Cellulose absorbable barrier for prevention of de-novo adhesion formation at the time of laparoscopic myomectomy: A systematic review and meta-analysis of randomized controlled trials

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Review

article

Cellulose

absorbable

barrier

for

prevention

of

de-novo

adhesion

formation

at

the

time

of

laparoscopic

myomectomy:

A

systematic

review

and

meta-analysis

of

randomized

controlled

trials

Diego

Raimondo

a

,

Antonio

Raffone

b,

*

,

Gabriele

Saccone

b

,

Antonio

Travaglino

c

,

Eugenia

Degli

Esposti

a

,

Manuela

Mastronardi

a

,

Giulia

Borghese

a

,

Fulvio

Zullo

a

,

Renato

Seracchioli

a

GynaecologyandHumanReproductionPhysiopathologyUnit,DepartmentofMedicalandSurgicalSciences(DIMEC),S.OrsolaHospital,Universityof Bologna,ViaMassarenti13,Bologna,Italy

b

GynecologyandObstetricsUnit,DepartmentofNeuroscience,ReproductiveSciencesandDentistry,SchoolofMedicine,UniversityofNaplesFedericoII, Naples,Italy

c

AnatomicPathologyUnit,DepartmentofAdvancedBiomedicalSciences,SchoolofMedicine,UniversityofNaplesFedericoII,Naples,Italy

ARTICLE INFO

Articlehistory:

Received5September2019

Receivedinrevisedform9December2019 Accepted23December2019 Availableonlinexxx Keywords: Laparotomy Laparoscopic Hemorrhage Surgery Gynecology Fertility ABSTRACT

Objective: Myomectomy is the standard surgical treatment for symptomatic uterine leiomyomas,

especiallyforpatientswishingtopreservetheirfertility.However,thisprocedureisassociatedwith

adhesionformation.Severalstrategieshavebeenproposedtoreducethem.Celluloseabsorbablebarrier

iswidelyused.Weaimedtoassessitseffectivenessinthepreventionofde-novoadhesionformationafter

laparoscopicmyomectomy.

Studydesign:Asystematicreviewandmeta-analysiswasperformedbysearchingelectronicdatabases

(i.e.MEDLINE,Scopus,ClinicalTrials.gov,EMBASE,Sciencedirect,theCochraneLibraryattheCENTRAL

RegisterofControlledTrials,Scielo)fromtheirinceptionuntilMay2019.Weincludedallrandomized

clinicaltrials(RCT)comparinguseofcelluloseabsorbablebarrier(i.e.interventiongroup)witheither

placeboornotreatment(i.e.controlgroup)inthepreventionofde-novoadhesionformationatthetime

oflaparoscopicmyomectomy.Primaryandsecondaryoutcomesweredeﬁnedbeforedataextraction.The

primaryoutcomewastheincidenceofadhesionsatsecond-looklaparoscopy.Thesecondaryoutcome

wastheoperativetime.

Results:ThreeRCT,including366participants,wereincluded.Alltrialsevaluatedwomenundergoing

laparoscopicmyomectomywhowererandomizedtointervention(eitheroxidizedregeneratedcellulose

orcarboxymethylcellulose powderadhesionbarrier)or notreatment(controlgroup).Womenwho

received treatment hadsigniﬁcantlylowerincidence of adhesionsatthe secondlook laparoscopy

(RR0.63,95%CI0.40–0.99).Interventionswithuseofcelluloseabsorbablebarrierwere4minlonger

(MD4min,95%CI2.82–5.18).

Conclusion:Useofcelluloseabsorbablebarrieratthetimeoflaparoscopicmyomectomyreducestherisk

ofpostoperativeadhesions.

Contents

Introduction ... 108

Materialsandmethods ... 108

Searchstrategyandselectioncriteria ... 108

Dataextractionandriskofbiasassessment ... 108

Statisticalanalysis ... 108

* Correspondingauthor.

E-mailaddress:anton.raffone@gmail.com(A.Raffone).

https://doi.org/10.1016/j.ejogrb.2019.12.033

ContentslistsavailableatScienceDirect

European

Journal

of

Obstetrics

&

Gynecology

and

Reproductive

Biology

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Results ... 109

Studyselectionandcharacteristics ... 109

Synthesisofresults ... 109 Comment ... 109 Mainﬁndings... 109 Interpretation ... 109 Conclusion ... 112 Disclosure ... 112 Financialsupport ... 112 References ... 112 Introduction

Ingynecologicalsurgery,laparoscopic/laparotomic myomecto-my is the standard surgical treatment for FIGO types 3–7 symptomaticuterineleiomyomas,especiallyforpatientswishing to preserve their fertility [1–3]. However, this procedure is associated with adhesion formation in up to 50 % of patients undergoing laparoscopic myomectomy and up to 94 % after laparotomicmyomectomyincisions[4,5].

Adhesionformationinvolvesacomplexinteractionofgrowth factors, cytokines, and numerous other molecules secreted by organs involved in surgical trauma [6], regulating the balance between fibrin deposition and degradation [7]. Postoperative adhesions consist therefore of pathological bonds betweenthe nearbynormal organs, either in abdomen (between omentum, bowelloopsandtheabdominalwall)orinpelvis(involvinggenital organs,urinarysystem, bowelloopsand pelvicwall)[8]. These bondsrepresent a normal response toinjury of the peritoneal surfaces during surgery, and may range from a thin film of connectivetissue,tofibrousbridgeswithbloodvesselsandnerves, or a tight connection between organs [9]. Depending on their severityand position,postoperativeadhesions maybesilentor causesignificantmorbidity,includingbowelobstruction,chronic abdominal pain, female infertility, and increased difficulty in subsequent surgeries, resulting in important consequences for patients and surgeons and cost-benefits issues for the health system[10,11].

Severalalternativestrategieshavebeenproposedwiththeaim ofreducingtheincidenceofpostoperativeadhesions[12,13]. Anti-adhesionphysicalbarriersincludenaturalandsyntheticpolymer materials.Amongthenaturalpolymers, cellulosederivatives,in particularoxidizedregeneratedcellulose(ORC)and carboxymeth-ylcellulose(CMC)arewidelyused,andappearedtohaveexcellent biocompatibility,watersolubility,retentiontimeandmechanical properties[12].CMCcanbecombinedwithahyaluronicacidsheet (sodiumhyaluronate–carboxymethylcellulose,HA-CMC),inorder tostrengthentheanti-adhesioneffectofthiscellulosepolymer.

The aim of this systematic review and meta-analysis of randomizedtrialswas toevaluatetheeffectivenessof cellulose absorbable barrier in the prevention of de-novo adhesion formationatthetimeoflaparoscopicmyomectomy.

Materialsandmethods

Searchstrategyandselectioncriteria

Thisreviewwasperformedaccordingtoaprotocoldesigneda priori and recommended for systematic review [14]. Electronic databases(i.e.MEDLINE,Scopus,ClinicalTrials.gov,EMBASE, Scien-cedirect,theCochraneLibraryattheCENTRALRegisterofControlled Trials,Scielo)weresearchedfromtheirinceptionuntilMay2019. Searchtermsusedwerethefollowingtextwords:“myomectomy,” “laparoscopic”, “laparoscopy”, “adhesion”, “robotic”, “spry”, “review,” “randomized,” “randomised,” and “clinical trial.” No

restrictionsforlanguage orgeographiclocation wereapplied.In addition,the reference lists ofallidentiﬁedarticleswereexaminedto identifystudiesnotcapturedbyelectronicsearches.Theelectronic searchandtheeligibilityofthestudieswereindependentlyassessed bytwoauthors(DR,AR).Differenceswerediscussedwithathird reviewer(GS),andconsensusreached.

We includedallrandomized clinicaltrials comparinguseof celluloseabsorbablebarrier (i.e.interventiongroup)witheither placeboornotreatment(i.e.controlgroup)inthepreventionof de-novoadhesionformationduringlaparoscopicmyomectomy.Only studiesevaluatingde-novoadhesionswithasecondlooksurgery wereconsideredfortheﬁnalanalysis.Studiesevaluatingbarriers based on only hyaluronic acid or other materials rather than cellulose were excluded from the review. Trials in women undergoing hysterectomy or open myomectomy, and quasi-randomizedtrials(i.e.trialsinwhichallocationwasdoneonthe basisofapseudo-randomsequence,e.g.odd/evenhospitalnumber ordateofbirth,alternation)werealsoexcluded.

Dataextractionandriskofbiasassessment

Theriskofbiasineachincludedstudywasassessedbyusingthe criteriaoutlinedintheCochraneHandbookforSystematicReviewsof Interventions.Sevendomainsrelatedtoriskofbiaswereassessed ineachincludedtrialsincethereisevidencethattheseissuesare associatedwithbiasedestimatesoftreatmenteffect:1)random sequence generation; 2) allocation concealment;3) blindingof participantsandpersonnel;4)blindingofoutcomeassessment;5) incompleteoutcomedata;6)selectivereporting;and7)otherbias. Reviewauthors’judgmentswerecategorizedas“lowrisk”,“high risk_”or_“unclearrisk_”ofbias[14].

Twoauthors(GS,FZ)independentlyassessedinclusioncriteria, riskofbiasanddataextraction.Disagreementswereresolvedby discussionwithathirdreviewer(DR).

Allanalysesweredoneusinganintention-to-treatapproach, evaluatingwomenaccordingtothetreatmentgrouptowhichthey wererandomlyallocatedintheoriginaltrials.

Primary and secondary outcomes were deﬁned before data extraction.Theprimaryoutcomewastheincidenceofadhesionsat second-looklaparoscopy.Atsecondlooklaparoscopy,adhesions wereevaluatedatthefollowingsites:uterus,eachovary,eachtube, omentum, cul-de-sac,pelvic sidewall(both sides,posteriorand anterior),bladder, largeboweland smallbowel. Thesecondary outcomewastheoperativetime.

Statisticalanalysis

Thedataanalysiswascompletedindependentlybytwoauthors (AR,GS)usingReviewManagerv.5.3(TheNordicCochraneCentre, CochraneCollaboration,2014,Copenhagen,Denmark).The com-pleted analyses were then compared, and any difference was resolvedbydiscussion.Thesummarymeasureswerereportedas summaryrelativerisk(RR)orassummarymeandifference(MD) with95 %of conﬁdenceinterval (CI)using therandom effects

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model ofDerSimonian and Laird.I-squared (HigginsI2₎ _greater

than0%wasusedtoidentifyheterogeneity.

Data from each eligible study were extracted without modiﬁcation of originaldataonto custom-madedatacollection forms.A2by2tablewasassessedforRR;forcontinuousoutcomes meansstandard deviations were extractedand imported into ReviewManager v. 5.3 (The Nordic CochraneCentre, Cochrane Collaboration,2014,Copenhagen,Denmark).

The meta-analysis was reported following the Preferred Reporting Item for Systematic Reviews and Meta-analyses (PRISMA)statement[15].

Results

Studyselectionandcharacteristics

TheflowofstudyidentificationisshowninFig.1.Threetrials, including 366 participants, were included [16–18]. Publication bias,assessedstatisticallybyusingBegg’sandEgger’stest,showed nosignificantbias(P=0.67andP=0.78,respectively).

The quality of the RCTs included in our meta-analysis was assessed by using the seven criteria outlined in the Cochrane Handbookfor SystematicReviewsof Interventions.Mostof the included studies werejudged as “low risk” of bias in most of thesevenCochrane domains relatedtotherisk ofbias. Allthe included studies had “low risk” of bias in “random sequence generation.” (Fig.2).Statistically heterogeneitywithinthetrials ranged from moderate to high with I2=38 % for the primary outcome.Noneof theincludedtrials weredouble blind,due to difﬁcultytomaintainthepatientnotawareoftheeventualbarrier application.Nevertheless,thesurgeonperformingthesecond-look laparoscopyandthereviewersexaminingthesecond-looksurgery videotapeswereblindedabouttheprevioustreatment.

Alltrialsevaluatedwomenundergoinglaparoscopic myomec-tomywhowererandomizedtointervention(eitherORCorCMC adhesion barrier) or no treatment (control group) (Table 1). Fossumetal.evaluatedacarboxymethylcellulosesheetcombined with hyaluronic acid, classiﬁed as a cellulose-based adhesion barrier.Meanparticipantsagewasabout33yearsinbothgroups, withameannumberofmyomasof2.7(Table2).

Synthesisofresults

Table3showstheprimaryandsecondaryoutcomes.Womenwho receivedtreatmenthadsigniﬁcantlylowerincidenceofadhesionsat thesecondlooklaparoscopy(RR0.63,95%CI0.40–0.99)(Fig.3). Interventionswithuseofcelluloseabsorbable barrierwere4min longer(MD4min,95%CI2.82–5.18).

Comment Mainﬁndings

This meta-analysis aimed to evaluate the effectiveness of celluloseabsorbablebarrierinthepreventionofde-novoadhesion formationafterlaparoscopicmyomectomy.Pooledresultsshowed that women who received cellulose absorbable barrier had signiﬁcantly lower incidence of adhesions at the second look laparoscopyby37%.Interventionswithuseofcelluloseabsorbable barrierwereonly4minlonger.

Interpretation

Gynecological surgery is often associated with the risk of postoperative adhesions, that represent a challenging problem becauseofthehealthissuesitimpliessuchasbowelobstruction,

chronicabdominalpain,femaleinfertility,andincreaseddifﬁculty insubsequentsurgeries,aswellastheheavyﬁnancialburdenfor thehealthsystem[10,11].

Thisriskappearedtobeparticularlyrelevantafterlaparoscopic/ laparotomic myomectomy, the standard surgical treatment for FIGOtype3–7uterineleiomyomasinpatientswishingtopreserve their fertility [3,19]. Minimally invasive approach appeared to

Fig.1.Flowdiagramofstudiesidentiﬁedinthesystematicreview.(Prismatemplate [PreferredReportingItemforSystematicReviewsandMeta-analyses]).

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signiﬁcantlyreducetheriskofdenovoadhesionformationbutdid noteliminateit[5,20–22].

AccordingtoCezaretal.,eveninpatientsfreefromadhesionat thetimeofsurgery,myomectomywascomplicatedbyasigniﬁcant rateofdenovoadhesionsformation[23],particularlyincaseof removalofposteriormyomas[24,25].

Biologicalandclinicalinvestigationshavethereforefocusedon the research of efficient methods to prevent postoperative adhesions [12]. Among those, physical barriers, including solid natural or synthetic materials and viscous fluids, areaimed at keepingperitonealsurfacesseparatedduringthe_first postopera-tive days, until re-epithelialization of the damaged areas has occurred.

There areconﬂictingdata regardingthe efﬁcacy ofdifferent biomaterialstodecreaseadhesionsformation.Althoughbarriers doappeartolimittheextentofadhesionformation,whetherthey improveclinicallyrelevantoutcomes(risksforintestinal obstruc-tion,infertility,andchronicpelvicpain)islessclear[10,20,26].

A recent literature review and meta-analysis showed a reduction in the incidence of adhesions re-formation after gynecologicalsurgery withtheuseof ORCat both laparoscopy and laparotomy, along with a reduction of de novo adhesion formationatlaparoscopy[20].Diamondetal.reportedareduced

adhesionseverityscorewiththeuseofCMCadhesionbarrierwith sodiumhyaluronateincomparisonwithnotreatment[27].

Basingonthesepromisingresults,wefocusedourattention on the use of cellulose polymers in preventing adhesion formation afterlaparoscopicmyomectomy. BothORCandCMC appearedtobeeffectivebarrierssigniﬁcantlyreducingdenovo adhesionformationafterlaparoscopicmyomectomy. Neverthe-less,theirefﬁcacyonlongtermoutcomes,suchaschronicpelvic pain, infertility and bowel obstruction, has to be further investigated.

Regarding the operative time, we found it only slightly increased(4min),withthemaximumincreaseof6.7minreported in theLiterature[28]. Theapplicationof anti-adhesionphysical barriers is performed thorough speciallydesigned laparoscopic devices,whichareintroducedintotheabdominalcavitythrough one of the ports [16–18]. To our knowledge, no work-related musculoskeletaldisordersorergonomicsworseningfor applica-tionofanti-adhesionphysicalbarriershavebeenreportedinthe Literature.

Concerning safety, a recent large retrospectivecohort study showedaslightlyincreasedincidenceoffeverandileusafteropen myomectomywithadhesionbarrierapplicationcomparedtono adhesion-prevention treatment. In the minimally invasive

Fig.2. Assessmentofriskofbias.(A)Summaryofriskofbiasforeachtrial;Plussign:lowriskofbias;minussign:highriskofbias;questionmark:unclearriskofbias.(B)Risk ofbiasgraphabouteachriskofbiasitempresentedaspercentagesacrossallincludedstudies.

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myomectomycohort(bothlaparoscopicandrobotic)the compli-cationratewas notincreasedbytheapplicationofanadhesion preventiondevice[29].Noneofthethreerandomizedclinicaltrials includedinourmetanalysisreportanyseriousadverseeventnor complicationrelatedtoadhesionbarrierapplication.

Strengthsofourmeta-analysisincludethemethodologyused toconductthe analysis which followedcriteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions. Furthermore,theincludedstudieshadlowriskofbias.Ourﬁndings werelimited by thesmall sample size and by theclinical and statisticalheterogeneitywithinthetrials.Moreover,weselected

fortheanalysisonlythreeRCTduetotheneedofasecondlook surgery [16–18,30]. These RCT adopted different inclusion and exclusion criteriafor participantsselection. In addition, RCTby Maisetal.wasperformedin1995,possiblyincludingachangein surgicalpractices[18].Anotherlimitationregardedthesecondary outcome (i.e.operativetime): only2studyreporteddatatobe pooledintheanalysis,andtheseresultsmightalsobeaffectedby the different cellulose derivatives adopted (i.e. ORC and CMC) [16,17].However,differenceintheoperativetimeweresimilarfor ORCandCMC(954.7vs915.3minforORCand102vs99min forCMC).

Table1

Characteristicsoftheincludedstudies.

Mais1995[14] Tinelli2011[13] Fossum2011[15]

Studylocation Italy Italy Reproductiveendocrinology

andinfertilityclinics

Studydesign RCT RCT RCT

Numberofcenters 1 Notstated 3

Monthsofstudy 18 78 Notstated

Losttofollow-up* 0 0 3(0vs3)

Numberofpatients included*

50(25vs25) 275(138vs137) 41(21vs20)

Inclusioncriteria Absenceofadhesionsandotherassociated lesions

Presenceofsubserousorintramuralmyomas Myomasnumberrangingfromonetofour Sizeofthelargestmyomarangingfrom3to6 cm

Patientsundergoingmyomectomyforpelvicpain menorrhagia,growthofﬁbroidsveriﬁedby ultrasound,infertility

Patientsagedbetween18and49 Patientsscheduledtoundergo laparoscopicmyomectomy

Presenceofatleastoneuterineﬁbroid Exclusioncriteria Notstated Previousuterineorpelvicsurgery

Previousabdominalgeneralsurgery PresurgicaltreatmentwithGnRHanalogues Gynecologicmalignancy

Pregnancy

Useofanyinstillation,suchas32%dextran-70, corticosteroids,anticoagulants,andnonsteroidal anti-inﬂammatorydrugs

Hematologicorcoagulationdisorders Presenceofongoingpelvicinfection

Presenceofanintra-abdominal infectionorabscess

Presenceofentryintotheendometrial cavityorthebowellumen

Patientsundergoingadhesiolysis involvingthebowel

Patientsundergoingaconcurrent, non-gynecologicprocedure

Interventiongroup oxidizedregeneratedcellulose oxidizedregeneratedcellulose carboxymethylcellulosepowder adhesionbarrier

Control Notreatment Notreatment Notreatment

Primaryoutcome preventionofde-novoadhesion formation

preventionofde-novoadhesionformation preventionofde-novoadhesion formation

Deﬁnitionof adhesions

AdhesionswerescoredusingtheOperative Laparoscopy

StudyGroup,1991[28]

AdhesionswerescoredusingtheAmericanFertility Societyscoringsystem

Adhesionswerescoredusingthe modiﬁedAmericanFertilitySociety scoringsystem

Dataarepresentedastotalnumber(numberintheinterventiongroupvsnumberinthecontrolgroup). RCT=randomizedcontrolledtrial.

Table2

Characteristicsoftheincludedpatients.

Mais1995

(interventionvscontrolgroup)

Tinelli2011

(interventionvscontrolgroup)

Fossum2011

(interventionvscontrolgroup) Age(years,meanSD) 34.15.7vs33.25.5 30.27.5vs30.16.8 37vs36

BMI(kg/m2

,meanSD) Notstated 22.90.3vs22.50.1 29vs27 Priorabdominalsurgery(n) Notstated 0 87(62vs25)

Priormyomectomy(n) Notstated 0 39(24vs15)

Myomas(n) 2.20.8vs2.00.9 Notstated 3.22.7vs3.63.2 Sizeofthelargestmyoma(mm) 439vs459 6015vs7013 Notstated Siteofmyomas Subserousorintramural Subserousorintramural Notstated n=number.

SD=standarddeviation.

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Conclusion

Inconclusion,useofcelluloseabsorbablebarrieratthetime oflaparoscopicmyomectomyreducestheriskofpostoperative adhesions,withan only minimaldifference inthe operative time (4min). The use of cellulose absorbable barrier might reducetheriskofbowelobstruction,chronicabdominalpain, femaleinfertility,increaseddifficultyinsubsequentsurgeries associatedwithadhesions,reducingtherelatedheavyfinancial burdenforthehealthsystem.Furtherstudiesarenecessaryto confirm these findings, with particular regard to long term outcomes.

Disclosure

Theauthorsreportnoconﬂictofinterest. Financialsupport

Noﬁnancialsupportwasreceivedforthisstudy. DeclarationofCompetingInterest

The authors declare that they have no known competing ﬁnancial interests or personal relationships that could have appearedtoinﬂuencetheworkreportedinthispaper.

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Table3

Primaryandsecondaryoutcomes.

Mais1995 Tinelli2011 Fossum2011 Total I2

RRorMD(95%CI) Patientswithadhesions 10/25vs22/25 22/138vs31/137 6/21vs5/20 38/184vs58/182 38% 0.63(0.40–0.99) Patientswithout

adhesions

15/25vs3/25 116/138vs106/137 20/21vs12/20 151/184vs121/182 84% 1.62(0.92–2.87) Timetosecond-look

(days)

Notreported(ranged from84to98)

94973vs912292 Notreported(ranged from21to84)

– N/A 37days( 13.39–87.39) Operativetime(min) Notreported(ranged

from45to130)

954.7vs915.3 102vs99 – N/A 4min(2.82–5.18) Totalscoreat

second-look 1.30.5vs1.90.8 1.80.8vs2.10.8 Notstated – 50% 0.41( 0.69to 0.13) Intraoperative complications 0/25vs0/25 0/138vs0/137 0/21vs0/20 0/184vs0/182 N/A N/A Postoperative complications 0/25vs0/25 9/138vs11/137 14/21vs12/20 23/184vs23/182 0% 1.03(0.69–1.56) *Dataarepresentedastotalnumberorasmeandifferencestandarddeviation(numberintheinterventiongroupvsnumberinthecontrolgroup). RR,relativerisk;CI,conﬁdenceinterval;MD,meandifference;N/A,notapplicable.Boldfacedata,statisticallysigniﬁcant.

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