Accepted Article

left by10.0(95%CI8.5-11.4) a with PEoccurringator before weeks.Theriskofdelivery was shifted to theleft by8.2(95%CI 7.2-9.1)weeks and in MC twinsit was shifted to the gestational ageatdelivery mean PEthe weeks. InDCtwinswith was 55 PE delivery with or antiphospholipid syndrome, themeanofGaussiandistribution ofgestational age at and nohistory ofPE ofdiabetesmellitus,systemiclupuserythematosus no familyhistory 69 kgat12weeks’ gestation, height of164cm,nulliparous, with spontaneousconception, racial origin,weightofResults: InsingletonpregnanciescomprisingCaucasian womenof and comparedtosingleton . and <42weeks’PE withdeliveryat<37 gestationintwinpregnancies was determined with PE was developedfromhistory.and variablesofcharacteristics maternal The risk of singleton pregnancies. Asurvival-time 93,297 Methods: model fordichorionic(DC) (MC) andmonochorionic twinpregnancies. previouslyreported.The and medicalhistorywas preeclampsia (PE)insingletonpregnanciesus Objective: A forthegestational survival-timeregressionmodel age atdeliverywith ABSTRACT Carla Francisco, article as doi: 10.10 differencesbetween version lead to this may been through the copyediting, typesetting, pagination andproofreading process, which This article hasbeen accepted for publication andundergone full peer review but has not Foundation (Charity No: 1037116). This paper is part of the PhD thesis of Carla Francisco 1037116). No: (Charity Foundation Francisco partofthePhDthesisCarla This paper is 1. HarrisBirthrightResearch CentreforFetalMedicine,King’s College,London, UK. Correspondence: Correspondence: Competing risks model in screening for preeclampsia in pregnanciesbyCompeting risksmodelinscreeningforpreeclampsiatwin The study was supported by grants from the Fetal Medicine Medicine theFetal grants by from The study was supported Acknowledgments: The study population included 1,789 DC and 430 MC twin pregnancies and MCtwin included1,789DCand430 The studypopulation This article isprotected bycopyright. Allrights reserved. 2. Instituteof HealthResearch,UniversityofExeter, Exeter, UK. College Hospital, 16-20 Windsor Walk, London SE5 8BB, UK. Tel: 00 44 2032998256, email: [email protected] Tel: [email protected] email: 2032998256, 44 00 1 DavidWright, for Universidade Nova de Lisboa,Lisbon, Portugal.for UniversidadeNova 02/uog.17529 maternal characteristicsandmedicalhistory Short title: Professor KH Nicolaides, Fetal Medicine Research Institute, King's King's Institute, Research Medicine Fetal KHNicolaides, Professor 2 Zsófia Benk Screening for preeclampsiaintwins

and the Versionof Record. Please cite this

ő , 1 Argyro Syngelaki, Argyro ing maternal demographic characteristics ing maternaldemographic model for the at deliveryat for thegestationalage model objective of this paper is to extend this objective ofthispaperistoextend 1 KyprosH.Nicolaides. 1

This articleis protectedbycopyright. Allrightsreserved. Accepted Article for estimation ofpatient-specific risks for PE in DCand MC twinpregnancies. Conclusions: and 36.5%. at <42weekswere3.6%,27.0% twins and14.2%forMCtwins;therespectivevaluesPE gestation, assuming noothercauseofdelivery, forsingletons, 9.0%forDC was0.6% reference population with theabovecharacteristics theestimated riskof PE at<37weeks’ fora specified gestational thefitteddistributioncurveand age theareaunder isgivenby care, Survival model,Bayestheorem pregnancy care,Survival Key words: effective methodsofscreening forthe disease. more to combinematernalfactorswithbiomarkersforthecontinuingdevelopmentof estimation ofthe

A model based onmaternalcharacteristicsand historyhas A modelbased been developed First trimester screening, Preeclampsia,Twin pregnancy, of Pyramid apriori risk for PE is an essential first step in the use of Bayes theorem anessentialfirststepintheuseof riskforPEis

Such This articleis protectedbycopyright. Allrightsreserved. Accepted Article related tothe inter-pregnancy interval,persists beyond 15years. in thelater,parous womenwithnopreviousPE; the protectiveeffect, whichisinversely in vitro antiphospholipid syndrome, andpersonalhistory conceptionby ofPEand familyhistory or history ofchronichypertension,diabetes mellitusandsystemiclupuserythematosus maternal age,increasing weight,Afro-CaribbeanandSouthAsianracial origin,medical distribution of thegestational age atdeliverywithPEto theleft, include advancing the higher is therisk for PE.Variables frommaternalfactors which shifttheGaussian pregnancies thedistribution isshifted totheleft and thesmallermeangestational age most pregnanciesdelivery willactuallyoccu for PEthegestational age distribution isshifted totheright withtheimplicationthat in of thedistribution of gestational age at deliverywithPEsothat in pregnancies atlow risk variables fromcharacteristics maternal andhi DC and MC twin pregnancies. DC andMC which wasdeveloped fromthestudyofsingleton pregnancies toinclude adjustments for delivery withPE,based onmaternal demographic characteristics and medicalhistory, The objective ofthisstudy istomodifythe In twinpregnancies,the rateofPE is about 10%, is 55weekswithestimatedstandard deviationof6.88weeks(Figure1). measurements. medical history withtheresultsofvarious combinations of biophysical and biochemical the useofBayes theoremtocombinethe In singleton pregnancies, effectivescreeningfor preeclampsia (PE)canbeachievedwith Introduction history ofdiabetesmellitus,systemiclupus no height 164cm,nulliparous,spontaneousPEand conception,nofamilyhistoryof for areferencepopulationage fordeliverywithPE(Caucasianracialorigin,weight69kg, orafterdevelopmentofPE.Inthismodelthemeangestational between deliverybefore whether theydosoor not before a s develop PEand would that ifthepregnancywastocontinueindefinitelyallwomen survival-time model for the gestationalPE. survival-time modelforageatdeliverywith monochorionic (MC)twinsaresimilar. 9-times higher;therates ofboth totaland preterm-PEfordichorionic (DC)and singleton pregnancies underestimate therelative riskofpreterm-PEintwinswhichis singletons and consequently comparisonof aredelivered atanearliergestationaltwins age However,than pregnancies. singleton

fertilization. 1-5 A fundamental componentofthisapproach isadoptionofa 1,3 The riskfor PEdecreaseswithincreasing maternalheightand in

16 pecified gestational age dependson competitionpecified gestationalage

erythematosus orantiphospolipid syndrome) a priori survival-time model forthegestational survival-time model age at story and biomarkers is to modify the mean story andbiomarkersistomean modify the the overall rates ofPEbetween twinand r before developmentofPE.Inhigh-risk riskfrom maternal characteristicsand 6-15 which is 3-times higher than in whichis3-timeshigher

1,3 This approachassumes

3 The effects of Theeffectsof

This articleis protectedbycopyright. Allrightsreserved. Accepted Article

ii eoe2 ek’gsaini h bec ftohbatcdsae. visit before 20 weeks’gestation inthe absence of trophoblastic disease). (history ofhypertension before conceptionor the presence of hypertension atthe booking should developafter20 weeksofgestationinwomen withknownchronic hypertension PE superimposedonchronic hypertensionsignificant proteinuria (as defined above) analysis of midstream orcatheterurine specimens ofatleast++ondipstick 24 hoursortworeadings also beproteinuriaof>300mgin developing after 20weeks of gestationinpr blood pressureshould be >90mmHg onatleast two occasions four hours apart Pregnancy. Hypertension in Studyof bytheInternational Societyfor condition wasPEasdefined pre-existing orpregnancy associated hypertensionwereexamined todetermineif the general medicalpractitioners ofthe women.The obstetricrecordsof allwomenwith Data onpregnancyoutcomewerecollectedfrom thehospitalmaternityrecordsor the Outcome measures height weremeasuredandtheBMIwascalculated. last childand estimateddateofconceptionthe currentpregnancy. weightand Maternal birth weight of theneonate inthe last pregnancyandinterval in yearsbetween birth of the pregnancies at> 24 weeks), previous pregnancy withPE,gestational age atdeliveryand patient and obstetric history includingparity(parousor nulliparous ifnoprevious motherofthe of PEinthe orantiphospholipidhistory syndrome, family erythematosus during pregnancy, historyofchronichypertension,diabetes mellitus, systemic lupus conception requiring South Asian, EastAsian andmixed),methodofconception (spontaneous orassisted Patient characteristics including maternal age,racial origin(Caucasian, Afro-Caribbean, Patient characteristics thesamehospitalsas theexamined in twinsandwereincluded inapreviouspublication. from twinpregnancies we obtainedresultsform 93,297singletonpregnanciesthat were days betweendeathof one fetusand livebirthof or fetaldeath before24weeksandthose withanintervalofmorethanthree pregnancies withaneuploidiesand major fetalabnormalities,thoseending intermination, phenotypically normallivebirthor first-trimester combined screening foraneuploidy and subsequently deliveringa The inclusion criteriafor thisstudyon screening for PEweretwinpregnancy undergoing participate in thestudy, EthicsCommittee. NHS Research whichwasapprovedbythe between January 2006andDecember 2015andgave written informed consentto atitsjunctionwiththe . the inter-twinmembrane fetal crown-rump length screening for aneuploidies. gestation, we recordmaternalcharacteristics and medicalhistoryandperformcombined Maritime Hospital,UK.Inthisvisit,at11College HospitalandMedway fortheirroutinefirsthospitaloutcomes inwomenattending visitpregnancyatKing’s from The dataforthisstudywerederived Study population Methods 20 Thesystolicbloodpressure shouldHgand/or thediastolic be>140mm in vitro 18 ofthe larger twin.Chorionicitywas determinedbyexamining 17 fertilization ortheuse ofovul Gestational age was determinedbytheofmeasurement eviously normotensivewomen.Thereshould prospective screening foradverseobstetric prospective at >24weeks’gestation. Weexcluded thesecond twin. Forcomparison of data ifno 24-hour collection isavailable.In ation drugs), cigarettesmoking 19 The women werescreened The women +0 –13 +6 weeks’ 3

This articleis protectedbycopyright. Allrightsreserved. Accepted Article The statisticalsoftware package R was usedfor dataanalyses. provide separateresultsforDCandMCtwins. compared tosingleton pregnancies; the numberofaffected cases was toosmall to with PEat<32,<37and <42weeks’ gestation in twinpregnancies wasdetermined and wereincludedascovariates. Theperformanceofscreeningand MCtwins fordelivery diabetes mellitusand systemic lupus erythem ofconception,chronichypertension,method PE, andwithout previous pregnancywith in kg, height incm,racial origin, inter-pregnanc censored observations. Established risk factors, includingmaternal ageinyears,weight pregnancies. Inthismodel deliveries fromcauses other thanPE were treatedas the time of delivery with PEbasedonmaternalfactors, the timeofdeliverywith Gaussian modelofa developed The previously Statistical analyses

was usedfor modelfitting. 22

atosus orantiphospholipid DC syndrome, distribution of gestational age inweeksat y intervalinyears,deliveryweeksof 3 was applied to DC and MC twin wasappliedtoMCtwin DC and 21 The survivalpackage This articleis protectedbycopyright. Allrightsreserved. Accepted Article virtually alltwinsarescreen positive. SPR ismuchhigherfor twinthan singletonpregnancies and atrisk cut-off of 1 in 75 weeks’with PEat<37 10, 1in50and75fordelivery gestation. Atallriskcut-offs the screening ofsingletonand twinpregnanciesatriskcut-offs amixedpopulation of 1 in Figure 4.Table 2providesthescreen positiv delivery at<32and<37 weeks’ gestation for singleton and twin pregnancies areshown in forpredictionReceiver operatingcharacteristic ofallPE (ROC)curves andPEwith and 14.2%forPEat<42weekswere3.6%,27.0%36.5%. twins and3.6% forMCtwins;therespective valuesforPEat<37weekswere0.6%,9.0% gestation, assuming no other cause fordelivery, was0.06% forsingletons, 1.9% for DC reference population with theabovecharacteristics theestimated riskof PE at<32weeks’ a specified gestational age isgivenbytheareaunderdistribution curveandfora TheriskofdeliverywithPEoccurringator weeks forDCtwinsand45MCtwins. before singletons, was55weeksfor 47 isillustrated gestation and MCtwins inFigure3;themean The Gaussiandistribution ofgestational age at deliverywithPEinsingletons, DCtwins difference between theeffects of wassignificant(P=0.038). DCandMCtwins deliveredwithPEonaverage10.0(95%CI8.5-11.4)and MCtwins weeksearlier. The chracteristics, DCtwins delivered withPEonaverage8.2(95% CI7.2-9.1) weeksearlier antiphospholipid syndrome. Comparedto singletons, withthe samematernal or historyofdiabetesmellitus,systemichistory ofPEandno lupuserythematosus weeks’ gestation, height of164cm,nulliparous, withspontaneousconception,nofamily at 12 racialorigin,weightof69kg Caucasian a referencepopulationcomprisingwomenof intervals) on meantimeto deliverywithPE The effect 93,297 The studypopulation included 1,789 DCtwinpregnancies, 430 MCtwinpregnanciesand Results DC twinsand6.0%(26of430)inMCtwins. Table 1.TherateofPEwas2.3%(2,16293,297)insingletons,8.1% (145of1,789)in singleton pregnancies. Maternal andpregnancy characteristicsare summarized in ofand pregnancycharacteristics(estimates95%confidence maternal is shown inFigure2. e rate(SPR) anddetectionrate(DR)in Theeffects arerelative to This articleis protectedbycopyright. Allrightsreserved. Accepted Article about 3-timeshigherthan insingleton pregnancies. pregnancies. Previousstudies intwin that therateofPEis pregnancies merelyreported In thisstudy thematernalfactor based modelhasbeen extendedtoinclude twin singleton pregnancies toinclude biomarkers. based factorsandexpanded onmaternal In previousstudiesweestablished acompetingriskmodel forthepredictionofPE in Comparison withpreviousstudies onindependent dataExternal validation fromdifferent sources isrequired. derived andtestedusing screening bymodel a of performance the that is singleton pregnancies is inevitablysmall.Anotherlimitation A limitationofthestudyisthatnumber any specifiedrequiring deliverybeforegestation. survival-time model which allows estimation ofindividual patient-specific risks of PE define their contribution inthepredictionof PE andthirdly, of a thedevelopment with PE,secondly, theuseofmultivariablesurvivalanalysistoidentify thefactorsand pregnancies inwhichspecific questions wereaskedto identifyknownfactors associated The majorstrengths of the studyare firstly, prospective examinationof twinand singleton context offirst-trimester combinedscreeningfor21 the trisomy used forstratificationofthe population inthe intohigh-andlow-riskgroups.Forexample, irresespective ofhowfavourable areallotherfactors the certain maternalcharacteristicsmaybeassociatedwithsuchhigh-riskthat programme virtually alltwins werescreenpositive. Thisis not surprising because in anyscreening gestation at riskcut-off of 1in 75, when theSPRforsingletonpregnancies was13%, population ofIn screeningsingletonand ofamixed twinpregnanciesfor PE at<37weeks’ MC twins. of PEat<37 weeks’ gestation was0.6% forsingletons,9.0% forDCtwinsand14.2% for weeks,respectively. PEisshiftedtotheleftby8and10 delivery with estimatedrisk The same characteristicsas singleton pregnancies thedistribution ofgestational age of with pregnancies the MC twin 55weeks.InDCand gestational age ofdeliverywithPEis diabetes mellitus, systemic lupus erythematos nulliparous, withspontaneousconception, noandhistoryof familyhistoryofPE population ofCaucasianof womenracialorigin,weight of 69kg,height of164 cm, and thisis reflected in thedistribution ofgestationalageIna ofdeliverywithPE. In twinpregnancies the riskof PEissubstantially higherthan insingleton pregnancies Principal findings ofthisstudy Discussion Strengths andlimitations PAPP-A. offetalnuchaltranslucencythickness measurements and ß-hCGand serumfree remain abovethescreenpositivecut-off irrespective ofhowfavourablearethe maternal ageandforawomanaged50yearsthe exponentially with twin pregnancies examined relative to that of pregnanciesrelativetothatof examined twin us orantiphospholipidus syndrome,themean 6-15 the samedatasetisoverestimated.

posterior posterior risk is abovea cut-off prior posterior riskincreases risk will riskwill 1-5 . This articleis protectedbycopyright. Allrightsreserved. Accepted Article surveillance policies ashas beenachieved forsingleton pregnancies. updating the riskatdifferent stages during pregnancy formingthebasis for stratified methods ofscreeningfor thedisease.for Bayestheoremalsoprovidesaframework maternal factorswith biomarkers forthecontinuingdevelopmentofmoreeffective PE intwins, whichisan essential first stepin theuse of Bayes theorem to combine

The proposedcompetingriskmodelallows Clinical implicationsofthe study estimationofpatient-specific 23-25

a priori

risk for This articleis protectedbycopyright. Allrightsreserved. Accepted Article 12. Bensdorp AJ, Hukkelhoven CW, van der Veen F, Mol BW, Lambalk CB, van Wely Lambalk CB,vanWely F, MolBW, derVeen BensdorpAJ,Hukkelhoven van CW, 12. 7. Savvidou MD, Karanastasi E, Skentou C, Geerts L, Nicolaides KH. Twin NicolaidesKH.Twin E,SkentouC,GeertsL, Karanastasi SavvidouMD, 7. U. Doppler M, SmrcekJ,Gembruch U,KatalinicA,Krapp Germer C, GeipelA,Berg 6. 11. Rizzo G, Pietrolucci ME, Aiello E, Capponi A, Arduini D. Uterine arteryDoppler ArduiniD. ME,AielloE,CapponiA, RizzoG,Pietrolucci 11. WrightD,AkolekarR, Syngelaki A,PoonLC,Nicolaides KH. Acompetingrisks 1. References 9. Klein K, Mailath-Pokorny M, Elhenicky M, Schmid M, Zeisler H, Worda C. Mean, H,WordaC.Mean, M,Zeisler M, Elhenicky M,Schmid KleinK,Mailath-Pokorny 9. YuCKH,PapageorghiouA,CachoAM,NicolaidesKH. Screeningfor AT,Boli 8. . AkolekarR,SyngelakiA,PoonL,WrightD,NicolaidesKH.Competingrisksmodel 2. 0 Sparks TN, Cheng YW, Phan N, Caughey AB Sparks J. Does riskof preeclampsia 10. 4. O’Gorman N, Wright O’Gorman Syngelaki D, A, Akolekar R,Wright KH. A, PoonLC,Nicolaides 4. risks NicolaidesKH.Competing WrightD,SyngelakiA,AkolekarR,PoonLC, 3. 5. O’Gorman N, Wright O’Gorman Rolnik DL,SyngelakiA,Wright PoonLC, D,LionaC. A, 5. Obstet Gynecol M. Dizygotic twinpregnancies after medically assistedreproductionM. Dizygotic andafter biomarkers at11-13biomarkers weeks’ gestation. in screeningfor risks model competing Papantoniou N,PersicoPlasenciaW, KH.Accuracy SinghM,Nicolaides of chorionicity andpreeclampsia. Gynecol Ultrasound Obstet prediction of pre-, fetalgrowth restriction andbirthweightdiscordance. assessment oftheuterinecirculation inthesecondtrimestertwinpregnancies: 20 evaluation intwinpregnanciesat 11 model inearlyscreening forpreeclampsia. outcome intwinpregnancies. lowest, and highest pulsatility index oftheuterine arteryandadverse pregnancy gestation by transvaginal uterine artery Doppler. pre-eclampsia andfetalgrowthrestriction in twin pregnanciesat 23 weeksof Diagn Ther in earlyscreening forpreeclampsia by biophysicalandbiochemical markers. differ bytwinchorionicity? biomarkers at11-13 weeks’ gestation. Competing risksmodelin screening forpr history. characteristics model inscreeningforand medical preeclampsiabymaternal Akolekar R, CiceroS, JangaD, JaniJ,Molina FS, De Paco Matallana C, 103.e1-103.e12. : 535–40. AmJ ObstetGynecol 2013; 2014; 33 : 8-15. 44 5-1 : 557-61. Matern Fetal NeonatalMed Matern Fetal 2002; 2015; Am JObstet Gynecol Ultrasound ObstetGynecol 20 213 : 541-5.

Ultrasound Obstet Gynecol Obstet Ultrasound +

0 to13 : 62.e1-10 preeclampsia bymaternalfactorsand preeclampsia Fetal DiagnTher Am J Obstet Gynecol Am J eeclampsia by maternalfactors and

+

UltrasoundGynecol Obstet 6

weeks of gestation. 2011; 2013; 2001; 205 2012; 26 : 549.e1–7. : 1273-7. 2016; in press. press. in 2016; 18 32 : 228–31. 2016; : 171-178. Ultrasound 2002; Fetal 214 : This articleis protectedbycopyright. Allrightsreserved. Accepted Article 13. Lu 15. Barda G, Gluck O,MizrachiY,BarJ.Acomparisonof BardaG, maternal andperinatal 15. WangYA,ChughtaiAA,FarquharCM,PollockW,LuiK, SullivanEA.Increased 14. 6 Francisco C,WrightD, Benk 16. 8 RobinsonHP, FlemingJE.A criticalevaluation ofsonar crownrumplength 18. Nicolaides KH. Screeningforfetal aneuploidies at11 to13weeks. 17. 19. Sepulveda W, Sepulveda signatNicolaides SebireNJ,HughesK,OdiboA, KH. Thelambda 19. 24. Panaitescu AM, Wright D, Militello A, Akolekar R, Nicolaides KH. Proposed clinical Panaitescu D, MilitelloA,AkolekarR,Nicolaides KH.Proposed AM, Wright 24. WrightD,DraganI,SyngelakiA, Akolekar R, Nicolaides KH. Proposedclinical 23. TherneauT(2014).APackagefor SurvivalAnalysis inS. Rpackage version 22. statistical Alanguageandenvironmentfor Team.R: Core RDevelopment 21. VanMA, LindheimerMD,deSwietM, Brown JM.The AsscheA,Moutquin 20. 371-377.e2. natural conception: maternaland perinatal outcomes. population-based study. anddizygoticTul N.Hypertensivedisordersduring twingestations: monozygotic A pregnancies. outcome betweeninvitrofertilization andspontaneous dichorionic-diamniotic twin technology treatment. incidence of andpreeclampsiaafter assistedreproductive 10.1080/14767058.2016.1270934. 2011; Gynecol singleton compared to pregnancies. preeclampsia intwin measurements. measurements. Ultrasound Obstet Gynecol Ultrasound Obstet 10-14 weeksofgestation asa predictor

weeks’ gestation. ofpregnancies aftermanagement combined screening for preeclampsia at35-37 weeks’ gestation. ofpregnancies aftermanagement combinedscreening forpreeclampsia at30-34 2.37-7, http://CRAN.R-project.org/package=survival. 3-900051-07-0, URLhttp://www.R-project.org/. computing. RFoundationforStatisticalComputing, Vienna, Austria. 2011;ISBN Hypertens Pregnancy from theinternational society forthe studyofhypertension in pregnancy(ISSHP). classificationdisorders of anddiagnosisofthehypertensivepregnancy:Statement

č ovnik M, BlicksteinI, Lasi 31 2017; : 7-15. J MaternFetalNeonatalMed Br JObstet Gynaecol Ultrasound ObstetGynecol Ultrasound ObstetGynecol 2001; Fertil Steril Hypertens Pregnancy 1996; 20 č ő M, Fabjan-Vodušek V, Bržan-Simenc G, Verdenik I, Verdenik I, M,Fabjan-VodušekV,Bržan-SimencG, Z,SyngelakiA, Nicolaides KH. Hiddenhighrate of : IX-XIV. 2016; 7 : 421-423. 1975; 105 : 920-926.e2. 2016; doi:10.1002/uog.17309. of chorionicityintwinpregnancies. 2016; 82 2016; : 702-710. 2017;Jan12:1-7.doi: 35 : 542-547. Fertil Steril Ultrasound Obstet Prenat Diagn 2016; 106 :

This articleis protectedbycopyright. Allrightsreserved. Accepted Article model. lines)pregnanciesaccordingtothecompeting risks singleton (blacklines)and twin(red delivery at<32weeks’ gestation (left), at <37 weeks(middle)and all PE(right) in Figure 4: antiphospholipid syndrome. history ofPE andno history ofdiabetes mellitus, systemic or lupuserythematosus racial origin, weight69 kg, height164 cmnulliparous, spontaneous conception, nofamily singleton, DCtwinand MC twinpregnancies with reference characteristics of Caucasian Figure 3: pregnancies withoutchronic hypertension. affectedweeks’ pregnancyPEat34 deliveringwith gestation. *thesetermsapplyto pregnancy at41weeks’ gestation andforparouswithPEtheeffect isforaprevious parous withoutPEtheeffectof anunaffected thebirth isfortheoneyearfrom intervalof diabetes mellitus, systemic lupuserythematos cm, nulliparous, spontaneous conception,nofamily historyofPEandno of reference levels ofsingletonpregnancy, Caucasianracialorigin, weight 69 kg, height 164 confidence intervals) on meantimetodeliverywithPE.The effects are relativeto the Figure 2: the low-risk group and30%forthehigh-riskgroup. area underthedistributioncurve(black);riskofPEat<42weeks’ gestation is1% for to theleft. The riskofPE occurring at orbefore a specified gestational age isgiven bythe at of PE.Inpregnancies high-riskfor before thedevelopment PE thedistributionisshifted low-risk for PE thedistribution is shifted tothe right and in mostcases delivery willoccur Figure 1: Figure legends clinical LitwinskaM, WrightD, EfeturkT, Ceccacci I, Nicolaides KH. Proposed 25. weeks’ gestation. ofpregnancies aftermanagement combinedscreening forpreeclampsia at19-24

Receiveroperatingcharacteristic (ROC) curvesforprediction of PErequiring Distribution of forgestational Distribution age atdeliverywithpreeclampsia apopulationof Gestational age distribution atdeliverywithPE. Effect of maternal andpregnancy characteristics (estimates and 95% Ultrasound ObstetGynecol us orantiphospholipid us syndrome. Forthe 2016;

In pregnanciesthatare at In-vitro fertilization Ovulation induction Spontaneous Conception Gestationof lastbirthin weeks Pregnancy interval in years Parous: no previous PE Parous: previous PE Nulliparous Parity Family historyofPE Cigarette smokers SLE/APS Diabetes mellitus Chronic hypertension Medical history Mixed East Asian South Asian Afro-Caribbean Caucasian Racial origin Gestational age inweeks Maternal heightincm Maternal weight inkg Maternal age in years Variable Variables givenasmean(interqu Table 1. This article isprotected bycopyright. Allrights reserved. Accepted Article Maternal andpregnancy Maternal characteristicsinthescreening population. 12.7 (12.3-13.1) 12.7 (12.3-13.1) 66.5 (59.0-77.0) 31.0 (26.4-35.0) artile range)or n(%);SLE= 164 (160-169) 164 (160-169) l n9,9) E(=,6) All (n=1,7 PE(n=2,162) All (n=93,297) 90,275 (96.8) 90,275 (96.8) 46,009 (49.3) 44,145 (47.3) 10,087 (10.8) 70,380 (75.4) 15,211 (16.3) 3.0 (2.0-5.0) 3.0 (2.0-5.0) 1,203 (1.3) 1,203 (1.3) 2,155 (2.3) 1,790 (1.9) 1,741 (1.9) 1,741 (1.9) 1,281 (1.4) 3,143 (3.4) 4,047 (4.3) 40 (39-40) 40 (39-40) 148 (0.2) 148 (0.2) 799 (0.9) 3761 (4) 3761 (4) igeo rgace Dcoincti rgace Monochorionic pregnancies twin pregnancies Dichorionictwin Singleton pregnancies

27(231.) 12.9(12.5-13.3) 12.7 (12.3-13.1) 33.2(29.1-36.5) 31.1 (26.4-35.6) 26 6-65 69.0(60.5-79.0) 72.65 (63-86.5) 6 1918 165(161-170) 163 (159-168) . 2571 3.1(2.0-5.3) 4.1 (2.5-7.1) ,7 5.) 1,390(77.7) 1,273 (58.9) ,4 9.) 1,162(65.0) 2,048 (94.7) 39 (37-40) 40 (39-40) (39-40) 40 (37-40) 39 4 2.) 769(43.0) 52(2.9) 968(54.1) 543 (25.1) 300 (13.9) 1,319 (61) 66(15.3) 33(22.8) 287(16.0) 716 (33.1) 4 1.) 7(.) 3(.) 3(0.7) 13(9.0) 27(1.5) 245 (11.3) 7 81 77(4.3) 160(8.9) 175 (8.1) 166 (7.7) 2(.) 575(32.1) 52(2.9) 0 5(1.2) 82 (3.8) 32 (1.5) 1(0.7) 10 (2.3) 11 (2.6) 4(2.8) 23 (5.3) 1(0.7) 4(0.2) 3(2.1) 18(1.0) 4(2.8) 33(1.8) 12 (0.6) 22(1.2) 46 (2.1) 57(3.2) 45 (2.1) 31 (1.4) 97 (4.5) systemic lupus erythematosus; APS

89) PE (n=145) All (n=430) PE (n=26) PE(n=26) (n=430) All PE(n=145) 89) 0 7.) 320 (74.4) 104(71.7) 20(318.) 53(877.) 71.9(60.0-84.0) 65.3(58.7-77.0) 72.0 (63.1-84.0) 28(241.) 28(251.) 13.0(12.5-13.5) 12.8(12.5-13.3) 12.8 (12.4-13.2) 31.0(28.0-36.6) 31.5(27.0-35.8) 34.0 (30.3-37.3) 6 1018 14(6-6) 163(159-169) 164(160-168) 165 (160-168) 4.1 (3.0-7.2) = antiphospholipid syndrome; PE 40 (38-40) (38-40) 40 0 6.) 1 5.) 13(50.0) 216(50.2) 101 (69.7) 0(21 35(95 24(92.3) 385(89.5) 90 (62.1) 0(45 4 98 2(7.7) 42(9.8) 50 (34.5) 3(28 18(60 12(46.0) 198(46.0) 33 (22.8) 1(.) 6(.) 1(3.8) 16(3.7) 11 (7.6) 48 2 47 2(7.7) 0 20(4.7) 43(10.0) 7 (4.8) 8 (5.5) 34 3(.) 0 3(0.7) 5 (3.4)

3.0 (1.7-4.9) 40 (39-40) (39-40) 40

=preeclampsia 3.4 (2.1-4.6) 40 (38-41) (38-41) 40 20 (76.9) 4 (15.4) 2 (7.7) 0 0 0 0 0 Preeclampsia Preeclampsia <42 w Preeclampsia <37 w Preeclampsia <32 w Detection rate(%) (%) positive rate Screen

Table 2: This article isprotected bycopyright. Allrights reserved. Accepted Article twin pregnancies. Screenpositiverateanddetection with 95%confidenceintervals inscreening bymaternalfactors forPEinsingletonand (12.7: 10.2-15.7) (12.7: 10.2-15.7) (16.1: 10.8-22.8) (8.2: 7.1-9.4) (8.2: 7.1-9.4) (0.8: 0.7-0.8) Singletons Singletons N =93,297 N =93,297 175/2,140 175/2,140 76/597 76/597 26/161 722 722

Risk cut-off 1 in 10 Risk cut-off 1 in 50 Risk cut-off 1 in 75 1in Riskcut-off 50 1in Riskcut-off 10 1in Risk cut-off (71.4: 47.8-88.7) (71.4: 47.8-88.7) (67.8: 60.3-74.8) (67.8: 60.3-74.8) (71.0: 62.1-78.8) (50.2: 48.1-52.3) N=2,219 N=2,219 116/171 88/124 88/124 Twins Twins 15/21 15/21 1,113 1,113 (31.5: 29.6-33.6) (31.5: 29.6-33.6) (37.2: 33.3-41.2) (37.2: 33.3-41.2) (46: 38.1-54) (46: 38.1-54) Singletons Singletons (7: 6.8-7.2) (7: 6.8-7.2) N =93,297 N =93,297 675/2,140 675/2,140 222/597 222/597 74/161 74/161 6,517 6,517 (98.8: 95.8-99.9) (98.8: 95.8-99.9) (99.2: 95.6-100) (99.2: 95.6-100) (100: 83.9-100) (100: 83.9-100) (97: 96.2-97.7) (97: 96.2-97.7) N=2,219 N=2,219 169/171 169/171 123/124 Twins Twins 21/21 21/21 2,152 (55.9: 47.9-63.7) (55.9: 47.9-63.7) (13.4: 13.2-13.6) (43.7: 41.6-45.8) (43.7: 41.6-45.8) (50.1: 46-54.2) (50.1: 46-54.2) Singletons Singletons N =93,297 N =93,297 935/2,140 935/2,140 299/597 299/597 12,512 12,512 90/161 90/161 (99.6: 99.3-99.8) (99.6: 99.3-99.8) (100: 83.9-100) (100: 83.9-100) (100: 97.9-100) (100: 97.9-100) (100: 97.1-100) N=2,219 N=2,219 171/171 171/171 124/124 Twins Twins 21/21 21/21 2,211

Figure 1

This article isprotected bycopyright. Allrights reserved. Accepted Article 42 23 04 85 66 46 27 80 76 72 68 64 60 56 52 48 44 40 36 32 28 24 42 23 04 85 66 46 27 80 76 72 68 64 60 56 52 48 44 40 36 32 28 24 Gestational age at delivery with preeclampsia (w) preeclampsia with at delivery Gestational age Gestational age at delivery with preeclampsia (w) preeclampsia with at delivery Gestational age 30% 1% Low risk Low High risk Figure 2

This article isprotected bycopyright. Allrights reserved. Accepted Article Age (every 5 y above 35) Weight (every10kg)* Height (every10 cm ) Chronic hypertension Family history ofPE* Family Monochorionic twins Parous without PE Parous without In vitro Diabetes mellitus* Dichorionic twins Parous with PE Parous with Afro-Caribbean South Asian fertilization SLE / APS 1 1 50510 5 0 -5 -10 -15 Effect on meantime to delivery with (w) PE Figure 3

This article isprotected bycopyright. Allrights reserved. Accepted Article 42 23 04 85 66 46 27 80 76 72 68 64 60 56 52 48 44 40 36 32 28 24 Gestational age at delivery with preeclampsia (w) Singletons DC twins MC twins Figure 4

This article isprotected bycopyright. Allrights reserved. Accepted Article Detection rate (%) 100 20 40 60 80 0 04 08 100 80 60 40 20 0 False positiverate (%)

Detection rate (%) 100 20 40 60 80 0 04 08 100 80 60 40 20 0 False positiverate (%)

Detection rate (%) 100 20 40 60 80 0 04 08 100 80 60 40 20 0 False positiverate (%)