Development of a nomogram for individual preterm birth risk evaluation

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Development of a nomogram for individual preterm

birth risk evaluation

Marion Gioan, Florence Fenollar, Anderson Loundou, Jean-Pierre Menard,

Julie Blanc, Claude d’Ercole, Florence Bretelle

To cite this version:

Marion Gioan, Florence Fenollar, Anderson Loundou, Jean-Pierre Menard, Julie Blanc, et al..

Devel-opment of a nomogram for individual preterm birth risk evaluation. Journal of Gynecology Obstetrics

and Human Reproduction, Elsevier, 2018, 47 (10), pp.545-548. �10.1016/j.jogoh.2018.08.014�.

�hal-02006582�

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Original

Article

Development

of

a

nomogram

for

individual

preterm

birth

risk

evaluation

Marion

Gioan

a

,

Florence

Fenollar

b

,

Anderson

Loundou

c

,

Jean-Pierre

Menard

d

,

Julie

Blanc

e

_,

_Claude

_D’Ercole

e,f

_,

_Florence

_Bretelle

e,f,

_*

a

CHGSainte-Musse,54,rueHenri-Sainte-Claire-Deville,83100Toulon,France

b

Unite´ derecherchesurlesmaladiesinfectieusestropicalesetemergentes,UM63,CNRS7278,IRD198,INSERM1095,13000Marseille,France

c

MedicalEvaluation,DepartmentofPublicHealth,Assistancepublique–hoˆpitauxdeMarseille,AMU,Aix-MarseilleUniversite´,13000MarseilleFrance

d_Conseil_{de´partemental}_du_{Val-de-Marne,}₉₄₀₀₀_Cre´teil,_France e

DepartmentofGynaecologyandObstetrics,Gynepole,AP–HM,Assistancepublique–hoˆpitauxdeMarseille,13000Marseille,France

f

AMU,Aix-MarseilleUniversite´,13000Marseille,France

Introduction

PretermBirth(PB)remainsthecauseofneonatalmorbidityand mortalityindevelopedcountrieswithupto9%ofpregnanciesword wile [1]. In EuropePB occursin 4.1 to 8.2%of birth leadingto maternalprolonghospitalisationsandtreatmentsespeciallyinhigh riskpregnancies[2,3].Basedonthe deﬁnition,anasymptomatic pregnant woman with a history of PB or late miscarriage is consideredathighriskforPB.Ultrasonographiccervical measure-mentisthestandardgoldtoevaluatethisrisk.Theriskdependson cervicallengthandgestationalageatmeasurement[4].Theaddition

ofriskfactorfortheevaluationofPBriskcouldbeacluetoimprove thepredictionofPBrisk.ForexampleBacterialvaginosis(BV)isarisk factorforobstetricalcomplications[5,6].Thedetectionbymolecular biology of microorganisms present in BV is a new diagnostic approach[7,8].Me´nardetalshowedthatthetimetodeliverywas shorterwhenhighatopobiumvaginalloadwasdetectedinahigh riskpopulation[8,9].Noreliablepredictivemethodexiststodayto deﬁnetheriskofPBinhigh-riskpregnancies[10].

Thenomogramisthegraphicrepresentationoftheprobability foreachpatientofanevent.Withthismodel,theriskcalculationis simple, reproducible and personalised. Two recent studies proposed an assessment of PB risk in high-risk populations [11,12].Unfortunately,theircalculationsdidnotincorporatemost ofthevariablesrecognisedasriskfactorsforPB,suchasvaginal swabresults,historyofadverseeventormaternalsmoking.Our studyaimwastodevelopanewtooltoevaluateindividualriskfor PBinahigh-riskpopulation.

ARTICLE INFO

Articlehistory: Received9May2018

Receivedinrevisedform16July2018 Accepted20August2018

Availableonline24August2018

Keywords: Prematurebirth Nomogram Highrisk Asymptomatic Bacterialvaginosis Shortcervix Latemiscarriage ABSTRACT

Objective. –Thisstudyaimedtodevelopanewtoolforpersonalisedpretermbirthriskevaluationin high-riskpopulation.

Study design. –813 high-risk asymptomatic pregnant women included in a French multicentric prospectivestudywereanalysed.Clinicalandparaclinicalvariables,includingscreeningforbacterial vaginosiswithmolecularbiology,cervicallength,havebeenusedtocreatethenomogram,basedonthe logisticregressionmodel.Thevaliditywascheckedbybootstrap.Adownloadablecalculatorwasbuild. Results. –Nineriskfactorswereincludedinthismodel:historyoflatemiscarriageand/orpreterm delivery,activesmoking,ultrasoundcervicallength,termofpregnancyatscreening,bacterialvaginosis, prematureruptureofmembranes,dailytravelmorethan30min.Discriminationandcalibrationofthe nomogramrevealedgoodpredictiveabilities.Theareaunderthereceiveroperatingcharacteristiccurve was0.77(95%CI;0.72–0.81).Themeanabsoluteerrorwas0.018,whichshowedpropercalibration.The optimalriskthresholdwas23.2%withasensitivityof74%,aspeciﬁcityof72.7%andapredictivenegative valueof90.6%.

Conclusion. –The nomogramcan help to better deﬁne individual preterm birth risk in high-risk pregnancies.

C 2018ElsevierMassonSAS.Allrightsreserved.

* Corresponding author. Unite´ de recherche sur les maladies infectieuses tropicales et emergentes,UM63, CNRS7278, IRD 198, INSERM1095, 13000 Marseille,France

E-mailaddresses:melkorsa@gmail.com(M.Gioan),ﬂorence.bretelle@ap-hm.fr

(F.Bretelle).

Available

online

at

ScienceDirect

www.sciencedirect.com

https://doi.org/10.1016/j.jogoh.2018.08.014

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Materialsandmethods Targetpopulation

Theestablishednomogramhasbeencreatedfromthedatabase ofaprospectivemulticentricFrenchcohort[13].Pregnantwomen, whoare14to34weeks(wks)pregnant,admittedforprenatalcare ineightFrenchteachinghospitals(amongthemtwolevelIIandsix levelIII,allwerepublichospitalexceptone),wishingtoparticipate inthestudy,wereeligible.

Takingintoaccounta30%proportionofpretermbirthsbefore 37weeksinourhighriskpopulation,asamplesizeof690women should show a hazard ratio (HR) of approximately 3.3 for Atopobium vaginae at a power at 80. With lost to follow-up patients and missing data (estimated at 20%) into account, 820womenisrequired.

Inclusioncriteria

Thepatientsincludedwereolderthan18yearsandatriskforPB. Thisriskwasdeﬁnedastheexistenceofashortcervix(acervical length<25mmmeasuredbytransvaginalultrasound)and/oran obstetrichistory:historyofpretermbirthand/orlatemiscarriage (spontaneousexpulsionofapregnancy14and<22wks).

The exclusion criteria were: multiple pregnancies, treated hypertension, foetal malformation, antiphospholipid syndrome, diabetes,pre-eclampsia,renaldisease,anyauto-immunedisease, oranantibiotictreatmentinthepast7days.

A completemedical examinationand interrogationcollected thedemographic data, medical history (age, parity, body mass index,smokingduringpregnancy,obstetrichistory, andcurrent pregnancydata) and theclinical characteristicsof each patient (uterinecontractions,clinicalsignsofBVorprematureruptureof membranes).

Vaginal sampleand ultrasound measurementof thecervical lengthwereperformed.Gestationalagewasdeterminedfromthe date of the last menstrual period or on the ﬁrst trimester ultrasoundincase ofaone-weeklag.Thedailytraveltimedata wascollected and divided into two groups: more or less than 30min.Obstetric and neonataloutcomes werecollected in the postpartumperiodthroughconsultationofmedicalﬁles. Bacteriologicalanalysis

Thebacteriologicalanalysiswasperformedwithself-collected vaginalswabs.Menardetal.[14]demonstratedthevalidityand reliabilityof this methodversuspractitioner-collected swabfor molecularquantiﬁcation.Eachvaginalsamplereceiveda molecu-larbiology analysisbasedonquantitativePCR.Theresultswere blinded for the medical team of obstetricians. The organisms targetedbyquantitativePCR andselectedin ourstudywereA. vaginaeandGardnerella vaginalis.Molecularquantiﬁcationof A. vaginae108 _copies/ml _and/or_G. _vaginalis ₁₀9 _copies/ml _has

beendescribedascommoninwomenwithBVflora[8].Thetrial wasregisteredatClinicalTrials.gov(identifierNCT00484653),and funded by the national hospital clinical research program (Programme de Recherche Clinique, number 2007-A00069-44). ‘‘Le Comite´ de Protection des Personnes Sud Me´diterraneé V’’ approved the project (number 07.019). Analysis method was previouslyreported[13].

Statisticalanalysis

StatisticalanalysiswasperformedwiththeIBMSPSSStatistics version20software.Theassociationbetweenthevariablesselected in the preliminary study and the risk for PB was tested with

univariateand multivariatelogistic regression analyses. Logistic model calibration was assessed using the Hosmer–Lemeshow goodness-of-ﬁttesttoevaluatethediscrepancybetweenobserved andexpectedvalues.Oddsratioswerereportedwith95%conﬁdence interval(CI95%).Qualitativevariableswerepresentedintheformof enrollment countsand percentages. Quantitativevariableswere expressedasmeanstandarddeviation.Theretainedandintegrated variables were the term (expressed asweeks ofgestation (wks)), history of preterm and late miscarriage, premature rupture of membranes,smoking,dailytraveltime,BVdiagnosedwithmolecular biology, sonographic measurement of cervical length, and the combination of history of preterm birth and cervical length <25mm.Discrimination,calibration,andnomogramwereperformed usingthe‘‘rms’’libraryoftheRsoftware(http://www.R-project.org) [15].Thepredictivemodelwasinternallyvalidatedforcalibrationwith bootstrap resampling. This compares predicted PB and actual PB probabilities.The calibration wasstudiedwith a

x

2_-test _with_two

degreesoffreedom.Discriminationwasexaminedusingtheareaunder the receiver operating characteristic (ROC) curve (AUC), graphic representationofthefalse-positiveratebasedonthesensitivityof eachmodelvalue.AUC>0.8representsanexcellentdiscriminating power,andisgoodwhencomprisedbetween0.7and0.8[16].AnAUC of0.5israndom.TheAUCisassociatedwith95%confidenceinterval (CI).TheoptimalthresholdvaluefortheriskofPBisthepointonthe ROCcurvethatisfurthestfromthediagonalandthatrepresentsthe zerocontributiontest[17].Allthetestsweretwo-sided.Thestatistical significancewasdefinedasP<.05.

Results Study

BetweenJuly2007andApril2012,813patientswereincluded. PCRscoreswereperformedon764vaginalsamples.Dataresults werereportedelsewhere[13].Inbrief,themeanmaternalagewas 29.4years(5.6)andthepercentageofmultiparous patientswas 17.5%.Meangestationalageofpregnanciesatinclusionwas26.3(5.1) wks.Atotalof220patients(28.8%)gavebirthbefore37wks,atotalof 142patientshadanobstetrichistoryofPBorlatemiscarriage.Among them,122women(86%)hadashortcervix.Acervixlength<25mm wasobservedin622patientswithoutadverseeventhistory.Basedon moleculardeﬁnitionofBV,70(9.2%)patientswereBVcarriers.

Amongwomenwhodeliveredprematurely,24(10.9%)hadBV versus46(8.5%)inthegroupwherewomendeliveredatterm. Predictivemodelofpretermbirthriskinhigh-riskpopulation

Theresultsoftheunivariateandmultivariateanalysisarelisted inTable1.Amultivariatelogisticregressionanalysisdemonstrated signiﬁcantandindependentassociationsbetweendeliverybefore

Table1

UnivariateandmultivariateanalysisofPretermbirthriskfactors.OR,oddsratio; aOR,adjustedOR;CI,conﬁdenceinterval;PB,pretermbirth;PROM,premature ruptureofmembranes.

Variables OR[CI95%] P aOR[CI95%]P HistoryofPB 1.5[1–2] 0.05*

3.6[1.2–11]0.019*

Historyoflatemiscarriage 1.2[0.7–1.9] 0.5 1.6[0.5–5] 0.41 Gestationalage 0.9[0.9–0.96]<.001*_0.9_{[0.8–0.9] 0.002}*

Bacterialvaginosis 1.3[0.8–2.2] 0.3 1.6[0.6–4] 0.33 Smokingduringpregnancy 1.2[0.8–1.7] 0.3 1.5[0.8–2.9] 0.23 Sonographiccervicallength 0.9[0.9–0.96]<.001*

0.9[0.8–0.9] 0.001*

HistoryofPB+cervicallength<25mm1.9[1.2–2.8] 0.002*

0.4[0.1–1.4] 0.16 Daytraveltime>30min 1.4[1.00–1.9]0.05*

2.6[1.4–4.9]0.002*

PROM 2.3[1.3–4.1] 0.002*_3.6_{[1.7–7.5]0.001}*

*

Signiﬁcantvariables. M.Gioanetal./JGynecolObstetHumReprod47(2018)545–548 546

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37wksandsonographiccervicallength,historyofpretermbirth, early gestational age at inclusion, premature rupture of mem-branes(PROM),andsuperiordailytraveltimeof30min.Historyof late miscarriage, combination of history of preterm birth and cervicallength<25mm,smokingduringpregnancyandmolecular

diagnosisofBVwerenotassociatedwithPBinourcohort,although these variables were signiﬁcantly associated with a PB in a univariate analysis in the preliminary study. The literature recognizesthesevariablesasriskfactorsforPB.Wehavechosen to integrate these elements into the calculator. The AUC after bootstrap for the validation set was 0.77 (95% CI; 0.72–0.81) (Fig.1).

We used500 bootstrap resamples for internal validation of accuracyestimatesandtoreduceoverﬁtbias.Themeanabsolute error was 0.018. The maximum error was 0.0682. The mean squarederrorwas0.00051.Itrepresentsthequalityofmeasureof anestimator,asaresultclosetozeroshowsgoodcalibration.We have therefore developed a nomogram to predict individual pretermbirthriskinasymptomatichigh-riskpopulation(Fig.2). The optimal predictive value of the PB risk in high-risk populationshasbeendeterminedfromtheROCcurve.Theoptimal probability thresholdis 23.2% which offers differentthresholds dependingonstatisticalvariables(Table2).Prioritizingsensitivity todeterminethethresholdtouseseemsessential.Itsuseinclinical practicewillallowminimisingtherateoffalse-negativeresults. Discussion

The present study developed a new predictive model for assessingtheindividualriskofPBinahigh-riskpopulation.Our nomogramevaluatesaprobabilityscorebasedonthemainwell known riskfactorsofspontaneousPBandincludesnewlyother risk factors. In our study according to literature [18], cervical lengthwasoneofthestrongestriskfactorforPBwiththehistoryof

Fig.1.ReceiverOperatingCharacteristiccurve:predictivemodeldiscrimination.

Fig.2.Nomogram.

Table2

Predictionoftheriskofindividualpretermbirthinhigh-riskpopulation.Se,sensitivity;Sp,speciﬁcity;LHR+,positivelikelihoodratio;LHR ,negativelikelihoodratio;PPV, positivepredictivevalue;NPV,negativepredictivevalue;95%CI,95%conﬁdenceinterval.

PBrate(%) [95%CI] 8 15 23,2 30 55 74 Se 100(95.4–100) 82(71.7–89.8) 74(63.2–83.6) 56(44.7–67.6) 23(14.3–34) 6.4(2–14) Sp 0(0.0–1.4) 52.3(46–58.4) 72.7(67–78) 80.7(75.4–85.3) 97.3(94.6–99) 100(98.6–100) LHR+ 1(1.0–1.0) 1.7(1.5–2) 2.7(2.2–3.5) 2.92(2.1–4.0) 8.7(3.8–20.1) NA LHR NA 0.34(0.2–0.6) 0.35(0.2–0.5) 0.54(0.4–0.7) 0.79(0.7–0.9) 0.94(0.9–1.0) PPV 22.8(18.7–27.5) 33.5(27.2–40.5) 44.6(36.3–53.12) 45.8(36.2–55.8) 72(52.4–85.7) 100(56.5–100) NPV NA 90.7(85–94.4) 90.6(85.8–93.8) 86.2(81.31–89.9) 81(76.4–85) 78.3(73.6–82.4)

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previousPB,PROMandlongdailytraveltime.Someofthelatest variableshaveneverbeenusedinanomogrambefore.Forexample ourresultsshowanindependentassociationbetweendailytravel timeand therisk ofPB and wasincludedin themodel.Active smokingwasalsoincludedinthemodel,evenifnon-signiﬁcantin ourresultsbecauseofitspreviouslywasreportedanassociation withPB(OR:1.27,95%CI:1.21–1.33)[19].PreviousPBwasastrong and independent risk factor for PB in our study as previously reportedin ameta-analysiswithanabsoluterecurrence riskof 20.2% (95% CI: 19.9–20.6) [2]. PROM was an independent and strongriskfactorforPBinourstudyandbuthadpreviouslybeen includedinarisk-calculatingnomogram[11,12].

Inourmodelbacterialvaginosiswasincludedevenifitdidnot increasetheriskforPBaftermultivariateanalysis.Theassociation betweenBVandPBhasbeenpreviouslyreported,withashorter time to delivery, reason why it was included in the model. A pregnantwoman carryingBV hastwicethe risk of givingbirth prematurely (OR: 2.16, 95% CI: 1.56–3.00) [20], especially if screening was performed early during pregnancy [6]. In this situationtheriskoflatemiscarriageissixtimeshigher(OR:6.32; 95%CI:3.65–10.94)[20].Neverthelessthescreeningandtreatment ofasymptomaticBVinlow-riskpatientsarenotrecommendedand remain controversial for high-risk patients [21,22]. Because of heterogeneousBVdeﬁnition,treatment,gestationalageat screen-ing.While waitingforthe resultsofan on-goingstudy[23],BV screeningandtreatmentarerecommendedforthesub-population ofasymptomatic patientswith a historyof adverseevents in a mother–foetalinfectiouscontext[24].

Areliablescreeningtoolshouldhelpforoptimalmanagement.The betteridentiﬁcationofhigh-riskPBpatientsbyusingapredictivetool couldlimitmedicalcosts.Thiscouldhelpalsotodecidethetimeof corticosteroidsinordertoavoidtooearlyorrepeatedtreatmentsthat couldbeinefﬁcientordangerousforchildren[25].

Ourpredictivetoolhasbeencreatedbasedonamulticentricstudy performedwithalargeFrenchcohortofpatients.Itcouldthereforebe reproducibleinhighriskpopulation.Untilnow,theonly recommen-ded monitoring tool was the length of the cervix or the foetal ﬁbronectinbetween16and22wks[26,27].Ourmodelproposesto personalisethecalculationofPBriskwithadditionalriskfactors.

Our study has some limits. To begin the use of molecular biologycannotbesetupeverywhereatthemoment.Ourmodel hasnotbeenvalidatedonanindependentpopulation. Wehave usedthere-samplingbybootstraptechniquetocounterthelackof external validity. The internal validity of our nomogram is improvedbyahighnumberofrepetitions.Unfortunately,atool isnotapplicabletopatientsatriskofpretermdeliveryformultiple pregnancyoruterinemalformation.Thelow-riskpopulationand inducedlabourarealsonotconcerned.Otherriskfactorsasthe numberofpreviousPBs,particularlyincaseofsuccessiveevents, andthegestationalofdeliveryofthepreviousPBcouldhavebeen alsoincludedinordertoimproveaccuracyofthenomogram[28]. Conclusion

Aninnovativecalculatortoolwasdevelopedinordertobetter deﬁne the individual risk of PB in high risk pregnancies. The accuracyofourpredictivetoolfortheriskofPBshouldbefurther evaluatedinaprospectivestudy.

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