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Malaria during Pregnancy

Michal Fried and Patrick E. Duffy

Laboratory of Malaria Immunology and Vaccinology, NIAID, NIH, Bethesda, MD 20892

Correspondence: [email protected]; [email protected]

One hundred and twenty-five million women in malaria-endemic areas become pregnanteach year (see Dellicour et al. PLoS Med 7: e1000221 [2010]) and require protection frominfection to avoid disease and death for themselves and their offspring. Chloroquine prophy-laxis was once a safe approach to prevention but has been abandoned because of drug-resistant parasites, and intermittent presumptive treatment with sulfadoxine–pyrimeth-amine, which is currently used to protect pregnant women throughout Africa, is rapidlylosing its benefits for the same reason. No other drugs have yet been shown to be safe,tolerable, and effective as prevention for pregnant women, although monthly dihydroarte-misinin–piperaquine has shown promise for reducing poor pregnancy outcomes. In-secticide-treated nets provide some benefits, such as reducing placental malaria and lowbirth weight. However, this leaves a heavy burden of maternal, fetal, and infant morbidityand mortality that could be avoided. Women naturally acquire resistance to Plasmodiumfalciparum over successive pregnancies as they acquire antibodies against parasitized redcells that bind chondroitin sulfate A in the placenta, suggesting that a vaccine is feasible.Pregnant women are an important reservoir of parasites in the community, and women ofreproductive age must be included in any elimination effort, but several features of malariaduring pregnancy will require special consideration during the implementation of elimina-tion programs.

Pregnant women and women of childbearingage will require special consideration during

mass campaigns for malaria elimination. Ma-laria susceptibility increases during pregnancy,making these women an important parasite res-ervoir in the community. Meanwhile, the biol-ogy and clinical presentations of Plasmodiumfalciparum in semi-immune women interferewith diagnosis during pregnancy, renderingtargeted interventions ineffective for control(Fig. 1). Furthermore, concerns for teratogenic-ity and embryotoxicity complicate the proposedapplication of any drugs, vaccines, or antivector

measures among women of reproductive age,greatly hindering mass campaign planning.For example, primaquine is the leading drugbeing assessed as a gametocytocidal agent toblock parasite transmission to mosquitoes, butis contraindicated in pregnancy because the glu-cose-6-phosphate dehydrogenase status andhence hemolysis risk of the fetus would be un-known. This chapter reviews malaria duringpregnancy, including its epidemiology and dis-ease burden, molecular pathogenesis, naturallyacquired immunity and potential for vaccines,diagnostic dilemmas, and drugs being used or

Editors: Dyann F. Wirth and Pedro L. Alonso

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considered for prevention and treatment, to en-vision future approaches for malaria elimina-tion that might be applied to women who maybe pregnant.

EPIDEMIOLOGY AND BURDEN OF DISEASE

Pregnancy malaria looks verydifferent inareas oflow and unstable transmission versus high andstable transmission, although overall diseaseburden in different transmission zones may besimilarly heavy in the absence of preventive

measures. Where malaria transmission is lowand unstable, women are infected infrequentlybut therefore have low immunity and often rap-idly progress to severe disease syndromes wheninfected. These women have higher risks of se-vere malaria and death than their nonpregnantcounterparts during P. falciparum infection(Duffy and Desowitz 2001) and are more likelyto develop syndromes like respiratory distress andcerebralmalaria(Nostenetal.1991). In low trans-mission areas, women of all parities have in-creased susceptibility to malaria (Nosten et al.

Capillary

CapillaryCT

ST CSA

Infectederythrocytes

VAR2CSA

CD36

ICAMPfEMP-1

Endothelialcell

Endothelialcell

Intervillous space

Intervillous space

PlacentaICAM-1

ICAM-1

CD36

Cord blood

Capillary

Peripheral blood

Peripheral blood

In semi-immune women, lifelong exposure toP. falciparum parasites has induced immunity thatcontrols infection with common parasite phenotypes,such as parasites expressing PfEMP1 variants thatbind CD36 on endothelium in the peripheralvasculature. Hence, total parasite biomass may below and difficult to diagnose with standard tools suchas bloodsmear microscopy, even in the presence ofconsiderable placental infection. Possibly as a result,efforts to target treatment to pregnant women basedon malaria diagnoses have generally failed as acontrol strategy, and control has relied on mass drugadministration programs.

In the placenta, infected erythrocytes (lEs)express the PfEMP1 variant VAR2CSA tobind chondroitin sulfate A (CSA) but notother common endothelial receptors such asCD36 or ICAM-1. First-time mothers lackimmunity to CSA-binding parasites and arehighly susceptible to parasitemia and tochronic infections, making this group animportant reservoir of infection in thecommunity. Over successive pregnancies,women can acquire antibodies againstCSA-binding lE and resistance to placentalmalaria, suggesting that a vaccine isfeasible.

Malaria during pregnancy takes its greatest toll on theoffspring, causing substantial perinatal mortality and, inpart due to low birth weight, significant infant mortality.Although congenital malaria can occur, convincingevidence for transplacental infection is lacking.The deployment of new drugs and vaccines in women ofreproductive age is hindered by safety concerns for thefetus. For example, the gametocytocidal drug primaquineis being explored at low doses as a mass administrationtool for elimination, but is contraindicated duringpregnancy owing to the risk of hemolysis inG6PD-deficient fetuses.

InfectedInfectederythrocyteserythrocytes

Infectederythrocytes

UninfectederythrocytesUninfected

erythrocytes

Figure 1. Malaria during pregnancy features several unique host–parasite interactions that require specialattention for elimination strategies. Although malaria is more common in pregnant women than other adults,it is difficult to diagnose and therefore to control. The few drugs known to be safe during pregnancy are losingefficacy to drug-resistant Plasmodium falciparum parasites, and the use of new drugs or other interventions ishindered by concerns for fetal safety. Based on the knowledge of malaria immunity during pregnancy, vaccineapproaches appear promising for the control of PM, but first-generation candidates are only now enteringclinical trials and it is unclear whether these products will interrupt malaria transmission in pregnant women.

M. Fried and P.E. Duffy

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1991). Women in these areas should be routinelyscreened and promptly treated for infection toprevent the risk of severe disease and death.

In areas of stable P. falciparum malariatransmission, where approximately 50 millionpregnancies occur each year, women are semi-immune and often carry their infections withfew or no symptoms. Disease for mother andoffspring often develops as an insidious process,and this can make it difficult to relate outcomessuch as severe maternal anemia or low birthweight (LBW) back to the infection that causedthese sequelae. In areas of stable transmission,primigravid women are at greatest risk, and oversuccessive pregnancies women naturally acquireresistance to P. falciparum that reduces parasitedensity and prevents disease. Resistance hasbeen associated with antibodies against the par-asitized red cells that bind chondroitin sulfate A(CSA) in the placenta (Fried et al. 1998a). Incommunities in which malaria control has im-proved and the incidence of malaria decreases,the incidence of P. falciparum pregnancy malar-ia also decreases, but malaria-specific antibod-ies wane and the parasite burden and sequelaeduring any individual infection increase (Mayoret al. 2015).

In areas of stable transmission, intervention-al studies have provided evidence to estimatethe burden of disease. Chemoprophylaxis withpyrimethamine/dapsone (Maloprim) in TheGambia provided significant benefits to primi-gravid (Greenwood et al. 1992) and grandmulti-gravid (parity .7) women (Greenwood et al.1989; Menendez et al. 1994): primigravidae onprophylaxis had lower rates of parasitemia andhigher hematocrits. The latter is an importanteffect, because maternal anemia increases risksof LBW, preterm delivery (PTD), perinatal mor-tality, and neonatal mortality in low- and mid-dle-income countries (Rahman et al. 2016). In arecent meta-analysis, chemoprevention reducedthe risk of moderate-to-severe maternal anemiain first- and second-time mothers by �40% inmalaria-endemic areas (Radeva-Petrova et al.2014); severe maternal anemia is a major riskfactor for maternal mortality when women suf-fer postpartum hemorrhage, a common eventin low-income countries (Tort et al. 2015).

Malaria prevention similarly improves childoutcomes, both before and after delivery. In ameta-analysis of interventional trials, relativerisk of perinatal mortality when mothers re-ceived prevention was 0.73 (95% CI, 0.53–0.99) (Garner and Gulmezoglu 2006). Effectiveprophylaxis reduces the risk of LBW newborns,and LBW is a strong predictor for infant mor-tality: extrapolating from this reduction inLBW, malaria prevention was estimated to re-duce the mortality of neonates born to Gambi-an primigravidae by 42%, and the postneonatalmortality by 18% (Greenwood et al. 1992). Inan observational birth cohort study, placentalmalaria (PM) in Tanzanian primigravidae wasdirectly related to increased postneonatal mor-tality: 9.3% mortality for offspring of infectedfirst-time mothers, compared with 2.6% for off-spring of uninfected first-time mothers (Duffyand Fried 2011). PM in multigravid women didnot significantly increase mortality risk of theiroffspring. In this community, the populationattributable risk percent (PAR%) of postneona-tal infant mortality owing to PM was 29.2% forfirst pregnancies.

The direct measurement of postneonatalmortality exceeds the estimates of mortalitythat would result from LBW, suggesting thatother PM-related mechanisms might contrib-ute to infant deaths. Several studies have relatedPM to increased risks of malaria infection(Schwarz et al. 2008; Goncalves et al. 2014)and to severe malaria (Goncalves et al. 2014)in offspring during infancy, but this relation-ship has not been observed in other studies(Awine et al. 2016). Interestingly, PM appearsto influence immune responses and milieu inthe offspring, which could influence their ma-laria susceptibility. Fetal sensitization to malariaantigens is common (Fievet et al. 1996; Kinget al. 2002; Malhotra et al. 2005). Some new-borns of infected mothers display a “tolerant”phenotype, and have an increased risk of infec-tion and lower hemoglobin levels during earlylife (Malhotra et al. 2009). Plasma cytokine lev-els at birth predict levels measured later duringinfancy, particularly for interleukin 1b (IL-1b)and tumor necrosis factor a (TNF-a), and alsopredict the risks of malaria infection and severe


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disease (Kabyemela et al. 2013); however, a re-lationship between PM and cord cytokine pro-files has not been defined. More work is neededto understand whether and how PM in themother may continue to influence malaria out-comes in her child.

Mixed malaria infections such as P. falcipa-rum and Plasmodium vivax might also alterpregnancy malaria outcomes, but many mixedinfections appear to be mono-infections whendiagnosed by peripheral blood smear (BS). P.vivax, like P. falciparum, is associated withpoor pregnancy outcomes, but, unlike P. falcip-arum, sequelae may be more common in mul-tigravid pregnancies (reviewed in Duffy 2001).Non-falciparum infections were infrequent anddid not appear to impact pregnancy outcomesin West Africa, where P. vivax was absent outsideMali (Williams et al. 2016). In P. vivax–endem-ic areas, women should be actively screened andtreated, but management is complicated be-cause primaquine is contraindicated due tofetal hemolysis risk and, therefore, liver hypno-zoite parasite forms remain and cause relapsesin the mother.

MOLECULAR PATHOGENESIS

In stable transmission zones, malaria duringpregnancy has a unique epidemiology charac-terized by parity-dependent susceptibility: pri-migravid women are infected more frequentlyand with higher placental parasite densitiesthan multigravid women. A prominent featureof P. falciparum malaria during pregnancy isthe accumulation of parasites in the placenta,whereas parasite density in the peripheral cir-culation is low or undetectable (Brabin 1983;McGregor 1984). For decades, the increasedsusceptibility to malaria during pregnancy wasattributed to immunological changes associatedwith pregnancy, but this could not explain thereduction in infection rate and placental para-site burden over successive pregnancies.

An alternative molecular model to explainparity-dependent susceptibility is based on theability of P. falciparum infected erythrocytes(IEs) to adhere to receptors on the vascular en-dothelium and thereby sequester in deep vascu-

lar beds. During pregnancy, IEs accumulate inthe intervillous spaces or bind to the surface ofthe syncytiotrophoblast in the placenta. In thismodel, the placenta presents a new receptor forIE adhesion, thereby selecting a parasite sub-population to which women are naıve beforetheir first pregnancy, making first-time mothersmost susceptible. Analyses of the binding pro-file of placental IE have shown that this parasitesubpopulation adheres to placental CSA, andnot to CD36, which commonly supports thebinding of IE from nonpregnant individuals(Fried and Duffy 1996). With successive preg-nancies, women develop specific antibodies toCSA binding and placental IEs that enable themto better control the infection (Fried et al.1998a); immunoepidemiology studies that sup-port this model are discussed below. Followingthe identification of CSA as the unique receptorthat supports parasite adhesion in the placenta,additional studies conducted at different siteshave confirmed this binding phenotype (Friedet al. 1998a, 2006; Beeson et al. 1999; Maubertet al. 2000; Muthusamy et al. 2007).

CSA is a glycosaminoglycan comprising re-peats of the disaccharide D-glucoronic acid andN-acetyl-D-galactosamine (GalNAc). CSA issulfated at the C4 position of GalNAc. Theclosely related glycosaminoglycans chondroitinsulfate B and chondroitin sulfate C do not sup-port placental IE adhesion. CSA chains vary intheir length and degree of sulfation, and furthercharacterization has shown that a low-sulfatedCSA (Achur et al. 2000; Alkhalil et al. 2000;Fried et al. 2000; Andrews et al. 2005) of at leastsix disaccharide repeats (Alkhalil et al. 2000) isoptimal to support placental IE adhesion.

IE sequestration in the placenta is followedby the accumulation of macrophages and B cellsin the intervillous spaces. The intensity of theinflammatory immune infiltrate varies betweenwomen and is inversely related to acquired im-munity: macrophages are more commonlyobserved in placentas from primigravidae wholack specific immunity to placental IE thanin those from multigravidae (Garnham 1938;Muehlenbachs et al. 2007).

The cytokine milieu in a healthy uninfectedplacenta displays a bias toward type 2 cytokines.



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PM leads to marked changes in the cytokinemilieu, including increased levels of TNF-a, in-terferon g (IFN-g), IL-10, monocyte chemoat-tractant protein 1, macrophage inflammatoryprotein 1 (MIP-1a and MIP-1b), CXC ligand8, CXC ligand 9, and CXC ligand 13 (Fried et al.1998b; Moormann et al. 1999; Abrams et al.2003; Chaisavaneeyakorn et al. 2003; Rogersonet al. 2003; Suguitan et al. 2003a,b; Kabyemelaet al. 2008; Dong et al. 2012). Increased levels ofthe cytokines TNF-a and IFN-g, and the che-mokine CXCL9 that is regulated by IFN-g, havebeen associated with LBW deliveries, especiallyamong primigravid women (Fried et al. 1998b;Rogerson et al. 2003; Kabyemela et al. 2008;Dong et al. 2012). Similarly, transcript levelsfor the chemokines CXCL13, CXCL9, andCCL18 negatively correlate with birth weight,and up-regulation of IL-8 and TNF-a transcrip-tion in the placenta has been associated withintrauterine growth retardation (Moormannet al. 1999; Muehlenbachs et al. 2007). Thesestudies support but do not prove that these in-flammatory mediators contribute to PM seque-lae. Animal models that reproduce placental se-questration and inflammation are needed formechanistic studies to better understand dis-ease pathogenesis.

IMMUNITY AND VACCINES

Parity-Dependent Acquisition of Antibodies

The unique epidemiology of pregnancy malariais characterized by parity-dependent suscepti-bility. Different approaches to evaluate parity-dependent humoral immunity have includedserum or plasma reactivity to the IE surface byflow cytometry, adhesion-blocking activity, ag-glutination of IE, and opsonizing activity (Table1). Regardless of assay, parity-dependent acqui-sition of antibody against placental parasites orCSA-binding laboratory isolates has been con-sistently observed across many studies. Levels ofantibodies that surface-react are higher in multi-gravidae compared with primigravidae in manydifferent countries (Fried et al. 1998a; Ricke etal. 2000; Staalsoe et al. 2001, 2004; Tuikue Ndamet al. 2004; Megnekou et al. 2005; Fievet et al.

2006; Feng et al. 2009; Aitken et al. 2010; Mayoret al. 2011). Adhesion-blocking antibody levelsare significantly higher among multigravid thanprimigravid women (Fried et al. 1998a; O’Neil-Dunne et al. 2001; Jaworowski et al. 2009; Ndamet al. 2015). Although agglutination of placentalparasites is uncommon (Beeson et al. 1999), theproportion of serum samples with agglutinat-ing antibodies was significantly higher amongmultigravidae than primigravidae (Beeson et al.1999; Maubert et al. 1999). Similarly, opsonicphagocytosis increased with parity (Keen et al.2007; Jaworowski et al. 2009). Thus, antibodiesto CSA-binding IE or placental parasites pro-vide a robust correlate of parity-dependent re-sistance, regardless of assay.

Antibodies to Placental Parasites andInfection Status or Infection Risk

Garnham (1938) described three phases of PMbased on histology. In the acute or active infec-tion phase, IE accumulate in the intervillousspaces. In the next phase, now called chronicinfection, maternal inflammatory cells accumu-late, notably monocytes–macrophages con-taining malaria pigment (hemozoin). After IEare cleared, parasite pigment remains in theintervillous fibrin, sometimes persisting formonths, depending on the parasite burden andcorresponding amount of pigment (McGreadyet al. 2002; Muehlenbachs et al. 2010). This lastphase of the infection is referred to as past in-fection. This chronology of PM is typical forprimigravidae, but not for multigravidae whousually clear placental parasites quickly and donot progress beyond the active infection phase.Poor outcomes related to PM, such as LBWandmaternal anemia, are most strongly associatedwith the chronic phase of infection (Ordi et al.1998; Ismail et al. 2000; Shulman et al. 2001;Muehlenbachs et al. 2010).

The relationship of antibodies to infectionstatus or infection risk has varied between stud-ies (Table 2). This may be due, in part, to theheterogeneous chronology of placental infec-tions, and in part to the effect of infection toboost antibodies. In three of four studies, anti-adhesion antibodies have been associated with a



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Table 1. Studies of naturally acquired antiparasite antibodies and parity

Reference/study

(year) Test Parasite tested

Plasma/sera

collected at n Results

Ricke et al. 2000 Surface proteinsby flow

CSA-selected Third trimester P: 30S: 30M: 103

Increase with parity

Staalsoe et al.2001, 2004

Surface proteinsby flow

CSA-selected Third trimester;delivery

P: 78S: 105


Megnekou et al.2005


CSA-selected Combined second–third trimesters

P: 101S/M: 114


Fievet et al. 2006 Surface proteinsby flow

Placentalparasites

Second trimester P: 62S: 50M: 153


Feng et al. 2009 Surface proteinsby flow

CSA-selected Second trimester P: 80S: 16M: 45


Aitken et al. 2010 Surface proteinsby flow

CSA-selected Second and thirdtrimesters

P: 131S: 108M: 310


Brolin et al. 2010 Surface proteinsby flow

CSA-selected Third trimester P: 189S: 21M: 72


Mayor et al. 2011 Surface proteinsby flow

CSA-selected,placentalparasites

Delivery P: 30M: 60

PM2: M . PPMþ: M . P for

placental isolates

Fried et al. 1998a Anti-adhesion Placentalparasites

Delivery P: 51S: 62M: 84


O’Neil-Dunneet al. 2001

Anti-adhesion CSA-selected During pregnancy P: 45S/M: 84

Increase with parityat gestational ageof 12–20 wk

Jaworowski et al.2009

Anti-adhesion CSA-selected Third trimester P: 44M: 29


Beeson et al.1999, 2004

Agglutination Placentalparasites

Second trimester P: 12M:12


Maubert et al.1999

Agglutination CSA-selected,placentalparasites

Delivery P: 13–76a

M: 17–143aPMþ: Increase with

parity for 2/4isolates

Keen et al. 2007 Opsonizingactivity

CSA-selected Postpartum P: 21M: 16


Jaworowski et al.2009

Opsonizingactivity

CSA-selected Third trimester P: 44M: 29


Feng et al. 2009 Opsonizingactivity

CSA-selected Second trimester P: 80S: 16M: 45


Only studies that analyzed more than five subjects per group are included.

P, Primigravidae; S, secundigravidae; M, multigravidae; PMþ, malaria-infected; PM2, uninfected; CSA, chondroitin

sulfate A.aNumber of plasma samples analyzed vary among tested isolates.



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Table 2. Studies of naturally acquired antiparasite antibodies and malaria infection status

Reference/study

(year) Test Parasite tested

Plasma/sera

collected at n Results

Staalsoe et al.2001


CSA-selected Thirdtrimester

P: 55M: 58

Multigravid: inverse correlationbetween Abs and parasitedensity

Staalsoe et al.2004


CSA-selected Delivery All 477 Chronic and past infection .

PM2 and acute infection,regardless of parity

Beeson et al.2004


CSA-selected Delivery P: 54M: 54

Primigravid: PMþ . PM2

Multigravid: no differences

Elliott et al. 2005 Surface proteinsby flow

CSA-selected Delivery P: 46M: 20

Primigravid: PMþ . PM2 forIgG1, IgG3


Ataide et al. 2010 Surface proteinsby flow


P: 268 Primigravid: PMþ . PM2

Ataide et al. 2011 Surface proteinsby flow


S: 187 Secundigravid: PMþ . PM2

Tutterrow et al.2012a


CSA-selected Second–thirdtrimester

Total 27 PM2 . PMþ

Mayor et al.2011, 2013


Placentalparasites

Delivery Total 293 Acute, chronic, and pastinfections . PM2, regardlessof parity

Fried et al. 1998 Anti-adhesion Placentalparasites

Delivery P: 29S: 68M: 46

Secundigravid: PM2 . PMþ

Primigravid: low activity, nodifferences

Multigravid: high activity, nodifferences

O’Neil-Dunneet al. 2001

Anti-adhesion CSA-selected Delivery Total 97 Inverse correlation between Absand placental parasite density

Beeson et al.2004

Anti-adhesion CSA-selected Delivery P: 54M: 54

Primigravid: PMþ . PM2


Ndam et al. 2015 Anti-adhesion CSA-selected Delivery Total 266 PM2 . PMþ

Beeson et al.2004

Agglutination CSA-selectedplacentalparasites

Delivery P:54M:54

Primigravid and multigravid:PMþ . PM2

Ataide et al. 2010 Opsonizingactivity


P:268 Primigravid: PMþ . PM2

Ataide et al. 2011 Opsonizingactivity


S: 187 Secundigravid: PMþ . PM2

PMþ, Placental malaria positive, defined by the presence of parasites in the placenta; PM2, no parasites or the evidence of

past infection by histology; CSA, chondroitin sulfate A.



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reduced risk of infection, or to reduced parasitedensities in infected women, supporting a rolein protection. Opsonizing activity, agglutinat-ing activity, and IE surface reactivity are elevatedduring and after an infection, which confoundsefforts to assess their relationship with pro-tection against infection. Because naturally ac-quired immunity to malaria controls infectionbut does not confer sterile resistance that com-pletely prevents infection, infections also occurin semi-immune multigravidae, and infectionboosts their antibody levels (Table 2). As a con-sequence, increased levels of antibodies, includ-ing those that agglutinate, opsonize, or react tothe surface of IE, can reflect current or recentexposure to the parasite and thereby confoundefforts to find correlates of protection (Ataideet al. 2010).

Immune Responses and PregnancyOutcomes

PM commonly leads to severe maternal anemiaand LBWdeliveries, especially among primigra-vidae. The association between naturally ac-quired antibodies and pregnancy outcomeshas been seen in some but not all studies, andnotably the target population and antibody as-say have differed between studies (Table 3).Among Kenyan women with chronic malaria,low serum reactivity to the surface of CSA-bind-ing laboratory IE was associated with lowerhemoglobin level and reduced birth weight(Staalsoe et al. 2004). Among 141 malaria-in-fected women in Malawi (Feng et al. 2009), se-rum reactivity to the IE surface during the sec-ond trimester was lower among the women whopresented with anemia (hemoglobin ,11 g/dL) at the time of delivery (Feng et al. 2009).Opsonic activity among malaria-infected se-cundigravid women in Malawi was associatedwith increased birth weight, and opsonic activi-ty was higher among nonanemic than anemicmalaria-infected multigravidae (Jaworowski etal. 2009; Ataide et al. 2011). Among Mozambi-can women who had been infected during preg-nancy, high serum reactivity to both placentaland children’s IE at the time of delivery wasassociated with increased birth weight and ges-

tational age (Mayor et al. 2013). In Kenya, levelsof anti-adhesion antibodies to placental IE wereassociated with increased birth weight and ges-tational age among offspring of secundigravi-dae (Duffy and Fried 2003). In Benin, anti-adhesion antibodies reduced the likelihood ofLBW deliveries (Ndam et al. 2015). Amongmultigravid women, anti-adhesion antibodieshave not been associated with risks of maternalanemia and LBW (Duffy and Fried 2003; Jawo-rowski et al. 2009), presumably because as agroup these women enjoy protective immunity.Together, these studies provide strong supportfor the idea that antibodies to placental IE con-fer protection, but do not indicate which anti-body effector mechanism(s) is primarily re-sponsible.

PREGNANCY MALARIA VACCINEDEVELOPMENT

Currently, the leading candidate for a vaccineto prevent pregnancy malaria is VAR2CSA, amember of the var gene or PfEMP1 proteinfamily that is up-regulated in placental parasitesas well as CSA-selected laboratory parasites(Salanti et al. 2003; Tuikue Ndam et al. 2005).VAR2CSA is a large protein of �350 kDa com-prising six extracellular Duffy-binding-like(DBL) domains and is too large to manufactureas an intact molecule. Therefore, immunogensbeing considered for product development in-corporate one or a few domains, with or with-out adjacent interdomain regions.

Several studies compared primigravid tomultigravid women for their seroreactivitywith different VAR2CSA domains (Table 4).Parity-dependent acquisition of VAR2CSA do-main-specific antibody has varied betweenstudies. This could reflect differences in the re-combinant proteins based on expression sys-tem, allelic variant, or domain boundaries, ordifferences in study populations such as trans-mission intensity, gestational age, or prevalenceof infection at the time of serum sampling.

Antibody boosting during infection canconfound attempts to distinguish between pro-tective antibodies and markers of exposure. Per-haps, for this reason, VAR2CSA antibodies have



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not been related to protection from infection inmany studies. After measuring antibody levelsto individual DBL domains and domain com-binations, Tutterrow et al. (2012a) concludedthat antibodies to multiple domains and allelesare needed to reduce PM risk. In Benin, highlevels of VAR2CSA-DBL3x antibody during the

first two trimesters reduced the risk of PM,although a similar trend was observed with an-tibody to an unrelated VAR domain (Ndamet al. 2015).

Relationships between VAR2CSA antibodiesand pregnancy outcomes have also variedbetween studies. Among Kenyan women with

Table 3. Studies of naturally acquired antiparasite antibodies and pregnancy outcomes

Reference/study

(year) Test Parasite tested Results

Staalsoe et al. 2004 Surface proteins by flow CSA-selected Among women with chronic malaria, highIgG associated to increased maternal HGBand BW

Beeson et al. 2004 Surface proteins by flow CSA-selected No association to BW or maternal HGB

Feng et al. 2009 Surface proteins by flow CSA-selected PMþ: Abs at weeks 14–26 associated todecreased maternal anemia (HGB ,

10 g/dL)

Aitken et al. 2010 Surface proteins by flow CSA-selected No association to maternal anemia, BW, andGA

Serra-Casas et al. 2010 Surface proteins by flow CSA-selected No association to LBW, GA, and maternalanemia

Ataide et al. 2010 Surface proteins by flow CSA-selected Primigravid: no association to LBW oranemia

Ataide et al. 2011 Surface proteins by flow CSA-selected Secundigravid PMþ: no correlation withBW or maternal HGB

Mayor et al. 2013 Surface proteins by flow Placentalparasites

High Abs to placental and child isolatesassociated to increased BW

Duffy and Fried 2003 Anti-adhesion Placentalparasites

Anti-adhesion Abs associated to increasedBW, GA

Beeson et al. 2004 Anti-adhesion CSA-selected No association to BW or maternal HGB

Jaworowski et al. 2009 Anti-adhesion CSA-selected Multigravid: no association to maternalHGB or BW

Ndam et al. 2015 Anti-adhesion CSA-selected Anti-adhesion Abs associated to decreasedLBW and SGA

Beeson et al. 2004 Agglutination CSA-selected No association to BW or maternal HGB

Feng et al. 2009 Opsonizing activity CSA-selected PMþ: Abs at weeks 14–26 associated todecreased maternal anemia (HGB ,

11 g/dL)

Jaworowski et al. 2009 Opsonizing activity CSA-selected Multigravid PMþ: lower opsonic activity inanemic (HGB , 11 g/dL); no associationto BW

Ataide et al. 2010 Opsonizing activity CSA-selected Primigravid: no association to LBW ormaternal anemia

Ataide et al. 2011 Opsonizing activity CSA-selected Secundigravid PMþ: correlated with BW

P, Primigravidae; S, secundigravidae; M, multigravidae; CSA, chondroitin sulfate A; PMþ, malaria-infected; PM2,

uninfected; HGB, hemoglobin; BW, birth weight; LBW, low birth weight; GA, gestational age.



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Table 4. Studies of naturally acquired VAR2CSA antibodies and parity

Domain

Parity

effect Abs measured at Study site year, transmission pattern References

DBL1 Yes Delivery 2001–2005, Muheza-Tanzania, perennial Oleinikov et al. 2007No Enrollmenta and delivery 2001, Thiadiaye-Senegal, seasonal Tuikue Ndam et al.

2006

DBL1–DBL2

Yes Enrollmenta and delivery 2008–2010, Come-Benin, perennial Ndam et al. 2015

DBL2 No Enrollmenta and delivery 2001, Thiadiaye-Senegal, seasonal Dechavanne et al.2015

Yes Delivery 2003–2006, Manhica-Mozambique,perennial

Mayor et al. 2013

ID1-ID2a No All trimesters 1994–1996 and 2001–2005, Ngali II andYaounde Cameroon, hightransmission and low transmission

Babakhanyan et al.2014

DBL3 Yes Delivery 2001–2005, Muheza-Tanzania,holoendemic

Oleinikov et al. 2007

Enrollmenta and delivery 2008–2010, Come-Benin, perennial Ndam et al. 2015No Third trimester 2000–2002, Blantyre-Malawi, perennial Brolin et al. 2010

Delivery 2003–2006, Manhica-Mozambique,perennial

Mayor et al. 2013

DBL4 Yes Delivery 2008–2010, Come-Benin, perennial Ndam et al. 2015No Delivery 2001–2005, Muheza-Tanzania, perennial Oleinikov et al. 2007

Enrollmenta 2008–2010, Come-Benin, perennial Ndam et al. 2015

DBL5 Yes Delivery Ghanab, seasonal Salanti et al. 2004Enrollmenta and delivery 2001, Thiadiaye-Senegal, seasonal Tuikue Ndam et al.

2006Third trimester 2000–2002, Blantyre-Malawi, perennial Brolin et al. 2010During pregnancyc 2005–2008, Ouidah-Benin, perennial Gnidehou et al. 2010Delivery 2003–2006, Manhica-Mozambique,

perennialMayor et al. 2013

Enrollmenta 2008–2010, Come-Benin, perennial Ndam et al. 2015No Delivery 2001–2005, Muheza-Tanzania, perennial Oleinikov et al. 2007

Enrollmenta and delivery 2001, Thiadiaye-Senegal, seasonal Dechavanne et al.2015

Delivery 2008–2010, Come-Benin, perennial Ndam et al. 2015

DBL6 Yes Enrollmenta and delivery 2001, Thiadiaye-Senegal, seasonal Tuikue Ndam et al.2006

Delivery 2001–2005, Muheza-Tanzania, perennial Oleinikov et al. 2007Delivery 2003–2006, Manhica-Mozambique,

perennialMayor et al. 2013

No Third trimester 2000–2002, Blantyre-Malawi, perennial Brolin et al. 2010Enrollmenta and delivery 2001, Thiadiaye-Senegal, seasonal Dechavanne et al.

2015aSamples collected at enrollment at any time during the first 6 months of gestation.bStudy year and site information not available.cSamples collected during pregnancy, but timing not specified.



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acute or chronic malaria infection, higherDBL5 antibody levels reduced the risk of LBWdelivery (Salanti et al. 2004). Among Mozam-bican women infected at least once duringtheir pregnancy, above-the-median antibodylevels to DBL3X and DBL61, as well as the un-related merozoite antigen AMA1, were associ-ated with increased birth weight and gestationalage (Mayor et al. 2013). In Benin, high DBL1-ID1-DBL2 antibody levels during the first twotrimesters reduced the risk of LBW (Ndam et al.2015). Additional studies that define relation-ships between specific antibody and protectionare needed to advance the development of avaccine to prevent malaria during pregnancy.

DIAGNOSIS

Despite its large burden of disease, P. falciparuminfection can be difficult to diagnose duringpregnancy, particularly in semi-immune wom-en who often are asymptomatic during infec-tion. Although IEs accumulate in the placenta,parasite density in peripheral blood can be toolow for detection by routine BS microscopy. BSis the gold standard for malaria diagnosis andis ideal for discriminating the different humanmalaria parasite species; however, quality variessubstantially, and the requirement for micro-scope and trained microscopist limits BS avail-ability or quality in many places. Paradoxically,although pregnancy malaria is difficult to rec-ognize and diagnose, many women in endemicareas unnecessarily receive antimalarial treat-ments in the absence of infection. In Mozam-bique, BS was negative in more than 70% ofpregnant women with clinical symptoms of ma-laria (Bardaji et al. 2008). Because antimalarialsare often prescribed on the basis of clinical andnot laboratory criteria, many pregnant womenreceive unnecessary treatment with drugs thathave an unclear safety profile especially in thefirst trimester.

Rapid diagnostic tests (RDTs) are a morerecent tool that is gaining wider acceptance fordiagnosis in the general population. RDTs useimmunochromatographic approaches to detectsoluble Plasmodium antigens, including histi-dine-rich protein-2 (HRP-2), aldolase, and

parasite lactate dehydrogenase (pLDH). TheOptiMAL test, based on pLDH detection, gavevarying results when compared with peripheralBS in different studies of pregnant women, withsensitivity ranging from 15% to 97% and spe-cificity from 91% to 98% (Mankhambo et al.2002; VanderJagt et al. 2005; Tagbor et al. 2008).The sensitivity of the OptiMAL test increaseswith parasite density, and all samples with par-asite density ,100 per ml were misdiagnosed inone study (VanderJagt et al. 2005). In a largerstudy (Tagbor et al. 2008), OptiMal had 100%sensitivity and 93% specificity for parasite den-sities .50 per ml blood, but sensitivity of only57% at lower densities. RDTs that detect pLDHhave the advantage that they are designed todetect only live parasites; however, gametocyte-mia in the absence of asexual blood stage para-sites can still produce positive results.

In general, RDTs that detect HRP-2 have ahigher sensitivity than those that detect pLDH.In one study, RDT-HRP-2 sensitivity was greaterthan 90% when compared with peripheral BS,and 80%–95% when compared with placentalBS with specificity between 61% and 94% (Lekeet al. 1999; Mockenhaupt et al. 2002; Singeret al. 2004; Mayor et al. 2012). In a multicenterstudy in West Africa, RDTs that combine thedetection of pLDH and HRP-2 showed similargood sensitivity at some but not all sites (range63.6%–95.1% in primigravidae) when com-pared with diagnoses using BS and PCR at firstantenatal visits, but not at subsequent visits or atdelivery in Ghanaian women (,60% sensitivityin all parity groups at delivery) (Williams et al.2015). In Papua New Guinea, HRP-2/pLDHRDTs were deemed insufficiently sensitive forintermittent screening of asymptomatic anemicwomen (Umbers et al. 2015). A weakness ofRDT-HRP-2 tests is the prolonged half-life ofthe antigen. HRP-2 can be identified in plasmasamples several weeks after parasite clearance,and therefore cannot distinguish current fromrecent infection (Wongsrichanalai et al. 1999;Mayxay et al. 2001; Tjitra et al. 2001). In BurkinaFaso, 2/32 parasitemic pregnant women con-tinued to have detectable HRP-2 antigen 28 dafter receiving artemisinin combination therapy(Kattenberg et al. 2012). These shortcomings



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hinder the use of existing RDTs for managingmalaria or monitoring treatment efficacy dur-ing pregnancy.

DRUGS FOR PREVENTION AND TREATMENT

Intermittent Presumptive Treatment (IPTp)

PM is associated with maternal anemia, LBWdeliveries, PTD, and fetal loss. Severe maternalanemia increases the risk of maternal death, andboth LBW and PTD increase the risk of infantdeath. To avoid these poor outcomes, measuresto prevent PM have been recommended by theWorld Health Organization (WHO). The firstagent used to prevent PM was weekly choloro-quine (CQ) at a prophylaxis dose. However, theemergence of CQ-resistant parasites in sub-Saharan Africa during the 1980s prompted thesearch for new strategies. A 1992 study in Ma-lawi showed that two treatment doses of SPgiven during the second and early third trimes-ter significantly reduced the prevalence of PMcompared with CQ (Schultz et al. 1994). A sub-sequent trial in Kenya confirmed that two SPtreatment doses reduced PM prevalence in HIV-infected women (Table 5) (Parise et al. 1998).

In the early 2000s, WHO recommended in-termittent presumptive treatment (IPTp) forpregnant women in malaria-endemic regions,with at least two curative doses of the antima-larial drug SP, one dose in the second and theother dose in the third trimester of pregnancy.In 2012, WHO updated the recommendation,increasing the number to three or more SP dos-es. In practice, women in areas of moderate–high malaria transmission should receive SP ateach antenatal care visit during the second andthird trimesters (because four visits are recom-mended), with 1 mo intervals between doses(www.who.int/malaria/areas/preventive_therapies/pregnancy/en).

Owing to the spread of SP resistance in sub-Saharan Africa, artemisinin-based combina-tions (ACTs) were adopted as the first-line treat-ment for uncomplicated malaria in the 2000s(Eastman and Fidock 2009). Even as the generalpopulation was switching to ACT as treatmentpolicy, the IPTp-SP strategy was being widely

adopted for pregnant women. At present,WHO continues to recommend IPTp-SP, evenin areas with high levels of SP resistance andtreatment failure. Here, we summarize studiesthat have examined the associations betweenIPTp-SP and malaria parasitemia detected inmaternal peripheral blood or placental blood(Table 5). We do not include studies that onlyreported an association between IPTp-SP andother pregnancy outcomes because the maingoal of IPTp-SP is to improve pregnancy out-comes by preventing PM. Improved outcomeswithout an effect on parasitological measuresare difficult to interpret.

During the years 1992–2002, IPTp-SP sig-nificantly reduced PM in studies conductedacross Africa. However, most data collected after2001–2002 in East and Southeast Africa indi-cate that IPTp-SP lost its efficacy to reduce PMprevalence and/or parasite density. This trendhas progressed to West Africa, where one site inGhana reported that IPTp-SP did not reducePM prevalence (van Spronsen et al. 2012).

SP resistance results from accumulatingmutations in dhfr and dhps genes. The quintu-ple P. falciparum mutations (three in Pfdhfr andtwo mutations in Pfdhps) have been associatedwith treatment failure (Kublin et al. 2002; Nai-doo and Roper 2013), and increased placentalparasite density with an increasing number ofPfdhfr mutations (Mockenhaupt et al. 2007). AWHO document published in November 2015(www.who.int/malaria/publications/atoz/istp-and-act-in-pregnancy.pdf ) stated that “An asso-ciation between sextuple mutant haplotypes ofP. falciparum and decreased birth weight hasbeen reported in observational studies in a fewsites in East Africa. Further studies are requiredto assess this and to devise the best and mostcost-effective prevention strategies in areas ofvery high SP resistance.” The policy of contin-uing IPTp-SP in areas of high resistance ispuzzling and inconsistent with WHO direc-tives for malaria treatment (Nosten and Mc-Gready 2015), as well as studies that stronglyrelate dhfr/dhps mutations to treatment failure.

Currently, IPTp-SP remains efficacious forreducing the rate of PM and/or parasite burdenat some sites in West Africa. However, even in



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http://www.who.int/malaria/areas/preventive_therapies/pregnancy/en/




http://www.who.int/malaria/publications/atoz/istp-and-act-in-pregnancy.pdf






Tabl

e5.

Studie

sofIP

Tp-S

Pef

fica

cya

Ref

eren

ces

Study

site

Study

year

sn

Study

des

ign

Outc

om

e

Sch

ult

zet

al.1

994

Man

goch

id

istr

ict,

Mal

awi,

hig

htr

ansm

issi

on

1992

357

(pla

cen

tal

BS

n¼

159)

Ass

ign

edto

on

eo

fth

ree

arm

s:(1

)w

eekl

yC

Q,

(2)

on

ed

ose

SPfo

llow

edb

yw

eekl

yC

Q,

(3)

two

do

ses

SP

Two

do

ses

sign

ifica

ntl

yre

du

ced

the

rate

of

per

iph

eral

and

pla

cen

tal

par

asit

emia

Ver

ho

eff

etal

.19

98C

hik

waw

ad

istr

ict,

Mal

awi,

hig

htr

ansm

issi

on

1993

–19

9418

37d

eliv

ery

dat

a:57

5O

bse

rvat

ion

al,

enro

llm

ent

atfi

rst

AN

Cvi

sit,

ou

tco

mes

mea

sure

dat

del

iver

y

Atd

eliv

ery,

no

dif

fere

nce

sin

pre

vale

nce

of

pla

cen

tal

or

per

iph

eral

par

asit

emia

bet

wee

no

ne

and

two

do

ses

Par

ise

etal

.19

98K

isu

mu

,K

enya

,h

igh

tran

smis

sio

n19

94–

1996

2077

Ass

ign

edto

on

eo

fth

ree

arm

s:(1

)tw

od

ose

sSP

,(2

)m

on

thly

do

ses

of

SPb

etw

een

enro

llm

ent

and

gest

atio

nal

wee

k34

,(3

)ca

sem

anag

emen

tw

ith

SP

Two

do

ses

or

mo

nth

lySP

sign

ifica

ntl

yre

du

ced

the

pre

vale

nce

of

infe

ctio

nd

etec

ted

inp

erip

her

alan

dp

lace

nta

lsa

mp

les

Shu

lman

etal

.19

99K

ilifi

,K

enya

,h

yper

ho

loen

dem

ican

dm

eso

end

emic

site

s

1996

–19

9712

64D

ou

ble

-bli

nd

,ra

nd

om

ized

,co

ntr

oll

ed;

nu

mb

ero

fSP

do

ses

(1–

3)b

ased

on

gest

atio

nal

age

aten

roll

men

t

At

gest

atio

nal

wee

k34

,�

on

ed

ose

of

IPT

p-S

Psi

gnifi

can

tly

red

uce

dth

ep

reva

len

ceo

fper

iph

eral

par

asit

emia

;P

M:

sign

ifica

ntl

yh

igh

erp

rop

ort

ion

of

neg

ativ

eb

yh

isto

logy

inth

etr

eatm

ent

gro

up

;n

od

iffe

ren

ces

by

BS

Fen

get

al.

2010

Bla

nty

re,

Mal

awi,

low

tran

smis

sio

n19

97–

2006

8131

Ob

serv

atio

nal

,en

roll

men

tat

del

iver

y19

97–

2001

:n

um

ber

of

IPT

p-S

Pd

ose

sas

soci

ated

wit

hp

rote

ctio

nfr

om

PM

2002

–20

06:

IPT

p-S

Pn

ot

asso

ciat

edw

ith

are

du

ctio

nin

PM

Har

rin

gto

net

al.

2009

Mu

hez

a,Ta

nza

nia

,h

igh

tran

smis

sio

n20

02–

2005

880

Ob

serv

atio

nal

,en

roll

men

tat

del

iver

yN

oIP

Tp

vers

us�

on

ed

ose

:SP

usa

geas

soci

ated

wit

hin

crea

sed

pla

cen

tal

par

asit

ed

ensi

ty

Gie

set

al.

2009

Bo

rom

o,

Bu

rkin

aFa

so,

seas

on

al,

hig

htr

ansm

issi

on

2004

–20

0691

5(p

erip

her

alb

loo

d)

878

(pla

cen

tal

blo

od

)

Sub

stu

dy

of

larg

erst

ud

yto

eval

uat

eIP

Tp

No

ne

too

ne

vers

us

.tw

od

ose

s:re

du

ctio

nin

the

pre

vale

nce

of

infe

ctio

nd

etec

ted

inp

erip

her

alan

dp

lace

nta

lb

loo

d

Con

tin

ued



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ecti

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Tabl

e5.

Continued

Ref

eren

ces

Study

site

Study

year

sn

Study

des

ign

Outc

om

e

Tio

no

etal

.20

09B

ou

sse

dis

tric

t,B

urk

ina

Faso

,se

aso

nal

,h

igh

tran

smis

sio

n20

04–

2005

648

Ran

do

miz

ed,

thre

etr

eatm

ent

arm

s:(1

)IP

Tp

-SP,

(2)

wee

kly

CQ

,(3

)IP

Tp

-CQ

At

del

iver

y,th

ep

reva

len

ceo

fm

ater

nal

per

iph

eral

par

asit

emia

sign

ifica

ntl

ylo

wer

inIP

Tp

-SP

than

CQ

gro

up

;si

gnifi

can

tre

du

ctio

nin

PM

inIP

Tp

-SP

vers

us

wee

kly

CQ

bu

tn

ot

vers

us

IPT

p-C

Q

Men

end

ezet

al.

2008

Man

hic

ad

istr

ict,

Mo

zam

biq

ue,

mo

der

ate

tran

smis

sio

n

2003

–20

0510

30D

ou

ble

-bli

nd

,ra

nd

om

ized

,p

lace

bo

-co

ntr

oll

edP

lace

boþ

ITN

vers

us

SPþ

ITN

:n

od

iffe

ren

cein

pla

cen

tal

infe

ctio

nR

edu

ctio

nin

the

pre

vale

nce

of

per

iph

eral

blo

od

par

asit

emia

and

acti

vep

lace

nta

lin

fect

ion

Nd

yom

ugy

enyi

etal

.20

11K

abal

ed

istr

ict,

Uga

nd

a,lo

wan

du

nst

able

tran

smis

sio

n20

04–

2007

5328

Ran

do

miz

ed,

pla

ceb

o-c

on

tro

lled

,b

lin

ded

for

SPve

rsu

sp

lace

bo

bu

tn

ot

for

ITN

use

IPT

pve

rsu

sIT

Nve

rsu

sIP

Tpþ

ITN

:n

od

iffe

ren

ces

inin

fect

ion

rate

atge

stat

ion

alw

eeks

36–

40an

dat

del

iver

y

Ho

mm

eric

het

al.

2007

Ago

go,

Gh

ana,

hyp

er-

toh

olo

end

emic

2006

226

Ob

serv

atio

nal

,en

roll

men

tat

del

iver

yN

oIP

Tp

vers

us�

on

eSP

do

se:

SPas

soci

ated

wit

hd

ecre

ased

pla

cen

tal

infe

ctio

nd

etec

ted

by

RD

Tan

dP

CR

bu

tn

ot

by

mic

rosc

op

y

Dia

kite

etal

.201

1B

lad

istr

ict,

Mal

i,se

aso

nal

,h

igh

tran

smis

sio

n20

06–

2008

814

Ran

do

miz

edto

two

trea

tmen

tar

ms:

(1)

two

SPd

oes

,(2

)th

ree

SPd

ose

s

PM

red

uce

db

yh

alf

afte

rth

ree

do

ses

vers

us

two

do

ses

Van

ga-B

oss

on

etal

.20

11C

ote

d’I

voir

e,si

xsi

tes

(fo

ur

urb

an,

two

sem

iurb

an)

inth

ree

regi

on

s

2008

2044

Ob

serv

atio

nal

,en

roll

men

tat

del

iver

yN

on

eve

rsu

so

ne

totw

od

ose

s:re

du

ctio

nin

PM

Wil

son

etal

.201

1A

ccra

,G

han

a,m

od

erat

etr

ansm

issi

on

2009

363

Ob

serv

atio

nal

,en

roll

men

tat

AN

C(t

hir

dtr

imes

ter)

Pri

or

use

of

IPT

psi

gnifi

can

tly

red

uce

dm

ater

nal

infe

ctio

n

Gu

tman

etal

.20

13M

ach

inga

,M

alaw

i,h

igh

tran

smis

sio

n20

1070

3O

bse

rvat

ion

al,

enro

llm

ent

atd

eliv

ery

No

ne

too

ne

do

seve

rsu

s�

two

do

ses:

nu

mb

ero

fd

ose

sh

adn

oef

fect

on

pla

cen

tala

nd

per

iph

eral

par

asit

emia

Gu

tman

etal

.20

15M

ach

inga

and

Bla

nty

re,

Mal

awi,

hig

han

dlo

wtr

ansm

issi

on

Mac

hin

ga:

2010

Bla

nty

re:

2009

–20

11

Mac

hin

ga:

710

Bla

nty

re:

1141

Ob

serv

atio

nal

,en

roll

men

tat

del

iver

ySe

xtu

ple

mu

tate

dh

aplo

typ

ein

Pfd

hfr

/P

fdh

ps

asso

ciat

edw

ith

sign

ifica

nt

incr

ease

inp

lace

nta

lan

dp

erip

her

alp

aras

item

iaan

dp

aras

ite

den

sity

Con

tin

ued



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Tabl

e5.

Continued

Ref

eren

ces

Study

site

Study

year

sn

Study

des

ign

Outc

om

e

Mac

eet

al.

2015

Man

sa,

Zam

bia

,h

igh

tran

smis

sio

n20

09–

2011

435

Ob

serv

atio

nal

,en

roll

men

tat

del

iver

y,

two

vers

us�

two

do

ses:

no

dif

fere

nce

inP

M,

ad

ecre

ase

inan

yin

fect

ion

(pla

cen

tal

incl

ud

ing

pas

tin

fect

ion

and

per

iph

eral

blo

od

)am

on

gp

rim

igra

vid

ae

Tou

reet

al.

2014

Co

ted

’Ivo

ire,

six

site

s(t

hre

eru

ral,

thre

eu

rban

),p

eren

nia

ltr

ansm

issi

on

wit

hse

aso

nal

pea

ks

2009

–20

1013

17O

bse

rvat

ion

al,

enro

llm

ent

atd

eliv

ery

No

ne

vers

us

on

eve

rsu

s�

two

do

ses:

no

dif

fere

nce

sin

PM

Cis

seet

al.

2014

Bo

bo

-Dio

ula

sso

,B

urk

ina

Faso

,se

aso

nal

,h

igh

tran

smis

sio

n

2010

579

Ob

serv

atio

nal

,en

roll

men

td

uri

ng

rou

tin

eA

NC

visi

tN

oas

soci

atio

nb

etw

een

SPu

sage

and

mal

aria

infe

ctio

np

reva

len

ced

uri

ng

pre

gnan

cy;

low

erp

aras

ite

den

sity

inw

om

enth

atu

sed

SP

Co

uli

bal

yet

al.

2014

Kit

aan

dK

ayes

regi

on

s,M

ali;

Zin

iare

,B

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areas with low or moderate SP resistance, theIPTp strategy does not completely prevent PMand the protective effects depend on the timingof the first dose and the interval between treat-ments (Nosten and McGready 2015).

Alternatives to IPTp-SP

Dihydroartemisinin–Piperaquine

A comparison between three doses of IPTp-SPand three doses or monthly dihydroartemisi-nin–piperaquine (DP) was recently conductedin Uganda (Kakuru et al. 2016). Peripheralblood parasitemia detected by LAMP was sig-nificantly higher in the IPTp-SP group thanthree doses or monthly DP. Similarly, PM (com-bined active and past infection) was significantlyhigher among women who received IPTp-SPthan women that received three doses or month-ly treatment with DP. Although, among primi-gravid women, the rate of PM was similar be-tween the three groups, the amount of pigmentdeposition was significantly higher in the IPTp-SP groups, which might indicate higher parasitedensities in past infections. The risk of any poorpregnancy outcome (PTD, LBW, congenitalanomaly, stillbirth, spontaneous abortion) wassignificantly lower among women receivingmonthly DP than women who received threedoses of DP or IPTp-SP.

Mefloquine

In a comparison of IPTp-SP and IPTp-meflo-quine (MQ) (Briand et al. 2009), Beninesewom-en received either two doses of IPTp-SP or twodoses of MQ (15 mg/kg) during pregnancy. PMwas significantly less frequent in the MQ group,but other endpoints including birth weight,LBW, and maternal anemia were similar (Briandet al. 2009). Adverse events were more commonwith MQ, and overall tolerability was lower (Bri-and et al. 2009). Another trial compared twodoses of IPTp with SP or MQ in women whoalso received long-lasting insecticide-treatednets. MQ was given as a single 15 mg/kg doseor as a split dose (Gonzalez et al. 2014a). Therates of maternal parasitemia (by BS) at delivery,

mild anemia at delivery, and clinical malariaduring pregnancy were significantly lower inthe MQ group, while PM (by BS or histology),birth weight, and LBW rates were similar (Gon-zalez et al. 2014a). As in Benin, tolerability waspoor even in the group that received MQ as asplit dose (Gonzalez et al. 2014a).

IPTp-SP is not recommended for HIV-in-fected women who take daily cotrimoxazoleprophylaxis, owing to the potential adverse ef-fects of taking two antifolate drugs with a com-mon mechanism of action (reviewed in Peterset al. 2007). Two trials evaluated MQ as IPTp inwomen taking cotrimoxazole (Gonzalez et al.2014b;). In a multicenter study conducted inEast and Southeast Africa, peripheral and pla-cental parasitemia (defined by BS, PCR, or his-tology) and nonobstetric admission were lessfrequent among women that received three dos-es of IPTp-MQ, while maternal anemia, birthweight, and gestational age at delivery were sim-ilar between groups (Gonzalez et al. 2014b).Notably, IPTp-MQ was associated with in-creased mother-to-child transmission of HIV,and again showed poor tolerability (Gonzalezet al. 2014b). In West Africa, IPTp with threeMQ doses (15 mg/kg) was compared with co-trimoxazole alone and cotrimoxazole plusIPTp-MQ (Denoeud-Ndam et al. 2014). At de-livery, PM was not detected by PCR in any ofthe 105 women in the cotrimoxazole þ IPTp-MQ group compared with 5/103 women in thecotrimoxazole alone group. Maternal anemia,infection rate during pregnancy detected byPCR, and birth weight did not differ betweengroups. Again, adverse events were more com-mon among women receiving MQ (Denoeud-Ndam et al. 2014). Although MQ can be effectiveto reduce infection, tolerability has been pooreven when used at a split dose, and thus mayresult in low compliance if used for prevention.

Chloroquine–Azithromycin Combination

The CQ–azithromycin combination was com-pared with SP for use as IPTp in a trial thatincluded six sites in Africa. However, interimanalyses showed that the new combination wasnot superior to the existing intervention, and



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the study was terminated early (ClinicalTrials.gov Identifier: NCT01103063).

Intermittent Screening and Treatment

The Intermittent Screening and Treatment inpregnancy (ISTp) strategy entails screeningwomen for malaria infection during antenatalclinic visits using an RDT and treating infec-tion with an antimalarial drug. A multicentertrial comparing ISTp-AL (artemether–lume-fantrine) with IPTp-SP was recently conductedin West Africa in sites with seasonal malaria andlow SP resistance (Tagbor et al. 2015). PM, birthweight, and maternal hemoglobin were similarbetween ISTp-AL and IPTp-SP in the overallanalysis and within individual sites (Tagboret al. 2015). Malaria infections between sched-uled visits were significantly more frequent inwomen randomized to the ISTp-AL (Tagboret al. 2015). In an area of high malaria transmis-sion and high SP resistance in Kenya, womenwere randomized to three interventions: ISTpwith dihydroartemisinin–piperaquine (DP),IPTp with DP, and IPTp-SP (Desai et al. 2015).Malaria infection at delivery was diagnosed bydetection of parasites with BS on peripheral orplacental blood, or with RDT or PCR on per-ipheral blood. Risks of malaria infection,mild anemia (HGB , 11 g/dL), stillbirth, andearly infant mortality were significantly re-duced in women receiving IPTp-DP ratherthan IPTp-SP or ISTp-DP, while ISTp-DPand IPTp-SP groups did not differ (Desai et al.2015). The failure of ISTp-DP to improve onIPTp with the failing drug SP echoes the earlyevaluation of IPTp-SP in 1992–1994 (Pariseet al. 1998) in which case management was infe-rior to IPTp-SP.

Differences in ISTp efficacy between the twostudies could result from different transmissionpatterns, being highly seasonal in West Africaversus perennial with seasonal peaks in Kenya.Peripheral parasite density at delivery in Kenyawas much lower than the density at enrollmentin West Africa. Although the different assess-ment times could influence BS results, lowerparasite densities might explain the lower sen-sitivity of RDT to detect PM, potentially ren-

dering the IST strategy ineffective in Kenya(Fried et al. 2012; Desai et al. 2015).

Treatment of Malaria during Pregnancy

Currently, artemisinin combination therapy(ACT) is the first-line treatment for malaria innonpregnant individuals. Owing to safety con-cerns, WHO recommends that pregnant wom-en be treated with quinine and clindamycinduring the first trimester and with ACT in thesecond and third trimesters. A multicenter trialreported high cure rate with four different ACTs(artemether–lumefantrine, amodiaquine–ar-tesunate, dihydroartemisinin–piperaquine, andmefloquine–artesunate), with artemether–lu-mefantrine showing the lowest cure rate of94.8% (The PREGACT Study Group 2016). Preg-nancy outcomes were similar between the fourgroups and both artemether–lumefantrine anddihydroartemisinin–piperaquine had feweradverse events than amodiaquine–artesunate,and mefloquine–artesunate (The PREGACTStudy Group 2016). Analyses of first-trimesterantimalarial treatment records at Shoklo Malar-ia Research Unit in Thailand have shown thatartesunate is as safe as choloroquine and qui-nine (McGready et al. 2012). In a similar studyin Kenya, ACT treatment during the first-tri-mester (based on the review of treatmentrecords) did not increase the risk of miscarriage,compared with women who did not receive anytreatment or women who received quinine(Dellicour et al. 2015). However, communitysurveillance, which included cases without atreatment record, suggested that exposure toACT may increase the risk of miscarriage com-pared with women that never received antima-larial drugs (Dellicour et al. 2015). Because bothsymptomatic and asymptomatic malaria infec-tions (with P. falciparum or P. vivax) during thefirst trimester increase the risk of miscarriage(McGready et al. 2012), it might be difficult toassess the contribution attributable to ACTwhen the comparison group includes never-in-fected women. Both studies had a small numberof women that received either ACT or quinine,and clinical trials to compare the safety of ACTto quinine during the first trimester are needed.



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FUTURE PERSPECTIVES

Pregnant women are at increased risk of malar-ia, making this demographic group an impor-tant parasite reservoir in the community and akey target for interventions during eliminationefforts (Fig. 1). However, pregnant women andwomen of childbearing age will require specialconsiderations during any mass administrationcampaigns. Semi-immune women often carryP. falciparum PM with low peripheral parasiteburdens and few acute symptoms, hinderingdiagnosis and complicating efforts to use tar-geted treatment as a strategy. Drugs currentlyused for malaria prevention during pregnancyhave lost or are losing their efficacy, and findingnew drugs is stymied by concerns for teratoge-nicity and embryotoxicity; dihydroartemisi-nin–piperaquine has shown promise as themonthly presumptive treatment to preventpoor pregnancy outcomes, although it maynot reduce PM prevalence. Vaccines have beenimportant tools for the elimination of otherinfectious pathogens, and women commonlyreceive vaccines such as tetanus toxoid duringpregnancy. Vaccines could be particularly usefulfor the control of PM: P. falciparum parasitessequester in the human placenta by adhesionto CSA, and women acquire antibodies againstCSA-binding parasites over successive pregnan-cies, rendering primigravidae most susceptibleand suggesting a vaccine is feasible. Vaccinesthat control PM, prevent human infection,or block onward transmission to mosquitoes,will require testing to assess their ability to in-terrupt transmission through pregnant women.More effort must be made to address the safetyof drugs, vaccines, and antivector measuresamong women of childbearing age, particularlyduring the first trimester of pregnancy whensafety concerns are greatest.

CONCLUDING REMARKS

Tens of millions of pregnant women are at riskof malaria every year, but the management ofmalaria is particularly complex in this popula-tion. In areas of low transmission, women lack-ing immunity are at increased risk of acute se-

vere disease and of death during P. falciparuminfection, and therefore active surveillance andprompt treatment of malaria in these women isparamount. In areas of high stable transmission,acquired immunity can mask acute symptomsbut leave women vulnerable to insidious effectssuch as severe maternal anemia and perinatal,neonatal, or postneonatal death for their off-spring. Existing diagnostic tools are inadequateto detect malaria infection in semi-immunewomen, and the drugs CQ and SP used as pre-ventive interventions have lost or are losing theirbenefits; a replacement drug has yet to be iden-tified that is sufficiently safe, tolerable, and ef-fective as prevention, although studies of dihy-droartemisinin–piperaquine are encouraging.Naturally acquired resistance to malaria sug-gests that vaccines are feasible by inducing an-tibodies against the CSA-binding parasites thatsequester in the human placenta. Passive or ac-tive immunization that provides women with awindow of coverage throughout pregnancy is anappealing alternative to drug prevention strate-gies. The need for new preventive and diagnos-tic tools for this vulnerable population is ur-gent, but is often overlooked by policymakersand funding agencies. This dearth of safe andeffective tools to control malaria in pregnantwomen will hinder future malaria eliminationcampaigns, because any woman of childbearingage will likely be excluded from participation ifpregnancy status is unknown.

ACKNOWLEDGMENTS

The authors acknowledge J. Patrick Gorres(Laboratory of Malaria Immunology and Vac-cinology, National Institutes of Health [NIH])for proofreading and editing this review, andAlan Hoofring (NIH Medical Arts, NIH) forpreparing the illustration. M.F. and P.E.D. aresupported by the Intramural Research Programof the National Institute of Allergy and Infec-tious Diseases (NIAID), NIH.

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published online February 17, 2017Cold Spring Harb Perspect Med Michal Fried and Patrick E. Duffy Malaria during Pregnancy

Subject Collection Malaria: Biology in the Era of Eradication

Modern Vector ControlNeil F. Lobo, Nicole L. Achee, John Greico, et al.

Malaria PathogenesisDanny A. Milner, Jr.

Malaria ControlVectorial Capacity and Potential Avenues for Anopheline Reproductive Biology: Impacts on

Sara N. Mitchell and Flaminia Catteruccia

Population LevelDeterminants of Malaria Transmission at the

Teun Bousema and Chris Drakeley

Malaria Transmission via the Use of InsecticidesCurrent and Future Prospects for Preventing

Hilary Ranson EliminationMalaria Parasites: Challenges for Malaria Host Cell Tropism and Adaptation of Blood-Stage

Caeul Lim, Selasi Dankwa, Aditya S. Paul, et al.

Malaria Parasites from Host ErythrocytesMolecular Signaling Involved in Entry and Exit of

Shailja Singh and Chetan E. ChitnisEradication: The Role of the EnvironmentMalaria Transmission and Prospects for Malaria

Marcia C. Castro

Eventual EradicationVaccines to Accelerate Malaria Elimination and

al.Julie Healer, Alan F. Cowman, David C. Kaslow, et

Plasmodium vivaxThe Biology of John H. Adams and Ivo Mueller

Immune Responses in MalariaCarole A. Long and Fidel Zavala

Malaria Genomics in the Era of EradicationDaniel E. Neafsey and Sarah K. Volkman

EliminationAntimalarial Drug Resistance: A Threat to Malaria

Didier Menard and Arjen Dondorp

Malaria EpigeneticsAlfred Cortés and Kirk W. Deitsch

Malaria during PregnancyMichal Fried and Patrick E. Duffy Exoerythrocytic Biology

Malaria Parasite Liver Infection and

Ashley M. Vaughan and Stefan H.I. Kappe

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