A self-administered questionnaire to measure the painful symptoms of endometriosis: Results of a modified DELPHI survey of patients and physicians.

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Original

Article

A

self-administered

questionnaire

to

measure

the

painful

symptoms

of

endometriosis:

Results

of

a

modiﬁed

DELPHI

survey

of

patients

and

physicians

A. Fauconnier

a,b,

*,

S. Staraci

b

,

E. Daraı¨

c

,

P. Descamps

d

,

M. Nisolle

e

,

P. Panel

f

,

H. Roman

g

,

R. Boulkedid

h,i

a

Departmentofgynecologyandobstetrics,centrehospitalierintercommunaldePoissy–Saint-Germain,universityofVersaillesSaint-Quentin(UVSQ),10,rue duChamp-Gaillard,78103Poissy,France

b_Research_unit_EA7285,_risk_and_safety_in_clinical_medicine_for_women_and_perinatal_health,_Versailles_St-Quentin_University,₇₈₁₈₀_{Montigny-le-Bretonneux,}_France c

Departmentofgynecologyandobstetrics,hoˆpitalTenon,75970Paris,France d

Departmentofgynecologyandobstetrics,Angersuniversityhospital,49033Angers,France e

Departmentofgynecologyandobstretrics,LaCitadelleregionalhospitalcentre,Lie`ge,Belgium f

Departmentofgynecologyandobstetrics,Andre´-Mignothospitalcentre,78157Versailles,France g

Departmentofgynecologyandobstetrics,Rouenuniversityhospitalcentre,76031Rouen,France h_Clinical_epidemiology_unit,_{Robert-Debre´ hospital,}_AP–HP,₇₅₀₁₉_Paris,_France

i_UMR-S₁₁₂₃_and_CIC-EC_1426,_ECEVE,_Paris_Diderot_university,_Sorbonne_Paris_Cite´,₇₅₀₁₀_Paris,_France

Introduction

Endometriosisisapainfulchronicdiseaseaffectingabout10%

of women in Organisation for economic co-operation and

development (OCDE)countries[1].Endometriosisisresponsible JGynecolObstetHumReprod47(2018)69–79

ARTICLE INFO Articlehistory: Received15July2017

Receivedinrevisedform3November2017 Accepted6November2017

Availableonline10November2017 Keywords:

Endometriosis Painsymptoms Questionnaires Delphimethods

Patient-relatedoutcomemeasures

ABSTRACT

Purpose.– Todevelopaquestionnairebasedonpatients’verbaldescriptors,tomeasurethepainful symptomsofendometriosis.

Methods.– Weperformedatwo-roundmodifiedDELPHIproceduremixingendometriosispatientsand physicianstoselectasetofstatementstodescribethepainfulsymptomsofendometriosis.Eachpanelist rated each statement based on diagnosis validity and clarity. The clinicians were experts in endometriosismanagementselectedfromvariousgeographicregionsinFrance.Patientswerewomen withsurgicallyconfirmedendometriosiswhovolunteeredfromapatientassociationandfromthe recruitmentoftheparticipatingphysicians.Thefirstroundquestionswerederivedfromwordsand phrasesinnarrativesofpainbyendometriosispatients.

Results. –Overall, 76 experts were invited, and of these 56 (74%), comprising 33 patients and 23gynecologists,respondedtothefirstroundquestionnaire,and40(71.4%)tothesecondround.Among the48statementsassessedinthefirst-roundquestionnaire,11wereselectedaftercompletionofthetwo roundDELPHIprocedure.Afterdiscussionandrewordingofsomeitems,atotalof21questionswere selectedduringafinalface-to-facemeeting.Thecontentofthefinalquestionnaireisorganizedaccording tofourdimensions:(i)spontaneouspelvicpainanddysmenorrhea,(ii)dyspareunia,(iii)painfulbowel symptoms,(iv)andothersymptoms.WealsoprovideanEnglish(UK)versionproducedusingseveral stepsoftranslationandback-translation.

Conclusions.–Thequestionnairehascontentvaliditytomeasurethesubjectiveexperiencesofpatients withpainfulendometriosisandcanprovideasolidbasisonwhichto developanefﬁcient patient-centered outcome to measure the painful symptoms in therapeutic or in diagnostic studies of endometriosis.

C ₂₀₁₇_Elsevier_Masson_SAS._All_rights_reserved.

* Correspondingauthorat:Department ofgynecologyandobstetrics, centre hospitalierintercommunaldePoissy–Saint-Germain,universityofVersailles Saint-Quentin(UVSQ),10,rueduChamp-Gaillard,78103Poissy,France.

E-mailaddress:afauconnier@chi-poissy-st-germain.fr(A.Fauconnier).

Available

online

at

ScienceDirect

www.sciencedirect.com

https://doi.org/10.1016/j.jogoh.2017.11.003

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forvariouspelvicpainsymptoms[2]thatcanhaveagreatimpact onallaspectsofthelifeofendometriosispatients[3].

MeasuringpainsymptomsandHealth-relatedqualityoflife

(HrQol)inendometriosispatientswasusefultoassesstreatment outcomeinclinicaltrialsincludingmedicaltherapy,orsurgery

[4,5].Variousmethodsofpainassessmentareavailableinthe

contextof endometriosis,some ofwhich havebeen validated

withahighlevelofevidence.Thevisualanalogscale(VAS)and

thenumericalratingscale(NRS)arethemostfrequentlyused

pain scales to assess each type of typical pain related to

endometriosis (dysmenorrhea, deep dyspareunia and

non-menstrual chronic pelvic pain). Although these scales are

appropriate for the measurement of the individual pain

symptoms[6],theydonottakeintoaccounttheheterogeneity ofthepainfulsymptomsofendometriosis.Furthermore,eachof

thepainsymptomsthatmayrelatetoendometriosisinvolves

numerous distinct descriptors and there was considerable

variability in symptom description and interpretation by

patientsandbyphysicians[7].

Therefore,thereisaneedforreliableandwell-deﬁned patient-reportedoutcomemeasures(PRO’s)thatcanbeusedtodetermine theclinicalbeneﬁtofmedicalinterventionsand/orpromoteearly diagnosisofendometriosis[8].Importanteffortshavebeenmade

todevelop and validate HrQol questionnaire in the context of

endometriosis,seeforexampleSF-36[9],orThe‘‘Endometriosis HealthProﬁle 30’’(EHP-30),specially developedto capture the impactofendometriosison speciﬁc domainsof HrQol[10].

Al-thoughendometriosissymptomquestionnaireshavealreadybeen

usedinanepidemiologicalsurveys[11]andinclinicalstudies[12],

to the best of our knowledge, the various existing pain

questionnaires and pain scales to assess symptoms related to

endometriosiswereprimarilydevelopedonthebasisofclinician input.Currently,therearefewdataonthepatients’descriptionsof symptomsandatthepresenttime,noquestionnaireisavailableto obtaindatafrompatients.

In a previous study, by analyzing in-depth interviews with

endometriosispatients,weidentiﬁednumerousverbaldescriptors representingthepatients’experience[7].Here,wedescribea ﬁrst-stepquestionnairedevelopmentbasedontheseverbaldescriptors

tomeasurethechronicpainsymptomsofendometriosisusinga

PRO’sapproach.Toachieve this,consensusneeds tobereached

amongthevariousstakeholdersinvolvedin thecareofwomen

withendometriosisaswellaspatientrepresentatives.Theaimwas toselectasetofrelevantstatementsbasedonpatients’perception

of painful symptoms to construct a short, standardized

self-administeredquestionnaire.

Methods

Weconductedatwo-roundmodiﬁedDELPHIsurveyamonga

multidisciplinaryexpertpanelcomprisingendometriosispatients

and physicians, whether gynecologists or not, involved in the

diagnosisandtreatmentofendometriosis.TheDelphimethodisa

practical and structured method to achieve a convergence of

opinionandageneralconsensusonaparticulartopicfromalarge

number of individuals. It has been used to develop medical

recommendations clinical guidelines, questionnaire or clinical

indicators such as indicators reﬂecting patient and general

practitionerperceptionsofchronicillness.Theparticipantstake

part anonymously in sequential questionnaires that constitute

different rounds [13]. The panellists rate the statements, and statementsmadebyparticipantsateachroundoftheprocesscan beusedtoformulatethenextroundofquestions.Forthepurpose ofthepresentstudy,weusedamodiﬁedDelphitechniqueinwhich questionnaireroundswerefollowedbyaphysicalmeetingofthe

panellists,toenhancethecomplexdecision-makingprocessandto clarifythelanguageusedtodescribeeachstatement[14]. Pre-selectionofstatements

First round questionnaire statements were developed from

previousqualitativeresearch[7]:Thestatementswerebasedon thefully-comprehensivedescriptionsofpainfulsymptoms

obtai-ned by qualitative, interview-based study and analyzed using

Colaizzi’s method[15], withendometriosis patients selectedto representdifferenttypesofendometriosis(i.e.superficial endo-metriosis,ovarianendometriosis, ordeeplyinfiltrating endome-triosis [DIE]).Toensurea properformulation ofthefirstround statements,wefirstdesignedanin-personfocusgroupdiscussions

with eights subjects with endometriosis and interested in

describing the word of pain (these subjects were not further

involved in the DELPHI). The discussion was centered on the

meaningofthewordsandsentencesusedtodescribe endometri-osispainrelatedsymptomsinordertoreformulatesomeofthe itemsandtoclarifysomeofthesentencesused.Nophysicianwas presentatthetimeofthefocusgroupdiscussion.Theparticipating

womenalsorecommendedtoaddtwothemes‘‘fearsfromsexual

intercourse because of the pain’’ #26 and ‘‘difficulties to get pregnant’’.Intotal,48statementswereidentifiedandwereused forthefirstroundquestionnaire.Thesestatementsfallintofive generalcategories:

severepelvicpainanddysmenorrhea(n=21); dyspareunia(n=6);

gastro-intestinalsymptoms(n=8); painfulurinarytractsigns(n=6); othersymptoms(n=7).

Panelmembers

Toformarepresentativeexpertpanel,theaimwastogathera heterogeneousgroupinordertoensurethatthebroadestspectrum ofopinionwasobtained.Theclinicianswererecognized

French-speaking experts in endometriosis including gynecologist

sur-geons,specialistsinreproductivemedicineandspecialistsinpelvic

imaging. They were selected from various geographic regions

within France and Belgium, and were in practice in university

teachinghospitals,generalhospitalsorinprivatecenterstoensure

that they represented a wide array of clinical approaches,

backgrounds and practices. The panelists werealso selectedto representabroadrangeofageandexperiencelevels.

Endometri-osispatients werevolunteers diagnosedwithendometriosis by

surgery;thepatientscamefromaFrenchassociationofpatients

with endometriosis (Endofrance, http://www.endofrance.org/)

and from the recruitment of the participating physicians. We

plannedtoincludeabout30panelistsbystakeholdercategory(i.e. physiciansandpatients).

Firstround

The panelists who agreed to participate received the ﬁrst

questionnairebye-mail.Non-responderswerere-contactedby

e-mail and telephone. Each panelist was invited to rate the

48statementsfortwoaspects:

diagnosis validity, i.e. the statement had the appropriate

characteristicstoeffectivelydiagnoseendometriosis,it appea-red tobe sufﬁciently sensitive and/orspeciﬁc tohelp detect endometriosispatientsfrompatientswithotherdiseasesorfree ofanypathology;

A.Fauconnieretal./JGynecolObstetHumReprod47(2018)69–79 70

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clarity, i.e. the statement is expressed in clear, precise and unambiguoustermsforbothcliniciansandpatients.

Diagnosis validity and claritywere each rated on a 9-point

scale, where 1 meant deﬁnitely not valid or not clear and

9 deﬁnitely valid or clear statements. The questionnaire also

invitedthepaneliststocommentoneachofthestatementsandto suggestadditionalstatementsnotincludedinthelist.

Thecentraltendencywasbasedonthemedianoftheratings

andagreement among panelistsexpressedas a percentage.We

selectedstatementsforwhichaconsensuswasachievedregarding diagnosisvalidityandclarity:i.e.forwhichthemedianscorewas inthetoptertile(7–9)andatleast65%ofpanelratingswereinthe toptertile,forbothdiagnosisvalidityandclarity.

Ifconsensuswasachievedregardingdiagnosisvalidityonly,the

statement could be rephrased according to the panelists’

commentsand proposedfor ratingin thesecondround. Atthe

endoftheﬁrstround,thequestionnairewasmodiﬁedandsome

statements were added or modiﬁed to take the panelists’

comments and suggestions into account. When the experts’

commentsseemrelevant,deletedstatementswereeithermodiﬁed

oraddedinthesecondroundwithoutanymodiﬁcation.

Secondround

Eachofthepanelistswhohadparticipatedintheﬁrstroundwas sentthesecond-roundquestionnairebymail.Thesepanelistswere alsogivenfeedbackontheresultsoftheﬁrstround(medianpanel ratingfordiagnosisvalidityandforclarity,frequencydistribution and their individual ratings). They were asked to re-rate each

statement based on both their own opinion and the panel

responsesobtainedduringtheﬁrstround.Tobeincludedinthe ﬁnalset,statementshadtohavemedian diagnosisvalidityand clarityratingsinthetoptertile(7–9)and75%agreementamong panelists that the rating was in the top tertile [14]. We also

compared patients’ and practitioners’ responses in term of

statementsselected. Face-to-facemeeting

Allpanelmembers wereinvited for this consensusmeeting

during which an overview of the results of the second round

ratingswasprovided.Themeeting waschairedby threeof the

authors (A.F., S.S. and R.B.).Results of the second round were discussed to identify areas of disagreement. This meeting also allowedclariﬁcationorrephrasingofacceptedstatements. TranslationintoEnglishoftheﬁnalsetofquestions

The translation was performed according to previously

publishedguidelines[16].ThreenativeEnglish-speakingwomen, bilingualinFrench,involvedinthefieldofgynecologytranslated theFrench version into an English draftversion. Together, the translatorsconsolidatedtheirtranslationsintoasinglefirstEnglish version.Then,threeFrenchnativebilingualhealth-careproviders experiencedingynecology,back-translatedthisfirstversioninto French(withouthavingseentheoriginalFrenchversion).Thethree initialtranslatorsthenreviewedthethreeback-translationagainst

the original English version, and provided a ﬁnal forward

translation. Results

Seventy-six patients and obstetricians/gynecologists were

invited to bepart of the DELPHI expert panel. The panelthus

consisted of 40 obstetricians/gynecologists and 36 patients.

Amongthem,56(74%)respondedtotheﬁrstroundquestionnaire. Ofthese,33werepatientsand23wereobstetricians/gynecologists (alllistedinalphabeticorderinthe‘‘Acknowledgment’’section).

Table 1 reports the main characteristics of the panelists who respondedtotheﬁrstroundquestionnaire.

Fig.1showstheworkﬂowofstatementsthatwereincluded,

deletedorsuggestedineachofthetworoundsandtheface-to-face

meeting. The ﬁnalresultswith levelsof agreement in the two

roundsarepresentedinTable2.

The ﬁrst round was performed from 15th January 2014 to

13thOctober2014.‘‘#2:verypainfulmenstruation’’and‘‘#29pain whenpassingastool,painfulbowelmovements’’hadthediagnosis validity ratingswiththestrongest agreement(respectively 93% and83.3%).‘‘#31:diarrheaduringmenstruation’’hadtheclarity ratingswiththestrongestagreement(96%).Twenty-threepercent ofstatementsreachedthefirstlevelofconsensus(11/48).Among these11statements,only4werenotmodified(‘‘#2:verypainful menstruation’’, ‘‘#24: pain in certain positions during sexual intercourse’’,‘‘#25: deepinternal pain feltduring sexual inter-course’’and‘‘#49:difficulttogetpregnant’’).Onestatement‘‘#22:

strong, sharp pain during sexual intercourse’’ was discarded

becauseitwasmergedwith‘‘#23:distractingpainthatpreventsor interruptssexualintercourse’’(Table2).Twentyotherstatements werediscarded(42%)becausetheydidn’treachtherequiredlevel

of consensus.16/48 (33%) statementsdidn’treachedconsensus

level but were maintained based on the feedback from the

participants.Modiﬁcationsweremadeto11ofthesestatements (Table2).Onenewstatementwasadded(needtostraintostart passingwater,difﬁculttoemptythebladdercompletely,especially duringmenstruation),producing28statementstoberatedforthe secondround.

The second round was conducted between November 11,

2014 andApril 01, 2015.Itwascompletedby 40(40/56: 71%)

panelists. Of these, 20 (50%) were patients and 20 (50%) were

clinicians.Atthisstepoftheprocess,28statementsweretherefore evaluated,includingmodiﬁed,retainedoradditionalstatements. Thepanelselected11/28(39%)ofstatementsasvalid.Amongthese ‘‘# 24:pain in certainpositionsduring sexualintercourse’’ and

‘‘#29: painwhenpassingastool.Bowelmovementsarepainful

duringmenstruation’’againshowedthestrongestagreementfor

diagnosis validity (respectively 100% and 94.4%). Seventeen

statementswerediscarded.Amongthese,12werethesubjectof adifference inopinionbetweenpatientsandphysicians,i.e.the obstetricians/gynecologists discarded allof themwhilepatients retainedallofthem(Table3).

Table1

Characteristicsofthepanelists.

Characteristic n Median(Q1–Q3) % Totalparticipants 56 Female 38 68 Male 18 32 Patients 33 Physician-basedrecruitment 15 45 Association-basedrecruitment 18 55

Ageofpatient,years(range) 35(31–37) Meantimesincediagnosis,years(range) 2(1–4)

III-IVstage 19 58

Intestinalendometriosis 7 21

Physiciansa

23

Ageofphysician,years(range) 49(44–57) Yearsofpractice(range) 18(11–29) Practicelocation

Teachinghospital 14 61

Non-teachinghospital 3 13

Privatepractice 6 26

a

Twenty-twoweregynecologistsandonearadiologist.

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Face-to-facemeeting

During thephysical meeting,3 patients and 6obstetricians/ gynecologistswerepresent.Theyﬁrstdiscussedthe11statements thatwereselectedinthesecondround.Allwereacceptedbutsome modiﬁcationsweremadetoimprovefaceandcontentvalidityfor

6 of them: for example ‘‘# 2:very painfulmenstruation’’ was

replaced by ‘‘pain located in the lower abdomen during

menstruation’’, ‘‘# 25: deep internal pain felt during sexual

intercourse’’into‘‘Intense,sharppaindeepinsideduringsexual intercourse’’.Forpainfulbowelsigns,theterm‘‘during menstrua-tion’’wasreplacedby‘‘especially(worse)duringmenstruation’’ (Table 2). Secondly, the 12 statements where patients and physiciansdidnotagree(Table3)werediscussed.Ofthese,6were deﬁnitivelydiscarded,mostlybecausetheydidnotprovideuseful

information at the medical level and/or may have multiple

interpretations(i.e. ‘‘# 15:pain located in theovaries’’,‘‘# 14:

uterine cramps’’, or ‘‘# 34: Bloating, bloated abdomen during

menstruation’’).Conversely, fouramong thesestatements were

ﬁnally re-instated because the practitioners and the patients

agreedthatthesestatements,althoughtheywerenotdiscriminant

for the diagnosis of endometriosis, they reﬂected well the

perceptionthat thepatients hadof theirpainsymptoms: ‘‘# 6: Painstartsafewdaysbeforemenstruationbeginsandcontinues fora few days aftermenstruationhasstopped’’; #17: thepain spreadsto your back, in the lower backarea’’;‘‘#18: thepain spreadstothelegsandhips;‘‘#20:painmakesstanding,walking

or moving difﬁcult if not impossible’’. Two statements were

reformulated:‘‘#1:painlocatedinthelowerabdomen’’became ‘‘Painlocatedinthelowerabdomen,outsidethemenstrualperiod’’ and‘‘#31:diarrheaduringmenstruation’’became‘‘Diarrheaand/

or constipation especially (worse) during menstruation’’. Two

statements regarding painful urinary tract signs that were

discarded during theﬁrst round, ‘‘# 36: theurge tourinate is painful,painwhenurinatingespeciallyduringmenstruation’’and ‘‘#42:needtostraintostartpassingwater,difﬁculttoemptythe bladdercompletely,especiallyduringmenstruation’’weremerged

into ‘‘difﬁculty and/or pain when urinating especially during

menstruation’’. One statement ‘‘#43: sciatica during

menstrua-tion’’, also discarded during the ﬁrst round, was added after

discussion by the panelists present at the meeting, producing

20statementsdeﬁnitivelyselected(Table2).

Participantswerealsoaskedtochoosethemeansofresponse betweenseveralproposalsfortheself-administeredquestionnaire

based on the selectedstatements. Theypointed out that some

questions(eg:#6or#18)naturallycallforayesornobinary

answer, whereas other questions that would give rise to a

numericalintensityresponse.Inordertomakeallthequestions homogeneousandtoallowestablishmentofscoresinthefutureit wasdecidedtochooseamixedmethodincludingabinaryanswer in‘‘Yes’’or‘‘No’’followedwitharatingofthesymptomby11-point NRS,including0.Assomeofthepainfulsymptomswerefoundto varyacrossthetime,itwasdecidedtoprovidetwodistinctNRSto describethepainintensityofthesymptomonaverage,andatit

worstmoment.

Thefinalquestionnairewasthenassessedinapilotstudyof 18endometriosispatientswhofilledoutafirstdraftversion(n=6) andthenafinalversion(n=12)ofthequestionnaire.Duringthe testphaseofthequestionnaire,thefirstversionunderwentseveral

minor modiﬁcations toincrease comprehensionand feasibility.

Thesecondanddeﬁnitive versionwaswellaccepted.Following

remarks made by two patients, with documented bladder

1rst ROUND 2nd ROUND Physical meeting 48 statements 17 statements discarded

- 12 with difference in opinion between patients and physicians - 5 without difference in opinion between patients and physicians 1 new statement

5 deleted but maintained 11 deleted but modified

28 statements

11 statements selected

21 statements discarred 7 items selected and

modified 28 statements discussed 9 statements discarded 9 statements modified 10 statements selected 1 statement added

Fig.1.Flowchartofstatements.

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Table 2

Results of round 1, 2 and panel physical meeting concerning the 48 statements scored in the ﬁrst round.

Round 1 Round 2 Physical meeting

# Item Diagnosis

validity

Clarity Status Modiﬁcation Diagnosis validity

Clarity Status Status Modiﬁcation Pelvic pain and dysmenorrhea

1 Lower abdominal pain 7 (54.5) 8 (77.8) Modiﬁed Pain located in the lower abdomen

7 (57.9) 8 (83.8) Discarded but discussed

Modiﬁed Pain located in the lower abdomen, outside the menstrual period

2 Very painful menstruation 9 (92.8) 9 (94.2) Retained 9 (91.9) 9 (100) Selected Modiﬁed Pain located in the lower abdomen during menstruation 3 Pain that is intense,

overwhelming, violent, unbearable

8 (64.2) 8 (72.7) Modiﬁed The pain is very intense; it is violent, obtrusive, unbearable

8 (76.3) 8 (78.4) Selected Selected

4 The pain increases in intensity over time

7 (66.1) 8 (72.7) Modiﬁed As the years go by, the pain gets worse with time

7 (86.8) 8 (89.2) Selected Selected 5 The pain lasts longer than

menstrual pain, and continues after the bleeding has stopped

7 (55.4) 8.5 (79.6) Discarded / / /

6 Pain starts a few days before menstruation begins

7 (50.9) 9 (90.4) Modiﬁed Pain starts a few days before menstruation begins and continues for a few days after menstruation has stopped

Selected

7 Pain before, during and after menstruation

7 (54.5) 9 (83.0) Discarded / / /

8 Pain depends on the time of the monthly cycle

7 (52.7) 7 (57.4) Discarded / / /

9 Pain throughout the monthly cycle, present all the time

6 (47.3) 8 (77.8) Discarded / / /

10 Continuous pain with peaks or attacks of more intense pain

7 (56.4) 8 (72.2) Discarded but maintained 7 (68.4) 8 (86.1) Discarded but discussed

Discarded Redundant with item #11

11 Stabbing pain 9 (83.0) 7 (59.2) Modiﬁed The pain comes by ﬁts and starts, a stabbing pain

8 (72.9) 8 (75.7) Selected Selected 12 Prickly pain, like being pricked

or having an injection

5 (27.8) 8 (69.8) Discarded / / /

13 Lower abdominal burning pain 5 (31.5) 8 (71.7) Discarded / / /

14 Uterine cramps 6.5 (50.0) 8 (66.7) Discarded but maintained 6 (40.5) 8 (70.3) Discarded but discussed

Discarded 15 Ovarian pain 7 (57.4) 8 (61.5) Modiﬁed Pain located in the ovaries 6 (45.9) 8 (69.4) Discarded but

discussed

Discarded 16 Pain on one side, pain stronger

on one side

6 (40.7) 8 (77.3) Discarded / / /

17 Pain spreads towards the back 7 (53.8) 9 (75.5) Modiﬁed Pain spreads towards the back, in the lumbar area

Selected 18 Pain spreads to the legs and

hips

Selected 19 Different types of pain at the

same time, several different pain symptoms

Discarded

20 Paralyzing, handicapping pain that affects mobility, difﬁculty walking

6 (49.1) 8.5 (73.1) Modiﬁed Pain makes standing, walking or moving difﬁcult if not impossible 7 (55.6) 9 (88.6) Discarded but discussed Selected A. Fauconnier et al. / J Gynecol Obstet Hum Reprod 47 (2018) 69–79 73

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Table 2 (Continued )

# Item Diagnosis

validity

Clarity Status Status Modiﬁcation

21 Pain interferes with daily life 9 (79.2) 9 (86.5) Modiﬁed Pain makes normal daily activities difﬁcult or impossible

8 (77.8) 9 (97.2) Selected Selected

Dyspareunia

22 Strong, sharp pain during sexual intercourse

7.5 (67.3) 9 (80.4) Discarded / / /

23 Distracting pain that prevents or interrupts sexual intercourse

8 (73.6) 9 (90.2) Modiﬁed Intense, sharp and disruptive pain, preventing or interrupting sexual intercourse

8 (78.4) 9 (97.1) Selected Modiﬁed The pain interferes with, prevents or interrupts sexual intercourse 24 Pain in certain positions during

sexual intercourse

8 (81.1) 9 (94.2) Retained 8 (100) 9 (100) Selected Selected 25 Deep internal pain felt during

sexual intercourse

8 (80.8) 9 (90.0) Retained 8 (89.2) 9 (100) Selected Modiﬁed Intense, sharp pain deep inside during sexual intercourse 26 Nervous about having sexual

intercourse because of the pain

8 (65.4) 9 (86.0) Modiﬁed Nervous about having sexual intercourse because of the pain, vaginismus

Discarded

27 Burning feeling during or after sexual intercourse

5 (37.8) 9 (76.5) Discarded / / /

Painful bowel signs

28 Anal pain 5 (37.0) 9 (78.4) Discarded / / /

29 Pain when passing a stool, painful bowel movements

8 (83.3) 9 (94.0) Modiﬁed Pain when passing a stool. Bowel movements are painful during menstruation

8.5 (94.4) 9 (100) Selected Modiﬁed Pain when passing a stool. Bowel movements painful especially (worse) during menstruation 30 Spasms, cramp, pain in the

bowel before having a bowel movement

8 (61.1) 9 (81.1) Modiﬁed Spasms, cramp, pain in the bowel before having a bowel movement during menstruation

8 (75) 9 (94.3) Selected Modiﬁed Spasms, cramp, pain in the bowel before having a bowel movement especially (worse) during menstruation 31 Diarrhea during menstruation 7 (59.3) 9 (96.2) Discarded but maintained 8 (70.3) 9 (97.1) Discarded but

discussed

Modiﬁed Diarrhea and/or constipation especially (worse) during menstruation 32 Diarrhea alternating with

constipation

6.5 (50.0) 9 (84.3) Discarded / / /

33 Constipation during menstruation

6 (49.1) 9 (86.5) Discarded / / /

34 Bloating, bloated abdomen 7 (51.8) 9 (76.9) Modiﬁed Bloating, bloated abdomen during menstruation

Discarded

35 Bloody stools 7 (52.8) 9 (92.4) Discarded / / /

Painful urinary tract signs

36 Pain or burning when urinating 4.5 (25.9) 9 (84.9) Modiﬁed The urge to urinate is painful, pain when urinating especially during menstruation

Modiﬁed Difﬁculty and/or pain when urinating especially during menstruation 37 Pain with urge to urinate, pain

when holding back

5 (37.0) 9 (77.3) Discarded / / / A. Fauconnier et al. / J Gynecol Obstet Hum Reprod 47 (2018) 69–79 74

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Table 2 (Continued )

# Item Diagnosis

validity

Clarity Status Status Modiﬁcation

38 Painful pressure on the bladder 5 (36.5) 8 (65.3) Modiﬁed Pain in the bladder, especially during menstruation

Discarded

39 Difﬁcult to start urination 4 (32.1) 9 (83.7) Discarded / / / 40 Feeling the need to urinate

often, only small quantities at a time

4.5 (33.3) 9 (84.3) Discarded / / /

41 Bloody urine 5 (37.2) 9 (88.5) Discarded / / /

42 Addeda

Need to strain to start passing water, difﬁcult to empty the bladder completely, especially during menstruation 7 (52.6) 8.5 (88.9) Discarded but discussed Discarded Other signs

43 Sciatica during menstruation 7 (53.7) 8 (65.4) Discarded / Rehabilitated Sciatica during menstruation 44 Pain in the right shoulder 5 (38.9) 8 (71.1) Modiﬁed Pain in the right shoulder or

below the right rib cage during menstruation

Selected

45 Pneumothorax – air between the lung and chest wall causing chest pain

3 (28.3) 7 (51.9) Discarded / / /

46 Nausea, vomiting 5 (38.5) 9 (83.0) Discarded / / /

47 Dizziness, fainting 5 (37.7) 9 (80.8) Discarded / / /

48 Becoming increasingly tired, extreme exhaustion, slowing down

8 (59.3) 9 (86.5) Modiﬁed Extreme fatigue, total exhaustion which interferes with daily life

Discarded

49 Difficult to get pregnant 9 (75.0) 9 (90.0) Retained 8 (80) 9 (88.9) Selected Modified Difficult to get pregnant, failure to conceive after several months or years of trying

a

Statement was added after ﬁrst round.

A. Fauconnier et al. / J Gynecol Obstet Hum Reprod 47 (2018) 69–79 75

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endometriosis and who expressly described the symptom, we introducedanewquestion‘‘Paininthebladder,whenyouwantto urinate,orwhenholdingback,especiallyduringyourperiod’’was finallyre-introducedbasedonquestions#37and38(Table2).The Frenchfinalversionisavailablein supplementarymaterial.The finalEnglishversionisgiveninAppendix.

Discussion

Weprovideabrief(21statement)self-assessedquestionnaire

tomeasurespeciﬁcallythepainfulsymptomsof endometriosis.

Thequestionswerederivedfromwordsandphrasesinnarratives ofpainfromendometriosispatients and selectedbya panelof patients and physicians to speciﬁcally represent accurate des-criptorsofendometriosispainsymptomsbutarealsousefulfroma

medical point of view. The content of the questionnaire is

displayedaccordingtofourdimensions:spontaneouspelvicpain

and dysmenorrhea, dyspareunia, painful bowel symptoms, and

othersymptoms,thatmayreﬂecttheheterogeneityofthepainful experienceofendometriosis.Thesetofquestionsandtheirmeans

of response enable one or several aggregated indexes to be

constructedtocharacterizethepainofendometriosisforuseasa PRO.

Ourmodeladdressesthedifﬁcultiesencounteredinmeasuring paininendometriosispatients.Firstofall,thepainsymptomsare

heterogeneousamongpatients,whichisproblematicwhenusing

painasanoutcome.Inanearlierrandomizedcontrolledtrial(RCT),

comparison of the effects of medroxyprogesterone acetate to

danazol and placebo involved six distinct before and after

measurementpainscores:pelvicpain,lowerbackpain,defecation pain,dysuria,dyspareunia,anddiarrhea.Bychancemostofthese symptomswereverysensitivetothetreatmentseffects[17]. Con-versely,thedifﬁcultiesweremoreobviousinoneRCTcomparing excisional laparoscopicsurgery toplacebo for thetreatment of

painful endometriosis [5]. Although surgery appeared to be

efﬁcientfor pain,it wasnot possibletodiscriminate theeffect ofsurgeryfromthatoftheplacebobymeasuringtheindividual painfulsymptomsseparately.

Furthermore,weusedaPROapproachbyformulatingreliable

questionsusingthewords,phrasesandpaindescriptorsusedby patientsratherthanthoseusuallyusedbyphysiciansandassessing

content validity by the DELPHI method. The DELPHI method

presentsmanyadvantagesthatenableittodealsuccessfullywith Table3

Twelveitemswithdiscrepancybetweenopinionsofthepatientsandphysiciansinround2.

Statements Diagnosisvalidity Clarity Statusafter2ndround Finalstatusafterdiscussion Median %agreement

(7–9)

Median %agreement (7–9)

#1:painlocatedinthelowerabdomen 7 55.3 8 83.8 Discarded Retainedbutmodiﬁed

Patients 8 88.9 9 88.2 Retained

Physicians 5.5 25 8 80 Discarded

#6:painstartsafewdaysbeforemenstruationbegins andcontinuesforafewdaysaftermenstruationhas stopped

7 63.2 9 94.4 Discarded Selected

Patients 8.5 94.4 9 100 Retained

Physicians 6 35 9 89.5 Discarded

#10:continuouspainwithpeaksorattacksofmore intensepain

7 68.4 8 86.1 Discarded Discardedbecauseredundancy

#14:uterinecramps 6 40.5 8 70.3 Discarded Discarded

#15:painlocatedintheovaries 6 45.9 8 69.4 Discarded Discarded

Patients 8 82.3 9 100 Retained

Physicians 5 15 6 42.1 Discarded

#17:painspreadstowardstheback,inthelumbararea 7 56.8 9 86.5 Discarded Selected

Physicians 6 35 8 75 Discarded

#18:painspreadstothelegsandhips 7 57.1 9 88.9 Discarded Selected

Physicians 6 38.9 8 78.9 Discarded

#19:differenttypesofpainatthesametime,several differentpainsymptoms

6 48.6 7 58.3 Discarded Discarded

#20:painmakesstanding,walkingormovingdifﬁcultif notimpossible

7 55.6 9 88.6 Discarded Selected

#31:diarrheaduringmenstruation 8 70.3 9 97.1 Discarded Retainedbutmodiﬁed

#34:bloating,bloatedabdomenduringmenstruation 7 59.5 9 88.9 Discarded Discarded

#48:extremefatigue,totalexhaustionwhichinterface withdailylife

7 51.4 9 86.1 Discarded Discarded

Boldresultsrepresentresultsofallthepanel(patients+physicians),andinitalictheresultssplittedaccordingthestatutofthepannelist. A.Fauconnieretal./JGynecolObstetHumReprod47(2018)69–79

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theheterogeneityofthedescriptionofendometriosissymptoms.

Unlike other consensus methods, individuals can be included

anonymouslyand withoutinteractingdirectly witheach other,

whichpreventstheviewsofaminorityfromdominatingthegroup

[18].Thestrengthofthepresentstudyliesinthefactthatboth

patients and practitioners were involved in the design of the

questionnaire.Itappearsthatdoctorsrejectcertainitemswhenthe informationprovidedbythepatientsabouttheirsymptomsisnot reallyusefulfor theirmanagement (non-discriminatorysign,or

withoutprognosticvalue) and/orwithambiguousor erroneous

meaningsdepending on the patient (see for example ‘‘ovarian

pain’’),andfavorthesignsthatareusefulformedicalmanagement ofthedisease.TheDELPHIprocess,mixingdifferentstakeholders, madeitpossibletoselectitemsthatareeasytounderstandand representthesubjectiveexperienceofendometriosis,butthatare alsousefulfromamedicalpointofview[19].

From the methodological point of view, the fact that some

statements(i.e.thoseinvolvingdifferencesinjudgmentbetween patientsandpractitioners)initiallydiscardedwerediscussedand ﬁnallyretainedthusbypassingtheapprovalcriteriadeﬁnedin

the method section might be a deviation with the strict

methodologyofDELPHI.However,themodiﬁedDelphimethod

thatweusedallowsforsomeﬂexibilityintheprocess.Indeed,

the methodallows the expertsto express themselves and to

comment on the proposed items. In the present cases, these

itemshadreceivedfavorablecomments,despitethe

disagree-mentbetween the panel of practitioners and patients. Sowe

decidedtokeepthemfordiscussionatthephysicalmeetingof theexperts.Theﬁnaldecisiononeachitemwasbasednotonly onthemedianscoreofvalidityandclarity,andtheagreement

among experts expressed as a percentage, but also on the

comments of the experts and the results of the discussions

betweentheexperts[14].Thephysicalmeeting,attheendofthe tworoundsofquestionnaires,isveryusefulwhenitisdifﬁcultto reachaconsensusorwhenuncertaintiespersist,aswasthecase

fortheseitems;converselyabsenceofameetingmay deprive

the Delphi procedure of beneﬁts related to face-to-face

exchange of information, such as clariﬁcation of reasons for

disagreements or discuss comments [20]. One of the main

limitationsofthisstudywasthedifﬁcultytoproperlyassessthe exactspectrumofthediseaseofthepatientswhowereincluded

inthe DELPHI panel, as some of them were enrolled from a

patientassociation.Althoughallthesepatientswerediagnosed surgically,wewerenotabletodocumentthelocationandtype ofthedisease,whicharecharacteristicswellknowntoinfluence thesymptoms[12].Bladderendometriosisisararelocationof thedisease[21],whichmayexplainthedifficultiestoreacha definitiveconclusionaboutpainfulurinarytractsymptoms.For thisreason,wetooktheunorthodoxstepofreintroducinga

non-selected item in the ﬁnal questionnaire. Nonetheless, it is

important to note that the statements used in the DELPHI

processwerealltakenfromapreviousqualitativestudywitha veryrobustcontrolofthespectrumofthedisease[7].Moreover,

thepresenceintheDELPHIpanelofphysiciansthatwerevery

familiarwiththespectrumofthediseaseislikelytohavelimited thisriskofbias.

Anobviousﬂawofthepresentquestionnairebuildingprocess liesinthefactthatitdoesnottakeintoaccountthepossibilityof sensitizationwhichisawell-knownphenomenonbythephysician dedicatedtopain.Indeed,none ofphysiciansdedicatedtopain

treatment have been included in the expert panel. The pain

mechanismsrelatedtoendometriosis,asinotherpainconditions, likelyincludesomedegreeofinterrelationbetweenendometriosis implantsandtheperipheralorcentralnervoussystems[22]. Sen-sitization might be an important source of variability in pain experience isthat patients withidenticalendometriotic lesions

[7].Nonetheless,theaimofthestudywastobuiltaquestionnaire focusedon painsymptomsthatdirectlyrelatetoendometriotic

lesions, for example related to microbleeding and or neural

invasion, and not by sensitization, which is a nonspeciﬁc

mechanismofpain,andthereforeunlikelytorespondtospeciﬁc

endometriosistreatment.

ValidatedPRO’sinendometriosisarealreadyavailable includ-ingtwoHrQOLinstruments,theSF-36andtheEHP-30.TheSF-36is

a generic instrument but has been speciﬁcally validated for

endometriosis[9].TheEHP-30isapatient-generatedinstrument,

speciﬁcally developedto measureHrQOL among endometriosis

patient.Ashorterandmorepracticalversion,theEHP-5andhave proventobeasimple,efﬁcientandvalidtoolforevaluatingquality oflifeindailypracticeandinclinicalstudiesevaluatingtreatment efﬁcacy[23].Contrarilytotheevaluationofthequalityoflife,there isclearlyalackofinstrumenttoevaluatesymptomsofthedisease

in daily clinical practice or in research setting. Since the

early 1990s, several questionnaires have been developed to

investigate the symptoms of endometriosis in epidemiological

studies.Thesequestionnairesmainlyexplorethreemajordomains,

severe dysmenorrhea, non-menstrual pelvic pain and deep

dyspareunia[11,24–28].Thesequestionnairesweremainlyused forresearchpurposes.Itisimportanttonotethatnoneofthemwas speciﬁcallydevelopedonthebasisofqualitativedescriptionofthe patients’painexperience.Thismayexplainthefactthatalimited

relationshipwasfoundbetweenpainsymptomsand

endometri-osisinthesestudies[22].

In the early 2000s, our group developed a questionnaire

speciﬁcally intended to evaluate endometriosis-related pain

symptoms in clinical practice[12].The list of symptomscame

from a comprehensive review of the literature and from

retrospective collectionofdata frompatients’charts. Sentences

were then constructed from interviews with patients with

conﬁrmed DIE. The questionnaire included items to evaluate

dysmenorrhea,dyspareuniaandnon-menstrualpain.Theintensity ofeachsymptomwasevaluatedaccordingtoa10-cmVAS.Patients

also recorded whether various (urinary or gastrointestinal)

symptoms occurred or increased during menses. Using this

questionnairewewereabletobuildanefﬁcientpredictionmodel ofDIEbasedsolelyonquestioning[12].However,thedevelopment ofthis earlierquestionnairewasnotbasedona structuredPRO process,unlikethecurrentone,whichincludesasolid,scientiﬁc rationaleonpatientdescriptionandcontentvalidation,including facevalidity[29].Indeed,facevalidityisanimportantpropertyin developmentofPROM’sbecauseitrepresentstheextenttowhicha testissubjectivelyviewedascoveringtheconceptitpurportsto measure.

Apart from ours, another questionnaire concerning painful

symptoms of endometriosis, thedaily electronic Endometriosis

Pain and Bleeding Diary, underwent a proper PRO process

development.Theitemsweredevelopedbasedonclinicianinput, butthecontentvaliditywasassessedbythemeanofseveralfocus

groups and three iterative sets of cognitive interviews with

endometriosis patients [30]. The diary covers four aspects:

dysmenorrhea, chronic pelvic pain, dyspareunia, and pain

interference.Asinourstudy,participantshighlightedthattwo distincttypesofpain(intermittentandcontinuous)existedand

were important to measure. Again as in our study, the

participantsin the qualitative partof the studyagreedthata

0-to10-NRSwouldbeappropriatetoratethepainsymptoms

[30].Thecollectionofsymptomsisbasedonadigitaldailydiary allowingthechangeofpainovertimetoberecorded,toavoid recallbiasandtotakeintoaccountthecyclicityofthesymptoms

[31].However, this renders ita complex scale to use andits

utilityremainstobedemonstratedincomparisonwithsimple

painscalessuchasours.

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Asendometriosissymptomsaregreatlyvariableaccordingto thespectrumofthedisease,havingasingleinstrumenttomeasure

the painful symptoms of endometriosis in therapeutic trials,

whethermedicalorsurgical,wouldhelptoanswertheproblemof thespectrumofthedisease[31].Forthisreason,theBiberogluand Behrmanscale[32]wasregularlyusedasaprimaryendpointin earlierRCTs[33,34].Thisscaletakesincombinationthethreemain

painsymptoms,dysmenorrhea,dyspareuniaand non-menstrual

pelvicpain,assesseddirectlybythephysician,aswellastwosigns

from physical examination. Although this scale is generally

regardedtorepresentthekeysymptomsandimpactof

endome-triosis,itnonethelesssuffersfromseveralmajorﬂawsandmostof allisnotaPRO[31].Wethussuggestthatthequestionnairewe havedevelopedcouldbeusedtomeasurethepainfulsymptomsof

endometriosis in therapeutic trials in a comprehensive and

multidimensionalway,andthusincludethepatient’sperspective. Funding

Thestudywasfundedbyindustry(IPSEN).

Compliancewithethicalstandards

Allproceduresperformedinstudiesinvolvinghuman

partici-pants were in accordance with the ethical standards of the

institutionaland/or national research committee and with the

1964Helsinkideclarationanditslateramendmentsorcomparable ethicalstandards.Ourstudyinvolvednointerventionandwasthus exemptfromtheFrenchstatuteonbiomedicalresearch(modified versionofLaw2004-806,dated August9,2004).Ethicalreview boardapprovalwasgivenbytheFrench‘‘Comite´ d’e´thiquedela rechercheenobste´triqueetgynećologie’’(CEROG).Wecomplied withallFrenchstatutesconcerning patientdata,confidentiality andrestrictions.

Disclosureofinterest

Theauthorsdeclarethattheyhavenocompetinginterest. Acknowledgments

IPSENwhoprovidesagrantforthestudy.

Association ENDOFRANCE and its president Mrs Yasmine

Candau.

The physicians who participated in the study but did not

includepatients:AubertAgostini,AlainAudebert,JeanBelaisch, NicolasBourdel,MichelCanis,RenaudDeTayrac,Herve´ Dechaud, PhilippeDescamps,GilDubernard,Herve´ Fernandez,XavierFritel, Franc¸ois Golﬁer, Pascaline Hagnere, Michel Lachowsky, Patrick

Madelenat, Christophe Poncelet, Fre´de´rique Renouvel, Chadi

YazbeckandEliseZareski.

TheEnglishmanuscriptwaseditedbyElizabethPetit.

The native English-speaking translators who provided the

Englishversionofthequestionnaire(MmeElizabethPetit, Mme

MelanieMoura, MmeDeidre Lepinat).The French obstetrician/

Gynecologist,JulieBouquierandThibaudQuibel,andthemidwife

FlorenceFrancillon who performed theback translation of the

Englishversionofthequestionnaire.

AppendixA. Supplementarydata

Supplementarydataassociatedwiththisarticlecanbefound,in theonlineversion,athttps://doi.org/10.1016/j.jogoh.2017.11.003.

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