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PREVENTION OF PRETERM BIRTH

ABOUBAKR ELNASHAR

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PREVENTION OF PRETERM BIRTH

  1. 1. PREVENTIONOFSPONTANEOUS PRETERMBIRTH EVIDENCE-BASEDGUIDELINES Prof.ABOUBAKRELNASHAR BenhaUniversityHospital ABOUBAKRELNASHAR GUIDELINES 1.FIGO,2015 2.FSOG,2017 3.NICE,2019 4.SOGC,2020 5.SMFM,2017,2020 6.USPSTF,2020 ABOUBAKRELNASHAR
  2. 2. CONTENTS I.INTRODUCTION II.PREDICTION III.PRIMARYPREVENTION IV.SECONDARYPREVENTION ▪CONCLUSION IV ABOUBAKRELNASHAR I.INTRODUCTION ▪Prevalence ▪11%oflivebirthswerebornpreterm ▪5%insomehigh-incomecountries(HICs) ▪upto25%inmanylow-&-middle-income countries(L&MICs) ▪Ofthe38countries(2017) ▪PTBrateshaveincreasedsince2000in26 countries ABOUBAKRELNASHAR
  3. 3. ▪ComplicationsOfPTB ▪NeonatalMortality: ▪Leadingcauseof deathinchildren under5ysofage ▪inHICsand L&MICs,despite advancesin neonatalcare ▪Neonatalmorbidity ▪Temperatureinstability ▪RDS,infections ▪Apnoea,hypoglycaemia ▪Seizures,jaundice ▪feedingdifficulties ▪Necrotizingenterocolitis ▪Periventricular leukomalacia ABOUBAKRELNASHAR PTLSyndrome(Romeroetal,2006) Uterine Overdistension Vascular Infection Cervical Disease Hormonal Immunological Unknown ABOUBAKRELNASHAR
  4. 4. ▪PreventionofPTBcanbeclassifiedas 1.Primary:whenthetargetisthegeneralpopulation, includingwomenathigher-or–lower-riskofPTB 2.Secondary:whenthetargetiswomenatrisk 3.Tertiary:interventionsusedafterPTLhas commenced,tooptimizeneonataloutcomes ABOUBAKRELNASHAR II.PREDICTION 1.ObstetricHistory(FSOG,2017) 1.HistoryofsPTB 2.Multiplepregnancy 3.Uterinemalformation, 4.Cervicaltreatment 5.Atleasttwopreviouselectiveabortions ▪Riskscoringsystems: ▪Age,race,andsmokingstatus ▪obstetrichistory ▪Lowdetectionrate&highfalse-positiverateABOUBAKRELNASHAR
  5. 5. 2.MeasurementOfCLByTVSAt16-24W ▪HasbeencorrelatedwiththeriskofPTBbothinsingleton& twinpregnancies ▪TheriskofPTBisinverselyrelatedtoCL ▪Indications: ▪HistoryofPTB:allsocieties ▪Otherriskfactors(SOGC,2018) ▪Twinpregnancy ▪Uterineanomaly ▪PreviousexcisionaltreatmentforCIN ▪Priormultipledilatation&evacuationbeyond13w’ CL(mm)sPTB(%) 600.2 251.1 154 578 ABOUBAKRELNASHAR ▪Universal: ▪Recommended:FIGO2015 ▪Notrecommended:FOGS,2017;SOGC,2018: {poorpositivepredictivevaluesandsensitivities lackofproveneffectiveinterventions}(II-2E). ▪Maybeconsidered:ACOG;SMFM,2012:. ▪SMFM,2019 1.UniversalCLscreeninghasgreatpromise. 2.Itfulfillsalmostallofthecriteriafora screeningtest. ABOUBAKRELNASHAR
  6. 6. ABOUBAKRELNASHAR 3.QUiPPApplication(Shennanetal.2018) ▪Freeofchargeontheinternetandasamobile application ▪Appliedfrom18ws’gestationonwards ▪8Variables:historyofcervicalsurgery;CL;quantitativefetal fibronectin(qfFN);currentgestation;numberoffetuses. ▪Probabilityofbirthwithin1,2&4w&priorto30,34& 37w. ABOUBAKRELNASHAR
  7. 7. ▪Increaseininterventionswithoutevidencethat currentlyavailabletreatmentoptionsarebeneficialfor thisparticulargroup(Goodfellowetal,2019) ABOUBAKRELNASHAR ▪Notrecommendation:(FOGS,2017) ▪Routinedigitalcervicalexaminationateach prenatalvisit ▪Regularrecordingofuterineactivity(GradeB). ▪Routinefetalfibronectinassays(GradeC). ABOUBAKRELNASHAR
  8. 8. III.PRIMARYPREVENTION 1.LDA ▪Anadeijdaetal,2018 ▪sPTB<34woccurredsignificantlylessintheaspirin-group (1.03%)comparedwiththeplacebo-group(2.34%) ▪Independentoftimeofinitiationoftherapy(<16vs≥16w) ▪SignificantafterexclusionofwomenwhodevelopedPET ▪Initiationofaspirintherapybetween8&16isimportantfor preventionofPET{thisistheperiodthatplacentation& transformationofspiralarteriesoccurs}. ▪IncaseofsPTBtheanti-inflammatorypropertiesofaspirinare beneficialthroughoutpregnancy. ABOUBAKRELNASHAR ▪Hoffmanetal,2020,Lancet ▪RCT,multicountry,double-masked: ▪NulliparouswithsingletonpregnanciesfromL&MICs. ▪(RR0·89[95%CI0·81to0·98],p=0·012). ❖Aspirin ▪Atadailydoseof81mg, ▪Initiatedbetween6&14Wupto37w:decrease PTBinnulliparouswomenwithsingleton pregnanciesfromL&MICs. LDAPlacebo Number59905986 PTB11.6%13.1% ABOUBAKRELNASHAR
  9. 9. 2.SmokingCessation(FOGS,2017) ▪Smooking: ▪hasadose-dependentrelationshipwithPTB ▪:increasedincidenceofplacentalabruption,placenta previa,PPROM,andFGR ▪Smokingcessation: ▪14%reductioninPTB ▪Recommendedforpregnantwomenatanystageof pregnancy(GradeA). ▪Nicotinesubstitutesalone,suchaspatches,havenoeffecton eithersmokingcessationorPTB. ABOUBAKRELNASHAR 3.DecreasingRatesOfMultipleGestationInART ▪TheincidenceofPTBis6-to-8timesinmultiple gestation. {overdistentionandearliercervicalshortening}. ▪ART: ▪increaseoftwin&HOMP. ▪1.Restrictingthenumberoftransferredembryos 2.Selectiveembryoreduction ABOUBAKRELNASHAR
  10. 10. 4.ReducingOccupationalFatigue(FOGS,2017) ▪Work≥40hoursaweekor ▪Highcumulativeworkfatiguescore ▪workinghours ▪standing, ▪lifting ▪amountofphysicalactivity ▪Avoidstressfactors. ▪Workweekof35hrs,sickleavebeforematernityleave isnotroutinelyrecommended(GradeB).. ABOUBAKRELNASHAR 5.ImprovingNutritionalHabits&MaintainingNormal BMI ▪Dietrichinfruit,vegetables,wholegrains:±reduced riskofPTB ▪Advisewomentoeatadietrichinfruit,vegetables wholegrains(GradeC)(FOGS,2017) ▪Zincsupplementationforpregnantwomen(CochraneSR, 2018) ▪VitD&Omega-3supplements:noeffectontermof delivery(FOGS,2017) ABOUBAKRELNASHAR
  11. 11. 6.AvoidingShortInterpregnancyIntervals(FSOG,2017) ▪Aninterval≤18monthsbetween2pregnanciesis associatedwithariskofPTB ▪Informwomenoftherisksofcloselyspaced pregnancies. ABOUBAKRELNASHAR ▪Regularsports&exerciseduringpregnancy(FSOG, 2017) ▪donotincreasetheriskofPTB ▪recommendedforwomenwithnormalpregnancies (GradeA). ▪Sexualrelationsduringpregnancy ▪donotincreasetheriskofPTB,eveninwomen withahistoryofPTB ▪Treatmentofperiodontaldiseasedoesnotreduce riskofPTB,itstreatmentshouldnotbedelayedonaccountof pregnancy(GradeB). ABOUBAKRELNASHAR
  12. 12. ▪Bedrest&hospitalization(FSOG,2017,SMFM,2020) ▪NotassociatedwithdecreasePTB ▪associatedwithahigherriskofDVT ▪Bedrestorreducedactivityisnotrecommendedin womenwith ▪previousPTB ▪shortCL,or ▪multiplepregnancy(strong/moderate). ABOUBAKRELNASHAR ▪Screeningforbacterialvaginosiscombinedwith treatmentininasymptomaticpopulationatlowrisk (definedbytheabsenceofahistoryofPTB) ▪CochraneSR,2018: ▪Clearevidenceofbenefitforprimaryprevention ▪FOGS,2017,USPSTF,2020 ▪NotreducetheriskofPTB ▪Nobenefits ABOUBAKRELNASHAR
  13. 13. IV.SECONDARYPREVENTION ▪Target ▪womenatrisk,withknownoridentifiedriskfactor/s ▪Aims ▪EarlydetectionofpatientsatriskforPTB ▪Treatmentbasedonthisdiagnosis. ▪Severalstrategies ▪withconflictingresultsconcerningtheirefficacy ABOUBAKRELNASHAR 1.Diagnosis&TreatmentOfGenitalTractInfectionin populationathighrisk(definedbyahistoryofPTB) ▪FSOG,2017: ▪Nobenefits ▪Notrecommended(GradeC) ▪USPSTF2020: ▪Conflicting&insufficientevidence ▪Balanceofbenefits&harmscannotbedetermined. ABOUBAKRELNASHAR
  14. 14. 2.CervicalPessary ▪Notrecommendedinthispopulation(GradeA)(FOGS, 2017) ▪Inconclusiveevidencethatcervicalpessaryuse, decreasestherateofPTBathighriskforPTB(SMFM, 2017) ABOUBAKRELNASHAR 3.ProgestationalAgents ▪SMFM,2017 ▪Singletongestationand ▪HistoryofsPTB:17OHP-Cat250IMweekly, startingat16-20wuntil36w ▪ShortCL:vaginalprogesterone ABOUBAKRELNASHAR
  15. 15. Maternal–FetalmedicineSociety, 2012 ABOUBAKRELNASHAR ▪FSOG,2017 ▪Theonlyindicationforprogestationaltreatmentis ▪asymptomaticpregnantwomenwith ▪singletonpregnancies& ▪NohistoryofPTBwhohave ▪shortCL≤20mmbetween16and24w: ▪VagNaturalmicronizedprogesterone(GradeB). ABOUBAKRELNASHAR
  16. 16. ▪SOGC,2020 ▪VaginalPisindicatedin 1.Singletonormultiplepregnancy&shortCL (≤25mmbetween16and24w(strong/moderate). 2.PreviousPTB:(strong/moderate). 3.Aneffective&potentiallysuperioralternate therapytocervicalcerclageinsingleton pregnancy&apreviousPTBorshortCL≤25 mmbetween16and24w(strong/moderate). ABOUBAKRELNASHAR ▪VaginalprogesteroneforpreventionofPTB: ▪Additionaltherapiessuchascerclage(with exceptionofarescuecerclage)orapessaryare notrecommended(strong/moderate) ▪Dose: ▪Insingletonpregnancy:daily200mg(strong/moderate) ▪Inamultiplepregnancy:daily400mg(conditional [weak]/low) ▪Startbetween16and24w,dependingonwhenthe riskedfactorisidentified(strong/moderate). ▪Continuedupto34–36w(strong/moderate).ABOUBAKRELNASHAR
  17. 17. 4.CERVICALCERCLAGE ▪MRCOG,2013;FSOG,2017: ▪Indicated 1.History:Singletonpregnancy&historyof3MTMorPTB (GradeA) 2.US:ShortCL&oneormoreMTM 3.HistoryofMTMorsPTBinsingletonpregnancy:US monitoringofCLifthecervixshortens≤25mmbefore24 w(GradeC). 4.Emergencyduring2ndT,majorclinicalmodificationsofthe cervix,insingletonpregnancieswithoutPROMor chorioamnionitis(GradeC). ABOUBAKRELNASHAR ▪Notindicated: 1.Shortcervixofasingletonpregnancywithno relevantobstetricorgynecologichistory(GradeB) 2.Historyofconization(GradeC), 3.uterinemalformation, 4.isolated́previousPTB(GradeB) 5.Twinpregnancies,forprimary(GradeB)orsecondary (GradeC)prevention. 6.Shortcervix&multiplepregnancy(GradeC). ▪SMFM2018:advisedagainstcerclageinwomen withshortcervix&twingestationABOUBAKRELNASHAR
  18. 18. ▪NICE,2019 ▪VaginalprogesteroneORcerclagetowomenwho haveboth: ▪HistoryofPTB(upto34+0wofpregnancy)orMTM (from16+0wofpregnancyonwards)and ▪Shortcervix:TVSbetween16+0and24+0wof pregnancythatshowCL25mmorless. ▪Discusstherisks&benefitsofbothoptionswiththe woman,andmakeashareddecisiononwhich treatmentismostsuitable ABOUBAKRELNASHAR ▪Considervaginalprogesteroneforwomenwhohave either: ▪Shortcervix:TVS.CL25mmorless.or ▪HistoryofPTBorMTM ▪Considercervicalcerclagewhen ▪Shortcervix:TVS.CL25mmorless,AND ▪whohavehadeither: ▪P-PROMinapreviouspregnancyor ▪Historyofcervicaltrauma. ABOUBAKRELNASHAR
  19. 19. CONCLUSION 1.Introduction:PTBisamajorpublichealthproblemwithhigh neonatalmorbidity&Mortality 2.Prediction:CLmeasuredbyTVSat16-24wisareliabletestto identifypregnancywithahigherriskforsPTB. 3.Primaryprevention: ▪LDA,smokingcessation ▪Reducemultiplepregnancy,reduceoccupationalfatigue ▪Znsupplementation,Avoidshortinterpregnancyintervals 4.Secondaryprevention ▪NaturalprogesteronehalvestheriskofPTBinsingleton pregnantwomenwithashortCL. ▪Cervicalcerclagemaybeindicatedhistoricallyorultrasound ABOUBAKRELNASHAR Youcangetthislecturefrom: 1.MyscientificpageonFacebook:Aboubakr ElnasharLectures. https://www.facebook.com/groups/2277448840913 51/ 2.Slidesharewebsite 3.elnashar53@hotmail.com 4.Myclinic:Althwarast,Mansura,Egypt 1/12/2021ABOUBAKRELNASHAR
  20. 20. Conclusions ▪Identificationofriskfactorsforpretermdeliverybefore conceptionorearlyinpregnancymayprovideanopportunityfor primaryprevention.Aninterpregnancyintervalofmorethansix monthsmayreducetheriskofPTB.Womenwithperiodontal diseaseareatincreasedriskof ▪pretermdelivery.Periodontaldiseaseshouldbetreatedasa componentofgooddentalhygiene,butthereareinadequate datatosuggestatreatmentforpreventionofPTB. ▪Thereisinsufficientevidencetosupporttheuseofbedrest;on thecontrary,dailyphysicalactivityshouldbesupportedamong womenatriskofsPTB. •Utilizingstrategiestopreventmultiplegestations resultingfromassistedreproductionshoulddecrease thenumberofpretermbirthsrelatedtomultiplegestations. ▪However,mostpretermbirthsoccuramongwomenwithno obviousriskfactorsandthenumberofeffectiveinterventionsis limited ▪Secondarypreventivestrategiessuchasacervicalcerclage, ABOUBAKRELNASHAR TheNationalInstituteofClinicalExcellenceintheUnitedKingdom,35 FIGO,andtheSMFMintheUnitedStatesallrecommendtheuse ofprogestogensforwomenathighriskofpretermbirth.Thelatter advisesthatwomenbetween20and366gestationalweeksreceive 17‐hydroxyprogesteronecaproate(250mgintramuscularlyweekly) startingat16–20weeksuntil36weeksordeliveryforwomenwitha singletongestationandahistoryofpriorspontaneouspretermbirth.36 Thetwoformerorganizationsendorsetheuseofvaginalprogesterone forwomenwithashortcervix. Asdiscussedinthisreview,however,theevidenceonefficacy forthoseatriskofpretermbirth,impactonpretermbirthrates,and long‐termeffectsforthebabyofimplementingtheserecommendations remainsinconclusive.Cliniciansandpregnantwomencanlook forwardtosomeresolutionoftheconflictingviewsonefficacyonce thePCORI‐fundedindividualpatientdatameta‐analysisispublished. Recommendationsshouldbeupdatedoncethefulldetailsofthe PCORIindividualpatientdatameta‐analysisisinthepublicdomain. ABOUBAKRELNASHAR
  21. 21. Conclusion 1.Introduction:PTBisamajorpublichealthproblemwithhighneonatal morbidityandMortality 2.Prediction:Cervicallength(CL)measuredbytransvaginalultrasoundat 20e24weeksisareliabletesttoidentifypregnancywithahigherriskfor spontaneousPTB. 3.Primaryprevention:LDA,smokingcessation,reducemultiplepregnancy, occupationalfatigue,znsupplementation,avoidshortinterpregnancy intervals 4.Secondaryprevention ▪NaturalprogesteronehalvestheriskofPTBinsingletonpregnant womenwithashortCL. ▪Cervicalcerclagemaybeindicatedhistoricallyorultrasound Insingletonpregnancywithmid-gestationultrasoundshortCL,vaginal progesteroneisassociatedwithastatisticallysignificantreductionintheriskof (RDS),LBW),verylowbirthweight(VLBW),andlessadmissiontothe neonatalintensivecareunit(NICU). Intwin-pregnantwomenwithaCLlessthan25mm,vaginalprogesterone mightbeassociatedwiththereductionofPTBandneonatalmorbidityincluding reductionintheriskofRDS,neonatalandperinataldeath,VLBW,andalsoless needformechanicalventilation. However,RCTareneededtoconfirmthesefindings. ABOUBAKRELNASHAR ABOUBAKRELNASHAR
  22. 22. Mateietal,2019 Intotal,112reviewswereincludedinthisstudy.Overalltherewere49Cochraneand63non- Cochranereviews.Eightwereindividualparticipantdata(IPD)reviews.Sixtyreviewsassessed theeffectofprimarypreventioninterventionsonriskofPTB.Positiveeffectswerereportedfor lifestyleandbehaviouralchanges(includingdietandexercise);nutritionalsupplements (includingcalciumandzincsupplementation);nutritionaleducation;screeningforlowergenital tractinfections.Eighty-threesystematicreviewswereidentifiedrelatingtosecondaryPTB preventioninterventions.Positiveeffectswerefoundforlowdoseaspirinamongwomenatrisk ofpreeclampsia;clindamycinfortreatmentofbacterialvaginosis;treatmentofvaginal candidiasis;progesteroneinwomenwithpriorspontaneousPTBandinthosewithshort midtrimestercervicallength;L-arginineinwomenatriskforpreeclampsia;levothyroxineamong womenwithtyroiddisease;calciumsupplementationinwomenatriskofhypertensive disorders;smokingcessation;cervicallengthscreeninginwomenwithhistoryofPTBwith placementofcerclageinthosewithshortcervix;cervicalpessaryinsingletongestationswith shortcervix;andtreatmentofperiodontaldisease.Conclusion:Theoverviewservesasaguide tocurrentevidencerelevanttoPTBprevention.Onlyafewinterventionshavebeen demononstratedtobeeffective,includingcerclage,progesterone,lowdoseaspirin,and lifestyleandbehaviouralchanges.Forseveraloftheinterventionsevaluated,therewas insufficientevidencetoassesswhethertheywereeffectiveornot. ABOUBAKRELNASHAR Conclusion ▪prophylacticprogesteroneadministrationinwomenpresentingwithashortCL reducestheincidenceofPTB. ▪Vaginalprogesteroneisassociatedwithastatisticallysignificantreductionintherisk ofneonatalmorbidityandalowerfrequencyofearlyPTB,loweradmissiontothe NICU,andshorterlengthofNICUstay[18e20]. ▪nosignificantrelationshipbetweenclinicallyadministerednaturalprogesteroneand congenitalmalformations[83,84]. ▪ProphylacticadministrationofprogesteroneforthepreventionofPTBshouldbe offeredtowomenwithapriorspontaneousPTBandtothosepregnantwomenwitha shortcervixof25mmorlessatmid-gestationscan. ▪ForsingletonpregnantwomenwithapriorhistoryofspontaneousearlyPTBanda shortCL(<25mm)incurrentpregnancy,bothcerclageandvaginalprogesteroneare aneffectivetreatmentforpreventingPTBandimprovingneonataloutcomes. However,thechoiceoftreatmentwilldependonadverseeventsand patient/physician'spreferences. ▪routineuseofprogesteroneintwinpregnancieswithCLlessthanorequalto25mm. Nevertheless,furtherRCTsareneededtoconfirmsuchevidenceandmaybe determinedifthereareotherindicationsforprogesteronetherapyfortheprevention ofPTBespeciallyinsymptomaticpatients. ABOUBAKRELNASHAR
  23. 23. thanks ABOUBAKRELNASHAR Preventionofspontaneouspretermbirth ▪Thereissubstantialevidenceshowingthatvaginalprogesteronesignificantlydecreasesthe riskofpretermbirth≤34weeksby34%amongwomenwithpriorhistoryofpretermdelivery and/oramidtrimesterCL≤25mm.Furthermore,pooledestimatesobtainedbycombining datafromfourtrialsindicatethatvaginalprogesteronewasassociatedwithastatistically significantreductionintheriskofpretermbirthfrom<28to<36weeks’gestation, respiratorydistresssyndrome,compositeneonatalmorbidityandmortality,birthweight <1500g,andadmissiontoNICU.Vaginalprogesteroneissafeandhadnoeffectontherisk ofbothfetaldeath[37]andontheriskofadverseneurodevelopmentaloutcomes.Therewere nosignificantdifferencesinthecognitivecompositescoresorratesofneurodevelopmental impairmentuptosixyearsofagebetweenchildrenexposedinuterotovaginalprogesterone andthoseexposedtoplacebo[37-41]. ▪Cervicalcerclagedoesnotappeartobeeffectiveforwomenwithashortcervixwhohave not hadapriorpretermbirth[42].Inameta-analysisoffourrandomizedtrialsinwhichsingleton pregnancieswerescreenedwithcervicalultrasoundexaminationandrandomlyassignedto cerclageornocerclageifthecervixwasshort,cerclageplacementinwomenwithnoprior 15pretermbirthdidnotresultinsignificantreductioninbirth<35weeks(21%vs31%without cerclage:relativerisk0.84,95%CI0.60-1.17)[42]. Inwomenwithashortcervix(≤25mm)atmidtrimester,singletongestationandpriorpreterm birthearlierthan34weeks,cerclageandvaginalprogesteroneareequallyeffectiveinan indirectcomparisonmeta-analysisforpreventingpretermbirthandimprovingperinatal outcomes[43].However,thechoiceoftreatmentshoulddependontheriskofadverseevents andcost-effectivenessofinterventions,andpatient/physician’spreferences.ABOUBAKRELNASHAR
  24. 24. Controversieswithinobservationalstudiesmaybe attributedtodifferentoperativeskillsandclinicalsurveillance. Itcanhardlybedeniedthattheefficacyofboththe vaginalandabdominalcerclageishighlydependentonthe surgeon`sskills,andunfortunately,thishasnotsufficiently beenconsideredorauditedinpublishedstudies.Therefore, itsimplementationcannotbeconsideredininexperienced handsastheclinicalrisks,althoughrarecanbedevastating, astheseincludehemorrhage,sepsis,perinatal,neonatal,or evenmaternaldeath. ABOUBAKRELNASHAR 4.Cervicalcerclage Inanindividualpatientmeta-analysis,Jorgensenetal.suggested thattheuseofcerclageeffectivelyreducestheriskofpregnancy lossorneonataldeathpriortodischargefromthe hospital[84].Twomaintechniqueshavebeendescribed,the McDonaldandtheShirodkarprocedure.Althoughthelatter permitstheintroductionofthestichinanuppercervical level,evidencedoesnotsupportitssuperioritycomparedto theMcDonaldtechnique[85].Theintroductionofasecond cervicalstichhasbeeninvestigatedbyameta-analysisthat includedsixobservationalstudiesandsuggestedthatthis approachmightreducesPTBrates<28and<34weeksABOUBAKRELNASHAR
  25. 25. SOGC,2020 ▪Progesteronetherapyreducestheriskofspontaneouspretermbirthin womenatanincreasedriskbasedonhistoryofpreviousspontaneous pretermbirthorinwomenwithashortcervicallength(moderate). ▪Thereisinsufficientevidencetosupporttheuseofprogesteronefor preventionofspontaneouspretermbirthinwomenwithapregnancyinthe absenceofcervicalshortening(moderate). ▪Thereisinsufficientevidencetosupporttheuseofprogesteronefor preventionofspontaneouspretermbirthinwomenwithanormalcervical lengthandapriorconizationprocedureonthecervixorabnormaluterine anatomy(low). ▪Useofvaginalprogesteroneforpreventionofspontaneouspretermbirthhas notbeenassociatedwithanincreaseincongenitalmalformationsorwitha worseningofpostnatalneurodevelopmentaloutcomes(moderate). ABOUBAKRELNASHAR FSOG,2017 ▪17OHPC ▪notrecommendedfortheprimarypreventionofpretermdeliveryina populationofwomenwithsingletonpregnanciesandnohistoryof pretermdelivery(GradeC). ▪Wecannotrecommendtheroutineadministrationof17OHPCtowomen withahistoryofpretermdeliverytoreducetheirriskonthebasisofthis singlerandomizedtrial,especiallyinviewofitslimitedexternalvalidity ▪notshownanybenefitsinwomenwithasingletonpregnancy,ahistory ofpretermdelivery,andacervicallengthlessthan25mmduringthe secondtrimester.Accordinglytheuseof17OHPCinthissituationisnot recommended(GradeB).Inthesamepopulation,vaginalprogesterone mightreducetheriskofpretermdelivery ▪Progestationalagents ▪whetheradministeredvaginallyorbyinjectionas17OHPC,arenot associatedwithareducedriskofpretermdelivery,afterpretermlabor,for asymptomatictwinpregnancieswithnormalorunknowncervicallength measurements.Theyarethereforenotrecommendedinthesetwotwin- pregnancysituations(respectivelyGradeAandGradeB). ▪Amongwomenwithtwinpregnanciesandacervixlessthan25mm,the preventiveadministrationof17OHPChasshownnobenefitsforprolonging pregnancyorreducingperinatalrisk.Itisthusnotrecommendedinthis ABOUBAKRELNASHAR
  26. 26. FSOG,2017 ▪Theonlypopulationforwhichprogestationaltreatmentisrecommendedis asymptomaticpregnantwomenwithsingletonpregnanciesandnohistoryof pretermdeliverywhohaveacervicallengthlessthan20mmbetween16 and24weeks. ▪17OHPC ▪notrecommendedfortheprimarypreventionofpretermdeliveryina populationofwomenwithsingletonpregnanciesandnohistoryof pretermdelivery(GradeC). ▪Wecannotrecommendtheroutineadministrationof17OHPCtowomen withahistoryofpretermdeliverytoreducetheirriskonthebasisofthis singlerandomizedtrial,especiallyinviewofitslimitedexternalvalidity ▪notshownanybenefitsinwomenwithasingletonpregnancy,ahistory ofpretermdelivery,andacervicallengthlessthan25mmduringthe secondtrimester.Accordinglytheuseof17OHPCinthissituationisnot recommended(GradeB).Inthesamepopulation,vaginalprogesterone mightreducetheriskofpretermdelivery ▪Progestationalagents ▪whetheradministeredvaginallyorbyinjectionas17OHPC,arenot associatedwithareducedriskofpretermdelivery,afterpretermlabor,for asymptomatictwinpregnancieswithnormalorunknowncervicallength measurements.Theyarethereforenotrecommendedinthesetwotwin- pregnancysituations(respectivelyGradeAandGradeB). ABOUBAKRELNASHAR 3.Progestationalagents(FSOG,2017) ▪17OHPCisnotrecommendedfortheprimarypreventionofpretermdelivery inapopulationofwomenwithsingletonpregnanciesandnohistoryof pretermdelivery(GradeC). ▪naturalmicronizedprogesteroneadministeredvaginallydailyforupto36 weeksisrecommendedforasymptomaticwomenwithasingleton pregnancy,nohistoryofpretermdelivery,andacervicallengthlessthan20 mmat16to24weeks(GradeB). ▪Onetrialhasassociated17OHPCwithareductionintheriskofdelivery before34weeksandwithareductioninneonatalmorbidity(LE3)in singletonpregnanciesamongwomenwithahistoryofatleastonedelivery before34weeks. ▪Wecannotrecommendtheroutineadministrationof17OHPCtowomenwith ahistoryofpretermdeliverytoreducetheirriskonthebasisofthissingle randomizedtrial,especiallyinviewofitslimitedexternalvalidity ▪Vaginalprogesteroneforasymptomaticwomenwithahistoryofpreterm deliverydoesnotappeartobeassociatedwithareducedriskofdelivery before34weeks ▪Thevaginaladministrationofprogesteronetoreducetheriskofpreterm deliveryinwomenwithahistoryofpretermdeliveryisnotrecommended ▪Treatmentwith17OHPChasnotshownanybenefitsinwomenwitha singletonpregnancy,ahistoryofpretermdelivery,andacervicallengthless ABOUBAKRELNASHAR
  27. 27. 2.Supplementalprogestogens SingletonpregnanciesThepreventiveeffectofprogestogens wasalreadydiscussedbyPapiernik-Berkhauerin 1970andthenbyKeirsein1990[62,63].Progestogens havebeenusedtoreducePTBintheformofthesynthetic 17α-hydroxyprogesteronecaproateadministeredweeklyas 250mgortheformofnaturalprogesteroneapplieddailyas vaginalsuppositoriesorgel.Bothsubstanceshavedifferent half-timelivesanddifferenteffectsandshouldbeseparately analyzed. Tworandomizedplacebo-controlledtrialsfrom2003 foundthatprogesterone,administeredaseitherweekly intramuscularinjectionsof250mgof17α-hydroxyprogesterone caproateordailyprogesteronevaginalsuppositories, reducedtherateofrecurrentpretermdeliverybyabouta third[64,65].Otherwise,thebenefitof17-OHPCiscontroversially discussed[66].ThestillongoingPROLONGtrial isintendedtoinvestigatetheuseof17-OHPCinhigh-risk pregnancieswiththepreviousPTB. ABOUBAKRELNASHAR Challengesinlow-andmiddle-incomecountries ▪WhilemosteffortsonpreventionofsPTBcomefromhigh- incomecountries,manyLMIChavetodealwithmore challengingconditions. ▪Poorlydevelopedpublicinstitutions,limitedfundinganda relativelylownumberofskilledstaffcompoundedbycontextual factorssuchascorruptionandpatronagemayleadtoadverse andunpredictableneonataloutcomes. Unfortunately,manyLMIChavefailedtopromotemodernisation inhealthcareadministration[125].Consequently, theremaybeakindofpublic/privatecollaboration, supportedinpartbyexternalaidagencies.These conditionsmaybemetinwell-equippedhospitals,butare oftenabsentinlowerlevelfacilities,suchassecond-level hospitalsandprimaryhealthcarecenters,wheremostof thedeliveriesoccurinthesecountries[126]. Ithasbeenrecognizedthatthelackofawarenessand educationofstakeholdersoutsidethehealthcaresector,asABOUBAKRELNASHAR
  28. 28. Singletonpregnancies SeveralstudieshaveshowedthattheriskofPTBisinverselyrelatedtothe lengthofthecervix[9e14],andearlypretermdeliveryincreaseswiththe decreaseinCL,fromabout0.2%at60mmto1.1%at25mm,4.0%at15mm, and78%at5mm[10]. Combineddatafromthethreelargeststudiesinvolvingatotalof7861women showedthatthedetectionrateofbirthbefore35weekswas34%forafalse- positiverateofabout5%[9,10,13].Celiketal.[13]conductedapopulation- basedprospectivemulticenterstudyin58,807womenwithsingleton pregnanciesattendingforroutinehospitalantenatalcare.Thecervicallength (CxL)measuredbyTVUat20e24þ6/7dayswasnormallydistributedwitha meanof36mm.Thelengthwas25mmorlessinabout10%ofwomen,20 mmorlessin5%,and15mmorlessinabout1%.Usingthesecutoffvalues,the respectivedetectionratesofspontaneousearlyPTBbefore32weekswere 35%,48%,and55%.Furthermore,theCLof15mmaccountsfor25.8%ofthe spontaneousearlydeliveriesbefore34weeksandbetween16and25mm accountsfor20.4%oftheearlydeliveriesbefore34weeks. Twinpregnancies Intwinpregnancies,therateofearlyPTBisabout10%,comparedwith1e2% insingletons[38].Inthelargeststudy,CLwasmeasuredat20e24weeksin 1163twinpregnanciesattendingforroutineantenatalcare[15,39].Therateof deliverywasinverselyrelatedtotheCL,being66%for10mm,24%for 20mm,12%for25mm,andlessthan1%for40mm.ThemedianCxLwas35 ABOUBAKRELNASHAR Universalscreeningforshortcervicallength Recommendationfortheuseofvaginalprogesteroneforpregnancieswithno historyofspontaneousPTDbutashortcervixbeforeorat24weeksraisesthe issueofuniversalCLmeasurementat18e24weeks(21).Theansweris complexandraisesthreeissues:first,giventhelowprevalenceofthe shortcervixmeasuringbetween10and20mmbefore24weeksinthegeneral population,between1.7%(27)and2.3%(29),itisnecessarytoscreen between400and588pregnanciestoavoidonePTB. However,thenumberofcaseswithashortCLneededtotreatisonly7e13.4to preventonePTB;second,disseminationofsuchscreeningrequiresthe developmentofqualitystandardsforthemeasurement ofCLbyTVU;andthird,thereisariskofinsidiousslidingwitharbitrary extensionoftheeligibilityandmanagementcriteria,suchasrepeated ultrasoundsperformedoutside18e24weeks,treatmentadministeredoutside theboundsofCLstudied(bordereffect),useofotherinterventionsnot justifiedincaseofshortCL,andthereforepotentiallyundesirable consequenceswithintramuscularinjectionsof17P[40]. Infact,theCLmeasuredbyTVUisaneffectivescreeningtestforthe preventionofPTB,andthecriteriaforaneffectivescreeningtestareallmetby CL.AlthoughroutineCLscreeningisnotclearlyrecommendedbysome internationalsocieties,suchscreeningisseenasreasonableforallofthem [41e44].Furthermore,bothAmericancollegeofobstetriciansandgynecologistsABOUBAKRELNASHAR
  29. 29. Treatmentofperiodontaldisease Severalstudiessuggestedthatperiodontaldiseasemaybea predisposingfactorforpretermbirth.Therationalebehind thisassociationisbasedontheactionofbacterialpathogens andinflammatorycytokinesthatarereleasedfromthe mother’smouthcavityperiodontalinfectionisnotadirect causeofPTB,butratheramarkerthatdesignatesa predispositiontowardstheinductionofanexcessivelocalor systemicinflammatoryresponsetobacterialinfections.Based onthisassumption,itisbelievedthatthesewomentendto hyperrespondtovaginalinfections,thusproducingan abundanceofinflammatorycytokinesthatultimatelyleadto preterm labororruptureofmembranes[118].Nevertheless,dataon theuseofmouthrinseareconflicting[119,120]andgood oralhealthisdesirable,sothatperiodontaldiseaseshouldbe treatedasacomponentofgooddentalhygiene. ABOUBAKRELNASHAR ▪Aproportionalinversecorrelationbetweengestationalageat deliveryandneonatalmortalityhasbeenobserved,but dependsalsoonthestandardofneonatalcareindifferent continents. ▪Moderateprematuritybetween32and36weeksismore prevalent,andepidemiologicstudiessuggestthattheratesstill increaseovertime[1]. ABOUBAKRELNASHAR
  30. 30. thattheriskofadelivery<33weekswasreducedby45% [67].Significantdifferenceswerealsoreportedconcerning theratesofsPTB28weeks,respiratorydistresssyndrome, andneonatalmorbidityandmortality.Thisstudywasdifferently analyzedbystatisticiansoftheFDAwhofoundno evidencewhencorrectingthesedataformaternalparameters andnodifferenceinoutcomeaftertwoyears.Thismight havebeenareasonwhytheFDAdidnotagreethatvaginal progesteronewasapprovedintheUS[68].Thereafter,the OPPTIMUMtrialinvestigatedthelong-termeffectofvaginal progesteroneversusplaceboforthepreventionofPTB untiltheageof2yearsandfoundneithersignificantbenefits norharmsrelatedtothepost-neonataloutcome,neithera significantprolongationofpregnancy[69].Therefore,the authorJaneNormanconcludedthatadrugforwhichno differencescouldbedeterminedaftertwoyearsshouldatleast requirethatpatientsarewell-informed.Criticsofthisstudy wererelatedtotheinclusioncriteriaandallowcompliance ofonly60%.Meanwhile,Romeroetal.haveconductedthree ABOUBAKRELNASHAR Indirectanddirectcomparisonsofcervicalpessary, cerclage,andprogesterone Currentresearchstillfocussesontheoptimaltreatmentof pregnancieswithashortcervixdetectedbytransvaginal ultrasound.In2013,Alfirevicetal.publishedthefirstretrospective studycomparingcerclage,vaginalprogesterone, andcervicalpessaryinpatientsatriskforPTBandashort CLandfoundthattheywereallefficaciousinpreventing PTBwithsomemorebenefitsofthecervicalpessary[92]. Conde-Agudeloetal.publishedanindirectcomparison meta-analysisofvaginalprogesteroneversuscervicalcerclage andfoundnoclinicallyrelevantdifferences[93]and a“networkmeta-analysis”whichincluded36trials,suggested thatprogesteroneseemstobebetterthancerclage andpessary[94].However,thereareseveralproblemsin theseindirectcomparisons.AnopenlabelmulticenterRCT iscurrentlyrecruitingpatientstodirectlycomparecervical cerclage,cervicalpessary,andvaginalprogesteronein womenwithashortcervix[95]. Somedirectcomparisonsoftwostrategieshave,meanwhile, beenpublishedasRCTscomparingvaginalprogesterone andcervicalpessaryinsingletonsandintwins[96, 97].TheRCTinsingletonpregnanciescouldnotfinda significantdifferencebetweencervicalpessaryandvaginal ABOUBAKRELNASHAR
  31. 31. Recently,Wolnickietal.[102]investigatedthecombined treatmentofcerclageandArabinpessaryversuscerclage aloneinsingletonpregnancieswithcervicalshortening. Althoughtherewerenodifferencesbetweenthetwostudy armsintheratesofpretermbirth<28,<32,<34,and< 37weeks,theauthorsstatedasignificantlyshorteradmission timeintheNICUaswellashigherratesofbirthweight infavorofthecombinedtreatmentarm.Thelowerincidence ofneonatalinfectionsfollowingtheadditionalpessarytreatment mightbetheresultofreductioninthestretchingofthe cervicalcellsandpreventionofatypicalinterleukinproduction asanimmunologicalbarrier[103]. ABOUBAKRELNASHAR Bacterialvaginosisandpretermbirth ▪Bacterialvaginosisisadysbiosisexpressedasan imbalanceofthevaginalflorafavoringthemultiplicationof anaerobicbacteriaandthesimultaneousdisappearanceof thelactobacilliconsideredtobeprotective. ▪ItsdiagnosisisbasedonAmsel'sclinicalcriteriaand/or GramstainingwiththedeterminationofaNugentscore. ▪Itsprevalencevariesaccordingtoethnicand/orgeographic origin(4-58%);inFranceitiscloseto7%inthefirsttrimester ofpregnancy(LE2). ▪Theassociationbetweenbacterialvaginosisand spontaneouspretermdeliveryislow,withoddsratios rangingfrom1.5to2inthemostrecentstudies(LE3). ▪Metronidazoleandclindamycinareeffectiveintreatingthis vaginosis(LE3).Oneoftheseantibioticsshouldbe prescribedforpregnantwomenwithsymptomaticbacterial vaginosisABOUBAKRELNASHAR
  32. 32. Diagnosisandtreatmentofgenitaltractinfection LowergenitaltractinfectionspredisposewomentoPTB [111,112].Ureaplasmaandmycoplasmainfectionsseem tobesignificantlymoreprevalentamongwomenwith sPTBthanamongcontrols.Positiveswabsseemtobe associatedwithneonatalsystemicinflammatoryresponse syndromeandbronchopulmonarydysplasia. SomestudiescouldnotshowareductioninPTBafter treatmentofasymptomaticvaginalorcervicalcolonization andacertainmicrobiome[113],butthedataareconflicting [114]. Onlyonemeta-analysiswhichwasbasedon10 studiesthatrecruited3696pregnantwomenwithbacterial vaginosissuggestedasignificantreductionPTBratesafter antibiotictreatment(OR0.42;95%CI0.27–0.67)[115]. Ontheotherhand,ameta-analysisthatevaluatedtheeffect ofprophylacticantibioticadministrationinwomenwith abnormalvaginalswabs,inwomenwithahistoryofthe previoussPTBandinthosewithpositivefetalfibronectin ABOUBAKRELNASHAR

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