ABOUBAKR ELNASHAR

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
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2. CONTENTS
I.INTRODUCTION
II.PREDICTION
III.PRIMARYPREVENTION
IV.SECONDARYPREVENTION
▪CONCLUSION
IV
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I.INTRODUCTION
▪Prevalence
▪11%oflivebirthswerebornpreterm
▪5%insomehigh-incomecountries(HICs)
▪upto25%inmanylow-&-middle-income
countries(L&MICs)
▪Ofthe38countries(2017)
▪PTBrateshaveincreasedsince2000in26
countries
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3. ▪ComplicationsOfPTB
▪NeonatalMortality:
▪Leadingcauseof
deathinchildren
under5ysofage
▪inHICsand
L&MICs,despite
advancesin
neonatalcare
▪Neonatalmorbidity
▪Temperatureinstability
▪RDS,infections
▪Apnoea,hypoglycaemia
▪Seizures,jaundice
▪feedingdifficulties
▪Necrotizingenterocolitis
▪Periventricular
leukomalacia
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PTLSyndrome(Romeroetal,2006)
Uterine
Overdistension
Vascular
Infection
Cervical
Disease
Hormonal
Immunological
Unknown
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4. ▪PreventionofPTBcanbeclassifiedas
1.Primary:whenthetargetisthegeneralpopulation,
includingwomenathigher-or–lower-riskofPTB
2.Secondary:whenthetargetiswomenatrisk
3.Tertiary:interventionsusedafterPTLhas
commenced,tooptimizeneonataloutcomes
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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. 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
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▪Universal:
▪Recommended:FIGO2015
▪Notrecommended:FOGS,2017;SOGC,2018:
{poorpositivepredictivevaluesandsensitivities
lackofproveneffectiveinterventions}(II-2E).
▪Maybeconsidered:ACOG;SMFM,2012:.
▪SMFM,2019
1.UniversalCLscreeninghasgreatpromise.
2.Itfulfillsalmostallofthecriteriafora
screeningtest.
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6. ABOUBAKRELNASHAR
3.QUiPPApplication(Shennanetal.2018)
▪Freeofchargeontheinternetandasamobile
application
▪Appliedfrom18ws’gestationonwards
▪8Variables:historyofcervicalsurgery;CL;quantitativefetal
fibronectin(qfFN);currentgestation;numberoffetuses.
▪Probabilityofbirthwithin1,2&4w&priorto30,34&
37w.
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7. ▪Increaseininterventionswithoutevidencethat
currentlyavailabletreatmentoptionsarebeneficialfor
thisparticulargroup(Goodfellowetal,2019)
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▪Notrecommendation:(FOGS,2017)
▪Routinedigitalcervicalexaminationateach
prenatalvisit
▪Regularrecordingofuterineactivity(GradeB).
▪Routinefetalfibronectinassays(GradeC).
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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.
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▪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%
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9. 2.SmokingCessation(FOGS,2017)
▪Smooking:
▪hasadose-dependentrelationshipwithPTB
▪:increasedincidenceofplacentalabruption,placenta
previa,PPROM,andFGR
▪Smokingcessation:
▪14%reductioninPTB
▪Recommendedforpregnantwomenatanystageof
pregnancy(GradeA).
▪Nicotinesubstitutesalone,suchaspatches,havenoeffecton
eithersmokingcessationorPTB.
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3.DecreasingRatesOfMultipleGestationInART
▪TheincidenceofPTBis6-to-8timesinmultiple
gestation.
{overdistentionandearliercervicalshortening}.
▪ART:
▪increaseoftwin&HOMP.
▪1.Restrictingthenumberoftransferredembryos
2.Selectiveembryoreduction
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10. 4.ReducingOccupationalFatigue(FOGS,2017)
▪Work≥40hoursaweekor
▪Highcumulativeworkfatiguescore
▪workinghours
▪standing,
▪lifting
▪amountofphysicalactivity
▪Avoidstressfactors.
▪Workweekof35hrs,sickleavebeforematernityleave
isnotroutinelyrecommended(GradeB)..
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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)
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11. 6.AvoidingShortInterpregnancyIntervals(FSOG,2017)
▪Aninterval≤18monthsbetween2pregnanciesis
associatedwithariskofPTB
▪Informwomenoftherisksofcloselyspaced
pregnancies.
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▪Regularsports&exerciseduringpregnancy(FSOG,
2017)
▪donotincreasetheriskofPTB
▪recommendedforwomenwithnormalpregnancies
(GradeA).
▪Sexualrelationsduringpregnancy
▪donotincreasetheriskofPTB,eveninwomen
withahistoryofPTB
▪Treatmentofperiodontaldiseasedoesnotreduce
riskofPTB,itstreatmentshouldnotbedelayedonaccountof
pregnancy(GradeB).
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12. ▪Bedrest&hospitalization(FSOG,2017,SMFM,2020)
▪NotassociatedwithdecreasePTB
▪associatedwithahigherriskofDVT
▪Bedrestorreducedactivityisnotrecommendedin
womenwith
▪previousPTB
▪shortCL,or
▪multiplepregnancy(strong/moderate).
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▪Screeningforbacterialvaginosiscombinedwith
treatmentininasymptomaticpopulationatlowrisk
(definedbytheabsenceofahistoryofPTB)
▪CochraneSR,2018:
▪Clearevidenceofbenefitforprimaryprevention
▪FOGS,2017,USPSTF,2020
▪NotreducetheriskofPTB
▪Nobenefits
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13. IV.SECONDARYPREVENTION
▪Target
▪womenatrisk,withknownoridentifiedriskfactor/s
▪Aims
▪EarlydetectionofpatientsatriskforPTB
▪Treatmentbasedonthisdiagnosis.
▪Severalstrategies
▪withconflictingresultsconcerningtheirefficacy
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1.Diagnosis&TreatmentOfGenitalTractInfectionin
populationathighrisk(definedbyahistoryofPTB)
▪FSOG,2017:
▪Nobenefits
▪Notrecommended(GradeC)
▪USPSTF2020:
▪Conflicting&insufficientevidence
▪Balanceofbenefits&harmscannotbedetermined.
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14. 2.CervicalPessary
▪Notrecommendedinthispopulation(GradeA)(FOGS,
2017)
▪Inconclusiveevidencethatcervicalpessaryuse,
decreasestherateofPTBathighriskforPTB(SMFM,
2017)
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3.ProgestationalAgents
▪SMFM,2017
▪Singletongestationand
▪HistoryofsPTB:17OHP-Cat250IMweekly,
startingat16-20wuntil36w
▪ShortCL:vaginalprogesterone
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15. Maternal–FetalmedicineSociety,
2012
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▪FSOG,2017
▪Theonlyindicationforprogestationaltreatmentis
▪asymptomaticpregnantwomenwith
▪singletonpregnancies&
▪NohistoryofPTBwhohave
▪shortCL≤20mmbetween16and24w:
▪VagNaturalmicronizedprogesterone(GradeB).
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16. ▪SOGC,2020
▪VaginalPisindicatedin
1.Singletonormultiplepregnancy&shortCL
(≤25mmbetween16and24w(strong/moderate).
2.PreviousPTB:(strong/moderate).
3.Aneffective&potentiallysuperioralternate
therapytocervicalcerclageinsingleton
pregnancy&apreviousPTBorshortCL≤25
mmbetween16and24w(strong/moderate).
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▪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. 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).
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▪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. ▪NICE,2019
▪VaginalprogesteroneORcerclagetowomenwho
haveboth:
▪HistoryofPTB(upto34+0wofpregnancy)orMTM
(from16+0wofpregnancyonwards)and
▪Shortcervix:TVSbetween16+0and24+0wof
pregnancythatshowCL25mmorless.
▪Discusstherisks&benefitsofbothoptionswiththe
woman,andmakeashareddecisiononwhich
treatmentismostsuitable
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▪Considervaginalprogesteroneforwomenwhohave
either:
▪Shortcervix:TVS.CL25mmorless.or
▪HistoryofPTBorMTM
▪Considercervicalcerclagewhen
▪Shortcervix:TVS.CL25mmorless,AND
▪whohavehadeither:
▪P-PROMinapreviouspregnancyor
▪Historyofcervicaltrauma.
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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
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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.
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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.
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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.
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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.
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23. thanks
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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. Controversieswithinobservationalstudiesmaybe
attributedtodifferentoperativeskillsandclinicalsurveillance.
Itcanhardlybedeniedthattheefficacyofboththe
vaginalandabdominalcerclageishighlydependentonthe
surgeon`sskills,andunfortunately,thishasnotsufficiently
beenconsideredorauditedinpublishedstudies.Therefore,
itsimplementationcannotbeconsideredininexperienced
handsastheclinicalrisks,althoughrarecanbedevastating,
astheseincludehemorrhage,sepsis,perinatal,neonatal,or
evenmaternaldeath.
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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. SOGC,2020
▪Progesteronetherapyreducestheriskofspontaneouspretermbirthin
womenatanincreasedriskbasedonhistoryofpreviousspontaneous
pretermbirthorinwomenwithashortcervicallength(moderate).
▪Thereisinsufficientevidencetosupporttheuseofprogesteronefor
preventionofspontaneouspretermbirthinwomenwithapregnancyinthe
absenceofcervicalshortening(moderate).
▪Thereisinsufficientevidencetosupporttheuseofprogesteronefor
preventionofspontaneouspretermbirthinwomenwithanormalcervical
lengthandapriorconizationprocedureonthecervixorabnormaluterine
anatomy(low).
▪Useofvaginalprogesteroneforpreventionofspontaneouspretermbirthhas
notbeenassociatedwithanincreaseincongenitalmalformationsorwitha
worseningofpostnatalneurodevelopmentaloutcomes(moderate).
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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. 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).
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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. 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. 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. 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. 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. 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. 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