International Federation of Gynecology and Obstetrics

• 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

IDENTIFYING RISK FACTORS AND CAUSES OF

PRETERM BIRTH

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

Other Preventive Measures (2016)

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)

PredictingPTBByRiskFactorCombinations

• DeterminewhichhealthcaresectorshouldbeassignedresponsibilitytolowerPTBrate:provider,publichealth/government,research

PretermBirth

PTBPerRisk Factors

Previous PTB and Preeclampsia: 1 and 2 only

49 5470 NoPTB

PTB

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)

MarchofDimesPrematurityResearchCenters

1 2

3 4

5

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

ExamplesofFundamentalInvestigationsUndertakentoExplainHowPregnancyis

MaintainedandLaborInitiated

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