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Cervical HI-RTE elastography and pregnancy outcome:
a prospective study
Laura Sabiani, Jean-Baptiste Haumonte, Anderson Loundou, Anne-Sophie
Caro, Julie Brunet, Jean-Francois Cocallemen, Claude d’Ercole, Florence
Bretelle
To cite this version:
Laura Sabiani, Jean-Baptiste Haumonte, Anderson Loundou, Anne-Sophie Caro, Julie Brunet,
et al..
Cervical HI-RTE elastography and pregnancy outcome: a prospective study.
European
Journal of Obstetrics & Gynecology and Reproductive Biology, Elsevier, 2015, 186, pp.80-84.
�10.1016/j.ejogrb.2015.01.016�. �hal-02914208�
Cervical
HI-RTE
elastography
and
pregnancy
outcome:
a
prospective
study
Laura
Sabiani
a,e,
Jean-Baptiste
Haumonte
a,e,
Anderson
Loundou
b,e,
Anne-Sophie
Caro
c,e,
Julie
Brunet
d,e,
Jean-Francois
Cocallemen
a,e,
Claude
D’ercole
a,b,e,
Florence
Bretelle
a,d,e,*
a
DepartmentofGynaecologyandObstetrics,AssistancePubliquedesHoˆpitauxdeMarseille(AP-HM),AixMarseilleUniversite´,AMU,Gyne´poleMarseille, HoˆpitalNord,ChemindesBourrely,13915Cedex20Marseille,France
bMedicalEvaluation,DepartmentofPublicHealth,AssistancePublique-HoˆpitauxdeMarseille,AMU,Aix-MarseilleUniversite´,Marseille,France cC2MA,EcoledesMinesd’Ale`s,Ale`s,France
d
CIC1409,AssistancePubliquedesHoˆpitauxdeMarseille(AP-HM),AixMarseilleUniversite´,AMU,HoˆpitaldelaConception,147bdBaille,13005Marseille, France
e
Aix-MarseilleUniversite´,Unite´ deRecherchesurlesMaladiesInfectieusesTropicalesetEmergentes,UM63,CNRS7278,IRD198,Inserm1095Marseille, France
Introduction
Preterm birth remains an important publichealth problem, responsible for 75% of perinatal mortality and morbidity and accountingfor7–12%ofdeliveriesworldwide[1].Recentliterature highlightstheneedfordevelopmentofinnovativeinterventionsto preventpretermbirth(PB)[2].
B-modeultrasoundusedtomeasurecervicallength,servesasa diagnosticandprognostictoolforassessingtheriskofPB[3–6].
Nonetheless,ithappens,afterall,thatwomenwithashortcervix givebirthatterm,andinversely,womenwithalongcervixdeliver preterm.Identificationofwomenatriskofpretermbirthinthe first trimester remains a real challenge [7]. Cervix ultrasound measurementgivesnoinformationconcerningtheconsistencyof thecervixwhichcouldhelptobetterdefinetheriskforpreterm birth.
Cervix elastography might improve the performance of ultrasoundscreeningevaluatingitsconsistency.Currently little-knowninobstetrics,elastographyprovidesinformationaboutthe mechanical propertiesof tissuesand canassesscervical consis-tency, using real-time color coding based on 2-dimensional imaging.Thistechniquehasbeendevelopedforstudyinguterine fibromasand,in particular,for cancersofthethyroid, prostate, liverandbreast[8–10].Intheseclinicalsituationsitispossibleto
Keywords: Transvaginalultrasound Pretermbirth Elastography Cervicallength ABSTRACT
Objective: Tostudycervixelastographymeasurementanditsrelationwithpregnancyoutcome. Design:AtwoyearprospectivelongitudinalstudyevaluatedcervicalelasticitybyHI-RTE(Hitachi real-timetissueelastography)imagingduringthreetrimestersofpregnancy.
Themainoutcomemeasurewaselastographyindexthecervicalelastogramcolor-coded. Results: Three hundred eighty seven measurements were realized among 72 pregnant women prospectivelyenrolled.Inthefirsttrimester,theelasticityindexwassignificantlylowerinwomenwho subsequentlyhadunfavorableoutcomethaninwomenwhodeliveredatterm(respectively,EI=0.51 (0.04)and 0.59 (0.02); P=0.037). Thenegative predictive valueofposterior lipcolor (blue, blue-green=hardcervix)washighNPV=83.895%CI[68.8–92.4]inthefirsttrimester(SE=64.795%CI[41.3– 82.7]; SP=60.8 95% CI [47.1–72.9]; VPP=35.5 95% CI [21.1–53.1]). A first-trimester elasticity index thresholdvalue0.38hadaspecificityof98.0%andaNPVof80.9%(Se29.4%,PPV83.3%).Thisindexvalue, whencombinedwithacervicallengthlessthanorequalto36mm,increasedtheriskofadverseoutcome(HR 8.8795%CI[3.22–23.7]).
Conclusions: Cervical elastography index is associated with unfavorable obstetrical outcomes, independentlyofcervicallength.
ThestudywasregisteredinClinicalTrials.govunderIdentifiernumberNCT01032564.
* Correspondingauthorat:DepartmentofGynaecologyandObstetrics,Hoˆpital Nord,ChemindesBourrely,13915Cedex20Marseille,France.
Tel.:+33491964853;fax:+33491964696.
quantifytissuestrain(deformation)withanalgorithmbasedona methodofextendedcombinedautocorrelation.Itsfirstobstetric usewasdescribedin2006,anditsfeasibilityandreproducibility forcervicalassessmentshavebeenpreviouslyreported[11–18]. During labor induction no elastographic cervical modifications throughalltrimestersofpregnancyinrelationtopretermdelivery havebeenobserved[16].Nonetheless,thesestudiesmostoften had few subjects, rarely detailed their measurement methods. Finally most explored 2nd or 3rd trimester of pregnancy and mainlyuncomplicatedpregnancies.
Theobjectiveofthisstudywastoexplorethecervicalelasticity throughoutpregnancyandevaluateitspotentialinterestasatool foridentificationobstetricalunfavorable outcomeina highrisk population.
Methods
Thisprospective,observational,pilotstudywasconductedina levelIIImaternitywardoveratwo-yearinclusionperiod(2010– 2012).Inclusioncriteriawerewomenatleast18yearsoldwith a singleton pregnancy that provided informed consent. The exclusion criteria were: suspected ectopic pregnancy, multiple pregnancy, substantial vaginal bleeding, maternal diabetes, hypertension,thepatient’srefusalorinabilitytoprovideinformed consent,andageyoungerthan18years.Theunfavorableoutcome groupwasdefinedbypretermbirth,needforemergencycerclage becauseof short cervix, prematurerupture of the membranes. The following characteristics were registeredfor each woman: age,parity,smokingstatus,workstatus,bodymassindex.
Each woman underwent an ultrasound screening during the first, second and third trimesters of the pregnancy; these examinations included transvaginal ultrasound elastography measurementsofthecervix.
After birth, the following additional data were collected: gestationalageatbirthandoccurrenceofobstetricalevents. ThetechniqueofHI-RTEelastography
Cervical elastographic measurements were performed on a standard2-dimensionalplane,thatis,thelongitudinalplaneofthe cervix,whichincludestheentirecervicalcanalfromtheinternalto theexternalorifice.Accordingly,wemeasuredthelengthofeach woman’scervixeachtrimester,beforetheelastography.
Thetechniqueof elastographyis usedtoevaluatethestrain distributionin tissueinresponse toexternalcompression. This straindistributionisusuallyrelatedtothedistributionoftissue elasticity:underlowlevelsofcompression,thetissue’smechanical response may follow Hooke’s law E=
s
/e
where E is Young’s modulus,s
thestressappliedbytheoperatoronachosenplane section, ande
the strain (relative elongation) of the observed section.Isotropicmechanicalbehaviorofthetissuewasassumed. Cervical elastography wasmeasured with a HITACHI-Hi-Vision ultrasoundsystemandahighfrequencytransvaginalprobe (EUP-V53W—5–9MHz)(HitachiEUB-8500,Wiesbaden,Germany).The correlationbetweenelasticityandstrainisdefinedasfollows:the softerthetissue,themoreeasilyitisstrained.Wecodedcolorsas follows:redissofttissue,greenintermediateandbluehard(Fig.1). Imagingthusmakesitpossibletomeasuretherelativeelasticityof thetissueofinterest.Byapposinganellipseatthetissuesite(with anareastandardizedat1cm2),itbecomespossibletodetermine elasticityindicesandtocolorcodetheelastogram(Fig.1).Basedon thestudyofthecolorcoding,acervixwasclassifiedassoftwhen thecolorrangedfromredtogreen,andashard,whenthecolor rangedfrombluetoblue-green.The real-time color coding must appear on the screen continuously.Toobtainit,movementsofcompression/relaxation
mustbecircumscribedandasregularaspossible,withregularand similarpressurerepresentedbythegreenscale3to4(Fig.1). Elasticitymeasuresandratios
For each woman, the following elastography measurements (expressed as percentages) were taken: the elasticity of the anterior and posterior lips on an area of 1cm2 at the upper, externalportion;anelasticityindexratio(EI)wasthencalculated: EI=E anteriorlip/(E anteriorlip+E posteriorlip). Elastography measurementinteroperatorvariabilitywasassessed.
The elastography measurements were realized by trained operators(mainlyJBH,LS).Twoindependentmeasurementswere realized during the first part of the study by two different operators.JBHdidthefirstmeasurement andsecondly another operatordidthesecondmeasurement.
The operators were blinded to the other elastography measurementsandtothefinalpregnancyissuebutnotblinded to the previous medical obstetrical history of women. The operators did not interfere in the medical treatment decisions during pregnancy and the statistical analysis was realized independently.Theelastographymeasurementresultswerenot giventothemedicalteam.
Statisticalanalysis
We used PASWSTATISTICS software Version 17 (SPSS Inc., Chicago,IL,USA).Abinomialproportionconfidenceintervalwas calculatedwiththeWilsonscoreandaKaplan–Meiercurveusedto evaluate the survival function and univariate Cox model to
Fig.1.Gradientofelastographycolorcodingandelastographicimageofcervix showingthemeasurementofitsanteriorandposteriorlipswithanellipseandcolor codingoftheelastogram.
estimateHazardratio(HR)withtheir95%Confidenceinterval.The receiver operating characteristic (ROC) curve was used to find optimalcut-offpointvalueforcervicallengthandEI.Atwo-sidedP valueoflessthan0.05wasconsideredstatisticallysignificant.The variabilityofthemeandifferencebetweenmatchedpairsofIEwas performed using paired student t test to assess inter operator variability.
Each woman received clear information about the study modalities and the anonymization of the data. Their oral and written consents were collected and recorded, in compliance withtheprotocolapprovedbytherelevantInstitutionalReview Board(Committeefortheprotection ofpersonsparticipatingin biomedical research, on November 4th 2009 CPP Marseille V (number09045),ELASTOGRAPHIEAORC2009,2009-A00814-53). Powercalculation. Cervicalmeasurementscandetect40%of the womenwhowillgivebirthprematurely.Ourtargetwastoscreen 60%ofthesewomenatotalof50womenwasnecessarytoobtaina statisticalpowerof80%.
Our study was a clinical research project funded by the Marseillepublichospitalsystem(AP-HM)andwasregisteredin ClinicalTrials.govunderIdentifiernumberNCT01032564.
Results
FromMarch2010throughMarch2012,thestudyprospectively included72 women, whose mean agewas 31 years (Table 1).
Table1summarizesthecharacteristicsofpregnancypopulation, 25%ofwomenhadanunfavorableoutcome.
Inter operator variability was assessed for elastography measurement.TwoEImeasurementswererealizedfor57women (79.1%) and show no significant difference (mean difference= 0.013; P=0.825). Three hundred eighty seven measurementswere realizedin 72 patients withtwo different operatorsmeasurementsateachtrimesterofpregnancy.
Cervicalmeasurements
Cervicallengthwassignificantlyshorteratallthreeultrasounds inthegroupofwomenwithanunfavorableoutcomecompared withwomenwithtermbirth(P<0.05)(Table2).Cervicallength lessthan orequal to36mmin thefirstquarter multiplied the riskofadverseoutcomeby6.36(HR=6.36,95%CI(2.39to16.92) Se38.9%,Sp94%,PPV70%,andNPV81.7%).
Cervicalelastography
Duringthefirsttrimester,theEIvaluewassignificantlylower forwomen withanunfavorable outcome,comparedwiththose who gave birth at term (0.51 vs 0.59; P=0.037) (Table 2). A threshold value of EI less than or equal to 0.38 yields had a specificityof98%(95%CI[89.9–99.7])andaNPVof81%(95%CI [69.6–88.8])(SE29.4%95%CI[13.3–53.1],PPV83.3%,95%CI[43.7– 97.0]).Thecolorcodingoftheposteriorliphadastrongnegative predictivevalue,withastrongprobabilityofnotadverseoutcome whenthecervixwashard(blue):theNPVwas80%,95%CI[58.4– 91.9] during the first trimester. SE=77.8 95% CI [54.8–91.0]; SP=31.495%CI[20.3–45.0],PPV=28.695%CI[17.8–42.4].
Analysis of cervical EI and color showed no significant differencesamongthe2ndand3rdtrimester(Table2).
Associationwithcervicalmeasurementsandcervical elastography
FinallyweassessthevalueofEIinassociationwithacervical lengthduringthefirsttrimester,inparticularamongwomenwith alongcervix.Therewasnocorrelationbetweenelasticityratios andcervicallength.Inthefirsttrimester,thecombinationofanEI valuelessthanorequalto0.38andacervicallengthlessthanor equalto36mm,increasedtheriskofanadverseoutcomeby8.87 (HR=8.87;95%CI[3.22–23.71],SE55.6%95%CI[31.3–77.6],SP 92.3%95%CI[80.6–97.5],PPV71.4%95%CI[42.0–90.4],NPV85.7% 95%CI[73.2–93.2])(Fig.2).
Comment
Thisprospectivestudyevaluatingcervicalelastographyamong pregnancyshowsthatitcan,atthefirsttrimester,madeitpossible toearlyidentifywomenatriskofunfavorableoutcomeandthis independently of cervical length. Our data are consistent with clinicalobservationfromdigitalcervicalexamination;softnessofa cervixattermisconsideredasfavorabletoinductionoflaborat term(aspartoftheBishopscore), andinthesamewayduring pregnancyariskfactorforPB.Evenifstillcontroversial,recently several teams proved the worth of cervical length in the first trimester, including measuring the isthmus length [7,18]. Our resultsconfirmthis,andshowinadditionthatanEI0.38onthe firsttrimesterultrasoundmightenhanceearlyscreeningofwomen atriskofunfavorableoutcome.
Themainstrengthsofthisstudyaretheserialmeasurements at each trimester during pregnancy and theexploration of the firsttrimestercervixelastography.Todatenostudyreportedthe interest ofelastography soearlyin pregnancy.Identification of womenatriskremainsachallengeinordertofindnewcluesto preventPB.
Ourstudyhaslimitationsrelatedtotheelastographytechnique and the study design. The dimension and location of the area of interest play a major role in the strain values obtained, independently oftheforceapplied[19].The precisesiteof the ellipse on thecervix,relative tothe probe,must betaken into account, becausethe tissuenear the probe deformsdifferently
[19].Thecoefficientofstrainisthushigherontheanteriorlips, closertotheprobe,thanontheposteriorlip.Tolimitthisvariation, wehave placed ourellipseon thesuperior,external portion of the cervix,a site chosen by earlier studies [15]. Moreover, the structureofthecervixisveryheterogeneous,composedasitisofa microstructure with layers of collagen, associated with cystic areas, blood vessels, and in thecentre, the endocervical canal. This heterogeneity can affectthe speed and the orientation of deformationandthusproducevaryingresults.Anotheraspectof cervicalstructural complexitythatalsoaffects theelastography
Table1
Clinicalpopulationcharacteristicsandpregnancy issue.
Clinicaldata (n=72) Age(years)(SE) 31.45(0.73) Parity1 46(63) Smoking 12(16) BMI25–29kg/m2 21(29) BMI>30kg/m2 14(19.4) Unfavorableoutcome 20(27.7) Pretermbirth 9(12.5) PROM 6(8.3) Emergencycerclage 5(6.9) BMI: body mass index, unfavorable outcome including preterm birth, premature rupture of membranes(PROM),needforemergencycerclage becauseofshortcervix.SE:standarderrorofthe mean.Exceptasspecificallyspecified,allvaluesas expressedasn(%).
measurementsisitscylindricalshape.Nonetheless,despitethese limitations,Fruscalzoetal.,hasshownthatthesemeasurements arereliable,especiallyfortermpregnancies[17].Inourstudy,the colorofthecervicalposteriorlipwasmorevaluablethananterior’s. Thishasbeenrecentlydiscussedandsomeauthorsfoundinversely toourfindingthatelasticityofcervixwaslinkedwithitslength
[20–22].Noclearexplanationisavailabletodatebutit’sadmitted that elastography measurement presents variability in relation with the pressure applied on the cervix. The methods of measurement are different among studies, for example Fuchs et al.do notuse a ratiobut elastographymeasurements ofan interestregionsetontheanteriorandtheposteriorcervicallip
[21].Anotherexplanationconcernsthegestationalageatmeasure. The results can be considerably different in comparison with 2ndorthirdtrimesterofpregnancybecauseofcervicalconsistency andtheapplypressurebecausetheorientationofcervixcanbe modifyamongtrimester.
AnotherissueishowtointerprettheEIvalue.Relyingonthe reasoningestablishedforothertissues.Inthebreastinparticular,a ratiothatcompareshealthytounhealthytissuehasbeenpropose. Inothertissuetypes,alowEIindicatesfairlyhardtissueandahigh EIratiosofttissue.Itisdifficulttoextrapolatethisinterpretationto the cervix,since there is no referencetissue. Our results have enabledustoconcludethatalowEIcouldplayaroleinthe first-trimesterpredictionofPB,butdonotjustifyanaffirmationthata lowvalueisequivalenttoasoftcervix.
Ourstudytookplaceinahighriskpopulation.Ourresultcould befurtherstudiedinamulticenterstudyandinapopulationmore representativebeforebeingroutinelyused.Themeasurementof theEIisthoughtnottoberelatedtothepressureappliedbythe operatorsinceitinvolvedaratio.Neverthelessitisexpectedthat thevalueoftheappliedpressureshouldnotexceedacriticalvalue thatwouldinvalidatetheassumptionoflinearelasticity;onthe otherhand,thecolorcodingisrelatedtopressureandmighthave influencedtheresults.
Several studieshavealreadydemonstratedreproducibilityof elastographymeasurements[17,19].Nonetheless,standardization ofthesettingsfortheelastographydevicesisnecessary,especially for the contact and velocity pressure. Under a low level of deformation,themechanicalbehavioroftissuecanbeconsidered as elastic; in some cases the elastic modulus is time and temperaturedependent [21]. Moreover someauthors havealso detected a non-linearity in mechanical behavior that calls into questionthevalidityoftheelasticassumption[22].Ourprotocol enablesanassessmentofelasticitybutinthefutureitmightbe necessarytoevaluatethedependenceofEIontimeandpressureto maketheprotocolfullynon-operatordependentandtocheckthe elasticityassumption(bymonitoringthestressandstrain).
An ultrasound transducer-type automated system, mounted ina mechanicalpistonthatregulatesthecompression,isunder evaluation[23].Currently,itiswidelyusedinliverdiseasetoavoid hepaticpuncture[24].
Some efforts should be made to standardize application pressuremethods,shearstressmethodscoulddecreasethisneed, butthisshouldalsobeexplore.
Firsttrimestercervicalelasticityappearstobeassociatedwith obstetrical outcome. Complementary research should work on standardizationofmeasurementmethods.
Disclosure
TheauthorsreportthatHitachilendtotheGynepoleMarseille anHITACHIHi-Visionultrasonographer withtransvaginalprobe (5–9MHz,Hybridgeneration)for6months.
Table2
Elasticityindex,ultrasoundmeasurementsofcervicallengthamongtrimester.SE:Standarderrorofthemean.EIElasticityindex(EI=Eanteriorlip/(Eanteriorlip+Eposterior lip).
Unfavorableoutcome(n=20) Atterm(n=52) P Eanteriorlip(SE) 1stT 0.53(0.06) 0.54(0.04) 0.879
2ndT 0.80(0.10) 0.79(0.04) 0.881 3rdT 0.52(0.05) 0.77(0.05) 0.002 Eposteriorlip(SE) 1stT 0.47(0.07) 0.37(0.03) 0.119 2ndT 0.48(0.08) 0.42(0.03) 0.433 3rdT 0.51(0.11) 0.49(0.03) 0.827
EI(SE) 1stT 0.51(0.04) 0.59(0.01) 0.037
2ndT 0.62(0.04) 0.65(0.02) 0.59 3rdT 0.54(0.06) 0.61(0.02) 0.257 Cervicallength(mm)(SE) 1stT 38.39(1.8) 47.85(1.13) 0.001 2ndT 34.63(5.02) 46.39(1.67) 0.007 3rdT 23.62(5.50) 39.47(1.38) 0.01
Fig.2.Proportion ofwomenundeliveredaccordingtogestationalagefor:a cervicallengthmeasurement36mm(continuousblackline–––),anelasticity index0.38andcervicallength>36mm(discontinuousline---)oranelasticity index0.38(–––).
Condensation
Cervical elastography index is associated during the first trimestertofurther unfavorable obstetricaloutcomes, indepen-dentlyofcervicallength.
Conflictofintereststatement
Hitachi lendtotheGynepoleMarseilleanHITACHIHi-Vision ultrasonographerwithtransvaginalprobe(5–9MHz)for6months. Ethicsapproval
TheprotocolwasapprovedbytheInstitutionalReviewBoard (Committee for the protection of persons participating in biomedical research, on November 4th 2009 CPP Marseille V; number09045),ELASTOGRAPHIEAORC2009,2009-A00814-53. Funding
AssistancepubliquedeshoˆpitauxdeMarseille(AP-HM)funded thisresearch(NationalPublicGrant).Thisstudywasregisteredat ClinicalTrials.gov,IdentifierNCT01032564.
Acknowledgements
Marie-Alice Coullomb, Claire Tourette, Melinda Petrovick, RenaudLeDu,AuroreAziz,SophieHamouda,Emannuelle Assou-line and Christelle Arbola for cervical length and elastography measurement.
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