Maternal colonization or infection with extended-spectrum beta-lactamase-producing Enterobacteriaceae in Africa : a systematic review and meta-analysis

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Maternal

colonization

or

infection

with

extended-spectrum

beta-lactamase-producing

Enterobacteriaceae

in

Africa:

A

systematic

review

and

meta-analysis

Andre

N.H.

Bulabula

a,b,

*

,

Angela

Dramowski

a,b

,

Shaheen

Mehtar

a,b a

DivisionofHealthSystemsandPublicHealth,DepartmentofGlobalHealth,AcademicUnitforInfectionPreventionandControl,FacultyofMedicineand HealthSciences,StellenboschUniversity,CapeTown,SouthAfrica

b_Infection_Control_Africa_Network_–_ICAN,_Cape_Town,_South_Africa

ARTICLE INFO Articlehistory: Received5June2017

Receivedinrevisedform22August2017 Accepted26August2017

CorrespondingEditor:EskildPetersen, Aar-hus,Denmark Keywords: Prevalence Maternalcolonization ESBL Enterobacteriaceae Pregnantwomen Post-partum Systematicreview Meta-analysisAfrica ABSTRACT

Objective:Tosummarizepublishedstudiesontheprevalenceofandriskfactorsformaternalbacterial colonizationand/or infectionwith extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E)inpregnantand/orpost-partumwomeninAfrica.

Methods:AsystematicreviewwasconductedusingthePubMed,Scopus,andGoogleScholardatabases. Bibliographies of includedeligible studieswere manually searchedto identifyadditional relevant articles.Nolanguagerestrictionwasapplied.Thetimeframeofthesearchincludedallrecordsfrom electronic database inceptionto July15, 2017. A random-effectsmeta-analysis was performed to summarizetheprevalenceandthe95%conﬁdenceintervals(CI)ofESBL-Ecolonizationorinfectionin pregnantor post-partumwomenin Africa. Themeta-analysiswas conductedusing STATAIC 13.1 softwareandthemetapropfunction/plugin.

Results:Ten studies(sevenonpregnantwomenandthreeonpost-partumwomen)wereincluded, documentinga17%prevalenceofmaternalcolonizationwithESBL-EinAfrica(95%CI10–23%).The prevalenceofESBL-Eincommunityisolatesexceededthatinisolatesfromthehospitalsetting(22%vs. 14%). The most frequently reported ESBL-encoding gene was CTX-M (cefotaxime hydrolyzing capabilities).DataonriskfactorsformaternalESBL-Ecolonizationandinfectionareverylimited. Conclusions:Theprevalenceofcolonizationand/orinfectionwithESBL-Einpregnantandpost-partum womeninAfricaexceedsthatreportedfromhigh-andmiddle-incomesettings,representingariskfor subsequentneonatalcolonizationand/orinfectionwithESBL-E.

http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Antimicrobialresistance(AMR)isagrowingthreattohuman healthglobally(WHO,2014;Frieden,2013).Amajormechanismof

AMR is the production of extended-spectrum beta-lactamase

(ESBL) enzymes, which confer resistance to penicillins,

cepha-losporins, and monobactams, but not to cephamycins and

carbapenems(PatersonandBonomo,2005;Pitoutetal., 2005), leavinglimitedtherapeuticoptionsforAMRinfections.In2013,the

US Centers for DiseaseControland Prevention (CDC)identiﬁed ESBL-producing Enterobacteriaceae (ESBL-E) as a serious threat (Frieden,2013).Inaddition,theWorldHealthOrganization(WHO) haspublishedaprioritypathogenslist,andresistantESBL-Eare classiﬁedas‘critical’,prioritynumber1(WHO,2017).

ESBL- E occur worldwide in both community and hospital

settings(Patersonand Bonomo,2005;Pitoutetal.,2005;Sonda et al.,2016; Storberg,2014;Luvsansharav etal., 2011), and the

reported incidence of infections in paediatric and neonatal

populations is increasing (Paterson and Bonomo, 2005; Sonda

etal.,2016;Storberg,2014;Flokasetal.,2017;PeiranoandPitout, 2010;Tansarlietal.,2014;Dramowskietal.,2015;Loganet al., 2014).ClinicalinfectionswithESBL-Eareassociatedwithincreased morbidity(including prolongedhospitalstay),increased health-carecosts,andhighermortalityratescomparedtoinfectionswith non-ESBL-E(Blombergetal.,2005;Zaoutisetal.,2005;Kimetal.,

*Corresponding author at: Division of Health Systems and Public Health, DepartmentofGlobalHealth,AcademicUnitforInfectionPreventionandControl, FacultyofMedicineandHealthSciences,StellenboschUniversity,CapeTown,South Africa.

E-mailaddress:andybulabula@gmail.com(A.N.H. Bulabula).

http://dx.doi.org/10.1016/j.ijid.2017.08.015

1201-9712/©2017TheAuthor(s).PublishedbyElsevierLtdonbehalfofInternationalSocietyforInfectiousDiseases.ThisisanopenaccessarticleundertheCCBY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).

ContentslistsavailableatScienceDirect

International

Journal

of

Infectious

Diseases

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2002;Ndiretal.,2016).Amongneonates,children,andpregnant/ post-partumwomen,ESBL-Earefrequentlyimplicatedinurinary tractinfections(UTI)(Pitoutetal.,2005;PeiranoandPitout,2010) andbloodstreaminfections(BSI)(Luvsansharavetal.,2011;Flokas etal.,2017;Dramowskietal.,2015;Zaoutisetal.,2005;Lohand Sivalingam.,2007).AmongneonatalESBL-Einfections, Klebsiella pneumoniaeandEscherichiacoliarethemostfrequentlyisolated species(Flokasetal.,2017;Dramowskiet al.,2015;Zaidietal., 2005).

Well-established risk factors for early-onset neonatal sepsis includematernalinfections(e.g.UTIsandchorioamnionitis)and prolongedruptureofthemembranes(Chanetal.,2013;Chanetal., 2015).Inawell-poweredsystematicreview,additionalriskfactors identiﬁedwerematernalbacterialcolonizationofthevaginaltract (Chan et al., 2013; Chan et al., 2015) and poor antenatal care

(deﬁned as less than four antenatal visits per pregnancy)

(Mizumotoetal.,2015;Lincettoetal.,2006).

Although ESBL-E are well-documented as important

blood-streampathogensinseveralAfricansettings(Flokasetal.,2017; Kimetal.,2002;Kangetal.,2004;Schiappaetal.,1996),littleis

known about the determinants and magnitude of maternal

colonizationwithESBL-E.Factorscontributingtothedevelopment

of AMR (including ESBL-E) in Africa include socio-economic

challenges and health-associated factors (Kariuki and Dougan, 2014)(suboptimalhygieneandsanitation(Tooleetal.,1995),weak health systems(Essacket al.,2016),lack oflaboratory capacity (Okekeetal.,1999),andmisuseofandeasyaccesstoantibiotics (Okeke et al., 1999)). A high burden of immunocompromised patients (HIV infection (Emacar et al., 2010) and diabetes

(Ntirenganyaetal.,2015)),environmental contamination(Dusé, 2005),andinadequatedecontaminationofmedicaldevices(Dusé, 2005), areother important factorsexacerbatingAMRpathogen transmissioninAfrica.Therelationshipbetweenthesefactorsand maternal colonization or infection with ESBL-E is unclear and requiresinvestigation.

This systematic review and meta-analysis summarizes the

magnitude of colonization or infection with ESBL-E among

pregnant andpost-partum women in Africaand theassociated

riskfactors.Knowledgeoftheburdenandriskfactorsofmaternal colonizationorinfectionwithESBL-Ewillassistwithclinicalcare, infectionprevention,andantibioticstewardship,andinformthe

future development of targeted interventions to reduce both

maternalandneonatalESBL-E-associatedmorbidityandmortality. Methods

Literaturesearch

A systematicreviewwas conductedin PubMed,Scopus, and

GoogleScholar.Thesearchstrategyincludedthefollowingwords,

medical subject heading(MeSH) terms, andBoolean operators:

“(enterobacteriaceaeORbacteria ORresistantORresistanceOR ‘non-susceptible’OR“nonsusceptible”OR“notsusceptible”)AND (coloni*ORinfect*ORcarri*)AND((AfricaORAlgeriaORAngolaOR BeninORBotswanaORBurkinaFasoORBurundiORCaboVerdeOR

CameroonORCentralAfricanRepublicORChadORComorosOR

DemocraticRepublicoftheCongoORRepublicoftheCongoOR

Coted’IvoireORDjiboutiOREgyptOREquatorialGuineaOREritrea

Table1

Characteristicsofstudiesincludedinthereview. Number Authorandyear

ofpublication

Country Study

design

Clinical samples

Population Numberofparticipantscolonizedwith ESBL-E/Totalparticipants(%colonized)

ESBL-Especiesincluded (isolate)andproportion

Setting 1 Olufunkeetal. (2014) Nigeria Cross-sectional Urine Pregnant women

69/264(26.1%) Escherichiacoli69/264 Hospital

2 Onwuezobe (2015) Nigeria Cross-sectional Urine Pregnant women 16/80(20%) Klebsiellapneumoniae8/ 16 Escherichiacoli6/16 Klebsiellaoxytoca1/16 Enterobactercloacae1/16 Community 3 Chereauetal. (2015) Madagascar Cross-sectional Stool Pregnant women 66/356(18.6%) Escherichiacoli46/66 Klebsiellapneumoniae11/ 66 Enterobactercloacae5/66 Citrobacterfreundii3/66 Morganellamorganii1/66 Community 4 Nelsonetal. (2014) Tanzania Cross-sectional Stool Post-partum women 16/113(15%) Escherichiacoli6/20 Enterobacterspp3/20 Klebsiellapneumoniae1/ 20 Citrobacterspp2/20 Pantoeaspp3/20 Proteusspp1/20 Hospital 5 Kabaetal. (2016)

SouthAfrica Cross-sectional Stool Post-partum women 4/90(4.4%) Klebsiellapneumoniae2/ 90 Escherichiacoli1/90 Enterobactercloacae1/90 Community 6 Sáez-lópezetal. (2016) Mozambique Cross-sectional Vaginal swabs Pregnant women

7 Djuikoue(2016) Cameroon

Cross-sectional

Stool Pregnant

women

15/26(57.7%) Escherichiacoli15/26 Community

8 Fortinietal. (2015) Nigeria Cross-sectional Stool Pregnant women

9 Bebelletal. (2017) Uganda Prospective cohort Urine Blood Post-partum women 8/174(4.6%) Escherichiacoli5/174 Klebsiellapneumoniae3/ 174 Hospital

10 Titoetal.(2017) Tanzania Cross-sectional

Urine Pregnant

women

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OREthiopiaORGabonORGambiaORGhanaORGuineaOR Guinea-BissauORKenyaORLesothoORLiberiaORLibyaORMadagascar

ORMalawiORMaliORMauritaniaORMauritiusORMoroccoOR

MozambiqueORNamibiaORNigerORNigeriaORRwandaOR“Sao

TomeandPrincipe”ORSenegalORSeychellesORSierraLeoneOR SomaliaORSouthAfricaORSouthSudanORSudanORSwaziland

OR Tanzania OR Togo OR Tunisia OR Uganda OR Zambia OR

Zimbabwe))AND(ESBLORextended-spectrum-beta-lactamaseOR

extended-spectrum-

b

-lactamase OR extended spectrum beta

lactamase)AND((pregnantORpregnancyORgestationOR post-delivery OR postdelivery OR “post delivery” OR post-part* OR

postpartum OR _“post partum_” OR perinatal OR antenatal OR

prenatal OR women))”. Bibliographies of eligible studies were manuallysearchedtoidentifyadditionalrelevantarticles.Itwas attemptedto contact theauthors of relevant studies to obtain speciﬁcdetails.Followingthescreeningofpublications,atotalof 10articleswereincluded(Table1).

Studyselectionandeligibilitycriteria

Allpublicationsdescribingcolonizationand/orinfectionwith

ESBL-E in pregnant or post-partum African women in both

communityand hospital settings wereselected, irrespective of thestudydesign.Primarystudydesignsreportingtheproportion orprevalenceof ESBL-Einpregnantor post-partumwomen,as wellas risk factors,were eligible. No language restriction was applied.Thetimeframe ofthe searchincludedall recordsfrom electronicdatabaseinceptiontoJuly15,2017.Thearticleselection andexclusionprocessisshowninFigure1.

Dataextraction

Adataextractionformwasdesignedtocapturethefollowing information:ﬁrstauthorandyearofpublication;country;study design(anytype); studysetting(communityorhospital);study

population; number and percentage of women colonized or

infectedwithESBL-E;totalnumberofwomenrecruitedintothe study;ESBL-Eisolatesandtheirproportions;molecularidenti ﬁ-cation ofESBL-Eisolates(if performed);factorsassociatedwith ESBL-Ecolonizationorinfectioninwomen.

Datasynthesis

Arandom-effectsmeta-analysiswasperformedtosummarize

theproportionsandthe95%conﬁdenceintervals(CI)ofESBL-Ein pregnantorpost-partumwomeninAfrica.Toensureproportionate

weight distribution to studies presenting extreme prevalence

(near0or1),theFreeman–Tukeyarcsinemethodologywasapplied (Nyaga et al., 2014). The between-study heterogeneity was assessed usingthe I2 _statistic_(which _quanti_ﬁes_the_percentage of variation acrossstudies due to heterogeneityrather than to chance): I2 _<75% _was _considered _as _moderate _{heterogeneity} (HigginsandThompson,2002)and>75%reﬂectedhigh heteroge-neity,inwhichcasesubsetanalyseswereperformed.The

random-effects modelwas chosen basedontheanticipated assumption

thatstudiesreportingonthemagnitudeofESBL-Einpregnantand

post-partum women used different laboratory methods, were

conductedindifferentsettings(hospitalandcommunity),orhad otherunknown factorsinﬂuencing the magnitudeof ESBL-E in

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pregnantand post-partum women in Africa. The meta-analysis

was performed using STATA IC version 13.1 software and the

metaprop function/plugin, which is a speciﬁc STATA program

designedforthemeta-analysisofbinomialdata,allowingpooling of proportions(Nyaga et al., 2014).Atotal of 1304 participants werepooledfromthestudiesincluded(927pregnantwomenand

377post-partumwomen).

Reportingofthemeta-analysisofobservationalstudies

This meta-analysis of observational studies is reported in compliancewiththeMOOSEstatementandchecklist(Stroupetal., 2000)(Meta-analysisofObservationalStudiesinEpidemiology).

Assessmentofbias

TheNewcastle–OttawaScale(Herzogetal.,2013)adaptedfor cross-sectionalstudies(seebelow)wasusedtoassesstheriskof biasforeachselectedstudy.Thisscaleincludesanevaluationof

participant selection, comparability,and outcome;each section hasamaximumnumberof‘stars’thatcanbeawardedasascore(5, 2, and 3, respectively). For the overall quality assessment, the

maximumscoreis10stars.Studieswitha minimumscoreof3

wereconsideredof acceptablemethodologicalqualityfor inclu-sioninthemeta-analysis(Table2).

Results

GeographicdistributionofarticlesdescribingESBL-Einwomenin Africa

Ten observational studies were included for quantitative

analysis. These were from Nigeria (n=3), Tanzania (n=2),

Madagascar (n=1), South Africa (n=1), Mozambique (n=1), Uganda (n=1), and Cameroon (n=1). Six studies reported on

pregnantwomenandfouronpost-partumwomen.Threestudies

reportedESBL-E isolatesfromurine,ﬁveothers fromstool,one fromvaginalswabs,andonefrombothurineandblood.

Table2

Riskofbiasassessmentforstudiesincludedinthequantitativesynthesis(allobservationalstudies).a Authorand

yearof publication

Selection Comparability Exposure Overall

quality assessment score(outofa maximumof 10) Representativenessofthesample Ascertainmentofexposure Comparabilityofthegroupson

thebasisofdesignoranalysis

Assessmentof outcome

Olufunke etal. (2014)

*Trulyrepresentativeofaverage pregnantwomenwithESBL Enterobacteriaceae

*Pregnantwomendiagnosedwith clinicalisolatesproducingESBL DDST

Studydidnotcontrolforother factors *Independentblind assessment 4 Onwuezobe (2015)

*Trulyrepresentativeofaverage pregnantwomenwithESBL Enterobacteriaceae

**Pregnantwomendiagnosedwith clinicalisolatesproducingESBL DDST

Studydidnotcontrolforother factors *Independentblind assessment 4 Kabaetal. (2016)

*Trulyrepresentativeofpost-partum womenwithESBLEnterobacteriaceaein thecommunity

**ESBLproductionwasconﬁrmed usingthecombinationdisctest

Studydidnotcontrolforother factors *Independentblind assessment 4 Chereau etal. (2015)

*Trulyrepresentativeofpregnant womenwithESBLEnterobacteriaceaein thecommunity

**ProductionofESBLinESC-resistant Enterobacteriaceaewasconﬁrmedby DDST(CASFM)

*Studycontrolledforother factors,multivariateanalysis

*Independentblind assessment

5

Nelsonetal. (2014)

*Trulyrepresentativeofpost-partum womenwithESBLEnterobacteriaceaein thehospital

*Rectalswabsplatedonto MacConkeyagar(OXOID,

Basingstoke,UK)supplementedwith cefotaxime2mg/lforpreliminary screeningofESBLbacterialisolates

Studydidnotcontrolforother factors *Independentblind assessment 3 Sáez-lópez etal. (2016)

Nodescriptionofparticipantselection **ESBLproducerswereidentiﬁedby DDSTusingCTX,AMCandCAZ

Studydidnotcontrolforother factors *Independentblind assessment 3 Djuikoue etal. (2016a,b)

*Trulyrepresentativeofoutpatient womenconsultingforasuspicionof UTI,duringthestudyperiod

**ThepresenceofESBLwas determinedusingthedoubledisc diffusionphenotypicmethod

5

Fortinietal. (2015)

*Trulyrepresentativeofhealthy pregnantwomenonthedayof admissiontohospitalinIbadan (Nigeria)

**Phenotypicandgenotypic characterizationofESBLproduction

Studydidnotcontrolforother factors *Independentblind assessment 4 Titoetal. (2017)

*TrulyrepresentativeofHIV-positive pregnantwomenattendingthePMTCT clinics;allconsentingHIV-positive pregnantwomenwereincludedduring thestudyperiod

**ESBLproductionwas

concomitantlytestedonthesame Mueller–Hintonagarplate,usingthe DDSTmethod

5

Bebelletal. (2017)

*Trulyrepresentativeoffebrile, hypothermic,ornormothermic post-partumwomeninthehospital

**ESBLphenotypeifsynergywas observedbetweenAMCandCAZor CTX

Thestudydesignalloweda4:1 ratioofnormothermicto febrile/hypothermic post-partumwomen,butdidnot controlforotherfactors

**Recordlinkageand thestatisticaltestused clearlydescribedand appropriate;p-value presented

5

AMC,amoxicillin–clavulanicacid;CASFM,CommittéAntibiogramme SociétéFrançaisedeMicrobiologie;CAZ,ceftazidime;CTX,cefotaxime;DDST,doublediscsynergy test;ESBL,extended-spectrumbeta-lactamase-producing;ESC,extended-spectrumcephalosporin;PMTCT,preventionofmothertochildtransmission;UTI,urinarytract infection.

a

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ProportionestimatesofESBL-Einpregnantandpost-partumwomen inAfrica

Through meta-analysis of the eligible studies, the overall pooledestimateoftheESBL-Eproportioninpregnantand post-partumwomeninAfricawasdeterminedtobe0.17(95%CI0.10– 0.23)or17%(95%CI10–23%)(Figure2).Theheterogeneitywas high(I2₌_93.6%,_p

<0.001).

ThepooledproportionofESBL-Einpregnantwomenwas0.22 (95%CI0.12–0.31)(Figure2)and thatofESBL-Einpost-partum womenwas 0.07 (95% CI 0.02–0.12). The pooled proportion of ESBL-Einhospitalsettingswas0.14(95%CI0.05–0.23)compared to0.22(95%CI0.09–0.34)incommunitysettings(Figure3).

The pooledproportionofESBL-E infectionswas 0.13(95%CI

0.01–0.27) compared to 0.19 (95% CI 0.01–0.27) for ESBL-E

colonizedpregnantandpost-partumwomen(Figure4). MolecularepidemiologyofESBL-Ecolonization/infection

Chereauetal.(2015)(Madagascar)identiﬁed66 ESBL-produc-ingisolatesinpregnantwomen,includingE.coli(n=46),Klebsiella spp(n=11),Enterobactercloacae(n=5),Citrobacterfreundii(n=3), andMorganellamorganii(n=1).Forty-ﬁveisolatescarriedabla CTX-Mgene,15carriedblaSHVandblaCTX-M genes,and twocarried a blaSHVgenealone.NoblaESBLgeneandnocefoxitinresistancewas detectedinfourESBL-producingE.coliisolates.Sáez-lópezetal.

(2016)identiﬁedoneESBL-EisolateanditcarriedtheCTX-M-15 gene.Kabaetal.(2016)reportedthatonemother–infantpairwas ESBL-positiveatbirthwithSHV-5-producingE.cloacae.Djuikoue etal.(2016a)reportedthatamong15E.coliESBL,allwereCTX-M group1(n=15).Fortinietal.(2015)foundE.coli(n=32)producing CTX-M-15.

Detectionandcon_ﬁrmationofESBLinthelaboratory:whatmethods wereused?

Fivestudies(Nelsonetal.,2014;Olufunkeetal.,2014;Aljabri etal., 2010;Bebellet al.,2017;Titoet al.,2017), detectedESBL production using thedouble discsynergy test (DDST). Chereau etal.(2015),Djuikoueetal.(2016b),andKabaetal.(2016)utilized both synergy testing and molecularidentiﬁcation of ESBL (PCR sequencing).Sáez-lópezetal.(2016)andFortinietal.(2015)used molecularidentiﬁcationofESBL.

FactorsassociatedwithESBL-EinpregnantwomeninAfrica Threestudiesincludedamultivariateanalysisofriskfactorsfor

ESBL-E colonization/infectionamong pregnantwomen. Chereau

et al. (2015) identiﬁedprivate indoor access todrinking water (oddsratio(OR)3.8,95%CI1.2–11.6)andlivinginanindividual house(OR2.2,95%CI1.0–4.8)asindependentriskfactorsfor

ESBL-E colonization among Malagasy women (after adjusting for

Heterogeneity between groups: p = 0.009 Overall (I^2 = 93.59%, p = 0.00); 1 Subtotal (I^2 = 94.10%, p = 0.00) 4 9 3 Post-partum 5 10 7 Subtotal (I^2 = .%, p = .) Pregnant Study 6 2 8 0.17 (0.10, 0.23) 0.26 (0.21, 0.32) 0.22 (0.12, 0.31) 0.19 (0.15, 0.23) 0.32 (0.23, 0.41) 0.04 (0.02, 0.11) 0.14 (0.09, 0.22) 0.58 (0.39, 0.74) 0.05 (0.02, 0.09) 0.07 (0.02, 0.12) ES (95% CI) 0.02 (0.00, 0.10) 0.20 (0.13, 0.30) 0.08 (0.03, 0.19) 100.00 10.66 67.59 10.97 9.46 10.92 10.34 5.98 11.15 32.41 Weight 11.02 9.57 9.94 % 0.17 (0.10, 0.23) 0.26 (0.21, 0.32) 0.22 (0.12, 0.31) 0.19 (0.15, 0.23) 0.32 (0.23, 0.41) 0.04 (0.02, 0.11) 0.14 (0.09, 0.22) 0.58 (0.39, 0.74) 0.05 (0.02, 0.09) 0.07 (0.02, 0.12) ES (95% CI) 0.02 (0.00, 0.10) 0.20 (0.13, 0.30) 0.08 (0.03, 0.19) 100.00 10.66 67.59 10.97 9.46 10.92 10.34 5.98 11.15 32.41 Weight 11.02 9.57 9.94 % -.5 0 .5 1

Poo

led prop

ortion of

ESBL-E in pregnan

t an

d po

st-partum

women

in Afric

a

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deliveryperiodandstudyarea).Djuikoueetal.(2016b))foundthat thedetectionofantimicrobialactivityinthestoolsamplewasthe onlyindependentriskfactorassociatedwithESBLE.colicarriagein Cameroonianwomen(OR5.4,95%CI2.0–14.7).Bebelletal.(2017)) identiﬁedsinglemaritalstatus(OR2.6,95%CI1.1–6.1,p=0.026), lowCD4+countof<200/

m

l(OR2.9,95%CI1.1–7.7,p=0.031),and

current UTI symptoms (OR 2.5, 95% CI 1.1–6.0, p=0.03) as

independentpredictorsofESBL-Einfection.

The following elements were not found to be signiﬁcantly

associated with ESBL-E colonization/infection in these three studies:beingemployedorbeingahousewife(Tito etal.2017), drinkingwatersupplyfromaspringorawell(Chereauetal.,2015), andhospitalizationinthelast3months(Djuikoueetal.2016a,b). Discussion

Thecloserelationshipofthemother–infantpairrepresentsa

potential risk for cross-transmission of maternal pathogens

leadingtoneonatalcolonizationorinfection.Severalstudieshave conﬁrmed therole of maternalcolonization in the subsequent developmentofneonatalsepsis(particularlyforgroupB Strepto-coccus,butalsoforESBL-E)(Chanetal.,2013;Kabaetal.,2016; Denkeletal.,2014;Rettedaletal.,2015).

However,thescarcityofresearchondeterminantsofmaternal colonizationinAfricaisworrisome.Thismeta-analysisofeligible published studies determined an overall pooled prevalence of

colonizationorinfectionwithESBL-Einpregnantandpost-partum womeninAfricaof17%(95%CI10–23%).Thisrateofcolonizationor infectionwithESBL-E isinlinewithawell-poweredsystematic reviewconductedinAfricabyTansarlietal.(2014),whoreported proportions varyingfrom1.5%to22.8%(pooledfrom13studies withisolatesfromclinicalurinesamples)amongpatientseither infected or colonized with Enterobacteriaceae. However, these

proportions were notfor pregnant andpost-partum women as

speciﬁc groups. The pooled ESBL-E rate documented herein is

substantially higher than therates foundin high-and middle-incomecountries, e.g.,Norway(2.9%)(Rettedaletal.,2015)and Argentina (5.4%) (Villar et al., 2013). Possible explanations for

increased ESBL-E carriage among African populations (both in

community(Pitoutetal.,2005;Pallecchietal.,2004)andhospital settings) includepoverty, suboptimalhygiene,contaminationof drinking water (faeces (Bain et al., 2014), antibiotics), water

sewage, communal toilets, easy access to antibiotics among

pregnant and post-partum women in Africa, and possibly also

increased use of antibiotics in livestock in Africa (Kariuki and Dougan, 2014).Anotherpossibleexplanationis thatthelack of trainedhealthcareworkers(Kimang’a,2012)andweaklaboratory andinfectioncontrolcapacity(Pettietal.,2006)maycontributeto

healthcare-associated transmission of ESBL-E to pregnant and

post-partumwomen.

Another important ﬁnding is that the pooled proportion of

ESBL-Eincommunitysettingsexceededthatinhospitalsettings

Heterogeneity between groups: p = 0.324 Overall (I^2 = 93.59%, p = 0.00); 6 Subtotal (I^2 = 93.52%, p = 0.00) Study Community 8 Subtotal (I^2 = 94.28%, p = 0.00) 4 3 7 1 9 5 10 2 Hospital 0.17 (0.10, 0.23) 0.02 (0.00, 0.10) 0.22 (0.09, 0.34) ES (95% CI) 0.08 (0.03, 0.19) 0.14 (0.05, 0.23) 0.19 (0.15, 0.23) 0.04 (0.02, 0.11) 0.05 (0.02, 0.09) 0.26 (0.21, 0.32) 0.32 (0.23, 0.41) 0.14 (0.09, 0.22) 0.58 (0.39, 0.74) 0.20 (0.13, 0.30) 100.00 11.02 37.43 Weight 9.94 62.57 10.97 10.92 11.15 10.66 9.46 10.34 5.98 9.57 % 0.17 (0.10, 0.23) 0.02 (0.00, 0.10) 0.22 (0.09, 0.34) ES (95% CI) 0.08 (0.03, 0.19) 0.14 (0.05, 0.23) 0.19 (0.15, 0.23) 0.04 (0.02, 0.11) 0.05 (0.02, 0.09) 0.26 (0.21, 0.32) 0.32 (0.23, 0.41) 0.14 (0.09, 0.22) 0.58 (0.39, 0.74) 0.20 (0.13, 0.30) 100.00 11.02 37.43 Weight 9.94 62.57 10.97 10.92 11.15 10.66 9.46 10.34 5.98 9.57 % -.5 0 .5 1

Pooled prop

ortion of ES

BL-E in women,

Hospital vs Community sett

ing

s

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(22%vs.14%)(Figure3).Thisﬁndingmayhavebeeninﬂuencedby thehighprevalenceofESBL-Eincommunityisolates(58%)inthe

Cameroonian study. However, another explanation may bethe

effectofhigh-levelESBL-Econtaminationofcommunitywaterand foodsources,lackofsanitation,andpossiblyoveruseofantibiotics.

TheapparentdifferenceinESBL-Eproportionsbetween

commu-nityandhospitalsettingscouldalsobeexplainedbythefactthat

all included studies from the community only studied ESBL-E

colonization. In this meta-analysis, the proportion of ESBL-E colonizationwasfoundtobegreaterthanESBL-Einfection.

ThedetectionofESBL-Einsamplesfromhospitalizedpregnant

women withshort lengths of stay may represent

community-acquiredcolonizationand/orinfectionwithESBL-E.Because ESBL-Estoolcarriagepersistsforavariablelengthoftime(Ahmedetal., 2014), the study population may have acquired ESBL-E during pregnancythatthenpersisteduptodeliveryandthepost-partum period, reﬂecting community-acquired antimicrobial resistance genesratherthanhealthcare-associatedacquisition.

ThepooledproportionofESBL-Ewashigheramongpregnant

womenthan post-partum women (22%vs. 7%)(Figure 2).This differencemaybeexplainedbyagreaterprobabilityofUTIswith ESBL-Eduringpregnancythaninthepost-partum period( Sáez-lópezetal.,2016).Itmayalsopossiblyrepresentdifferencesin asymptomaticbacteriuriaduringpregnancy,differencesin antibi-otic prescribing practices, and different decision-making when choosingtosendsamplesfrompregnantvs.post-partumwomen forculture.

The clinical signiﬁcance of increased ESBL-E-associated UTI

during pregnancy is the potential for adverse pregnancy and

neonataloutcomes,includingintrauterinegrowthrestriction,low birthweight,prematureruptureofthemembranes,foetaldeath, andneonatalinfections(LohandSivalingam.,2007;Romeroetal., 1989;OvalleandLevancini,2001;Matuszkiewicz-Rowinskaetal., 2015).

In this systematic review and meta-analysis, a few studies attemptedtoreportonfactorsassociatedwithESBL-Ecolonization inwomeninAfrica;however,theriskfactorsanalysedvariedfrom

one study to anotherand their pooled estimates could not be

produced. The molecular epidemiology of theESBL-E enzymes

identiﬁedintheMadagascar(Chereauetal.,2015),Nigeria(Fortini etal.,2015),Cameroon(Djuikoueetal.,2016b),andMozambique (Sáez-lópezetal.,2016)studieswas inkeepingwiththeglobal predominanceoftheCTX-Mclone,whichisalsowidelyreportedin community-acquiredUTI(Pitoutetal.,2005;PeiranoandPitout, 2010;Pallecchietal.,2004;Livermoreetal.,2007).

Thissystematicreviewhasseveralstrengths.Acomprehensive searchofseveralelectronicdatabaseswasperformed,inaddition tomanualsearchesandattemptstocontactauthorsofrelevant studiestoobtainspeciﬁcdetails.Theauthorsmadeaneffortto search the ‘grey literature’ by using Google Scholar, as many African publications are not listed in PubMed or Scopus. This appearstobe theﬁrstsystematic reviewand meta-analysison ESBL-E colonization and/or infection focusing onpregnant and

post-partum women in Africa. This group is of particular

Heterogeneity between groups: p = 0.505

Overall (I^2 = 93.59%, p = 0.00); Infection 1 10 3 9 5 2 4 Subtotal (I^2 = .%, p = .) 8 6 7 Colonization Study Subtotal (I^2 = 93.50%, p = 0.00) 0.17 (0.10, 0.23) 0.26 (0.21, 0.32) 0.58 (0.39, 0.74) 0.04 (0.02, 0.11) 0.32 (0.23, 0.41) 0.14 (0.09, 0.22) 0.20 (0.13, 0.30) 0.19 (0.15, 0.23) 0.13 (-0.01, 0.27) 0.08 (0.03, 0.19) 0.02 (0.00, 0.10) 0.05 (0.02, 0.09) ES (95% CI) 0.19 (0.10, 0.27) 100.00 10.66 5.98 10.92 % 9.46 10.34 9.57 10.97 31.75 9.94 11.02 11.15 Weight 68.25 0.17 (0.10, 0.23) 0.26 (0.21, 0.32) 0.58 (0.39, 0.74) 0.04 (0.02, 0.11) 0.32 (0.23, 0.41) 0.14 (0.09, 0.22) 0.20 (0.13, 0.30) 0.19 (0.15, 0.23) 0.13 (-0.01, 0.27) 0.08 (0.03, 0.19) 0.02 (0.00, 0.10) 0.05 (0.02, 0.09) ES (95% CI) 0.19 (0.10, 0.27) 100.00 10.66 5.98 10.92 % 9.46 10.34 9.57 10.97 31.75 9.94 11.02 11.15 Weight 68.25 -.5 0 .5 1

Pooled

proportion of

ESBL-E in women

by "infe

ction or colon

ization" statu

s

(8)

importance for vertical transmission and subsequent neonatal colonizationand/orinfection.Eachstudywasthoroughlyassessed forriskofbias.

While informative,thissystematic reviewand meta-analysis hasanumberoflimitations.Thenumberofeligiblestudieswas

small, demonstrating the apparent lack of studies on ESBL-E

colonizationandinfectioninthispopulationgroup:pregnantand post-partumwomeninAfrica.Giventhelimitedsamplesize,the ﬁndingsofthissystematicreviewandmeta-analysismaynotbe generalizabletoallpregnantand/orpost-partumwomeninAfrica. Thepublicationsretrievedandincludedinthemeta-analysiswere allobservationalstudies,astudytypethatispronetomanybiases, including selection and information biases (Archer and Horn, 2006).

Morerobuststudiesareneededtounderstandhowfrequently

pregnant and/or post-partum women become colonized or

infectedwithESBL-EinAfrica,aswellastherelatedriskfactors

in both community and hospital settings, to inform future

interventionstoreduce theirrates. Interventions couldinclude improvedsanitationandwatersupplies,educationofmotherson personalhygiene,restrictionofantibiotic useduringpregnancy, andstrengtheningofinfectionpreventioninhealthcarefacilities. Plainlanguagesummary

The level of colonization and/or infection with ESBL-E in

pregnantand post-partumwomenin Africaishigher thanthat

reported from high- and middle -income settings. In African

pregnantand post-partumwomen,theprevalence ofESBL-E in

community isolates exceeds that in hospital isolates. Maternal ESBL-Ecolonization/infectionrepresentsariskformothertochild pathogentransmissionwiththepotentialforsubsequentneonatal colonizationand/orinfection.

Keyrecommendation

FurtherstudiesareneededtoestablishESBL-Ecolonizationand

infectionrates amongst pregnantand post-partumwomen and

theirdeterminantsinallAfricanregions.Interventionstoreduce

ESBL-E colonization and carriage in Africa should focus on

preventing both community- and healthcare-associated ESBL-E

acquisition.Potentialinterventionscouldincludetheprovisionof safesanitationandcleanwatersupplies,educationofmotherson personalhygiene,restricteduseofantibioticsinpregnancy,and

strengthening of infection prevention efforts in healthcare

facilities(handhygieneandappropriatedisinfectionofobstetric

equipmentandtheenvironment).

Researchgaps

Itisnotwellunderstoodhowfrequently pregnantand post-partumwomenbecomecolonizedandinfectedwithESBL-E,which riskfactorspromoteESBL-Ecolonization/infection,andhowthis couldbepreventedormanaged,bothincommunityandhospital settingsinAfrica.Inaddition,healthsystemsresearchisneededto

increase the understanding of the problem of antimicrobial

resistance in maternal and neonatal infections at the macro

(leadership or governance), meso (healthcare facilities and

programmes),andmicro(pregnantwomenorserviceconsumers) levels.

Fundingsources

None.

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