Post on 03-Jul-2018
transcript
• JoeLeighSimpson(US):Chair
• GianCarloDiRenzo(IT):Co-Chair,FIGO
• JamesMartin(US)
• MaryD'Alton(US)
• OladapoAshiru(NG)
• JaneNorman(UK)
• T.Y.Leung(HK)
Members• BoJacobson(SE)
• ErnestoCastelazo (MX)
• EduardoFonseca(BR)
• Madhuri Patel(IN)
• JenniferHowse(US)exofficio
FIGO/MarchofDimesWorkingGroupforPretermBirthPrevention
Preterm Birth Rates
1) 15millionbabiesareborntoosooneveryyear
2) Worldwideyearlyratesupto>15%;1.1milliondeathsmostlyinLow/MiddleIncomeCountries(LMIC)
3) 5– 10%pretermbirthrateinhighincomecountries(HIC),varyingwidelycountrytocountry
Evidence Based Prevention (2012)
1. Eliminate Early Elective Deliveries (<39 weeks)
2. Progesterone given a previous PTB
3. Better ART practices (fewer embryos transferred per cycle)
4. Cervical cerclage when increased
5. Eliminate maternal smoking
Preventing Preterm Births• Ifcomplianceexistedforallevidence-based
interventions(2012)thePTBreductionwouldonlybe0.5%:9.6%to9.1%
• EveninHighResourcecountries,wecanfewpretermbirths– especially24-34weekscanbeprevented
• Buttherearedifferencesamountcountries
― PTBrates5.5%inSwedenversus7.8%inU.K.and9.2%inGermany
Lancet 2013; 381:223-24
Other Preventive Measures (2016)
• PregnancySpacing(Delivery-conceptioninterval>18months)Biologicalexplanationprovidedin2015:alteredvaginalmicrobiomeafterdelivery
FIGOBestPractices(2015)
• Vaginalprogesteroneforshortcervicallength(FIGO)
• Aspirinforpre-eclampsia
FIGO/March ofDimes(MOD)Memorandum ofAgreement (2014)
• Committeememberexchangestoassuretransparency
• SymposiaonPTBatFIGOtriennialCongress(Vancouver2015)andatFIGOregionalmeetings
• GenerateGoodPracticedocumentsforPreventionofPretermBirth
• ShareMODbasicdiscoveries,translation,andimplementationstrategies
• Translategoodpracticeglobally
Intra-CountryAnalysistoCharacterizeOutcomesbyPracticePatterns
• Largeststudyandfirstcross-countrystudy:4.1Mbirthswithindividual-leveldatafromfourcountriesandonecomparatorUSstate
• CzechRepublic:NationalRegistryofReproductionHealth-MothersatChildbirthandNewborns:1.3M
• NewZealand:NationalMaternityCollectionmaintainedbytheNewZealandMinistryofHealth:247K
• Slovenia:SlovenianNationalPerinatalInformationSystemmaintainedbytheSlovenianNationalInstituteofPublicHealth:175K
• Sweden:SwedishMedicalBirthRegistermaintainedbytheSwedishNationalBoardofHealthandWelfarecomplementedbydatafromStatisticsSweden:1.1M
• California:vitalstatisticslinkedbirth/deathfilefromtheCaliforniaDepartmentofHealthServices:1.3M PLOSOne,2016
IndividualPatientData(CountryAnalysis)
• Identify individual significant risk factors (prior preterm birth, preeclampsia)
• Identify most significant single risk factor among those overlapping (low education, low socioeconomic status)
• Identify risk factors with lower odds ratios that are nonetheless highly prevalent and having greater population impact (nulliparity, male sex)
FIGOWorkingGroupMultivariateAnalysis:PretermBirthOddsRatios
• PriorPTB• Hypertension/Preeclampsia
• Diabetes• MaternalAge• BMI• PrenatalCare• Education• Poverty
HighIndividualRiskLowerPopulationPrevalence
18reportson20factors
LowIndividualRiskHigherPopulationPrevalence
WaterfallAnalysis─DeterminingHowMuchKnownRiskFactor(s)ExplainPTBRate:Best
PracticevsPopulationRate
6
0
4
2
PTBRate(%)Best
TotalFactor12
Factor4Factor3
Factor2 Factor14
Base-line
Factor11
Factor10
Factor9
Factor13
Factor8
Factor7
Factor6
Factor5
Factor1
Unknown(Sex)
Policy& Publichealth(Tobacco)
ClinicalPractice(EarlyInduction)
Risk Factors
PTBRate(%)Observed
8
CzechRepublic
NewZealand Slovenia Sweden
Prior Preterm 6.2 5.7 4.6 6.0Preeclampsia 4.8 3.4 2.8 5.7Diabetes 3.4 1.9 3.6Hypertension 2.1 1.7Age>40 1.6 1.3 1.6 1.4Age35-40 1.4 1.2 1.2 1.2Nulliparity 1.5 1.4 1.6 2.1Smoking 1.3 1.5 1.3 1.3Education,low 1.4 1.2 1.2MaleSex 1.2 1.2 1.2 1.1
PretermBirthIndividualOddsRatio(FIGO)
• DeterminewhichhealthcaresectorshouldbeassignedresponsibilitytolowerPTBrate:provider,publichealth/government,research
PretermBirth
CategorizationofRiskFactorsbyInterventions
Examples
• PriorPTB • Smoking • EarlyInduction
Research71%
PolicyandPublicHealth22– 23%
ClinicalPractice5– 6%
Preterm Birth:Swedish BestPractice vPopulation
SwedenResearch
71%Policy and Public Health
22-23%Clinical Practice
5-6%PTB rate (%)
2.13
4.97
• UnexplainedknowledgegapexistsbetweenbestpracticePTBratesandpopulationPTBrates
• Notexplainedbysociodemographicorknownclinicalriskfactors
FIGO/MarchofDimesWorkingGroupforPretermBirthPrevention
TakeHomeMessages:
FIGO/MarchofDimesWorkingGroupforPretermBirthPrevention
• 2/3ofallpretermbirthsareassociatedwithriskfactorslackingaknownbiologicalbasis
• Theseriskfactorsarenotamenabletochangesinclinicalpracticeorpublichealth/policy
CausesofPretermBirth:
NextSteps:WorkingGroupforPretermBirth(PTB)Prevention
• ApplylessonslearnedinHighIncomeCountriestoMiddleIncomeCountries
• GeneraterobustpredictivemodelsforPTBbasedonavailableriskfactors
• IntegrateWorkingGroupresultswithbiologicalstudiesintoinitiationoflabor(MarchofDimesPrematurityResearchCenters)
WhatInitiatesLabor?
• Geneticfactors• Dysfunctionalenergymetabolism(mother
andfetus)– mitochondria,diet• Inflammatory/Infectiousetiologies• Fetalormaternalsignalsthatinitiatelabor• Anatomicchangesinuterus,cervixor
placenta
StrategiesforElucidatingWhatInitiatesLaborandPretermLabor
• MarchofDimesPrematurityResearchCenters:Investigatorsnotpreviouslyinpretermbirthresearch
• Diverseteamofmulti-specialtyphysicianinvestigators,engineers,physicists,geneticists,genomicists,socialscientists,epidemiologists
• Big-datainformatics:multiple-layeranalysistointegratebiologicalfindingswithenvironmentalandsociodemographicfactors
WhatGeneticFactorsCouldInfluenceLabor?
• 30%heritability.Recurrenceriskupto30%• Protein-codinggenesgoverninginflammation,
gestationallength,onsetoflabor• Mitochondrialgenesgoverningbioenergetics
(nutritionanddiet)• Regulatorygenesandnetworkscouldif
disturbedbeplausibleexplanationsforinter-generationalpersistenceofsociodemographicdisparities(stress;racism)
WhyDetermineGenesAffectingPretermBirth?
• Causativecodinggene=potentialtherapeuticstrategyincludingpharmaceuticalagents:e.g.,hyper-activeion-channelmyometrialgenecouldbeinhibited
• Atriskpredictionandaggressivepreventiontherapyforatriskcohorts
• Minimizeexposuretodeleteriousagentsforatriskcohorts
• Afterexpressionofregulatorygenessusceptibletostress
Whatisthemicrobiome?
• Microbiomecommensalmicroorganismslivingwithinthehumanbody
• Colonizeall“exposed”tissues(oral,respiratory,digestive,skin,uro-genital
• 10timesmoreorganismsthanhumancells;100timesmoreDNA
LackofLactobacillus(CST4)ObservedinPretermBirth(ReproductiveTract)
DiGiulio, Callahan, McMurdie, et al., PNAS, 2015
PTB
VeryPre
Sample
Taxa
Relativeabundance
HowareUterineContractionsInitiatedandProceedVoluntarily
• Whereareuterinepacemakers?
• Locatepacemakersusingthesamestrategybywhichcardiologistslocatefociofcardiacarrhythmias.
• Aberrantpacemakeractivitycouldbealteredtopretermbirth
Electromyometrial Imaging(EMMI)toidentifyUterinePacemakers
ED F
ElectricalSensing
MRI =Localization+
MODPrematurityResearchCenterNetwork
Stanford University
Chronodisruption
Microbiome and
Gestational Length
Placental Transcriptome
U Pittsburgh
Bioenergetics & Mitochondria
Cervical Remodeling
Columbia
Cervical Photoacoustic
Endoscopy
Texas A&M
Sociobiology
Vanderbilt
Evolutionary Synthesis
Washington University
Ohio Collaborative
University of Pennsylvania
Mt. Sinai
UChicago-Duke-
Northwestern
Princeton
Models of Pregnancy
Gene Regulation in Pregnancy and Preterm
Birth
U South Florida
Progesterone
3D Electrophysiology of the Uterus
Gene Identification and Function
MOD PRC Data Co-ordinationUCSF
UT South-western
Placental Dysfunction
U Iowa
Biological Responses to
Maternal Stress