Primary and secondary prevention of preterm birth: a review of systematic reviews and ongoing randomized controlled trials

Review

article

Primary

and

secondary

prevention

of

preterm

birth:

a

review

of

systematic

reviews

and

ongoing

randomized

controlled

trials

Anca

Matei

,

Gabriele

Saccone

*

,

Joshua

P.

Vogel

,

Anthony

B.

Armson

b

DepartmentofNeuroscience,ReproductiveSciencesandDentistry,SchoolofMedicine,UniversityofNaplesFedericoII,Naples,Italy

c

UNDP/UNFPA/UNICEF/WHO/WorldBankSpecialProgrammeofResearch,DevelopmentandResearchTraininginHumanReproduction(HRP),Departmentof ReproductiveHealthandResearch,WorldHealthOrganization,Headquarters,20AvenueAppia,Geneva,1211,Switzerland

d

MaternalandChildHealthProgram,BurnetInstitute,Melbourne,Victoria,Australia

ARTICLE INFO Articlehistory: Received2December2018 Accepted13December2018 Availableonlinexxx Keywords: Pretermbirth Prevention Prematurity Neonatal Obstetrics ABSTRACT

Background:Pretermbirth(PTB)isaleadingcauseofperinatalmorbidityandmortality.Interventions aimedatpreventingPTBcanbeclassifiedasprimary,secondary,ortertiaryprevention.

Objective:Toconductareviewofsystematicreviewsontheeffectivenessandsafetyofprimaryand secondarypretermbirthpreventioninterventions.

Searchstrategy:AsystematicliteraturesearchoftheCochrane,PubMed/Medline,EMBASEandCINAHL databaseswasconductedon2September2015,andupdatedon21November2016.

Selectioncriteria:Weincludedanypublishedsystematicreviewofrandomizedcontrolledtrials(RCTs)or individualpatientdata(IPD) ofRCTs relatedtoprimaryorsecondarypreventionofPTB,published between2005–2016wheregestationalageatbirth (of anyinterval) wasapre-specifiedoutcome. Individualtrialsandnon-systematicreviewswerenoteligible.

Datacollectionandanalysis:Thepopulationofinterestwasallpregnantwomen,regardlessofPTBrisk. TheprimaryoutcomewasPTB<37weeks.

MainResults:Intotal,112reviewswereincludedinthisstudy.Overalltherewere49Cochraneand63 non-Cochranereviews.Eightwereindividualparticipantdata(IPD)reviews.Sixtyreviewsassessedthe effectofprimarypreventioninterventionsonriskofPTB.Positiveeffectswerereportedforlifestyleand behaviouralchanges(includingdietandexercise);nutritionalsupplements(includingcalciumandzinc supplementation); nutritional education; screening forlower genital tract infections. Eighty-three systematicreviewswereidentifiedrelatingtosecondaryPTBpreventioninterventions.Positiveeffects werefoundforlowdoseaspirinamongwomenatriskofpreeclampsia;clindamycinfortreatmentof bacterialvaginosis;treatmentofvaginalcandidiasis;progesteroneinwomenwithpriorspontaneousPTB andinthosewithshortmidtrimestercervicallength;L-arginineinwomenatriskforpreeclampsia; levothyroxine among women with tyroid disease; calcium supplementation in women at risk of hypertensivedisorders;smokingcessation;cervicallengthscreeninginwomenwithhistoryofPTBwith placementofcerclageinthosewithshortcervix;cervicalpessaryinsingletongestationswithshort cervix;andtreatmentofperiodontaldisease.

Conclusion:TheoverviewservesasaguidetocurrentevidencerelevanttoPTBprevention.Onlyafew interventionshavebeendemononstratedtobeeffective,includingcerclage,progesterone,lowdose aspirin,andlifestyleandbehaviouralchanges.Forseveraloftheinterventionsevaluated,therewas insufficientevidencetoassesswhethertheywereeffectiveornot.

©2019ElsevierB.V.Allrightsreserved.

Contents

Introduction ... 00 Methods ... 00

* Correspondingauthor.

E-mailaddress:gabriele.saccone.1990@gmail.com(G.Saccone).

https://doi.org/10.1016/j.ejogrb.2018.12.022

0301-2115/©2019ElsevierB.V.Allrightsreserved.

xxx–xxx

ContentslistsavailableatScienceDirect

European

Journal

of

Obstetrics

&

Gynecology

and

Reproductive

Biology

Eligibilitycriteria ... 00

Literaturesearch,screeningandextraction ... 00

Outcomes... 00

Classification,analysisandreporting ... 00

Results ... 00

Studyselection ... 00

Interventioneffectsonprimaryoutcome(pretermbirth<37weeks) ... 00

Discussion ... 00 Keyfindings ... 00 Disclosure ... 00 Financialsupport ... 00 Condensation ... 00 Authorscontribution ... 00 References ... 00 Introduction

Anestimated11%oflivebirthswerebornpreterm,equatingto nearly15 millionpreterm babiesborn in 2014 [23]. Of the 38 countries with high-quality data, preterm birth rates have increasedsince2000in26countries.ComplicationsofPTBwere theleading cause of death in children underfive years of age globallyin2016,accountingforapproximately16%ofalldeaths, and 35% of deaths among newborns [1]. In general, preterm-associatedneonatalandchildsurvivalratesaremuch poorerin low-andmiddle-incomecountries[1–3].

Interventions aimed at preventing PTB can be classified as primary (i.e. directed at all women, including populations of womenathigher-or–lower-riskofPTB),secondary(i.e.directedat asub-groupofwomenwithknownoridentifiedriskfactor/s),or tertiaryprevention(interventionsusedafterpretermlabor(PTL) hascommenced)[4].Primaryandsecondarypreventionincludesa wide range of interventions, including pharmacological treat-ments, such as low-dose aspirin [5] or progesterone [6–9]; nutritionalinterventions[10];surgicalprocedures,suchascervical cerclage[11,12];devices,suchascervicalpessary[13–15];aswell asmorecomplex,population-levelorhealth system-level inter-ventions,suchasdietaryeducationandscreeningandtreatment programmes[16].

In 2015, a review of systematic reviews on primary and secondarypreterm birth(PTB) interventionswas initiated with twomainobjectives:

1) to systematically assess existing literature regarding effectivenessand safetyofinterventionstopreventPTB;and2) toprioritizeinterventionsforfurtherresearchinlow-and middle-incomecountrysettings.Reviewsof systematicreviews onPTB preventionhavebeenconductedpreviously(2014).(16)However, these have focused only on Cochrane reviews. There is an increasingnumberofhigh-qualitysystematicreviewsof random-izedcontrolledtrials(RCTs)onPTBpreventionpublishedinother journals.Furthermore,anumberofimportantreviewshavebeen published or updated in the past five years, including several individualpatientdata(IPD)meta-analyses.

In this paper, we present the findings of the review of systematic reviews of primary and secondary PTB prevention interventions,aswellasareviewofplannedandongoingRCTs. Methods

Thisreviewofsystematicreviewswasconductedaccordingto standards of the Cochrane Handbook of Systematic Reviews of Interventions[17],andreportedaccordingtothePRISMA Check-list[18].ThereviewwasregisteredwiththePROSPERO Interna-tional Prospective Register of Systematic Reviews (CRD42015 027440).

Eligibilitycriteria

WeincludedanypublishedsystematicrevieworIPDofRCTs relatedtoprimaryorsecondaryPTBpreventionpublishedbetween January2005toOctober2016wheregestationalageatbirth(ofany interval)wasapre-specifiedoutcome.Individualtrialsand non-systematic reviews were excluded. Systematic reviews of non-randomizedstudieswerealsoexcluded.

Wedefineda systematicreviewasreviewsthat:hada clear research question, described a comprehensive literature search (including at least two databases), used a duplicated study selectionanddataextractionprocess,anddescribedthe character-isticsoftheincludedstudies.Thepopulationof interestwas all pregnantwomen,regardlessof PTBrisk,includingwomenwith singleton or multiple pregnancies,without clinically confirmed pretermlabor(PTL).Interventionsofanytype,atanylevelofthe health system (facility, health system, and health policy) were eligible. Reviews of pre-conception, tertiary prevention or postpartum/postnatal interventions were excluded. In order to maximizeinclusiveness,systematicreviewsofinterventionsthat mayhave anindirect effectonPTB (i.e.interventionsaimed at otherconditionsinpregnancy,butpotentiallyalsoaffectingPTB) werealsoeligible.IfthereviewincludedbothRCTsandnon-RCTs, weincludedthereviewifresultsfromRCTsonlywerereported separately. Where two or more reviews addressed the same research question, we included all reviews.However, where a systematicreviewhadbeenspecificallyupdated,weincludedonly themostrecentversion.

Literaturesearch,screeningandextraction

A systematic literature search of the Cochrane, PubMed/ Medline,EMBASEand CINAHLdatabaseswasconductedon2nd September 2015,and updated on 21st November2016. As the publicationsofinterestarehigh-qualitysystematicreviews,grey literaturesourceswerenotincluded(searchstrategyprovidedin Supplementarymaterial). Allcitations weredownloaded intoa referencemanagerandduplicatecitationsremoved.Twoauthors independentlyscreenedtitlesandabstractsofeachcitation,and includedthoseforfulltextreview(accordingtocriteriadefined above). Each retrieved full text article was independently evaluatedforinclusionbytwo authors.Wedevelopedand pre-testedadataextractionform,capturingreviewcharacteristicsand outcome data for comparisons of interest. Where the GRADE criteria [19] wereused for our primary outcome (i.e. PTB<37 weeks),thecertaintyofevidencewasextracted.Anydifferences duringscreeningandextractionwereresolvedthroughdiscussion and/or consultationwith a third author.Two authors indepen-dentlyalsoassessed themethodological qualityoftheincluded reviewsusingtheAMSTARtool[20].

We alsoconducted a systematic search of the International ClinicalTrialsRegistryPlatform(ICTRP)on15thNovember2016. ICTRP aggregates 17 national and international trial registries (includingClinicaltrials.gov,theEUClinicalTrialsRegisterandthe PanAfricanClinicalTrialsRegistry),providingasingle,regularly updatedsearchportalforallregisteredtrials.Weusedakeyword search in ICTRP (using “premature” or “preterm birth” or “prematurity”)toidentifyanyRCTsofprimaryorsecondaryPTB preventioninterventionswithdateofregistrationfrom1st_January,

2005to31st_{December,2016.Weextractedcharacteristicsofany}

eligibleregisteredRCTs.Identifiedtrialswerereviewed indepen-dently for inclusion by two authors, and classi_fied by type of intervention.

Outcomes

Primaryandsecondaryoutcomeswerepre-definedbeforedata extraction.Selectionofoutcomeswasinformedbyfindingsofthe COPOPprojectoncoreoutcomesforPTBprevention[21].aswellas criticaloutcomesusedintheWHOantenatalcarerecommendations forapositivepregnancyexperience[22].Theprimaryoutcomewas

PTB<37weeks.ThesecondaryoutcomeswerePTB<34,<32,and <28 weeks (or any other reported GA threshold), maternal satisfaction, and neonatal outcomes including low birth weight (LBW)(i.e.birthweight<2500g),admissiontoneonatalintensive careunit(NICU),fetalmortality(i.e.fetaldeathafter20weeks), neonatalmortality(asdefinedbythetrials)andperinataldeath(i.e. eitherfetalmortalityorneonatalmortality).

Ourreviewprotocolpre-specifiedseveralothermaternaland neonatal morbidity outcomes (Prospero registration number CRD42015027440). However, during piloting of data extraction wefoundthesecondaryoutcomelisttobeunmanageablylarge. Thegroupagreedthroughconsensustoreducethelist,considering whatdatawerelikelytobeavailable.

Classification,analysisandreporting

We aimed to classify all identified interventions as either primaryorsecondarypreventioninterventions,orboth.Analysis andreportingwasprimarilydescriptive,presentingtheidentified interventions and the magnitude of effect on primary and secondaryoutcomes.

Fig.1.Flowchartforsearchandidentificationofstudiesinthereviewofsystematicreviews. xxx–xxx

Results Studyselection

Theinitialsearchidentified1,372uniquecitations;132were included for full text review. An updated search was run in November 2016, which identified an additional 300 citations, yielding 40 for full text review. Of the 172 full text articles reviewed,72wereexcluded.Anadditional12paperswereadded, astheywerethelatestversionofapublishedreview.Intotal,112 reviewswereincluded(Fig.1).

Anoverviewof typesofinterventionsidenti_fiedis shownin Table1.Classificationoftheincludedreviewsaccordingtotypesof interventionsisshowninSupplementarymaterial.Table2shows the results of searching the ICTRP trial database. Overall 172 registeredtrialswerefound,47onprimaryPTBpreventionand125 onsecondary PTB prevention. Mostof the trials evaluatedthe effectofdifferentdrugs,mostlyaspirinandprogesterone.Twenty fourtrials evaluatedbenefits of nutritionalsupplementation in preventionofPTB.Ofthem,eightwereonantenatal supplemen-tationofpolyunsaturatedfattyacids.

Supplementarymaterialshowsthedescriptivecharacteristics ofincludedsystematicreviews. Overalltherewere49Cochrane and 63 non-Cochrane reviews. Eight were IPD reviews. The publicationdateofthetrialsincludedinthereviewsrangedfrom 1953to2016.Thenumberofincludedtrialsineachreviewranged from0to86.Only38reviewsusedtheGRADEcriteria.Figs.2and3 showtheeffectestimatesofprimary(Fig.2)andsecondary(Fig.3) preventioninterventiononPTB<37weeks.

Interventioneffectsonprimaryoutcome(pretermbirth<37weeks) IPrimarypreventionofpretermbirth

Sixty reviews assessed the effect of primary prevention strategiesonriskofPTB(Fig.2).Formanyinterventions,there weremultiple,overlappingsystematicreviews.

1Medications:Thinkhamrop(2015)compareduseofantenatal prophylacticantibioticswithplaceboamongwomen(lowor highriskofPTB)(5trials,1480women)andshowednoeffect onriskofPTB(RR0.85,95%CI0.64–1.14).

2 Modelsofcare:Tworeviewsevaluatedmodelsofhealthcare. Catlingetal.(2015)conductedaCochranereviewoffourtrials and2350womenenrolledingroupantenatalcarecompared tostandardcare.Therewasamarginaldifferenceinriskof PTB(RR0.75,95%CI0.57–1.00,moderate-qualityevidence). FernandezTurienzoetal.(2016)meta-analysed15trialsof 22,437womenrandomizedtoalternatemodelsofantenatal care(comparedtostandardcare).Thisincluded“midwife-led continuity models of care, PTB prevention programmes, clinic-basedspecialisedcareand stand-aloneinterventions involvingtheprovisionofhealthorsocialcaredeliveredin conjunction with standard antenatal care_”. They found a statisticallysignificantdecreaseinriskofPTB<37weeksin womenreceivingalternatemodelsofcare(RR0.84,95%CI 0.74–0.96). Theauthorsidentifiedsignificantheterogeneity amongtrials.

3 Lifestyleandbehaviouralchanges:Dietand/orinterventions targetedatincreasingphysicalactivitywereevaluatedinfour reviews.Bainetal.(2015)compareddietandexerciseadvice withnoadviceinanunselectedgroupofpregnantwomen(5 trials,2,713women).Theirprimaryinterestwasprevention ofexcessiveweightgaininpregnancy.TheriskofPTBwas reducedamongwomenenrolledindietandexercise(RR0.71, 95%CI0.55–0.93).Thisfindingwasnot replicatedinother systematicreviews,althoughinterventiondefinitions were somewhatdifferent.

Benjaetal.(2015)conductedaCochranereviewontheeffect of diet and exercise advice compared to no advice in an unselected group of women in preventing gestational diabetes mellitus (GDM) (16 trials, 5923 women). They foundnodifferenceinriskofPTB(RR0.91,95%CI0.68–1.22), howevereligiblestudieswerethosethatrelatedto address-ingGDMriskasopposedtogestationalweightgain. Thangaratinam et al. (2012) compared any dietary or lifestyle intervention to standard care among a group of unselectedpregnantwomen,includingwomenwithGDMor obesity.TheyidentifiednoeffectsonPTBrisk(13trials,2652 women, RR 0.78, 95% CI 0.60–1.02), nor when stratified based onintervention (dietaryadvice, physicalactivity, or both).

Table1

Overviewoftypesofinterventionsidentified.

Primaryprevention Secondaryprevention

Drug Antiplatelet Antibiotics Antiplatelet Antibiotics Progestogens Other Device – Pessary

Psychosocial Telephonesupport Supportforsmokingcessation

Surgical/procedural – Cerclage

Dentaltreatment Modeofdelivery Nutritionalsupplementationortreatment Calcium

Iron+/-folicacid Polyunsaturatedfattyacids Vitamins(A,B6,B12,C,D,E) Zinc Multiplemicronutrients Antioxidants Probiotics Other

Iron+/-folicacid Polyunsaturatedfattyacids Vitamins(A)

Other

Lifestyleorbehavioural Diet Exercise

Bedrest Activityrestriction Screening+/-treatment

(useofinvestigations,examinationsorspecialtests,

whichmayormaynotprompttheuseofcertaininterventions)

Screeningwholepopulation Screeningaselectedsub-grouponly

Healthsystem Alternativemodelofcare – xxx–xxx

Kramer and McDonald (2009) evaluated the effects of increased exercise in sedentary women and decreased exercise in _fit women (they did not include dietary interventions).Therewas noeffecton PTB withincreased exerciseamong sedentarywomen(3trials,111women,RR 1.82,95%CI0.35–9.57)orwithreductioninexerciseamong

physicallyfitwomen(1trial,61women,RR1.18,95%CI0.08– 17.99).

4Nutritional supplementation: Nutritional supplementation interventionswereevaluatedin34systematicreviews. Calcium supplementation was evaluated in five reviews. CalciumofanydosewasevaluatedbyImdadetal.(2011)ina

Table2

ResultsofsearchingICTRPtrialdatabase(N=172).

Primaryprevention (N=47) Secondaryprevention (n=125) Drug(n=71) Antiplatelet-1 Antibiotics–1 Other–1 Antiplatelet-2 Antibiotics-7 Progestogens-51 Other–8 Device(n=21) Pessary–21 Psychosocial(n=1) 1 0 Surgical/procedural (n=15) 0 Cerclage-11 Dentaltreatment-1 Modeofdelivery-3 Nutritionalsupplementationortreatment(n=24) Iron+/-folicacid-1

Polyunsaturatedfattyacids-7 Vitamins-3

Multiplemicronutrients-3 Probiotics-3

Other–3

Polyunsaturatedfattyacids-1 Zinc-1 Probiotics-2 Lifestyleorbehavioural(n=8) 6 2 Screening+/-treatment(n=14) 9 5 Healthsystem(n=6) 5 1 Multiple(n=12) 3 9

Fig.2.Effectestimatesofprimarypreventioninterventiononpretermbirth.

reviewoftheroleofcalciuminreducingriskofhypertensive disordersofpregnancy(5trials,9919women).Calcium(of anydose)initiatedpriorto32weeksgestationwasfoundto reduce risk of PTB (RR 0.88, 95% CI 0.78–0.99) when compared to placebo or no supplementation. Hofmeyr etal.(2014)alsoevaluatedtheeffectsofcalcium supplemen-tation for prevention of hypertensive disorders (11 trials, 15,275women),andshowedadecreaseinPTBriskwithhigh dosecalcium>1g/dayadministeredtoallpregnantwomen (RR0.76,95%CI0.60to0.97,high-qualityevidence). TheCochranereviewbyBuppasirietal.(2015)evaluatedthe role of calcium supplementation in improving obstetrical

outcomesotherthanhypertensivedisorders.TheriskofPTB wasnotreducedwithcalciumsupplementationcomparedto placeboornosupplementation,(13trials,16139womenRR 0.86,95%CI0.70–1.05).However,highdose(>1g/day)butnot lowdose(<1g/day)calciumsupplementationwasassociated withareductioninriskofPTB(RR0.81,95%CI0.66to0.99). Ironsupplementationwasevaluatedin fourreviews.Daily ironsupplementationwithironaloneorincombinationwith folicacidorothermineralsorvitaminswasfoundtoreduce PTB<34weekswhencomparedtoplacebo,notreatment,or anequivalentnon-ironsupplement(RR0.51,95%CI0.29to 0.91),but theriskof PTB<37 weekswas not significantly

Fig.2.(Continued)

reduced(13trials,19,286women,RR0.93,95%CI0.84–1.03) (Pena Rosa et al., 2015a). In a separate review assessing intermittentironsupplementation,theriskofPTB<37weeks or<34weekswasnotreduced(PenaRosaetal.,2015b). Haideretal.,(2013)identified12trials(unspecifiednumber ofwomen)thatevaluatedtheeffectonPTB<37weekswith ironsupplementation,aloneorincombinationwithfolicacid. TherewasnosignificanteffectonPTB(RR0.84,95%CI0.68– 1.03).Cantoretal.(2015),usingadifferenttimeframeand differentdatabases,comparedroutineironsupplementation toanunspeci_ficedplacebo.Theyidenti_fiedtwotrials(1010 women)and nosignificant effectonPTB (RR0.88, 95% CI 0.55–1.42).

Folicacidsupplementationwas evaluatedin two reviews. Sacconeand Berghella (2016) compared folicacid supple-mentationtoplaceboornotreatmentandidentifiedonetrial (1654women).Inthistrial,therewasnosignificanteffecton PTB (RR 0.99, 95% CI 0.82–1.18). Lassi Zohra et al. (2013) evaluated folic acid with or without other supplements compared to placebo or non-folate supplements. They identifiedthreetrials(2959women),andnoeffectonPTB (RR1.01,95%CI0.73–1.38).

VitaminAsupplementation wasevaluatedintworeviews.Both comparedvitaminAsupplementationtoplacebo.McCauley

etal.(2015)conductedaCochranereviewontheeffectsof VitaminAonobstetricaloutcomes.TheycomparedvitaminA aloneversusplacebo(4trials,40137women,RR0.98,95%CI 0.94–1.01),vitaminAversusamultivitaminlackingvitaminA (0trials),andavitaminAcontainingmultivitaminversusa multivitamin without(1trial,136women,RR0.39,95%CI0.08– 1.93,high qualityevidence).Thorne-Lyman&Fawzi(2012b) wasanon-CochranereviewthatcomparedvitaminAalone versusplacebo(7trials,19799women)andfoundnoeffecton PTBrisk(RR0.99,95%CI0.88–1.10).

Vitamin D supplementation, alone or in conjunction with othersupplements,wasevaluatedinthreereviews,andnone showedsignificanceintermsofriskofPTBThorne-Lyman& Fawzi(2012a)evaluatedvitaminDsupplementationatany dose,comparedtoplacebo,amonglowriskwomen(2trials, 529women).Therewas noeffectonPTB(RR 0.77,95% CI 0.35–1.66). Pérez-López et al.(2015) compared vitamin D, aloneorin combinationwithcalciumandvitamin supple-ments,toplacebo,nosupplement,orsupplementswithout vitaminD(3trials,384women)andalsofoundnoeffecton PTB(RR1.26, 95%CI0.60–2.63).De-Regiletal.(2012)also evaluatedvitamin D(atanydose)aloneorincombination with another supplement, compared to placebo or no supplements. They identi_fied 6 trials (1023 women) but

Fig.2.(Continued)

noneincludedpretermbirthasanoutcome.Intheirupdate (De-Regil et al.,2016) three trials(477 women)compared vitaminDalonecomparedtoplacebo.Therewasanoverall decreasedriskofPTB(RR0.36,95%CI0.14-0.93). Interesting-ly, women who received vitamin D with calcium had an increasedriskofPTBcomparedtowomenwhoreceivedno supplementationorplacebo (3trials,798women,RR1.57, 95%CI1.01–2.43).Theauthorsnotedthattheriskofbiasin

mosttrialsisunclearandmanytrialswereathighriskofbias forblindingatattritionrates.

VitaminEsupplementationwasnotshowntoreducePTBrisk inonereview(Rumboldetal.,2015;11trials,20565women, RR0.98,95%CI0.88–1.09).

SalamRehanaetal.(2015)aimedtoevaluatetheeffectof pyridoxine on PTB and did not find any trials that met inclusioncriteria.

Fig.3.Effectestimatesofsecondarypreventioninterventiononpretermbirth.

Tworeviewsaddressedzincsupplementationinpregnancy. ChaffeeandKing(2012)comparedzincsupplementationto placebo/nointervention(16trials,7818women)andshowed areductioninPTB(RR0.86,95%CI0.75to0.99,low-quality evidence).Otaetal.(2015a)comparedzincsupplementation toplaceboornointerventionornon-zincinterventionand alsoshowedareductioninPTBbasedon16trialsincluding 7637women(RR0.86,95%CI0.76to0.97,moderate-quality evidence).

Fishoil,marineoil,andomega-3fattyacidswasevaluatedin sixreviews.Karetal.(2016)comparedomega-3fattyacid supplementationwithanunspecifiedcontrolgroupin9trials and5980womenandfoundareductioninPTB(RR0.83,95%

CI 0.70 to 0.98).Salvig and Lamont (2011) evaluated long chainn-3fattyacidsupplementationcomparedtoplaceboor nosupplementation(4trials,1187women)andalsofounda reductioninPTB(RR0.61,95%CI0.40to0.93).Theremaining fourreviewsdidnotshowastatisticallysignificanteffecton PTBriskbutChenetal.(2016)foundareductioninPTB<34 weeks (RR 0.78, 95% CI 0.64 to 0.95) with fish oil supplementation.

Dietarysupplementation with multiplemicronutrients was evaluated in fourreviews. Suchdev et al. (2015) evaluated micronutrients in powder forms for fortification of foods comparedtoawiderangeofcontrols(nointervention,placebo, ironandfolatesupplements,ironalone,folatealone,orother

Fig.3.(Continued)

multiple micronutrients). They identified6 trials but none reportedontheiroutcomesofinterest,includingpretermbirth. HaiderandBhutta(2015),compared3ormoremicronutrients including iron and folic acid compared to placebo or no supplementation(1trial,unspecifiednumberofwomen),and compared to iron with or without folic acid (15 trials, unspecifiednumberofwomen).Neithercomparisonshowed asignificanteffectonPTB.Twonon-Cochranereviewswere identified. Ramakrishnan et al. (2012) found no effect on pretermbirthwithsupplementationwith5ormore micro-nutrientscomparedto3orlessmicronutrientsincludingiron

andfolicacid(9trials,45909women,RR0.99,95%CI0.96– 1.03), while Fall et al., (2009) compared “multiple micro-nutrients” to an unspecified placebo and also found a nonsignificanteffectonPTB(12trials,unspecifiednumberof women,RR1.00,95%CI0.93–1.09).

Nutritionaleducationcomparedtononutritionaleducation or a different form of consultation was assessed in one systematicreview(Otaetal.,2015b).Thisincludedtwotrials and 449 women. Risk of PTB was lower in women who receivednutrionaleducation(RR0.46,95%CI0.21–0.98,low quality evidence). The same review also evaluated high

Fig.3.(Continued)

proteindietcomparedtolowornoproteinsupplementation during pregnancyand foundno effect onPTB. Therewas insufficientdataforcomparisonsinvolvingbalanced protein-energy intake and isocaloric protein supplementation. Dietaryadvicewasalso evaluatedby Thangaratinametal. (2012). Compared to standard care, dietary advice was associatedwithareducedriskofPTB(4trials,1474women, RR0.68,95%CI0.48–0.96).

Probioticswereevaluatedin onereview byOthman etal. (2007). Routine probiotics to prevent or treat urogenital infectionsinallpregnantwomendidnotshowaneffecton PTBrisk(1trial,238women,RR3.95,95%CI0.36–42.91). 5 Psychosocialinterventions: One review(Dennis & Kingston,

2008)comparedtelephonesupportbyalaypersonorhealth careprofessionalwithnointerventionandfoundnoeffecton PTB(14trials,8037women,RR0.87,95%CI0.75–1.01). 6 Screeningwithandwithouttreatment:Repeatdigitalcervical

examinations(Alexanderetal.,2010;2trials,7163women) anduniversalscreeningforthyroiddisease(Spenceretal.,

2015;1trial,4516women)wereshowntohavenoeffecton PTB.Tworeviewssetouttoevaluateuniversalscreeningfor bacterial vaginosis (Nygren et al., 2008) and PTB scoring systems(Daveyetal.,2013)buttheyfoundnoeligblestudies. Sangkomkamhangetal.(2015)evaluatedroutinescreening forlowergenitaltractinfectionsinpregnancybywetmount, gramstainorvaginalculturecomparedtoroutineantenatal care withoutscreening. Theyincluded a single trial(4155 women)andfoundareductioninPTB(RR0.55,95%CI0.41to 0.75,moderatequalityevidence).

7Specialtestsorinvestigations:Tworeviewsevaluated antena-tal carewith routine Doppler sonography (Alfirevic et al., 2015;4 trials,12162women),or routinetestsofplacental function with results available to clinician (Heazell et al., 2015;1trial,118women)andfoundnoeffectonPTBrisk. IISecondaryoutcomes–primarypretermbirthprevention:

Secondary outcomes were infrequently reported. The mostcommonly reportedwereperinatal, fetal and neonatal mortality.

Fig.3.(Continued)

Perinatal, fetal or neonatal mortality were not significantly differentwiththefollowingprimarypreventioninterventions: omega3(Karetal.,2016;Saccone&Berghella,2015),marineoil (Makridesetal.,2006),vitaminD(De-Regiletal.,2012),vitamin A (McCauley et al., 2015; Thorne-Lyman & Fawzi, 2012), vitaminsBorC(Droretal.,2012),vitaminE(Rumboldetal., 2012), antioxidants (Rumbold et al., 2008), zinc (Ota et al., 2015a), iron supplementation (Cantor et al., 2015), group antenatalcare(Catlingetal.,2015),aerobicexercise(Kramer et al., 2009), folic acid supplementation (Lassi Zohra et al., 2013),nutritionaleducationandsupplementationforenergyor protein(Otaetal.,2015b)ormultiplevitaminsandminerals (Pena-Rosasetal.,2015;Ramakrishnanetal.,2012),androutine antibioticprophylaxis(Thinkhamropetal.,2015).When multi-plemicronutrientswithironandfolicacidwerecomparedto folicacidandironalonetherewasareductioninfetalmortality withaRR0.91,95%CI0.85–0.98,buttherewasnodifference when the control group included placebo or no treatment (Haideretal.,2015).Routinecalciumsupplementationdidnot affect mortality in three reviews (Buppasiri et al., 2015; Hofmeyr et al., 2014; Al Dorazi et al., 2014), however one (Imdad,2011)foundareductioninneonatalmortality(RR0.70, 95%CI0.56to0.88).OnereviewofroutineDopplersonography foundreducedneonatalmortality(Alfirevicetal.,2015;RR0.34, 95%CI0.12–0.95).

Theothersecondaryoutcomeswereassessedinfewreviews, andwheretheywerereportedtheywerelargelynotdifferent. Low birth weight was reduced with certain micronutrients supplementation(Haideretal.,2015),screeningandtreatment for lower genital tract infections (Sangkomkamhang et al., 2015), vitamin D (Thorne-Lyman et al., 2012), and fish oil supplements(Chenetal.,2012).

Maternaloutcomeswereveryinfrequentlyreported.Maternal satisfaction was reported in only three reviews. Women in groupantenatalcareweremoresatisfiedthanwomenreceiving conventionalcare(Catlingetal.,2015).Therewasasignificant reductioninmaternaldeathsandICUadmissionswithcalcium supplemtation in women regardless of risk factors and in women with low intake (Hofmeyr et al., 2014). Calcium supplementation in all pregnant women was also found to reducematernaldeathinanotherreview(Imdad,2011). Thefindings of theindividual reviewsare shownin Supple-mentarymaterial.

IIISecondarypreventionofpretermbirth

There were 83 systematic reviews of secondary prevention strategies(Fig.3).

1Devices:Urquhartetal.(2015)comparedhomemonitoring activityversusstandardcareamongwomenconsideredto be at risk of PTB. The risk of PTB was not statistically differentbetweenthetwogroups (8trials,4834women, RR0.85,95% CI0.72_–1.01). Sealingproceduresfor women withprematureruptureofmembraneswasshowntoreduce PTB(2trials,124women,RR0.48,95%CI0.38to0.68)inone review (Crowley et al., 2016) however the number of participantswassmall.

2Lifestyleandbehaviouralchanges:Tworeviewsevaluatedbed restathomeorinthehospitalforwomenathighriskofPTB andfoundnosignificanteffect.(Sosaetal.,2015;1trial, 1266 women;andCrowtheretal.2010;7trials,713women). 3Anticoagulant and antiplatelets agents: Eleven reviews

evaluated the effect of aspirin, other COX inhibitors or heparin.Onereview(Meheretal.,2016)wasanIPD meta-analysison theeffects of usingone or more antiplatelet agents (low dose aspirin or another agent) to prevent preeclampsia. They did not report on PTB<37 weeks, however reported ona reduction in PTB<34 weeks (26

trials,31272women,RR0.90,95%CI0.83to0.98).However, subgroup analyses of women randomized to start anti-plateletsbefore16weeksgestation(19trials,9155women, RR0.90,95%CI0.88–1.04)orafter16weeks(25trials,22117 women,RR0.82,95%CI0.82–1.00)showednostatistically significanteffectonPTB.

Low dose aspirin (LDASA) alone or in combination with dipyridamolewasfoundtoreduceriskofPTBamongwomen atriskforpreeclampsiain eightsystematicreviews.Askie etal.(2007)wasanIPDmeta-analysisthatcomparedLDASA withorwithout dipyridamoleto placeboornotreatment among women at risk of preeclampsia (26 trials, 31316 women).TherewasareductioninriskofPTB<37weeks(RR 0.93,95%CI0.89-0.98)and<34weeks(RR0.90,95%CI 0.83-0.98),butnot<28weeks(RR0.87,95%CI0.75–1.02).Theydid not assess antiplatelets given at a specific gestational, however 59% of women were randomized and received therapyat<=20 weeksgestation.A subsequentsubgroup analysisofthisIPDbyvanVlietetal.(2017)showedasimilar trendinriskreductionofspontaneousPTB<37weeks(17 trials,28797women,RR0.93,95%CI0.86-0.996),PTB<34 weeks(RR0.86,95%CI0.76–0.99).TheriskofPTB<28weeks wasnotsignificantlyreduced(RR0.81,95%CI0.59–1.12). Robergeetal.(2012)evaluatedtheadministrationofLDASA withorwithoutdipyridamoleat16weeksgestationorless, compared to placebo or no treatment and identified a decreasedriskofPTB<37weeks(5trials,556women,RR 0.11, 95% CI 0.04–0.33). Roberge et al., (2013) compared administrationofLDASA+/-dipyridamolebeforeorafter16 weeksgestation.Therewasanoverallreductioninriskof PTB(22trials,11302women,RR0.81,95%CI0.71-0.92),but there was a greater reduction with administration at or before16weeks(6trials,904women,RR0.35,95%CI0.22– 0.57)comparedtoafter16weeks(16trials,10398women, RR0.90,95%CI0.83–0.97).

CristinaRossietal.,(2009)observedareductioninPTBwith LDASAalonecomparedtoplaceboadministeredtowomen athighriskforpre-eclampsia(6studies,9966women,OR 0.85,95%CI0.77–0.94).Thesefindingsweresupportedby subsequent reviews (Henderson et al., 2014; 10 studies, 11779women,RR0.86,95%CI0.76–0.98;Xuetal.,2015;29 trials,21403women, OR0.81,95% CI 0.75–0.88; andYao etal.,2015;5trials,860womenwithtreatmentstartedprior to16weeksgestation,RR0.20,95%CI0.08–0.48).Ofnote, CristinaRossietal.,(2009)alsoassessedvitaminCand E versusplacebo in reducingPTB among women at riskof preeclampsiaandfoundnoeffect.

Lowmolecularweightheparinandaspirindidnotreduce riskofPTBwhencomparedtoaspirinaloneamongwomen withinheritedthrombophilia(4trials,222women,RR0.99 (0.4_–2.08)(Areiaetal.,2016).

ACochranereview(Khanprakobetal.,2012)identifiedone trial(98women)randomizedtoaCOXinhibitors(refecoxib) comparedtoplaceboandidenti_fiedanincreasedriskofPTB inthecomparisongroup(RR1.65,95%CI1.11–2.45). 4 Antibiotics:The use of antibiotics was evaluated in nine

reviews.

Interventions that did not affect the preterm birth rate included:antibioticsforprematureruptureofmembranes (Kenyonetal.,2013;3trials,4931women),anytreatment forbacterialvaginosisortrichomoniasis(Okunetal.,2005, 11trials,6052women;Blocklehurstetal.,2013,13trials, 6491 women), nitrofurantoin prophylaxis for recurrent urinarytractinfections(Schneebergeretal.,2015);1trial, 147women),andprophylacticprenatalantibiotics (Think-hamropetal.2015),2trials,758women).

One review (Lamont et al., 2011; 5 trials, 2346 women) foundthatclindamycinfortreatmentofbacterialvaginosis reduced PTB risk (RR 0.60, 95% CI 0.42 to 0.86), while metronidazole for trichomoniasis was associatedwithan increasedriskinonereview(Gülmezogluetal.,2011;1trial, 604women,RR1.78,95%CI1.19–2.66).Treatmentofvaginal candidiasiswasassociatedwithareductioninPTBriskin onereview (Robertsetal.,2015;2trials,685women,RR 0.36,95%CI0.17-0.75).

5Progesterone:Ten reviews evaluatedprogesterone supple-mentationinwomenwithhighriskpregnancies.

aWomenwithsingletonpregnanciesandpreviouspreterm bith: Progesterone (oral or intramuscular) was an effectivePTBpreventionstrategyinwomenwith single-ton gestationsand withpreviouspretermbirthin two reviews. Likis et al. (2012) included 5 trials and 372 womenandshowedaRR0.78(95%CI0.68to0.88)among women on any form of progesterone compared toan unspecifiedcontrol.Doddetal.,(2013)included10trials, 1750women,andfoundaRR0.55(95%CI0.42to0.74) withprogesteronesupplementationcomparedtoplacebo or no treatment. One review (Saccone et al., 2016) reportedthatdailyvaginalprogesterone(either supposi-toryorgel)isabetteralternativetoweeklyintramuscular 17α-hydroxyprogesterone caproate (17-OHPC) in pre-venting PTB<34 weeks (3 trials,680 women,RR 0.71, 95% CI 0.53-0.95, low quality evidence) and PTB<32 weeks(RR0.62,95%CI0.40-0.94,lowqualityevidence). bMultiple gestations: Progesterone supplementation for unselected women with multiple pregnancies did not reducePTB inthreereviews:Likis etal.,2012;4trials, unspecifiednumberofwomen,RR1.02,95%CI0.87–1.17; Doddetal.,2013;8trials,2674women,RR1.04,95%CI 0.95-1.14.Schuitetal.(2015)wasanIPDmeta-analysison twinpregnanciesthatdefinedgestationalageatdelivery to include intrauterine fetal demise. Neither vaginal progesterone(7trials,929women,RR0.97,95% CI0.85-1.10) nor intramuscular progesterone (6 trials, 2021 women, RR 1.10,95% CI 0.94–1.20) reduced PTB when comparedtoplaceboornotreatment.

cWomen inpretermlabour:Progesteronefor womenin pretermlabourwasfoundtobeeffectiveinonereview (Likisetal.,2012;5trials,unspecifiednumberofwomen, RR 0.62, 95% CI 0.47to 0.79) but supplementationfor womeninthreatenedpretermlabour(andnotinactive PTL)didnotshowabenefitinanotherreview(Doddetal., 2013;2trials,223women,RR0.51,95%CI0.20–1.31). dSonographically short cervix: Progesterone for women

withsonographicallyshortcervixdidnotreduceriskof PTB<37weeksinfourreviews(Doddetal.,2013;3trials, 1303women,RR0.97,95%CI0.82_–1.15;Conde-Agudelo etal.,2013;4trials,158women,RR0.84,95%CI0.61–1.14; Romeroetal.,2016,5trials,723women,RR0.89,95%CI 0.74_–1.08). However,the IPDmeta-analysisby Romero et al. (2016) found a significant reduction in PTB34 weeksorfetaldeath(5trials,974women,RR0.66,95%CI 0.52-0.83),PTB<34 weeksonly (RR0.60, 95% CI 0.44-0.82)andspontaneousPTB<34weeks(RR0.63,95%CI 0.44-0.88), and at earlier gestational ages (PTB<32 weeks, RR 0.56, 95%CI 0.38-0.82; andPTB<28 weeks, RR 0.51, 95% CI 0.31-0.85). One review also compared progesterone to cerclage in women with short cervix (Conde-Agudelo et al., 2013) and found no difference (unspecificednumberoftrials,RR1.20,95%CI0.84–1.72). eAnyriskfactorsforPTB:Progesteroneinwomenwithany risk factors for PTB was evaluated in three reviews

(Coomarasamyetal.,2006;Doddetal.,2013;Sotiriadis et al., 2012). Only one found a reduction in PTB risk (Coomarasamyetal.,2006;8trials,unspecifiednumberof women) with a RR 0.42 (95% CI 0.31 to 0.57). One (Sotiriadis et al., 2012) didnot identifyany applicable trials.

6 Othermedications:L-argininewasevaluatedinonereview. Dorniak-Walletal.(2014)foundareductioninPTBrisk(RR 0.48,95%CI0.28to0.81)inwomenatriskforpreeclampsia treatedwithL-arginineversusplacebo(1trial,672women). Levothyroxine was found to reduce risk of PTB among women with thyroid disease when compared to no treatment(Reidetal.,2013; 1trial,115women;RR0.28, 95%CI0.10to0.80).Oralbetamimeticsintwinpregnancies wasnotfoundtoreducePTBriskwhencomparedtoplacebo orotherinterventionstopreventPTB(Yamasmitetal.,2015; 4trials,276women,RR0.85,95%CI0.65–1.1).

7 Models of health care: Two reviewsevaluated specialized modelsofantenatalcareamongwomenathighriskforPTB. Doddetal.(2015)setouttoevaluatespecializedantenatal careforwomenwithtwingestationsanddidnotindentify anyeligiblestudiesthatassessedPTBrisk,althoughtheydid reportonneonataloutcomesincludinganincreasedriskof NICUadmission(RR1.43,95%CI1.02–2.00)andC-section rate(RR1.38, 95%CI 1.06–1.81).Whitworth etal., (2011) included3trialsand3400womenandcomparedspecialized caretostandardcareinwomenwithsingletonpregnancies atriskforPTB.Therewasnodifferencedetectedinriskfor PTB(RR0.87,95%CI0.69–1.08).

8 Nutritionalsupplements:Antioxidantsforwomenatriskof preeclampsia(Rumboldetal.,2008;3trials,3131women, RR1.09,95%CI0.97–1.22),longchainpolyunsaturatedfatty acidsforwomenatriskofPTB(Horvathetal.,2007;4trials, 523women,RR0.82,95%CI0.60–1.12),omega-3forwomen withpreviousPTB (Sacconeet al.,2015a;2 women,1080 women,RR0.81,95%CI0.59–1.21),calciuminwomenwith lowintake(Hofmeyretal.,2015;7trials,10242women,RR 0.81,95%CI0.64–1.02),selenium(Reidetal.,2013;1trial, 169 women, RR 0.96, 95% CI 0.20–4.61), and vitamin A amongHIVpositivewomen(Wiysongeetal.,2011,3trials, 2110women,RR0.88,95%CI0.65–1.19)didnothaveeffects onPTBinhigh-riskwomen.Calciumsupplementationwas foundtoreduceriskofPTBinwomenatriskofhypertensive disordersinonereview(Hofmeyretal.,2015,4trials,568 women,RR0.45,95%CI0.24to0.83).

9 Psychosocialinterventions:Onereviewfoundthatsmoking cessation or relapse prevention programs for high risk womenresultedinareducedriskofPTBwhencomparedto usualcare,lessintensivecareoralternativecare,basedon14 reviewsand7852women(Chamberlainetal.,2013),RR0.82 (95%CI0.71to0.96).Therewasnosigni_ficanteffectonPTB withsocialsupportforwomenathighriskofPTB(Hodnett etal.,2010;17trials,12,264women,RR0.92,95%CI0.83– 1.01), relaxation therapy for women in preterm labour (Khianmanetal.,2012;1trial,120women,RR0.95,95%CI 0.57–1.59),or“anypsychosocialintervention” forteenage pregnantwomen(Sukhatoetal.,2015;4trials,684women, RR0.67,95%CI0.42–1.05).

10Screening+/-treatment:Berghellaetal.,(2011)showedthat cervical length screening in singleton gestations with history of preterm birth, and placement of cerclage in women with short cervix resulted in a PTB reduction comparabletocerclageplacementbasedonhistoryonly(4 trials,467women,RR0.97,95%CI0.73–1.29).

11 Cerclageandpessary:Womenatriskofpretermbirthwho hadacerclagehadalowerriskofpretermbirththanwomen

withoutcerclage(Alfirevicetal.,2012;9trials,2898women, RR 0.80, 95% CI 0.69-0.95). Threereviews evaluated two specificsubpopulationsofwomen.AnIPDmeta-analysisby Berghellaetal.(2010)evaluatedtheeffectivenessofcerclage for women with singleton pregnancies and short cervix <25mmonmidtrimesterultrasoundandfoundadecreased riskofPTB(4trials,552women,RR0.79,95%CI0.65-0.95).A non-CochranereviewbyBerghellaetal.(2011b)lookedat cerclageforasymptomaticwomenwithsingletongestation, history of pretermbirth, and short midtrimestercervical lengthonultrasoundandfoundadecreasedriskofPTBas well(5trials,874women,RR0.70,95%CI0.58-0.83).These results were supported by Conde-Agudelo et al. (2013), whosepopulationalsoincludedsingletonpregnancieswith shortmidtrimesterultrasoundandhistoryofpretermbirth andwhofoundaRR0.70,95%CI0.58-0.83,across5trials and504women.

Tworeviewsinvestigatedcerclageformultiplepregnancies andbothidentifiedanonsignificanteffectonPTB(Rafaeletal., 2014;5trials,128women,RR1.12,95%CI0.89–1.43;andLiu etal.2013;5trials,310women,RR1.01,95%CI0.77–1.33). One Cochrane review assessed cervical pessary versus expectantmanagement insingletongestationswithshort cervixof25mmorless,andfoundareductioninPTB (Abdel-Aleemetal.,2013;1trial,385women;RR0.36,95%CI0.27 to0.49).

12Treatmentofperiodontaldisease:Twooutoftheninereviews that evaluated this intervention showed a significant reductioninPTBinwomenwithperiodontaldiseasewho receivetreatment(Georgeetal.,2011:10trial,5496women, RR0.65,95%CI0.45to0.93;Uppaletal.,2010;10trials,6142 women,RR0.59,95%CI0.40to0.88).

But a majorityofreviews foundnoeffectonPTBfor this intervention.Schwendickeetal.(2015)evaluatedsubgingival scalingandrootplanningwithorwithoutadjunctantibiotics for womenwith periodontaldisease (5 trials,unspecified numberofwomen,OR0.79,95%CI0.57–1.10).Boutinetal. (2013)alsoevaluatedperiodontaltreatmentforwomenwith periodontal disease but included a wide range of control groupsincludingnocare,hygieneeducation,orsupragingival treatment (12 trials, 7018, RR 0.89, 95% CI 0.73–1.08). Chambroneetal.(2011)comparedscalingandrootplanning withorwithoutantibioticsforplaqueinducedginigivitistono treatment,supragingivaldebridementandtoothpolishing(11 trials,5752women,RR0.88,95%CI0.72–1.09).Fogaccietal. (2011)comparedtreatmentof destructiveperiodontaldisease orperiodontitistonotreatmentordentalplaqueinstruction, prophylaxis,orsupragingivalscaling.RiskofPTBwasreported controlledformultiparityonthebasisthatitwasthelargest numberoftrialsforthisoutcome(8trials,5270women,RR 0.92,95%CI0.72_–1.17).Kimetal.(2012)comparedscalingand root planning to placeboor notreatment(11 trials, 5655 women,RR0.81,95%CI0.64–1.01).Anearliercomparisonof scaling and root planning to placebo or no treatment conductedbyPolyzosetal.(2010)identified11trials,6558 women,andRR0.93,95%CI0.79-1.10.Rosaetal.(2012)used morestringentinclusioncriteriaandcomparedperiodontal treatment to standard care for women with singleton gestation at 22 weeks of less and stringent criteria for definitingperiodontaldisease.Theyidentified13trials,6988 women,andnoeffectonPTB(RR0.90,95%CI0.68–1.19). IVSecondaryoutcomes–secondaryprevention:

Perinatal,fetalorneonatalmortalityweregenerallynotdifferent withthefollowingsecondarypreventioninterventions:cervical cerclageinhighriskwomen(Alfirevicetal.,2012;Berghellaand MacKeen,2011aandb;Conde-Agudeloetal.,2013,Jorgensenetal.,

2007,Rafaeletal.,2014,Sacconeetal.2015b;Meheretal.,2017), antiplateletagentsinwomenatriskforpreeclampsia(Askieetal, 2007;Robergeetal.,2013;Xuetal.,2015;Cristinaetal.,2009), treatmentforvaginitis(Brocklehurstetal.,2013;Lamontetal., 2011;Okunetal.,2005),routineprophylacticantibiotics (Think-hamrop et al., 2015), antibiotics for premature rupture of membranes (Kenyon et al., 2013), planned early delivery for womenwithprematureruptureofmembranes(Buchananetal., 2010),psychosocialinterventionsforsmokingcessation (Cham-berlainetal.,2013),nicotinereplacementforsmokingcessation (Coleman etal., 2011),antenatalbedrestformultiplegestation (Crowtheretal.,2010),specializedantenatalcareinwomenwith multiplegestation(Doddetal.,2015)andinwomenatriskof havingapretermorgrowthrestrictedbaby(Hodnettetal.,2010; Whitworthetal.,2011),periodontaltreatmentforwomenwith periodontal disease (George et al., 2011; Polyzos et al., 2010; Schwendicke et al., 2015), calcium supplementation (Hofmeyr et al., 2014), long chain polyunsaturated fattyacid supplementation (Horvathetal.,2007)andomega3(Saccone&Berghella,2015a), vitaminAforHIVpositivewomen(Wiysongeetal.,2011),and homeuterinemonitoring(Urquhartetal.,2015),

Progesteroneinhighriskwomendidnothaveasignificanteffect onperinatalmortalityinmultiplereviews(Conde-Agudeloetal., 2013;Doddetal.,2013;Likisetal.,2012;Romeroetal.,2012,and 2016;Schuitetal.,2015;Sotiriadisetal.,2012;Combsetal.,2012), exceptinwomenwithasingleton pregnancy andhistory ofPTB.In this subpopulation, Dodd et al., (2013) showed decreased perinatal mortality (RR 0.50, 95% CI 0.33 to 0.75), neonatal mortality(RR0.45,95%CI0.27to0.76),lowbirthweight(RR0.58, 95%CI0.42to0.79),andNICUadmission(RR0.24,95%CI0.14to 0.40).Likisetal.(2012)alsoshoweddecreasedneonatalmortality withprogesteroneinasubpopulationofwomenwithprevious pretermbirth(RR0.58,95%CI0.27to0.98),asymptomaticshort cervix(RR0.40,95%CI0.09to0.91),andwomenwithpreterm labour,but notinmultiplegestations.Risk oflowbirth weight was alsodecreasedinwomenwithpreviousPTB(RR0.66,95%CI0.51 to 0.87). There was a reduced risk of NICU admission with progesterone in women with short cervix and singleton pregnancies (Romero et al., 2016), women with singleton gestation, short cervix and history of preterm birth (Conde-Agudelo et al., 2013), and a reduced riskwith vaginalprogesterone compared to intramuscular progesterone in asymptomatic singletonswithhistoryofPTB(Sacconeetal.,2016).

Sealing procedures for women with premature rupture of membraneswasshowntoreduceneonatalmortality(RR0.38, 95%CI0.19to0.75)inonereview(Crowleyetal.,2016). Theothersecondaryoutcomeswereassessedinfewreviews and mostinterventionshadnoeffect.Psychosocialprograms (Chamberlain etal., 2013)and nicotinereplacement therapy (Coleman et al., 2011) for smoking cessation werefound to reduceriskoflowbirthweight.Periodontaltreatmentwasalso foundtoreduceLBWinonereview(Georgeetal.2011). Dataformaternaloutcomeswererarelyavailable.Therewasno differenceinmaternalsatisfactionwithvaginalprogesterone compared tocontrol(Dodd etal., 2013)and inwomenwith multiplegestationreceivingspecializedantenatalcare(Dodd etal.,2015).

Discussion Keyfindings

Thisreviewofreviewsaimedtosystematicallyassessexisting literatureregarding effectivenessand safety of interventionsto preventPTB.Intotal,112reviewswereincluded.

Sixty reviews assessed the effect of primary prevention interventions on risk of PTB. Positive effects were found for lifestyle and behavioural changes, including diet and exercise; nutritionalsupplements,includingcalciumandzinc supplemen-tation; nutritional education; screening for lower genital tract infections.However,therewerenoorminimaldataavailablefor mostofoursecondaryoutcomes.

There were 83 systematic reviews of secondary prevention interventions.Positive effects were foundfor low dose aspirin amongwomenatriskofpreeclampsia;clindamycinfortreatment of bacterial vaginosis and treatment of vaginal candidiasis; progesteroneinwomenwithpriorspontaneousPTBandinthose withshortmidtrimestercervicallength;L-arginineinwomenat riskforpreeclampsia;levothyroxineamongwomenwiththyroid disease;calciumsupplementationinwomenatriskof hyperten-sive disorders; smoking cessation; cervical length screening in high-risk singleton gestations; cervical pessary in singleton gestationswithshortcervix;andtreatmentofperiodontaldisease. COXinhibitorsandmetronidazolefortrichomoniasisseemtobe associatedwithanincreasedriskofPTB.

Ourresultsmaybeinfluencedbythemethodologicalqualityof theincludedreviewsand RCTs.Interventionsthatmayhavean effectonPTBbutareusedforotherconditionscouldpotentially havebeenmissed,howeverweusedabroadsearch strategyto minimizethisrisk.Themajorshortcomingofareviewofreviewsis thelossofmoredetailedinformationbyqualitativelyaggregating information. For example, women at risk of PTB were defined preciselyinsomereviews,butnotinothers.

Thepreventionofprematurityisarapidlyevolvingmaternal andchild healthtopic.Therefore, summarizingevidenceof this topicisanimportantpriority.

Thisarticleis,toourknowledge,thefirstreviewofreviewson primaryandsecondarypreventionofPTBthathasconsideredall formsofsystematic reviewsaswellasa reviewofplannedand ongoingtrials.Thepossibleeffectsofadiverserangeofinterventions forprimaryandsecondarypreventionofPTBhavebeenevaluatedin several systematicreviewsofRCTs. Altoughthereis alargenumber of reviews,fewinterventionshavebeendefinitvelydemonstratedtobe safeandeffective.Forseveraloftheinterventionsevaluated,there wasinsufficientevidencetoassesswhethertheinterventionwas effectiveornot.Thereislittlehigh-qualityevidenceformostofthe interventionsstudied,whichshouldbetakenintoaccountwhen makingmagenementdecisions.

The difficulty in interpreting the results of this review highlights theimportanceofhaving a specificpopulationtobe studiedintrialsonPTB,suchasthoseatriskofPTB,andconducting RCTsincomparinginterventions.Thereshouldbeanagreed-upon set of clearly-defined and measurable outcomes, including maternalsecondaryoutcomessuchasmaternaldeths,satisfaction, admissiontointensivecareunit,infuturePTBinterventiontrials, sothatoutcomesoftrials canbeeasilymeta-analysedThevast majority of the trials in included reviews were small; review authorsoftenemphasizedtheneedforlarger,well-designedRCTs. Disclosure

Theauthorsreportnoconflictofinterest. Financialsupport

Atthetimeofconductingthisreviewofsystematicreviews,JPV was employed at the UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research TraininginHumanReproduction(HRP),Departmentof Reproduc-tiveHealthandResearch.JPViscurrentlyemployedbytheBurnet Institute(Melbourne,Australia).

Condensation

Only a few interventions have been demononstrated to be effectiveinprimaryandsecondarypreventionofpretermbirth, includingcerclage, progesterone,low doseaspirin, and lifestyle andbehaviouralchanges.

Authorscontribution

Allauthorscontributedequallytothiswork. AppendixA.Supplementarydata

Supplementarymaterialrelatedtothisarticlecanbefound,in the online version, at doi:https://doi.org/10.1016/j. ejogrb.2018.12.022.

References

[1]BlencoweH,CousensS,OestergaardMZ,ChouD,MollerA-B,NarwalR,etal. National,regional,andworldwideestimatesofpretermbirthratesintheyear 2010withtimetrendssince1990forselectedcountries:asystematicanalysis andimplications.Lancet2012;379(9832):2162–72.

[2]LawnJ,CousensS,ZupanJ.4millionneonataldeaths:when?where?why?. Lancet2005.

[3]LiuL,JohnsonHL,CousensS,PerinJ,ScottS,LawnJE,etal.Global,regional,and nationalcausesofchildmortality:anupdatedsystematicanalysisfor2010 withtimetrendssince2000.Lancet2012;379(9832):2151–61.

[4]IamsJD,RomeroR, CulhaneJF,GoldenbergRL.Pretermbirth2:primary, secondary,andtertiaryinterventionstoreducethemorbidityandmortalityof pretermbirth.ObstetAnesthDig2009;29(March(1)):7–8.

[5]RobergeS,DemersS,BujoldE.Low-doseaspirinforpreventionofmorbidity andmortalityfrompreeclampsia.AnnInternMed2014;161(October(8)):613. [6]DoddJM,JonesL,FlenadyV,CincottaR,CrowtherCA.Prenataladministration ofprogesteroneforpreventingpretermbirthinwomenconsideredtobeat riskofpretermbirth.CochraneDbSystRev.2012;7(December)CD004947–7. [7]SacconeG,SuhagA,BerghellaV.17-alpha-hydroxyprogesteronecaproatefor maintenancetocolysis:asystematicreviewandmetaanalysisofrandomized trials.AmJObstetGynecol2015;213(July(1)):16–22,doi:http://dx.doi.org/ 10.1016/j.ajog.2015.01.05.

[8]SuhagA, Saccone G, BerghellaV. Vaginal progesterone formaintenance tocolysis:asystematicreviewandmetaanalysisofrandomizedtrials.AmJ ObstetGynecol2015;213(October(4)):479–87,doi:http://dx.doi.org/10.1016/j. ajog.2015.03.031.

[9]SacconeG,KhalifehA,ElimianA,BahramiE,Chaman-AraK,BahramiMA,etal. Vaginalprogesteronevsintramuscular17α-hydroxyprogesteronecaproatefor preventionofrecurrentspontaneouspretermbirthinsingletongestations: systematic review and meta-analysis of randomized controlled trials. Ultrasound Obstet Gynecol 2017;49(March (3)):315–21, doi:http://dx.doi. org/10.1002/uog.17245.

[10]OtaE,HoriH,MoriR,Tobe-GaiR,FarrarD.Antenataldietaryeducationand supplementationtoincreaseenergyandproteinintake.CochraneDbSystRev 2015;(June)6CD000032.

[11]BerghellaV,CiardulliA,RustOA,ToM,OtsukiK,AlthuisiusS,etal.Cerclagefor sonographicshortcervixinsingletongestationswithoutpriorspontaneous pretermbirth:systematicreviewandmeta-analysisofrandomizedcontrolled trialsusingindividualpatient-leveldata.UltrasoundObstetGynecol2017;50 (November(5)):569–77,doi:http://dx.doi.org/10.1002/uog.17457.

[12]SacconeG,RustO,AlthuisiusS,RomanA.BerghellaV.Cerclageforshortcervix intwinpregnancies:systematicreviewandmeta-analysisofrandomized trialsusingindividualpatient-leveldata.ActaObstetGynecolScand2015;94 (April(4)):352–8,doi:http://dx.doi.org/10.1111/aogs.12600.

[13]SacconeG,MaruottiGM,GiudicepietroA,MartinelliP.Italianpretermbirth prevention(IPP)workinggroup.Effectofcervicalpessaryonspontaneous pretermbirthinwomenwithsingletonpregnanciesandshortcervicallength: arandomized clinicaltrial. JAMA2017;318(December(23)):2317–24,doi: http://dx.doi.org/10.1001/jama.2017.18956.

[14]SacconeG,CiardulliA,XodoS,DugoffL,LudmirJ,D’AntonioF,etal.Berghella V.CErvicalpessaryforpreventingpretermbirthintwinpregnancieswithshort cervical length: a systematic review and meta-analysis. J Matern Fetal Neonatal Med 2017;30(December (24)):2918–25, doi:http://dx.doi.org/ 10.1080/14767058.2016.1268595.

[15]SacconeG,CiardulliA,XodoS,DugoffL,LudmirJ,PaganiG,etal.BerghellaV. CErvicalpessaryforpreventingpretermbirthinsingletonpregnancieswith shortcervicallength:asystematicreviewandmeta-analysis.JUltrasound Med 2017;36(August (8)):1535–43, doi:http://dx.doi.org/10.7863/ul-tra.16.08054.

[16]PisoB, Zechmeister-KossI,Winkler R. Antenatalinterventionsto reduce pretermbirth:anoverviewofCochranesystematicreviews.BMCRes.Notes BioMedCent.2014;7(1):265.

[17]TheCochraneCollaboration.Cochranehandbookforsystematicreviewsof interventions.In:HigginsJ,GreenS,editors.Cochranecollaboration.5ed... Availablefrom:training.cochrane.org/handbook(Accessed11February2018. [18]Moher D,LiberatiA,TetzlaffJ,AltmanDG. Preferredreporting itemsfor systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol2009;62:1006–12.

[19]GuyattGH,OxmanAD,VistGE,KunzR,Falck-YtterY,Alonso-CoelloP,etal. GRADE:anemergingconsensusonratingqualityofevidenceandstrengthof recommendations.BMJ2008;336(7650):924–6.

[20]SheaBJ,GrimshawJM,WellsGA,BoersM,AnderssonN,HamelC,etal. DevelopmentofAMSTAR:ameasurementtooltoassessthemethodological

qualityofsystematicreviews.BMCMedResMethodol2006;7(December) 10–0.

[21]van’tHooftJ,DuffyJM,DalyM,WilliamsonPR,MeherS,ThomE,etal.Global Obstetrics Network (GONet). A core outcome set for evaluation of interventionstopreventpretermbirth.ObstetGynecol2016;127:49–58. [22]Geneva:WorldHealthOrganization.WHOrecommendationsonantenatal

careforapositivepregnancyexperience.2016.

[23]ChawanpaiboonS,VogelJP,MollerAB,LumbiganonP,PetzoldM,HoganD, etal.Global,regional,andnationalestimatesoflevelsofpretermbirthin2014: asystematicreviewandmodellinganalysis.LancetGlobHealth2018(October) PubMedPMID:30389451.Epub2018/10/30.