a systematic review and meta‐analysis of ...€¦ · of plasmodium falciparuminfectionhave...

Int J Gynecol Obstet 2019; 1–13 wileyonlinelibrary.com/journal/ijgo | 1© 2019 International Federation of Gynecology and Obstetrics

Received:2November2018 | Revised:23March2019 | Accepted:1May2019DOI: 10.1002/ijgo.12835

R E V I E W A R T I C L EO b s t e t r i c s

A systematic review and meta- analysis of dihydroartemisinin- piperaquine versus sulphadoxine- pyrimethamine for malaria prevention in pregnancy

Atinuke Olaleye1,* | Babasola O. Okusanya2 | Olabisi Oduwole3 | Ekpereonne Esu4 | Martin Meremikwu5

1Maternal–FetalMedicineUnit,DepartmentofObstetricsandGynecology,BenjaminCarson(Sr)SchoolofMedicine,BabcockUniversity,Ilishan-Remo,Nigeria2ExperimentalandMaternalMedicineUnit,DepartmentofObstetricsandGynecology,FacultyofClinicalSciences,CollegeofMedicine,UniversityofLagos,Lagos,Nigeria3DepartmentofMedicalLaboratoryScience,AchieversUniversity,Owo,Nigeria4DepartmentofPublicHealth,FacultyofAlliedMedicalSciences,CollegeofMedicalSciences,UniversityofCalabar, Calabar,Nigeria5DepartmentofPediatrics,CollegeofMedicalSciences,UniversityofCalabar,Calabar,Nigeria

*CorrespondenceAtinukeOlaleye,DepartmentofObstetricsandGynecology,BenjaminCarson(Sr)SchoolofMedicine,BabcockUniversity,Ilishan-Remo,OgunState,Nigeria.Emails:[email protected]; [email protected]

AbstractBackground:Intermittentpreventivetreatment(IPT)withsulphadoxine-pyrimethamine (SP) is recommended for preventingmaternal and fetal effects ofmalaria in preg-nancy. Increasing parasite resistance to SP has necessitated the search for analternativemedication.Objective: To compare dihydroartemisinin-piperaquine (DP) and sulphadoxine-pyrimethamineinpreventingmalariaduringpregnancy.Search strategy:DatabasesincludingCENTRAL,MEDLINE,andICTRPweresearcheduntilAugust2018.Selection criteria:Randomizedandquasi-randomizedcontrolled trials thatcomparedDPwithSPgiventopregnantwomentopreventadversematernalorfetaleffectsofmalaria were included.Data collection and analysis:QualityofevidencewasdeterminedwithGRADEcriteria.Effectivenessmeasureswerecalculatedusingoddsratiosat95%confidenceintervals.Results:Threerandomizedcontrolledtrialswereincluded.ComparedwithIPT-SP,mod-eratecertaintyevidenceindicatedthatwomenwhoreceivedIPT-DPhadsignificantlylowerrisksofclinicalmalariaduringpregnancy.Highcertaintyevidenceshowedinter-mittentscreeningandtreatmentwithDPdidnotreduceplacentalmalariaormaternalparasitemiaatdelivery.EffectofDPonlowbirthweightandadversebirthoutcomeswasminimal.Conclusions:ModeratecertaintyevidencesuggeststhatIPT-DPmayreducematernalandplacentalmalariacomparedwithIPT-SP,andmonthlyDPismoreeffectivethanSPinreducingplacentalmalaria.PROSPEROID:CRD42018084651.

K E Y W O R D S

Artemisinin-basedcombinationtherapy;Dihydroartemisinin-piperaquine;Intermittentpreventivetreatment;Intermittentscreeningandtreatment;Malaria;Pregnancy; Sulphadoxine-pyrimethamine

www.wileyonlinelibrary.com/journal/ijgo

mailto:[email protected]

mailto:[email protected]

2 | Olaleye eT al.

1 | INTRODUCTION

Malaria in pregnancy is a serious public health issue.Malaria para-sitemiaoccurringinapregnantwomanisassociatedwiththedistinc-tiveriskofplacentalandfetalinvolvement.Inregionsoflowmalariaendemicity,malaria inpregnancycauses febrile illness, spontaneousabortion,andfetalandmaternaldeath.Theconditionmaybeasymp-tomaticwithsubclinicalplacentalinfectioninhighendemicregions.InSub-SaharanAfrica,anestimated6250000pregnantwomenatriskof Plasmodium falciparuminfectionhaveplacentalevidenceofmalariainfection at the time of delivery.1 Without protective measures inpregnancy,malariainfectioncanresultinthedeliveryofupto900000lowbirthweightnewbornsannuallyinAfrica.2

TheWHOrecommends theuseof sulphadoxine-pyrimethamine(SP) for intermittent preventive treatment (IPT) in pregnancy, as ithasbeen reported to reducemalaria infectionsand improvemater-nalandneonataloutcomes.3–6However,thereareincreasingreportsofresistancetoSP,7–10whichmayerodethegainsobtainedfromtheeffectoftheintervention.Thesereportshavenecessitatedtheeval-uationof theevidence fromagrowingnumberof studiesassessingothercombinationtherapiesaspotentialalternativestoSPasIPTinpregnancy(IPTp)agents.11–13

Artemisinin-based combination therapy (ACT) has been recom-mended for the treatment of malaria across all ages, including thesecondandthirdtrimestersofpregnancy.14Theefficacy,safety,andeffectiveness of dihydroartemisinin-piperaquine (DP), an ACT, havebeen assessed in various trials,with reported effectiveness of 98%orhigher in thegeneralpopulation, includingpregnantwomen.15–17 Recent reports from some clinical trials in malaria-endemic regionshaveshownthepotentialofDPasanIPTpagent.Themonthlyprophy-lacticdosageofDPasanIPTphasalsobeenreportedtobefeasible.18 In addition, theuseofDP for intermittent screening and treatment(IST)ofmalariaduringpregnancyhasbeenreported.12,19Assessingtheuse of such anACT as an agent for chemopreventionofmalaria inpregnancyisthusessential.

Theobjectiveofthissystematicreviewandmeta-analysiswastoassessthecurrentevidenceonfeto-maternaloutcomesfollowingtheuseofDPcomparedwithSPformalariapreventionduringpregnancy.We used the methodology outlined in the Cochrane Handbook ofSystematicreviews20toconductthisreview.

2 | MATERIALS AND METHODS

These databases were searched from inception up to August 21,2018: Cochrane Central Register of Controlled Trials (CENTRAL);MEDLINE (PubMed); EMBASE (OVID); and LILACS (BIREME). TheWHO International Clinical Trials Registry Platform (ICTRP; http://www.who.int/ictrp/en/) and ClinicalTrials.gov (https://clinicaltrials.gov/ct2/home)werealsosearchedtoAugust21,2018, for trials inprogress.AcombinationofkeywordsandMedicalSubjectHeadings(MeSH terms)wereused to identify studies assessing theeffectofIPT-DP on predefined health outcomes. For instance, on PubMed

the following were used as search terms: “malaria,” “prophylaxis,”“chemoprophylaxis,” “intermittent preventive treatment,” “intermit-tentscreeningandtreatment,”and“dihydroartemisinin-piperaquine.”

Our searchwas restricted to randomized and quasi-randomizedcontrolledtrialswithDPgivenastheinterventionandSPasthecon-trol.TheMultilateralInitiativeonMalaria(MIM)conferenceabstractsofApril2018werealsosearched.Attemptsweremadetoidentifyallrelevanttrialswithoutprejudicetolanguageorpublicationstatus.Thereferencelistsofretrievedstudieswerealsoreviewedforadditionalrelevant studies. The PRISMA guidelines and flow diagram21 were usedtoreportthesearchandselectionofstudies.

Theoutcomeswereprespecifiedandtheprimaryoutcomeswereclin-icalmalariaepisodesduringpregnancy(withthepresenceofasexualpar-asitesandfever),andplacentalmalaria(asdefinedbyauthors).Secondaryoutcomesincludedmeanhemoglobinandmaternalanemia(hemoglobin<11g/dL);maternalperipheralparasitemia(asdefinedbyauthors);lowbirthweightprevalence(<2500g);andsafety(seriousadverseeventsandotheradverseevents).Publisheddatawere included inthissystematicreview,thusnoethicscommitteeapprovalwasrequired.

Oneofthereviewauthors(EE)conductedaliteraturesearchusingthe electronic search methods described. Two review authors (AOandBO)independentlyscreenedthetitlesandabstractsofresultsofthe literature search for potentially relevant trials and obtained thefull reportsofthesetrials.Theeligibilitycriteriawere independentlyappliedtothefullreportsaspublishedinthereviewprotocolusinganeligibilityformandpublicationswerescrutinizedtoensureeachtrialwas included inthereviewonlyonce.Disagreementswereresolvedthrough discussionwith another teammember (MM).The includedstudieswerelisted,aswellastheexcludedstudiesandthereasonsfortheirexclusion.Theprotocol forthisreviewwasregisteredwiththeInternationalProspectiveRegisterofSystematicReviews(PROSPERO)withregistrationIDCRD42018084651.

Two team members (AO and OO) extracted data from eligiblestudies using a predefineddata extraction form, and independentlyassessed the risk of bias of each trial usingCochranemethods. Sixdomainsofbiaswereassessedforeach includedtrial:generationofrandomization sequence; allocation concealment; blinding; incom-plete outcome data; selective outcome reporting; and other biases(suchasearlyterminationofthetrial).

Tworeviewauthors(EEandAO)evaluatedthequalityofevidencefor each outcome using the GRADE (Grading of RecommendationsAssessment,DevelopmentandEvaluation)approach.22Disagreementswere resolved through discussions among all review authors. Thequalityoftheevidencewasappraisedintheresultsofthesystematicreviewashigh,moderate,low,orverylow.

Data obtained were entered into RevMan 5.3 (The NordicCochrane Center, Copenhagen, Denmark). The software was usedto combinedata usingfixed-effectmeta-analysiswhere itwas rea-sonabletoassumethestudiesestimatedthesameunderlyingtreat-ment effect, as was for low birthweight prevalence and maternalperipheralmalariaatdelivery.Wheretherewasclinicalheterogene-itysufficienttoexpectthattheunderlyingtreatmenteffectsdifferedbetween studies, or substantial statistical heterogeneity detected,

http://www.who.int/ictrp/en/

http://www.who.int/ictrp/en/

https://clinicaltrials.gov/ct2/home

https://clinicaltrials.gov/ct2/home

| 3Olaleye eT al.

random effects meta-analysis was used to produce an overallsummaryoraveragetreatmenteffectasseeninthemeta-analysisforplacentalmalaria.

Meta-analysisofdichotomousdatawasconducted,andtheresultsarepresentedassummaryoddsratio(OR)with95%confidenceinter-vals (CI), while the incidence rateswere analyzedwith the genericinverse variance method. Statistical heterogeneity in each meta-analysiswasassessedusingtheI-square(I2)statistics.HeterogeneitywasregardedasmoderateifanI2wasgreaterthan40%,substantialifI2wasgreaterthan60%,andconsiderableifI2wasgreaterthan80%.Whenoutcomedatawerepresentedinanonuniformformat,narrativesummaryofresultswasmade,andmeta-analysiswasnotdoneasseeninmaternaladverseevents.

3 | RESULTS

Thesearchoutputidentifiedatotalof348references,ofwhich17wereduplicatereports.FiveothertrialswerefoundregisteredonClinicaltrials.gov.Of these,onewasaduplicate trial report,whilethreewere yet to be completed.Out of the 336titles remainingfollowingremovaloftheduplicatereports,332titlesandabstractswere screened out. The full-text articles of four studies wereretrievedforeligibilityscreening,afterwhichonlythreestudiesmettheinclusioncriteriaforthisreview.Aflowdiagramshowingstudyselection is given in Figure 1. The characteristics of the includedstudiesareshowninTable1(theexcludedstudiesandthereasonsfortheirexclusionaregiveninSupplementaryinformationTableS1).

F IGURE 1 Flowdiagramofidentifiedstudies.

Iden

tific

atio

n Records identified through database searching (n=348)

Additional records identified through other sources (n=5)

Records after duplicates removed (n=336)

Scre

enin

g

Records excluded (n=332)

Records screened (n=336)

Full-text articles excluded, with reasons (n=1)

Comparison drug: trimethoprim-sulfamethoxazole, not SP

Elig

ibilit

y

Full-text articles assessed for eligibility (n=4)

Studies included in qualitative synthesis (n=0)

Incl

uded

Studies included in quantitative synthesis (meta-analysis) (n=3)

4 | Olaleye eT al.

TABLE 1 Characteristicsoftheincludedstudies.

Stud

y ID

Stud

y de

sign

Sam

ple

size

Popu

latio

nSe

tting

Inte

rven

tion(

s)Co

mpa

rison

(s)

Out

com

e(s)

repo

rted

Risk

of

bias

Desaietal.,

12

2015

RCT

1546

516:IPT-DP

515:IST-DP

515:IPT-SP

HIV-negativepregnant

women;16–32wkof

pregnancy

FourruralhealthfacilitiesinSiaya

County,westernKenya

IPT-DP

IST-DP

IPT-SP

Malariainfectionatdelivery(composite

ofperipheralorplacentalparasitemia);

Incidenceofmalariainfectionandclinical

malariaduringpregnancy;prevalence

ofadversenewbornmorbidityatbirth

(compositeofeitherpretermdelivery,low

birthweight,orsmallforgestationalage);

anemiaduringpregnancyoratdelivery

Low

Kakuru

etal.,

23

2016

RCT

300 94:three-

doseDP

106:IPT-SP

100:monthly

DP


women;12–20wkof

pregnancy

StudyclinicandTororoDistrict

Hospital,Tororo,Uganda

Three-doseDP

MonthlyDP

IPT-SP

Prevalenceofplacentalmalaria;incidence

ofsymptomaticmalaria;prevalenceof:

parasitemia;anemiaduringpregnancy;

parasitemiaatdelivery(placental,cord,

andmaternalblood);incidenceofadverse

birthoutcomes(includingacompositeof

spontaneousabortion,stillbirth,lowbirth-

weight,pretermdelivery,andcongenital

anomaly)

Unclear

Madanitsa

etal.,

19

2016

RCT

1873

937:IST-DP

936:IPT-SP


women;16–28wkof

pregnancy

MpembaandMadziabangoHealth

Centers;ChikwawaDistrict

HospitalinsouthernMalawi

IST-DP

IPT-SP

Adverselivebirthoutcome(compositeofsmallfor

gestationalage,lowbirthweight,orpreterm);plas-

modiuminfectionatdeliveryinperipheralmaternal

bloodorplacenta;fetalloss;maternalanemia;clinical

malaria;plasmodiuminfection;meanbirthweight;

meangestationalageatdelivery;congenitalplasmo-

diuminfection;neonatalandinfantclinicalmalaria;

all-causesevereanemia;perinatalandinfantmortality

by6–8wk

Abbreviations:RCT,randomizedcontrolledtrial;IPT,intermittentpreventivetreatment;DP,dihydroartemisinin-piperaquine;IST,intermittentscreeningandtreatment;SP,sulphadoxine-pyrimethamine.

| 5Olaleye eT al.

The risk of bias assessment of the included studies is shown intheriskofbiasgraph(Fig.2)andtheriskofbiassummary(Fig.3).Tables2–4present the effects andquality of evidence accordingtoGRADE.

Three randomized controlled trials involving 3719 participantswere included.12,19,23 The trials commenced in 2011, 2012, and2014inMalawi,Kenya,andUganda,respectively.Theincludedstud-ies involvedpregnantwomenwhoweregivenDP (as routine IPT,athree-doseregimen,monthlyregimen,orasIST)andcomparedwiththosegivenSP.Intwoofthestudies,drugadministrationwaspartlysupervised,asonlytheinitialdosesofeachdrugweregivenasdirectlyobserved therapy.12,23 Women in all parity groups were recruitedin all studies and resultswere disaggregated for parity (pauci- andmultigravid)intwoofthetrials.12,19

In the three studies, all participants received long-lastinginsecticide-treated nets at enrollment. The trials were individu-ally randomized, with multiple intervention arms, and the resultspresented for each arm. Kakuru et al.23 compared IPT-SP withtwo IPT-DP regimens: a scheduled three-dose DP regimen and amonthlyDPregimen.StudyparticipantsassignedtotheIPT-SPandscheduledthree-doseDPgroupsreceivedtherespectiveinterven-tions at 20, 28, and36weeks of pregnancy,while participants inthe monthly DP group received the intervention every 4 weeksfrom16 or 20weeks.Madanitsa et al.19 compared IPT-SPversusIST-DP, where study participants made scheduled prenatal visitsevery4–6weeksinthesecondandthirdtrimesters.FortheIST-DPgroup,studyparticipantswerescreenedformalariausingtherapiddetectiontest (RDT)kitateachvisit,andtreatedwithDP, ifRDT-positive.Desai et al.12 compared IPT-SPversus IPT-DPor IST-DP.Thestudyparticipantswereenrolledat16–32weeksofpregnancyandreceivedtheinterventionsatintervalsof4–6weeks.Themeanage of the participants in the three studies was 23.4, 22.5, and22years, respectively12,19,23; theywerepredominantlypaucigravid(i.e.primigravidandsecundigravid).

3.1 | Comparison 1: Scheduled three- dose IPT- DP versus IPT- SP

The two RCTs12,23 compared feto-maternal outcomes follow-ing the use of three doses ofDP versus SP as intermittent pre-ventive treatment. Regarding the occurrence of clinical malariaduring pregnancy (defined as presence of asexual parasites andfever), one study23 reported fewer occurrences of symptomaticmalaria events per person-year at risk, in the three-dose DPgroup (11 events vs 32 in the IPT-SP group). The other study12 alsoreportedthatratesofclinicalmalariaduringpregnancywerelower in the three-dose IPT-DPgroup (6.1events vs37.9 in theIPT-SPgroup).Hence,moderatecertaintyevidenceindicatesthatthree doses of DP probably results in a large reduction in clini-calmalariaduringpregnancy (OR0.17;95%CI,0.10–0.29;1171participants)(Fig.4).

Moderate certainty evidence suggests that three doses of DPresults in little or no difference in placental malaria reduction (OR0.73;95%CI,0.50–1.06;2studies,1231participants)(SupplementaryinformationFig.S1).

Onestudy12indicatedthatthree-doseIPT-DPusewasassociatedwith statistically significant loweroddsofmaternalperipheral para-sitemiaatdeliverycomparedwithwomenreceivingIPT-SP.Moderatecertainty evidence indicates that a three-dose DP regimen for IPTprobably reduces maternal peripheral malaria at delivery (OR 0.27;95% CI, 0.15–0.47; 2 studies, 1231 participants) (SupplementaryinformationFig.S2).

Comparingtheoccurrenceofmaternalanemiaatdelivery(hemo-globin<11g/dL) betweenwomenwho received three-dose IPT-DPand those who received IPT-SP, moderate certainty evidence indi-catesthatthree-doseDPprobablyreducesmaternalanemia(OR0.72;95%CI,0.54–0.95;1study,1031participants)(Fig.5).Inbothstudies,theoccurrenceofanemiaduringpregnancywashigherinwomenwhoreceivedIPT-SPthaninthosewhoreceivedIPT-DP.

F IGURE 2 Riskofbiasgraph:dihydroartemisinin-piperaquinevssulphadoxine-pyrimethamineformalariapreventioninpregnancy.

6 | Olaleye eT al.

Low certainty evidence suggests that three-doseDPmay resultin littleornodifferenceintheprevalenceof lowbirthweight,whencomparedwithIPT-SP(OR1.20;95%CI,0.73–1.97;2studies,1231participants)(SupplementaryinformationFig.S3).

Kakuru et al.23 reportedno significant differences inmaternaladverse events among the treatment groups, except for a higherincidenceofdysphagiainthemonthlyDPgroupthaninthethree-doseDPgroup(P=0.02).Desaietal.12reportedahigherincidenceof maternal adverse events in the IPT-SP group. Low certaintyevidence suggests that a three-dose IPT-DP regimen comparedwithIPT-SPmaybeassociatedwithfewermaternalseriousadverseevents(OR0.42;95%CI,0.29–0.62;2studies,1231participants)(Supplementary information Fig. S4). Kakuru et al.23 reportedno clinically important differences in the risk of adverse eventsamong the treatment groups. The maternal deaths reported byDesaietal.12wereindicatedasunrelatedtotheinterventionortomalaria.Follow-upofparticipantsinbothtrialswasuntil6–8weeksafterdelivery.

Withrespecttoadversebirthoutcomes(i.e.smallforgestationalage,pretermbirth,lowbirthweight,stillbirth,spontaneousabortion,low certainty evidence suggests little or no difference in the inci-denceofadversebirthoutcomeswiththree-doseDPcomparedwithIPT-SP (OR 0.94; 95% CI, 0.66–1.34; 2 studies, 1231 participants)(SupplementaryinformationFig.S4).

3.2 | Comparison 2: Monthly IPT- DP versus IPT- SP

Onestudy23comparedmaternalandfetaloutcomesfollowingmonthlyDPdoseswiththeusual threedosesof IPT-SP.ModeratecertaintyevidenceindicatesthatmonthlyDPprobablyresultsinalargereduc-tioninclinicalmalariaduringpregnancy(OR0.01;95%CI,0.00–0.19;1study,206participants)(Fig.6).

The study also indicated a statistically significant lower odds ofplacentalmalariafollowingdeliveryinwomenwhoreceivedmonthlyDPcomparedwithwomenwhoreceivedIPT-SP.ModeratecertaintyevidencethusshowsthatamonthlyDPregimenprobablyresultsinareductioninplacentalmalariainfection(OR0.41;95%CI,0.23–0.74;1study,206participants)(Fig.7).

Moderate certainty evidence indicates monthly DP probablyresultsinlittletonodifferenceinmaternalperipheralmalariaparasite-miaatdelivery(OR0.09;95%CI,0.01–1.68;1study,206participants)(SupplementaryinformationFig.S5).

ModeratecertaintyevidenceindicatesmonthlyDPprobablyresultsin littletonodifference inprevalenceof lowbirthweight (OR0.57;95%CI,0.23–1.43;1study,206participants) (Supplementary infor-mationFig. S6).Moderate certaintyevidence shows that amonthlyDPregimenprobablyresultsinlittletonodifferenceinmaternalseri-ousadverseevents (OR0.62;95%CI,0.19–2.54;1study,206par-ticipants)(SupplementaryinformationFig.S7).Noneofthematernalseriousadverseevents(SAEs)werereportedasbeingpossiblyrelatedtothestudyagents.23

Regarding adverse birth outcomes,moderate certainty evidencesuggeststhatmonthlyDPprobablyresultsinasmall,possiblyunim-portant effect on adverse birth outcomes (OR 0.45; 95%CI, 0.19–1.06;1study,206participants)(SupplementaryinformationFig.S7).

3.3 | Comparison 3: IST- DP versus IPT- SP

Two trials compared feto-maternal outcomes following intermittentscreeningformalariausingrapiddiagnostictest(RDT)andtreatmentifpositive,withDP(IST-DP)versusintermittentpreventivetreatmentwith SP (IPT-SP).12,19 Evidenceon the effect of IST-DPon the inci-denceofclinicalmalariaduringpregnancywasconflicting.Therewassubstantial heterogeneity I2=75% (Supplementary information Fig.S8),whichmadepooledestimatesunnecessary.WhileDesaietal.12 reported in favor of IPT-SP (crude IRR 1.41; 95% CI, 1.00–1.98;P=0.0475),Madanitsaetal.19reportedlittleornodifferenceinbenefitwiththeuseofIST-DP(crudeIRR0.91;95%CI,0.70–1.19;P=0.499).

Thestudiesshowedstatisticallysignificantloweroddsofplacen-talmalariainwomenwhoreceivedIPT-SPcomparedwiththosewhoreceivedIST-DP.HighcertaintyevidenceindicatesISTwithDPdoesnotreduceplacentalmalaria(OR1.29;95%CI,1.10–1.50;2studies,2903participants)(Fig.8).HighcertaintyevidencealsoindicatesISTwithDPdoesnotreducematernalperipheralmalariaatdelivery(OR1.39;95%CI,1.14–1.69;2studies,2903participants)(Fig.9).

In addition, moderate certainty evidence on the prevalence ofmaternalanemiaatdelivery(hemoglobin<11g/dL)indicatesISTwithDPprobablymakeslittletonodifferencetomaternalanemia(OR0.88;

F IGURE 3 Riskofbiassummary:dihydroartemisinin-piperaquinevssulphadoxine-pyrimethamineformalariapreventioninpregnancy.

| 7Olaleye eT al.

TABLE 2 GRADEsummaryoffindings:Three-dosedihydroartemisinin-piperaquinevsintermittentpreventivetreatmentwithsulphadoxine-pyrimethamine.

Out

com

es

Anti

cipa

ted

abso

lute

effe

ctsa (9

5% C

I)Re

lativ

e eff

ect

(95%

CI)

No.

of

parti

cipa

nts

(stu

dies

)Ce

rtai

nty

of th

e

evid

ence

(GRA

DE)

bCo

mm

ents

Risk

with

sulp

hado

xine

- py

rimet

ham

ine

Risk

with

dih

ydro

arte

mis

inin

- pi

pera

quin

e (3

dos

es)

Clin

ical

mal

aria

dur

ing

pregnancy

302per1000

68per1000(41to111)

OR

0.17

(0.10–0.29)

200(1RCT)

⨁⨁

⨁◯

MODERATE

c,d,e,f

Dihydroartemisinin-piperaquine(3doses)

appearstoresultinalargereductionin

clinicalmalariaduringpregnancy

Placentalmalaria

335per1000

269per1000(201to348)

OR

0.73

(0.50–1.06)

1231(2RCTs)

⨁⨁

⨁◯

MODERATE

c,d,e


likelyresultsinasmallpossiblyunimpor-

tanteffectinplacentalmalaria

Maternalperipheral

malariaatdelivery

95per1000

28per1000(16to47)

OR

0.27

(0.15–0.47)

1231(2RCTs)

⨁⨁

⨁◯

MODERATE

c,d,e


likelyreducesmaternalperipheralmalaria

atdelivery.

Maternalanemia

assessedwithhemo-

globinconcentration

285per1000

231per1000(193to273)

OR

0.75

(0.60–0.94)

1031(1RCT)

⨁⨁

⨁◯

MODERATE

d,e,f,g


appearstoreducematernalanemia

slightly

Prevalenceoflowbirth

weight

52per1000

61per1000(38to97)

OR

1.20

(0.73–1.97)

1231(2RCTs)

⨁⨁

◯◯

LO

Wc,e,h


appearstoresultinlittletonodifference

inprevalenceoflowbirthweight

Maternalseriousadverse

events(SAEs)

151per1000

70per1000(49to100)

OR

0.42

(0.29–0.62)

1231(2RCTs)

⨁⨁

◯◯

LO

Wc,e,i,j


mayreducematernalseriousadverse

events

Adversebirthoutcomes

assessedwithSGA/

LBW/pretermbirth/

fetalloss

118per1000

111per1000(81to151)

OR

0.94

(0.66–1.34)

1231(2RCTs)

⨁⨁

◯◯

LO

Wc,e,h,i


appearstoresultinlittletonodiffer-

enceintheincidenceofadversebirth

outcomes

Abbreviations:CI,confidenceinterval;OR,oddsratio;RCT,randomizedcontrolledtrial.

a Theriskintheinterventiongroup(andits95%confidenceinterval)isbasedontheassumedriskinthecomparisongroupandtherelativeeffectoftheintervention(andits95%CI).

b GRADEWorkingGroupgradesofevidence:H

igh

cert

aint

y:Weareveryconfidentthatthetrueeffectliesclosetothatoftheestimateoftheeffect.

Mod

erat

e ce

rtai

nty:Wearemoderatelyconfidentintheeffect

estimate:Thetrueeffectislikelytobeclosetotheestimateoftheeffect,butthereisapossibilitythatitissubstantiallydifferent.

Low

cert

aint

y:Ourconfidenceintheeffectestimateislimited:Thetrueeffectmay

besubstantiallydifferentfromtheestimateoftheeffect.

Very

low

cer

tain

ty:Wehaveverylittleconfidenceintheeffectestimate:Thetrueeffectislikelytobesubstantiallydifferentfromtheestimateofeffect.

c Riskofbias:downgradedby1.Drugcompliancepartiallyassesseddirectly,asadministrationwasobservedforonlythefirstofthreedosespercourse.

d Noseriousriskofinconsistency.

e Noseriousriskofindirectness:thestudypopulation,interventionsandmethodsareappropriateforthereviewquestion.

f Noseriousriskofimprecision.

g Riskofbias:downgradedby1.DrugcomplianceforDPpartiallyassesseddirectly,asadministrationwasobservedononlythefirstof3dayspercourse.

h Imprecision:downgradedby1.Thereisuncertaintyaboutthemagnitudeofeffectoftheintervention,asitfailstoexcludebenefitorharm.

i Inconsistency:downgradedby1.Theeffectisnotconsistentacrossthetrials,thoughstatisticalheterogeneityislow.

j Imprecision:downgradedby1.Onestudy(Kakuruetal.,

232016)showedasmallnumberofeventswithwide95%confidenceintervals.

8 | Olaleye eT al.

TABLE 3 GRADEsummaryoffindings:Monthlydihydroartemisinin-piperaquinevsintermittentpreventivetreatmentwithsulphadoxine-pyrimethamine.

Out

com

es

Anti

cipa

ted

abso

lute

effe

ctsa (9

5% C

I)Re

lativ

e eff

ect

(95%

CI)

No.

of

parti

cipa

nts

(stu

dies

)Ce

rtai

nty

of th

e ev

iden

ce (G

RAD

E)b

Com

men

tsRi

sk w

ith su

lpha

doxi

ne-

pyrim

etha

min

eRi

sk w

ith d

ihyd

roar

tem

isin

in-

pipe

raqu

ine

(mon

thly

dos

e)

Clin

ical

mal

aria

dur

ing

pregnancy

302per1000

4per1000(0to76)

OR

0.01

(0.00–0.19)

206(1RCT)

⨁⨁

⨁◯

MODERATE

c,d,e

Dihydroartemisinin-piperaquine(monthly

dose)probablyresultsinalargereduction

inclinicalmalariaduringpregnancy

Placentalmalaria

462per1000

261per1000(165to389)

OR

0.41

(0.23–0.74)

206(1RCT)

⨁⨁

⨁◯

MODERATE

c,d,e,f


dose)probablyreducesplacentalmalaria

Maternalperipheral

malariaatdelivery

47per1000

4per1000(0to77)

OR

0.09

(0.01–1.68)

206(1RCT)

⨁⨁

⨁◯

MODERATE

c,d,f,g


dose)probablyresultsinlittletonodif-

ferenceinmaternalperipheralmalariaat

deliv

ery

Maternalanae-

miaassessed

with:Hemoglobin

concentration

349per1000

238per1000(173to311)

OR

0.58

(0.39–0.84)

527(1RCT)

⨁⨁

⨁◯

MODERATE

c,d,e,f


dose)resultsinreductioninmaternal

anem

ia


weight

132per1000

80per1000(34to179)

OR

0.57

(0.23–1.43)

206(1RCT)

⨁⨁

⨁◯

MODERATE

c,d,f,g


dose)likelyresultsinlittletonodifference

inprevalenceoflowbirthweight

Adverseevents

-Maternalserious

adverseevents

57per1000

40per1000(11to132)

OR0.69

(0.19–2.54)

206(1RCT)

⨁⨁

⨁◯

MODERATE

c,d,f,g


dose)probablyresultsinlittletonodiffer-

enceinadverseevents-Maternalserious

adverseevents

Adverseevents—

Adversebirth

outcomes

179per1000

89per1000(40to188)

OR

0.45

(0.19–1.06)

206(1RCT)

⨁⨁

⨁◯

MODERATE

c,d,e,f


dose)resultsinasmallpossiblyunimpor-

tanteffectonadversebirthoutcomes




igh

cert

aint


Mod

erat

e ce

rtai



Low

cert

aint



Very

low

cer

tain


c Noseriousriskofbias:therewaslittlelosstofollow-up,withadequatelydescribedrandomsequencegenerationandallocationconcealment.

d Noseriousriskofindirectness:patients,interventions,methods,andoutcomewereappropriateforthereviewquestion.

e Imprecision:downgradedby1.Theresultsarefromonestudywithasmallsamplesize.

f Noseriousriskofinconsistency:theoutcomewasreportedacrossallgroups.

g Riskofimprecision:downgradedby1.Thereisuncertaintyaboutthemagnitudeofeffectoftheintervention.

| 9Olaleye eT al.

TABLE 4 GRADEsummaryoffindings:Intermittentscreeningandtreatmentwithdihydroartemisinin-piperaquinevsintermittentpreventivetreatmentwithsulphadoxine-pyrimethamine.

Out

com

es

Anti

cipa

ted

abso

lute

effe

ctsa (9

5% C

I)

Rela

tive

effec

t (9

5% C

I)

No.

of

parti

cipa

nts

(stu

dies

)Ce

rtai

nty

of th

e ev

iden

ce (G

RAD

E)b

Com

men

tsRi

sk w

ith su

lpha

doxi

ne-

pyrim

etha

min

e

Risk

with

di

hydr

oart

emis

inin

- pi

pera

quin

e (in

term

itten

t sc

reen

ing

and

trea

tmen

t)

Clin

ical

mal

aria

dur

ing

pregnancy

423per1000

457per1000(389to525)

OR1.15(0.87–1.51)

803(2RCTs)

⨁⨁

◯◯

LO

Wc,d,e,f

Dihydroartemisinin-piperaquine(intermittent

screeningandtreatment)mayresultinlittleto

nodifferenceinclinicalmalariaduringpregnancy

Placentalmalaria

307per1000

363per1000(327to399)

OR1.29(1.10–1.50)

2903(2RCTs)

⨁⨁

⨁⨁

HIGHc,e,g,h


screeningandtreatment)doesnotreduce

placentalmalaria

Maternalperipheral

malariaatdelivery

145per1000

190per1000(162to222)

OR1.39(1.14–1.69)

2903(2RCTs)

⨁⨁

⨁⨁

HIGHc,e,g,h


screeningandtreatment)doesnotreduce

maternalperipheralmalariaatdelivery

Maternalanemia

assessedwithhemo-

globinconcentration

257per1000

233per1000(204to265)

OR0.88(0.74–1.04)

2903(2RCTs)

⨁⨁

⨁◯

MODERATE

c,e,g,i


screeningandtreatment)likelyresultsinasmall

possiblyunimportanteffectinmaternalanemia


weight

65per1000

81per1000(62to104)

OR1.27(0.96–1.68)

2903(2RCTs)

⨁⨁

⨁◯

MODERATE

e,g,h,j

Dihydroartemisinin-piperaquine(intermit-

tentscreeningandtreatment)likelydoesnot

reduceprevalenceoflowbirthweight

Maternalserious

adverseevents

90per1000

86per1000(68to109)

OR0.96(0.74–1.24)

2903(2RCTs)

⨁⨁

⨁◯

MODERATE

c,e,g,k


screeningandtreatment)probablyreduces

maternalseriousadverseeventsslightly

Adversebirth

outcomes

214per1000

236per1000(206to269)

OR1.13(0.95–1.35)

2903(2RCTs)

⨁⨁

⨁◯

MODERATE

e,g,h,l

Dihydroartemisinin-piperaquine(intermit-

tentscreeningandtreatment)likelydoesnot

reduceadversebirthoutcomes




igh

cert

aint


Mod

erat

e ce

rtai



Low

cert

aint



Very

low

cer

tain


c Noseriousriskofbias:therewaslittlelosstofollow-up,withadequatelydescribedrandomsequencegenerationandallocationconcealment.

d Inconsistency:downgradedby1.Thereisminimaloverlapofconfidenceintervals,andconsiderableheterogeneity(I

2 =86%,P=0.007).

e Noseriousriskofindirectness:thestudypopulation,interventions,andmethodswereappropriateforthereviewquestion.

f Riskofimprecision:downgradedby1.Thereisuncertaintyaboutthemagnitudeofeffect,astheinterventioneitherreducesriskofclinicalmalariaduringpregnancy(by0.13)orincreasesit(by0.51).

g Noseriousriskofinconsistency:nostatisticallysignificantheterogeneity.

h Noseriousriskofimprecision:thenumberofeventswereadequate,witharelativelynarrow95%confidenceintervalaroundtheestimateofeffect.

i Riskofimprecision:downgradedby1.Thereisuncertaintyaboutthemagnitudeofeffect,astheinterventioneitherreducesriskofanemia(by0.26)orincreasesit(by0.04).

j Riskofbias:downgradedby1.Inonestudy,morethan10%oftherandomizedsubjectsdidnotcontributetotheanalysisoflowbirthweight.

k Riskofimprecision:downgradedby1.Thereisuncertaintyaboutthemagnitudeofeffect,astheinterventioneitherreducesriskofmaternalseriousadverseevents(by0.26)orincreasesit(by0.24).

l Riskofbias:downgradedby1.Inonestudy,morethan10%oftherandomizedsubjectsdidnotcontributetotheanalysisofneonatalmorbidity(compositeofsmallforgestationalage,pretermbirth,andlow

birthweight).

10 | Olaleye eT al.

95%CI0.74–1.04;2studies,2903participants)(Supplementaryinfor-mationFig.S9).

Comparing theoccurrenceof lowbirthweightbetweenwomenwhoreceivedIST-DPandthosewhoreceivedIPT-SP,moderatecer-tainty evidence indicates IST with DP probably makes little to nodifferencetoprevalenceoflowbirthweight(OR1.27;95%CI,0.96–1.68;2studies,2903participants)(Fig.10).

Moderate certainty evidence shows that ISTwithDP comparedwithIPT-SPprobablymakeslittletonodifferencetomaternalseriousadverseevents(OR0.96;95%CI,0.74–1.24;2studies,2903partici-pants)(SupplementaryinformationFig.S10).

Regarding adverse birth outcomes, moderate certainty evi-dence suggests that ISTwithDPcomparedwith IPT-SPprobablymakeslittletonodifferencetoadversebirthoutcomes(OR1.13;95%CI, 0.95–1.35; 2 studies, 2903 participants) (SupplementaryinformationFig.S10).

4 | DISCUSSION

Malariainpregnancycausescomplicationsinalltrimestersofpreg-nancy.IntermittentpreventivetreatmentwithSPiscurrentlyused

F IGURE 4 Dihydroartemisinin-piperaquine(3doses)vssulphadoxine-pyrimethamine.Clinicalmalariaduringpregnancy.

F IGURE 5 Dihydroartemisinin-piperaquine(3doses)vssulphadoxine-pyrimethamine.Maternalanemiaatdelivery.

F IGURE 6 Dihydroartemisinin-piperaquine(monthly)vssulphadoxine-pyrimethamine.Clinicalmalariaduringpregnancy.

F IGURE 7 Dihydroartemisinin-piperaquine(monthly)vssulphadoxine-pyrimethamine.Placentalmalaria.

| 11Olaleye eT al.

inSub-SaharanAfricaasacost-effectivechemopreventiveinterven-tionformalariainpregnancywithbeneficialmaternalandfetalout-comes.TherearefewcompletedrandomizedtrialsofACTregimens,includingDP,asapossiblealternativedrugformalariapreventioninpregnancy,despitereportsofincreasingIPT-SPresistance.WhilethissystematicreviewfoundonlytwopublishedtrialsthatassessedtheuseofDPforIPTpincomparisonwithSP,12,23asearchofmajorclinicaltrialregistersindicatesthattherearethreeongoingtrialsofACT regimens for IPTp. Two published trials compared IST usingDP(IST-DP)withIPT-SP.12,19Anoverviewofinterventionsforthepreventionofmalaria inpregnancyreportedthreepublishedtrialsofACTs involvingDPaseither IPTor IST,andsuggestedDPasapotentialalternativetoIPT-SP.24

Thethreestudiesincludedinthisreviewinvolvedatotalof3719participants.TwoofthetrialswereconductedinEastAfrica,andoneinSouthernAfrica.Oneofthethreestudiesincludedintheanalysiswasassessedashaving“unclear’’overallriskofbias.Therewasunclearriskofbiasinthedomainof“blinding”(detectionbias),withthestudy

contributing data to all the outcomes, exceptmaternal anemia andmaternaladverseeventsinthethree-doseDPgroup.

ModeratetohighcertaintyevidenceindicatesthatcomparedwithIPT-SP,thethree-doseandmonthlyDPregimensappeartoresultinasignificantreduction inclinicalmalariaduringpregnancy.The longerhalf-lifeofDP,inadditiontothepost-treatmentprophylaxisprovidedbyACTsingeneral,couldcontributetothisfinding.StudiesfromEastandSouthernAfricahavereportedhighlevelsofSPresistance,withprevalenceofP. falciparumquintuplemutationsnearingfixation lev-els, and some sextuple mutations.10,25–27 Despite the resistance toSP, previous studies have shown that it is effective in reducing theincidence of clinicalmaternalmalaria and placental infection.28,29 Itisunclearwhethertheeffectsizeofotheroutcomesassessedinthisreviewwould vary significantly with respect to marked differencesinSPresistance.

TheeffectofDPonreductionofplacentalmalaria infectionwassignificant formonthlyDPdosing,however thiseffectwasnot rep-licated in theotherDPapproaches, i.e. the three-dose regimenand

F IGURE 8 Dihydroartemisinin-piperaquine(intermittentscreeningandtreatment)vssulphadoxine-pyrimethamine(IPT).Placentalmalaria.

F IGURE 9 Dihydroartemisinin-piperaquine(intermittentscreeningandtreatment)vssulphadoxine-pyrimethamine(IPT).Maternalperipheralparasitemiaatdelivery.

F IGURE 10 Dihydroartemisinin-piperaquine(intermittentscreeningandtreatment)vssulphadoxine-pyrimethamine(IPT).Lowbirth weightprevalence.

12 | Olaleye eT al.

IST.ModeratecertaintyevidencesuggeststhatlimitingthenumberofpreventivetreatmentswithDPtothreescheduleddosesthroughoutagivenpregnancy likelyresults inasmalleffect inplacentalmalariareduction while high certainty evidence indicates IST-DP does notreduce placental malaria. The fact thatwomen onmonthly DP arelikely to receivemoredosesof thedrug fromtheperiodof recruit-menttilldelivery,comparedwithwomeninotherinterventiongroups,maybe responsible for this finding.However, themethods used todetectplacentalmalariabythe includedstudiescomprisedmethodsthat reflectedbothpast andpresent infection.Thoughanoverviewof interventions to preventmalaria in pregnancy suggested a lowerriskofactiveplacentalmalaria infectionswiththreeor fourcoursesof IPT-DP,24 this associationwas not supportedwith any certaintyof evidence.

Low certainty evidence indicated little to no difference in theprevalence of lowbirthweightwhen the three-doseDP regimen,andmoderatecertaintyevidencewhenmonthlyDP,wascomparedwithSP.IST-DPdidnotimprovebirthweight,asindicatedbymoder-atecertaintyevidence.TheeffectofDPonadversebirthoutcomes(pretermbirth,lowbirthweight,andsmallforgestationalage)wasalsominimal.

IncomparisonwithIPT-SP,IST-DPmadelittleornodifferencetomostmaternalandfetaloutcomes,exceptthat itprobably increasestheriskofplacentalmalariacomparedwithIPT-SP.

Overall,moderatecertaintyevidenceshowsthatIPT-DPisproba-blymoreeffectivethanIPT-SPaspreventivetreatmentformalariainpregnancy;butIST-DPisprobablynoteffective.

Thisreviewusedacomprehensivesearchstrategydevelopedbyoneoftheauthorsandhadtwoteammembersindependentlyscreenidentifiedstudiesforeligibility.Althoughtheaimwastobecompre-hensive,somestudiesmighthavebeenmissedbecausetimedidnotpermithandsearchingofall thegrey literature.Tworeviewauthorsconducted independentdataextractionand riskofbias assessmentofincludedstudies.

Inconclusion, theefficacyofDPasapotentialagentfor IPTformalariainpregnancyreportedinthisreviewislimitedbyfewstudiesandmoderatecertaintyoftheevidence.Althoughalsolimitedbyfewstudies,thereismoderatetohighcertaintyofevidencethattheuseofDPfor ISTofmalaria isnotsuperiorto IPT-SP.Thefindingsfromthestudies included in this review indicate that furtherhigh-qualityresearchwith largenumbersofparticipants, in settingsendemic formalariainfection,isneededtoprovidereliableevidenceforpolicyandpracticerecommendations.

AUTHOR CONTRIBUTIONS

AOwrotethedraftofthebackgroundandthemethodssection,whileBO andOO reviewed the draft. EE developed the search strategyandconductedtheliteraturesearch.AOandBOconductedeligibilityscreeningwhileAOandOOperformedthedataextraction.AOandEEconductedthedataanalysisandGRADEassessment.ThedraftofthereviewwaswrittenbyAOwhileEE,OO,BO,andMMsupervisedthe review process and commented on drafts of the protocol and

thereview.Allreviewauthorssubsequentlymodifiedthereviewandagreedtothecontentsofthefinalversion.

CONFLICTS OF INTEREST

Theauthorshavenoconflictsofinteresttodeclare.

REFERENCES

1. DesaiM,terKuileFO,NostenF,etal.Epidemiologyandburdenofmalariainpregnancy.Lancet Infectious Diseases. 2007;7:93–104.

2. Walker PGT, ter Kuile FO, Garske T, Menendez C, Ghani AC.EstimatedriskofplacentalinfectionandlowbirthweightattributabletoPlasmodium falciparummalariainAfricain2010:Amodellingstudy.Lancet Global Health.2014;2:e460–e467.

3. SchultzLJ,SteketeeRW,MachesoA,etal.Theefficacyofantima-larialregimenscontainingsulfadoxine-pyrimethamineand/orchloro-quine inpreventingperipheral andplacentalPlasmodium falciparum infection among pregnant women in Malawi. Am J Trop Med Hyg. 1994;51:515–522.

4. ShulmanCE,DormanEK,CuttsF, et al. Intermittent sulphadoxine-pyrimethamine to prevent severe anemia secondary to malariain pregnancy: A randomised placebo-controlled trial. Lancet. 1999;353:632–636.

5. WorldHealthOrganization.Astrategicframeworkformalariapreven-tionandcontrolduringpregnancyintheAfricanRegion.WorldHealthOrganizationRegionalofficeforAfrica.2004;AFR/MAL/04/01.

6. WilsonNO,CeesayFK,ObedSA,etal.Intermittentpreventivetreat-mentwithsulfadoxine-pyrimethamineagainstmalariaandanemiainpregnantwomen.Am J Trop Med Hyg. 2011;85:12–21.

7. BarakaV, IshengomaDS,FransisF,etal.High-levelPlasmodium fal-ciparum sulfadoxine-pyrimethamine resistance with the concomi-tantoccurrenceofseptuplethaplotype inTanzania.Malaria Journal. 2015;14:439.

8. BassatQ,MulengaM,TintoH,etal.Dihydroartemisinin-piperaquineand artemether-lumefantrine for treating uncomplicated malariain african children: A randomised, non-inferiority trial. PLoS ONE. 2009;4:e7871.

9. GutmanJ,KalilaniL,TaylorS,etal.TheA581Gmutationinthegeneencoding Plasmodium falciparumdihydropteroatesynthetasereducesthe effectiveness of sulfadoxine-pyrimethamine preventive therapyinMalawianpregnantwomen.J Infect Dis. 2015;211:1997–2005.

10. Iriemenam NC, Shah M, Gatei W, et al. Temporal trends ofsulphadoxine-pyrimethamine(SP)drug-resistancemolecularmarkersin Plasmodium falciparumparasitesfrompregnantwomeninwesternKenya.Malar J. 2012;11:134.

11. BenjaminJM,MooreBR,SalmanS,etal.Populationpharmacokinet-ics, tolerability, and safety of dihydroartemisinin-piperaquine andsulfadoxine-pyrimethaminepiperaquine in pregnant and nonpreg-nant Papua New Guinean women. Antimicrob Agents Chemother. 2015;59:4260–4271.

12. Desai M, Gutman J, L'lanziva A, et al. Intermittent screening andtreatmentorintermittentpreventivetreatmentwithdihydroartemis-inin–piperaquineversusintermittentpreventivetreatmentwithsulf-adoxine–pyrimethamineforthecontrolofmalariaduringpregnancyinwesternKenya:Anopen-label,three-group,randomisedcontrolledsuperioritytrial.Lancet.2015;386:2507–2519.

13. GonzálezR,Mombo-NgomaG,OuédraogoS,etal.Intermittentpre-ventive treatmentofmalaria inpregnancywithmefloquine inHIV-negativewomen:Amulticentrerandomizedcontrolledtrial.PLoS Med. 2014;11:e1001733.

14. WorldHealthOrganization.Guidelines for the treatment of malaria,3rdedn.Geneva:WHO;2015.

| 13Olaleye eT al.

15. Smithuis F, Kyaw MK, Phe O, et al. Efficacy and effectiveness ofdihydroartemisinin-piperaquine versus artesunate-mefloquine infalciparum malaria: An open-label randomised comparison. Lancet. 2006;367:2075–2085.

16. ZongoI,MilliganP,CompaoreYD,etal.Randomizednon-inferioritytrial of dihydroartemisinin-piperaquine comparedwith sulfadoxine-pyrimethamineplusamodiaquineforSMCinBurkinaFaso.Antimicrob Agents Chemother.2015;59:4387–4396.

17. PekyiD,AmpromfiAA,TintoH,etal.Fourartemisinin-basedtreat-ments in African pregnant women with malaria. N Engl J Med. 2016;374:913–927.

18. RijkenMJ,McGready R, PhyoAP, et al. Pharmacokinetics of dihy-droartemisininandpiperaquineinpregnantandnonpregnantwomenwithuncomplicatedfalciparummalaria.Antimicrob Agents Chemother. 2011;55:5500–5506.

19. Madanitsa M, Kalilani L, Mwapasa V, et al. Scheduled intermit-tent screening with rapid diagnostic tests and treatment withdihydroartemisinin-piperaquine versus intermittent preventivetherapy with sulfadoxine-pyrimethamine for malaria in pregnancyin Malawi: An open-label randomized controlled trial. PLoS Med. 2016;13:e1002124.

20. HigginsJPT,GreenS.CochraneHandbookforSystematicReviewsof Interventions. Version 5.1.0. The Cochrane Collaboration,2011. http://www.cochrane-handbook.org. Accessed December5,2017.

21. MoherD,LiberatiA,TetzlaffJ,AltmanDG;PRISMAGroup.Preferredreporting items for systematic reviews and meta-analysis: ThePRISMAStatement.PLoS Med.2009;6:e1000097.

22. GuyattGH,OxmanAD,VistGE,etal.GRADE:Anemergingconsen-susonratingqualityofevidenceandstrengthofrecommendations.BMJ.2008;336:924–926.

23. KakuruA, Jagannathan P,MuhindoMK, et al. Dihydroartemisinin-piperaquineforthepreventionofmalariainpregnancy.N Engl J Med. 2016;374:928–939.

24. DesaiM,HillJ,FernandesS,etal.Preventionofmalariainpregnancy.Lancet Infect Disease. 2018;18:e119–e132.

25. MbonyeAK,Biringi J,YanowSK, et al. Prevalence ofPlasmodium falciparum resistance markers to sulfadoxine-pyrimethamineamong pregnant women receiving intermittent preventive treat-ment for malaria in Uganda. Antimicrob Agents Chemother. 2015;59:5475–5482.

26. Koukouikila-Koussounda F, Bakoua D, Fesser A, Nkombo M,Vouvoungui C, Ntoumi F. High prevalence of sulphadoxine-pyrimethamine resistance-associatedmutations inPlasmodium falci-parumfieldisolatesfrompregnantwomeninBrazzaville.Republic of Congo. Infect Genet Evol.2015;33:32–36.

27. Matondo SI, Temba GS, Kavishe AA. High levels of sulphadoxine-pyrimethamineresistancePfdhfr-Pfdhpsquintuplemutations:AcrosssectionalsurveyofsixregionsinTanzania.Malar J. 2014;13:152.

28. WalkerPGT,FloydJ,terKuileF,CairnsM.Estimatedimpactonbirthweightofscalingupintermittentpreventivetreatmentofmalaria in

pregnancygivensulphadoxine-pyrimethamineresistanceinAfrica:Amathematicalmodel.PLoS Med. 2017;14:e1002243.

29. Desai M, Gutman J, Taylor SM, et al. Impact of sulfadoxine-pyrimethamineresistanceoneffectivenessofintermittentpreventivetherapyformalariainpregnancyatclearinginfectionsandpreventinglowbirthweight.Clin Infect Dis.2015;62:323–333.

SUPPORTING INFORMATION

Additional supporting information may be found online in theSupportingInformationsectionattheendofthearticle.

Figure S1. Dihydroartemisinin-piperaquine (3 doses) versussulphadoxine-pyrimethamine.Placentalmalaria.

Figure S2.Dihydroartemisinin-piperaquine(3doses)versussulphadoxine-pyrimethamine.Maternalperipheralparasitemiaatdelivery.

Figure S3. Dihydroartemisinin-piperaquine (3 doses) versussulphadoxine-pyrimethamine.Lowbirthweightprevalence.

Figure S4. Dihydroartemisinin-piperaquine (3 doses) versussulphadoxine-pyrimethamine. Adverse events (maternal seriousadverseeventsandadversebirthoutcomes).

Figure S5.Dihydroartemisinin-piperaquine(monthly)versussulphadoxine-pyrimethamine.Maternalperipheralparasitemiaatdelivery.

Figure S6. Dihydroartemisinin-piperaquine (monthly) versussulphadoxine-pyrimethamine.Lowbirthweightprevalence.

Figure S7. Dihydroartemisinin-piperaquine (monthly) versussulphadoxine-pyrimethamine. Adverse events (Maternal seriousadverseeventsandadversebirthoutcomes).

Figure S8.Dihydroartemisinin-piperaquine(intermittentscreeningandtreatment)versussulphadoxine-pyrimethamine(IPT).Clinicalmalariaduringpregnancy.

Figure S9.Dihydroartemisinin-piperaquine (intermittentscreeningandtreatment)versussulphadoxine-pyrimethamine(IPT).Maternalanemia.

Figure S10. Dihydroartemisinin-piperaquine (intermittent screeningand treatment) versus sulphadoxine-pyrimethamine (IPT). (Maternalseriousadverseeventsandadversebirthoutcomes).

Table S1.Characteristicsofexcludedstudies.

http://www.cochrane-handbook.org

a systematic review and meta‐analysis of ...€¦ · of plasmodium falciparuminfectionhave...

Documents