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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
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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
Malaria during Pregnancy
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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
Malaria during Pregnancy
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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
Increase with parity
Megnekou et al.2005
Surface proteinsby flow
CSA-selected Combined second–third trimesters
P: 101S/M: 114
Increase with parity
Fievet et al. 2006 Surface proteinsby flow
Placentalparasites
Second trimester P: 62S: 50M: 153
Increase with parity
Feng et al. 2009 Surface proteinsby flow
CSA-selected Second trimester P: 80S: 16M: 45
Increase with parity
Aitken et al. 2010 Surface proteinsby flow
CSA-selected Second and thirdtrimesters
P: 131S: 108M: 310
Increase with parity
Brolin et al. 2010 Surface proteinsby flow
CSA-selected Third trimester P: 189S: 21M: 72
Increase with parity
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
Increase with parity
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
Increase with parity
Beeson et al.1999, 2004
Agglutination Placentalparasites
Second trimester P: 12M:12
Increase with parity
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
Increase with parity
Jaworowski et al.2009
Opsonizingactivity
CSA-selected Third trimester P: 44M: 29
Increase with parity
Feng et al. 2009 Opsonizingactivity
CSA-selected Second trimester P: 80S: 16M: 45
Increase with parity
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
Surface proteinsby flow
CSA-selected Thirdtrimester
P: 55M: 58
Multigravid: inverse correlationbetween Abs and parasitedensity
Staalsoe et al.2004
Surface proteinsby flow
CSA-selected Delivery All 477 Chronic and past infection .
PM2 and acute infection,regardless of parity
Beeson et al.2004
Surface proteinsby flow
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
Multigravid: no differences
Ataide et al. 2010 Surface proteinsby flow
CSA-selected Thirdtrimester
P: 268 Primigravid: PMþ . PM2
Ataide et al. 2011 Surface proteinsby flow
CSA-selected Thirdtrimester
S: 187 Secundigravid: PMþ . PM2
Tutterrow et al.2012a
Surface proteinsby flow
CSA-selected Second–thirdtrimester
Total 27 PM2 . PMþ
Mayor et al.2011, 2013
Surface proteinsby flow
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
Multigravid: no differences
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
CSA-selected Thirdtrimester
P:268 Primigravid: PMþ . PM2
Ataide et al. 2011 Opsonizingactivity
CSA-selected Thirdtrimester
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.
Malaria during Pregnancy
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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
Malaria during Pregnancy
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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
M. Fried and P.E. Duffy
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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
Malaria during Pregnancy
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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
M. Fried and P.E. Duffy
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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
urk
ina
Faso
,se
aso
nal
hig
htr
ansm
issi
on
2009
–20
1020
10–
2011
268
(Mal
i)31
2(B
F)
IPT
p-S
Pfo
rcl
eari
ng
asym
pto
mat
icin
fect
ion
du
rin
gp
regn
ancy
Low
trea
tmen
tfa
ilu
re:
1.1%
atd
ay42
,P
CR
adju
sted
van
Spro
nse
net
al.
2012
Gu
sheg
u,
Gh
ana,
hig
htr
ansm
issi
on
2010
145
Ob
serv
atio
nal
,en
roll
men
tat
del
iver
yN
oas
soci
atio
nb
etw
een
IPT
pu
sage
,n
um
ber
of
SPd
ose
s,an
dP
M
Ton
gaet
al.
2013
San
aga-
Mar
itim
eL
itto
ral
regi
on
,C
amer
oo
n,
hyp
eren
dem
ic
2011
–20
1220
1O
bse
rvat
ion
al,
enro
llm
ent
atd
eliv
ery
No
ne
too
ne
vers
us
.tw
od
ose
sIP
Tp
:n
od
iffe
ren
cein
PM
rate
Ari
nai
twe
etal
.20
13To
roro
,U
gan
da,
hig
htr
ansm
issi
on
2011
566
Ob
serv
atio
nal
,en
roll
men
tat
del
iver
y,
two
vers
us�
two
do
ses:
no
dif
fere
nce
sin
PM
rate
or
par
asit
ed
ensi
ty
Bra
un
etal
.20
15Fo
rtP
ort
al,
wes
tern
Uga
nd
a,m
eso
end
emic
2013
728
Ob
serv
atio
nal
,en
roll
men
tat
del
iver
yN
on
eve
rsu
so
ne
totw
od
ose
s:n
od
iffe
ren
ces
inp
lace
nta
lor
per
iph
eral
infe
ctio
nra
te
Mp
ogo
roet
al.
2014
Gei
tare
gio
n,
Tan
zan
ia,
hig
htr
ansm
issi
on
2014
431
Ob
serv
atio
nal
,en
roll
men
tat
del
iver
y,
thre
eve
rsu
s�
thre
eSP
do
ses:
�th
ree
do
ses
asso
ciat
edw
ith
are
du
ctio
nin
PM
(26/
431
rece
ived
�th
ree
do
ses)
SP,
Sulf
ado
xin
e–
pyr
imet
ham
ine;
CQ
,ch
loro
qu
ine;
BW
,b
irth
wei
ght;
LB
W,
low
bir
thw
eigh
t;P
TD
,p
rete
rmd
eliv
ery;
SGA
,sm
all
for
gest
atio
nal
age;
ITN
,in
sect
icid
e-tr
eate
dn
et.
a Res
ult
sfr
om
adju
sted
mo
del
sp
rese
nte
d.
Malaria during Pregnancy
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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
M. Fried and P.E. Duffy
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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.
Malaria during Pregnancy
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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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M. Fried and P.E. Duffy
24 Advanced Online Article. Cite this article as Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a025551
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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
http://perspectivesinmedicine.cshlp.org/cgi/collection/ For additional articles in this collection, see
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