Vaginal Microbiome & Pregnancy 2016 presentations/Stout VMB Wilmington Symposium.pdfpregnancy 2)...
37
Vaginal Microbiome & Pregnancy Molly J. Stout MD MSCI Maternal Fetal Medicine Washington University in St. Louis
Transcript of Vaginal Microbiome & Pregnancy 2016 presentations/Stout VMB Wilmington Symposium.pdfpregnancy 2)...
VaginalMicrobiome&Pregnancy
MollyJ.StoutMDMSCIMaternalFetalMedicine
WashingtonUniversityinSt.Louis
Agenda
• Pretermbirthepidemiology• SeEngthestage:MajorvaginalMBpapers• VaginalMBdatafromWashU• NeonatalMicrobiomeDevelopment
PretermBirthEpidemiology&ClinicalConsideraLons• Pretermbirth12%inUS• Racialdisparity• PredicLonpoor
– SmallimpactonPTBrate:12.1%à11.8%for17-OHP
PetriniJR.ObstetricsandGynecology105(2).2005.
TRIMESTER'1'Weeks'1-13'
TRIMESTER'2'Weeks''''''14-27'
TRIMESTER'3'Weeks'28-40'
WEEK$23$“Viability”'
WEEK$37$“FULL$TERM”'
PRETERM''
TERM
InfecLon&PretermBirth
PRETERMBIRTH
InfecLon/InflammaLonAmnioLcFluidChorionicMembranesVaginalInfecLonsSystemicInfecLons
• Evidenceforcausality?AnimalModels• Nospecificagent/microbeknown
CareyJCNEJM2000;GoldenbergRAmJPerinatology1997;MeisPJAJOG1995;RiduanJAJOG1995;HillierSNEJM1995;WaesDHObstetGynecol1992;DiGiulioDBPLoSONE2008;DondersGGBJOG2009
Enigma:TreatmentwithAnLbioLcsNotEffecLve
GroupBStreptococcus(Erythromycin):NoeffectofGBSTXonPTBorLBW
(Klebanoffetal.AmericanJournalofObstetricsandGynecology)
Trichomonas(Metronidazole):NoeffectoftreatmentonPTB…infacthigherPTBrateintreatmentgroup(19%TXvs.10%placebo)
(Klebanoffetal.NEJM2001)
Chlamydia(Erythromycin):NoeffectofTXofChlamydia(MarLnetal.InfectDisObstetGynecol1997)
Ureaplasma(Erythromycin):NoeffectofTXofUreaplasmaonPTB(Eschenbachetal.AmericanJournalofObstetricsandGynecology1991)
Whytheenigma?
• Toobroad?• Killsbeneficialbacteria?• Notcausal?
• Boeomline:poorlyunderstood• Needtoapproachthisecologically:
– Clarifywhatisnormal– Understandabnormal– MechanismsàSmartlydesigntherapy
“Normal”VaginalFlora
• ConvenLonalthinking– Lactobacillusà↓pHà↓pathogenicbacteria
• BV(alteraLoninflora):– ↑ STD,endometriLs
• Suggests“normal”vaginalbacteriaareprotecLve
• But,“NORMAL”:Difficulttodefine.
WisenfeldHCHIV/AIDS2003;CherpesTLClinicalInfectDis2003;TahaTEAIDS1998.
LANDMARKSTUDIES:CURRENTSTATEOFKNOWLEDGE
“Normal”VaginalFlora• N=300ReproducLveageasymptomaLcwomen• SingleLmepoint
Raveletal.PNAS2011
TwoMajorFindings:1) NON-lactobacilluscommunity(heterogeneous)maybeNORMAL2) Importantracialdifferences
PregnancyVaginalMicrobiome• Healthypregnantwomansecondtrimester(n=24)vs.non-pregnantcontrols(n=60)
• Keyfindings:– Uniquevaginalmicrobiomeinpregnancy
– Decreasedspeciesrichnessanddiversity
AagaardK.PLoSOne.2012
Non-Pregnant
Pregnant
VaginalMicrobiome&PTB(EarlyStudy)
RacialDifferences
Caucasiansonly30Term7PTBSiglowerSDIinPTB
Hyman2013ReproducLveSciences
• N=49women–sampledweekly• VeryfewAAsubjects(n=2)• Findings:
– Stability/instabilitydidnotcorrelatewithPTB– NosignificantdifferenceinShannondiversityoverLmeinpregnancy
– TaxafromhighdiversityheterogeneousgroupassociatedwithPTB(ureaplasma,gardnerella)
DiGiulioPNAS2015
WASHINGTONUNIVERSITYVAGINALMICROBIOMESTUDY
1) Knownassocia`onbetweenmicrobialchangesandpretermbirth2) Notableracialdifferences3) Evidenceofpregnancyspecificchanges4) WashingtonUniversity:highriskcohort+racialdemographics
Hypothesis&SpecificAims
Hypothesis:Differencesinvaginalcommunity(structure,taxaetc.)areassociatedwithpretermbirthSpecificAim:LongitudinallycharacterizevaginalcommuniLesofacohortofpregnantwomenfollowedprospecLvelyfortermorpretermbirth
Methods
• ProspecLvecohort2012-2015• Singletons• Mid-vaginalswabwithspeculum• 16SV1V3region• Specimensobtainedbeforeevent
CohortCharacterisLcsCharacteris`c TotalCohort TermDelivery PretermDeliveryTotalSubjects 77 53(69%) 24(31%)TotalSwabs 149 101(68%) 48(32%)
Trimester1 27 18 9Trimester2 61 41 20Trimester3 61 43 18
RaceAfricanAmerican 53(69%) 37(70%) 16(67%)
Non-AA 24(31%) 16(30%) 8(33%)
CohortCharacterisLcs
Characteris`c TotalCohort TermDelivery
PretermDelivery
P-value
MeanGestaLonalAgeofDelivery
37weeks 38weeks 34weeks 0.01
BMI 32 33 30 0.3TobaccoUse 25% 25% 25% 0.9PregestaLonalDiabetes
35% 32% 41% 0.4
GestaLonalDiabetes
13% 15% 8% 0.5
FullCohort:Richness&Diversity
TT
T
T TT
PTPT
PT
PT PTPT
TermBirthStable
PretermBirthSignificantdecreaseinrichnessanddiversityoverpregnancy(p<0.01)
AASubgroupT T T
T TT
PTPT
PT
PT
PTPT
TermBirthMarginalchangeoverpregnancy(p=0.05richness,p=0.06diversity)
PretermBirthSignificantdecreaseinrichnessanddiversityoverpregnancy(p<0.01)
Blackvs.WhiteSubgroupsBlack White
QuesLon:CanwelookatasingleLmepointandpredictpretermbirth?--staLsLcallynon-significant
P=0.4
P=0.2Cut-pointtoidenLfyPTB?
Correctlycapture75%ofPTBIncorrectlycapture50%of
termbirth
BlackSubgroupCorrectlycapturePTB83%
IncorrectlycaptureTerm50%
Interes`ngIdeaMain`mingofdifferenceEARLYpregnancy—NOTimmediatelypreceding
pretermbirth
Dominanttaxa:Lactobacillus
IncreasedinPTB:Sneathia(G-Rod)Ureaplasma(G-;nocellwall)DecreasedinPTB:Coriobacteriaceae(G+acLnobacteria)
SpecificBugs?
EarlyTiming!
Summary
1)Termbirth:stablerichnessanddiversityoverpregnancy2)Pretermbirth:decreasedrichnessanddiversityoverpregnancy3)ChangesappeartooccurEARLYinpregnancy4)HighorlowdiversityaloneinanytrimesterisnotstaLsLcallyassociatedwithPTB5)SuggesLonoftaxadifferences—butnotaxa(presence/absence)predictedPTB
Conclusions
• Predominantlyblackcohort—differentfrompublishedliteraturethusfar
• CandidatesignatureofPTB–firsttrimesterdiscriminaLon
• EarlypregnancyimportantecologicalLme
DEVELOPMENTOFTHENEONATALMICROBIOME
• Background:1) Babiesfromvaginalversuscesareandelivery
developdifferentcolonizaLon2) BabiesfromCShaveincreased:obesity,
asthma,allergiesetc.Istherealink?
• 18infants(11CS,7VD)• Vaginalgauze(GBSnegaLve,noacLvevaginalinfecLons)
• “MicrobialrestoraLonprocedure”• Vaginalgauzeàswabbaby(mouth,face,body)• Trackedoral,skin,analx1month
ParLalMicrobialRestoraLonDay1:CSexposedtovaginalfluidresembledvaginaldeliveredpaeernWeek2:analsamplesLBandbacteroidesenrichmentinVD,andVD+seed,butnotinCS
Morecomplicatedthan“seeding”
• Allbabieshadgut-derivedbacteriainanalsamplesimmediatelyaxerbirth
• Majordifference:LmingandratedevelopmentofgutbacterialpopulaLons(regardlessoftreatmentgroup)
• LargefracLonofbacteriainallgroupscouldnotbeassignedbodysiteorigin
• PaLentswhogetVDmaybedifferentfromthosewithCS
ORMicrobiota
• Mostsimilartohumanskin• Skincellsdetectedbystaining/petridishdeposits
• TopofORlamps:dustandliveskinbacteria(grow-ableinculture)
• Goodnews:30%ofsamplesweresequencefailures(toolieleDNA)
• SampledAFTERc-secLon
• N=39women• Majortaxa:staph,enterobacteriaceae,pseudomonas
• Nodifference:gestaLonalage,modeofdelivery,infantgender
• EffectsofbacteriadirectlyORbacterialinfluenceonhumanmilkcomponents?
• Goal:examinepaeernofhowgutmicrobiomegetsestablishedinpreterminfants
• N=58infantsN=922specimen• Birthweight<1500gfromSt.LouisChildren’sHospital
Paeern:Progressionfrombacillitoclostridialabundance(andflourishofGammproteobacteriasoonaxerbirth)Unrelatedto:modeofdelivery,anLbioLcs,breastversusformulafeedsWhatdrivesthis?
TeamScience• Microbiologists• Genomics• InformaLcs• Bothsidesoftheplacenta
– Maternal– Neonatal
• Epidemiologists• SeniorandNewInvesLgators• PaLents&Babies
GeorgeMaconesMethodiusTuuliPhilTarrKrisLneWylie
