diagnosis, their results are quite similar to oursif we use the respective scenarios in Table 5 (higher frequency,lower prices, and more effective treatment).

Our study has several limitations: (1) Our model assumes apractice in which risk stratification is followed by referring womenwho are screened positive (high risk for developing pre-eclampsia)to ‘full surveillance’ and treatment, in the samemanner as women

with prior medical or obstetrical risk factors in the no-screen arm.In reality, despite an abundance of studies on screening methods,we are short of studies combining risk stratificationwith respectivepregnancymanagement.23,48 (2)While there are some studies thatused Doppler criteria for randomizing pregnant women forpreventive agents such as low-dose aspirin,20 prevention in thecontext of screening has not been established yet. For this reason,in our model we had to use data that were obtained from studiesthat randomized patients to treatment based on maternal riskfactors rather than on a positive screening test. (3) Ourcalculations are based on a database from one medical center inIsrael. Our data need to be confirmed in other populations.(4) There is an abundance of marker candidates and becauseof the limited scope of this analysis we choose PP13, PIGF,and uterine Doppler PI and neglect other promising markerssuch as PAPP-A, Activin A, Inhibin A, fetal RNA, and DNA inthe second trimester, or Pentraxin 3 and endoglin in the firsttrimester.23,31 The impact of adding these to the cost evaluationmay be considered in the next studies.

In conclusion, it seems that routine screening for pre-eclampsia,if utilized to direct the pregnancy management and coupled withthe use of current preventive means, may be a cost-effective wayto reduce the medical and economical burden of pre-eclampsiain developed and developing societies. Further verification of thiscost-effectiveness would be possible with more data on the long-term effects of pre-eclampsia on the subsequent morbidity andmortality risks to the mother and newborn, and with results ofadditional clinical trials that will combine screening tests andpreventive measures.23,44

ACKNOWLEDGEMENTSPart of this study was presented at the 18th Annual Meetingof the International Society of Ultrasound in Obstetrics andGynecology, Prague, the Czech Republic (October 12, 2010).

WHAT’S ALREADY KNOWN ABOUT THIS TOPIC?

• Preeclampsia places a heavy burden on fetal and maternalhealth as well as on healthcare costs, years-of-life and quality-of-life lost.

• Aspirin effectively prevents preeclampsia especially if startedin the first trimester.

• No study analyzed economical benefits from first trimester multiplemarker screening.

WHAT DOES THIS STUDY ADD?

• An economic model was developed to evaluate first trimestermultiple markers screening for early and late preeclampsia.

• Evidence that routine screening provides a good value for themoney.

• Benefits increase with reduced screening price, with increasingaccuracy of the test, and with increased preeclampsiafrequency.

• There are tradeoffs between accuracy, cost, and treatmenteffectiveness.

A. Shmueli et al.36


REFERENCES

1. Clark SL, Belfort MA, Dildy GA, et al. Maternal death in the 21st century:causes, prevention, and relationship to cesarean delivery. Am J ObstetGynecol 2008; 199: 36.e1–e5.

2. Roberts JM, Cooper DW. Pathogenesis and genetics of pre-eclampsia.Lancet 2001; 357: 53–6.

3. Redman CW, Sargent IL. Latest advances in understandingpreeclampsia. Science 2005; 308: 1592–4.

4. von Dadelszen P, Magee LA, Roberts JM. Subclassification ofpreeclampsia. Hypertens Pregnancy 2003; 22: 143–8.

5. Altman D, Carroli G, Duley L, et al. Magpie Trial Collaboration Group.Do women with pre-eclampsia, and their babies, benefit frommagnesium sulphate? The Magpie Trial: a randomised placebo-controlled trial. Lancet 2002; 359: 1877–90.

6. Perez-Cuevas R, Fraser W, Reyes H, et al. Critical pathways for themanagement of preeclampsia and severe preeclampsia in institutionalisedhealth care settings. BMC Pregnancy Childbirth 2003; 3: 6–10.

7. Koonin LM, MacKay AP, Berg CJ, et al. Pregnancy-related mortalitysurveillance--United States, 1987–1990. MMWR CDC Surveill Summ1997; 46: 17–36.

8. Mathers CD, Lopez AD, Murray CJL. The Global Burden of Disease andMortality by Condition: Data, Methods, and Results for 2001. In GlobalBurden of Disease and Risk Factors. Lopez AD, Mathers CD, Ezzati M,et al., (eds): World Bank. New York: Oxford University Press: Washington(DC) 2006; 45–93.

9. McDonald SD, Malinowski A, Zhou Q, et al. Cardiovascular sequleae ofpreeclampsia/eclampsia: a systematic review and meta-analyses. AmHeart J 2008; 156: 918–30.

10. Libby G, Murphy DG, McEwan NF, et al. Preeclampsia and laterdevelopment of type 2 diabetes in mothers and their children anintergenerational study from the Walker Cohort. Diabetologia 2007;50: 523–30.

11. Geelhoed JJM, Fraser A, Tilling K, et al. Preeclampsia andgestational hypertension are Associated with childhood bloodpressure independently of family adiposity measures. The Avonlongitudinal study of parents and children. Circulation 2010; 122:1192–9.

12. Poston L, Briley AL, Seed PT, et al. Vitamin C and vitamin E in pregnantwomen at risk for pre-eclampsia (VIP trial): randomised placebo-controlled trial. Lancet 2006; 367: 1145–54.

13. Xu H, Perez-Cuevas R, Xiong X, et al. An international trial ofantioxidants in the prevention of preeclampsia (INTAPP). Am J ObstetGynecol 2010; 202(239): e1-10.

14. Askie LM, Duley L, Henderson-Smart DJ, Stewart LA. (on behalf of thePARIS Collaborative Group). Antiplatelet agents for prevention of pre-eclampsia: a meta-analysis of individual patient data. Lancet 2007; 369:1791–8.

15. Hofmeyr GJ, Lawrie TA, Atallah AN, Duley L. Calcium supplementationduring pregnancy for preventing hypertensive disorders and relatedproblems. Cochrane Database Syst Rev Aug 2010; 4(8): CD001059. Update of:Cochrane Database Syst Rev. 2006;3:CD001059.

16. Nilsen RM, Vollset SE, Rasmussen SA, et al. Folic acid andmultivitamin supplement use and risk of placental abruption:A population-based registry study. Am J Epidemiol 2008;167: 867–74.

17. Triche EW, Grosso LM, Belanger K, et al. Chocolate consumption inpregnancy and reduced likelihood of preeclampsia. Epidemiology 2008;19: 459–64.

18. Haugen M, Brantsaeter AL, Trogstad L, et al. Vitamin DSupplementation and Reduced Risk of Preeclampsia in NulliparousWomen. Epidemiology 2009; 20: 720–6.

19. Qiu C, Coughlin KB, Frederick IO, et al. Dietary fiber intake in earlypregnancy and risk of subsequent preeclampsia. Am J Hypertens 2008;21: 903–9.

20. Bujold E, Roberge S, Lacass Y, et al. Prevention of preeclampsia andintrauterine growth restriction with aspirin started in early pregnancy. Ameta-analysis. Obstet Gynecol 2010; 116: 402–14.

21. Conde-Agudelo A, Romero R, Lindheimer MD. Tests to PredictPreeclampsia. In: Chesley’s Hypertensive Disorders in Pregnancy (3rdedn.) Lindheimer MD, Roberts JM, Cunningham FG. (eds.) Chesley LC,Academic Press: Amsterdam; 2009; 191–214.

22. Giguère Y, Charland M, Bujold E, et al. Combining Biochemical andUltrasonographic Markers in Predicting Preeclampsia: A SystematicReview. Clin Chem 2010; 56: 361–75.

23. Cetin I, Huppertz B, Burton G, et al. Pregenesys pre-eclampsia markers aconsensus meeting: what do we require from markers, risk assessmentand model systems to tailor preventive strategies? Placenta 2011; 32(S1):S4–S16.

24. Romero R, Kusanovic JP, Than NG, et al. First-trimester maternal serumPP13 in the risk assessment for preeclampsia. Am J Obstet Gynecol 2008;199(122): e1–e11.

25. Gonen R, Shahar R, Grimpel YI, et al. Placental protein 13 as an earlymarker for pre-eclampsia: a prospective longitudinal study. BJOG 2010;115: 1465–72.

26. Spencer K, Cowans NJ, Nicolaides KH. Low levels of maternal serumPAPP-A in the first trimester and the risk of pre-eclampsia. Prenat Diagn2008; 28: 7–10.

27. Wortelboer, EJ, Koster, MPH , Cuckle HS, et al. First-trimester placentalprotein 13 and placental growth factor: markers for identification ofwomen destined to develop early-onset pre-eclampsia. BJOG 2010; 117:1384–9.

28. Spencer K, CowansNJ, Chefetz I, et al. First-trimestermaternal serumPP-13,PAPP-A and second-trimester uterine artery Doppler pulsatility index asmarkers of pre-eclampsia. Ultrasound Obstet Gynecol 2007; 29: 128–34.

29. Akolekar R, Syngelaki S, Sarquis R, et al. Prediction of early,intermediate and late pre-eclampsia from maternal factors,biophysical and biochemical markers at 11–13 weeks. Prenat Diagn2011; 31: 66–74.

30. Khalil A, Cowans NJ, Spencer K, et al. First trimester markers for theprediction of preeclampsia in women with a-priori high risk.UltrasoundObstet Gynecol 2010; 35: 671–9.

31. Cuckle H. Screening for pre-eclampsia - lessons from aneuploidyscreening Placenta Supplement Early Non-Invasive Markers. Placenta.2011; 32S1: S42–S8.

32. Marlow N, Wolke D, Bracewell MA, Samara M. EPICure Study Group:Neurologic and developmental disability at six years of age afterextremely preterm birth. N Engl J Med 2005; 352: 9–19.

33. Fanaroff AA, Stoll BJ, Wright LL, et al. Trends in neonatal morbidity andmortality for very low birthweight infants. Am J Obstet Gynecol 2007;196: 147.e1–e8.

34. Chodick G, Porath A, Alapi H, et al. The direct medical cost ofcardiovascular diseases, hypertension, diabetes, cancer, pregnancyand female infertility in a large HMO in Israel. Health Policy 2010;95: 271–6.

35. Calderon-Margalit R, Friedlander Y, Yanetz R, et al. Late stillbirthsand long-term mortality of mothers. Obstet Gynecol 2007; 109:1301–8.

36. Calderon-Margalit R, Friedlander Y, Manor O, et al. Cardiovascularhealth of mothers and offspring following pregnancies complicated withpreeclampsia. The Israel Medical Association Society for research,prevention and treatment of atherosclerosis conference, Eilat, October2010.

37. Tsadok MA, Friedlander Y, Paltiel O, et al. A. J Obstet. Gynecol 2008; 199(6):SUPP/A: S33

38. Lindheimer MD, Taler SJ, Cunningham FG. American Society ofHypertension position paper: hypertension in pregnancy. ClinHypertens Greenwich 2009; 11: 214–25.

39. Israel Central Bureau of Statistics. Annuals Reports for 2005–2008,Jerusalem, Israel.

40. Harlap S, Davies AM, Deutsch L, et al. The Jerusalem Perinatal Studycohort, 1964–2005: methods and a review of the main results.Paediatr Perinat Epidemiol 2007; 21: 256–73.

41. Matusevitch A. An economic evaluation of physical activity andimplications for its promotion,MPH thesis, The HebrewUniversity Schoolof Public Health, January 2010.



42. WorldHealthOrganization (WHO).Make EveryMother andChild Count.WorldHealth Organization: World Health Report, Geneva, Switzerland, 2nd ed. 2005.

43. Eichler HG, Kong SX, Gerth WC, et al. Use of cost-effectiveness analysis inhealth-care resource allocation decision-making: How are cost-effectivenessthresholds expected to emerge? Value Health 2004; 7: 518–28.

44. Nicolaides KH. A model for a new pyramid of prenatal care based onthe 11 to 13weeks’ assessment. Prenat Diagn 2011; 31: 3–6.

45. Hadker N, Garg S, Costanzo C, et al. Financial impact of a novelpreeclampsia diagnosis test versus standard practice: a decision-anlytical modeling analysis from a UK healthcare payer perspective.J Med Econ 2010; 13: 728–37.

46. Levine RJ, Maynard SE, Qian C, et al. Circulating angiogenicfactors and the risk of preeclampsia. N Engl J Med 2004;350: 672–83.

47. Simon J, Gray A, Duley LMagpie Trial collaborative group. Cost-effectiveness of prophylactic magnesium sulphate for 9996 women withpre-eclampsia from 33 countries: economic evaluation of the MagpieTrial. BJOG 2006; 113: 144–51.

48. Meads CA, Cnossen JS, Meher S, et al. Methods of prediction andprevention of pre-eclampsia: systematic reviews of accuracy andeffectiveness literature with economic modelling. Health TechnolAssess 2008; 12: 5–285.

A. Shmueli et al.38


ORIGINAL ARTICLE - i-med.sk

Documents

Transcript of ORIGINAL ARTICLE - i-med.sk