• View in gallery
    Figure 1.

    Relationship between timing of IPTp, fetal growth rates, and potential vulnerability of mother and fetus to deleterious effects of malaria. The fetal growth rate varies over the course of pregnancy, peaking at about 36 weeks (curve). In the context of moderate SP resistance, IPTp (vertical arrows) may or may not clear infection, and offers a shortened period of prophylaxis against reinfection (attached horizontal black arrows).104 Reinfection during the period of vulnerability may affect fetal growth (double-headed arrow). The effects of malaria early in pregnancy (dotted arrow) on fetal growth are less well understood.

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    Figure 2.

    Some potential pathogenic mechanisms by which placental malaria affects placental function and results in IUGR or PTD. IRBC, infected red blood cell; CSA, chondroitin sulfate A; IUGR, intrauterine growth retardation; PTD, preterm delivery.

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Malaria in Pregnancy: Linking Immunity and Pathogenesis to Prevention

Stephen J. RogersonDepartment of Medicine (RMH/WH), The University of Melbourne, Royal Melbourne Hospital, Australia; Department of Community Health, College of Medicine, University of Malawi, Blantyre, Malawi; Department of Epidemiology, Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina

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Victor MwapasaDepartment of Medicine (RMH/WH), The University of Melbourne, Royal Melbourne Hospital, Australia; Department of Community Health, College of Medicine, University of Malawi, Blantyre, Malawi; Department of Epidemiology, Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina

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Steven R. MeshnickDepartment of Medicine (RMH/WH), The University of Melbourne, Royal Melbourne Hospital, Australia; Department of Community Health, College of Medicine, University of Malawi, Blantyre, Malawi; Department of Epidemiology, Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina

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Pregnant women are susceptible to malaria during pregnancy. Plasmodium falciparum, which sequesters in the placenta, causes the greatest disease, contributing significantly to maternal and infant mortality. Parasitized cells in the placenta express unique variant surface antigens (VSA), predominantly the VAR2CSA protein, and lack of immunity to these pregnancy-specific variant surface antigens explains some of the pregnancy-associated malaria susceptibility. Changes in acquired cellular immunity during pregnancy also appear important. Placental inflammatory responses, particularly monocyte infiltrates, predispose to fetal growth restriction and maternal anemia. Preventing malaria in pregnancy relies on insecticide treated bed nets, intermittent preventive treatment with antimalarials such as sulphadoxine–pyrimethamine, and potentially relies on the development of effective vaccines. The optimal deployment of each may depend heavily on the relationship between the timing of placental malaria infection and its deleterious consequences. Improved understanding of the relationship between pathogenesis, immunity, and pregnancy outcome will allow better targeting of our interventions to prevent the consequences of malaria in pregnancy.

INTRODUCTION TO MALARIA IN PREGNANCY

Each year, 25–30 million women become pregnant in malaria-endemic areas of Africa, and similar numbers are exposed to malaria in Asia, Oceania, and South America.1 Malaria is an important cause of severe anemia in pregnant African women, and by this mechanism malaria causes an estimated 10,000 maternal deaths each year.2 Moreover, malaria infections result in 75,000–200,000 low birth weight (LBW) babies each year, due to combinations of preterm delivery (PTD) and fetal growth restriction (FGR).1,3 Effects on miscarriage and stillbirth are unknown, but adequate malaria control alone could prevent 3–8% of infant deaths.1

To tackle this enormous burden, we have two proven tools. First, insecticide treated nets (ITNs) decrease parasite prevalence in all gravidities, decrease LBW and stillbirth in first to fourth pregnancy, and show trends toward benefits against anemia and clinical malaria.4 Second, intermittent preventive treatment in pregnancy (IPTp), using regular treatment doses of the antimalarial sulphadoxine–pyrimethamine (SP) has been shown to decrease peripheral and placental parasitemia, and to increase maternal hemoglobin and infant birth weight, especially in primi- and secundigravidae.59 Unfortunately, high-level coverage with SP IPTp and ITNs has not yet been achieved.1013

The development and evaluation of programs to prevent malaria in pregnancy can be facilitated by a better understanding of the pathogenesis of malaria. This article will review aspects of malaria parasite biology and of the pathogenesis and immunity of malaria in pregnancy. We will highlight areas where these aspects can inform future study of how best to control and prevent this major health problem.

SUSCEPTIBILITY TO MALARIA IN PREGNANCY

Malaria is dangerous to both the mother and fetus. Pregnant women are at greater risk of malaria infection and of symptomatic malaria disease than non-pregnant adults.14 They are more attractive to mosquitoes.15 Parasite densities are higher in pregnant women than in non-pregnant adults. In two studies, complexity of infections did not differ,16,17 whereas a third study showed an increase in young pregnant women.18 Together these studies suggest that the ability to limit parasite replication is impaired in pregnancy.

Malaria is most frequent in first pregnancy,19 peaking between 13 and 16 weeks,14 and declining toward term. Age may be an independent risk factor, as younger pregnant women have been found to be more susceptible to malaria in some settings.17,20,21 Adolescent and young adult women are more commonly parasitemic than older adults,22 and this may reflect continuing development of malarial immunity. HIV infection increases susceptibility to malaria, resulting in more prevalent and higher-density infection, and a relative loss of gravidity-dependent immunity.23

Other species, other regions.

Where malaria transmission rates are low, maternal disease is often severe due to lack of pre-existing immunity.24,25 Non-immune pregnant women appear to be at higher risk of cerebral malaria and pulmonary edema than other adults. They also may experience increased risk for abortions and stillbirths. In settings of infrequent exposure to infection, malaria is equally dangerous to primi-and multigravidae. P. vivax infections also cause LBW and maternal anemia, albeit at lower rates than P. falciparum.26,27 In contrast, susceptibility to P. malariae and P. ovale does not increase in pregnancy.28 However, an early study in Vietnam (van Hung 1951, cited in 29) showed that both P. vivax and P. malariae cause abortions and preterm delivery in women with little immunity.

Placental pathology.

P. falciparum causes three specific changes in the placenta. Infected erythrocytes (IE) containing mature trophozoite and schizont parasite stages accumulate in the intervillous spaces (the lake-like structures through which maternal blood circulates), sometimes to high densities.30 High placental parasitemia has been associated with preterm delivery (PTD).31 Placental malaria may be accompanied by intervillous infiltrates of monocytes and macrophages, some containing malaria pigment (hemozoin). High-density monocyte infiltrates are especially common in first pregnancy, and are associated with LBW and anemia.3236 Finally, hemozoin may also be seen in fibrin deposits. Detection of hemozoin alone indicates previous infection, and has been associated with decreased birth weight.37 Hemozoin probably remains in the placenta for long periods, but is diluted out by rapid placental growth.38 The role of hemozoin in the pathogenesis of malaria in pregnancy remains to be elucidated.

Unlike P. falciparum, P. vivax does not sequester in the placenta,39 and P. vivax-infected placentas show no pathologic changes. This suggests that P. vivax may cause LBW by systemic rather than local changes.

Parasite accumulation in the placenta.

The process of sequestration of IE in the placenta differs in important ways from sequestration in organs like the brain, in which close apposition of IE to endothelial cells is mediated by receptors such as CD36 and ICAM-1.40,41 In vitro, placental IE can adhere to chondroitin sulphate A (CSA) and hyaluronic acid (HA), and not to ICAM-1 and CD36.42,43 CSA and HA are expressed by syncytiotrophoblast that line the placental intervillous spaces,44,45 and IE can adhere to placental frozen sections. However, in placental biopsies, many IE are not adherent to the syncytiotrophoblast46; they may in part be retained by different glycoforms of CSA secreted into the intervillous space,47 or by fibrin deposition.48 Rosette formation (the adhesion of two or more uninfected erythrocytes to IE) may be important in cerebral malaria pathogenesis,49 but plays little role in placental infection.50,51 And CSA binding IE, unlike other IE, adsorb IgM, which may also promote sequestration.52

Relevance of placental pathology to evaluating interventions.

Studies on malaria in pregnancy usually use “placental malaria” as an outcome. Placental malaria can be measured either by preparing and staining slides from placental blood, or by evaluation of stained placental biopsies (histopathology). Histopathology is almost twice as sensitive as placental blood slides for detection of current parasitemia.37 Placental histopathology reflects not only current malaria infections, but infections preceding delivery by up to one month. Useful schemes to categorize placental histologic changes have been developed.53 Collection and examination of placental biopsies for signs of past and present malaria infection requires little technological support, and detection of malaria-associated changes can be readily taught. The most sensitive way to assess malaria during pregnancy is by frequent (e.g., weekly) examination of blood slides made at antenatal visits, but this is rarely possible. Thus, in comparing studies and designing new ones, the advantages and disadvantages of the various methods of detecting malaria in pregnancy must be weighed.

Parasite proteins causing placental infection.

Placental IE express unique variant surface antigens (VSA), which mediate placental adhesion, have unique antigenic properties, and are recognized in a gender- and parity-specific manner.42,54,55 Moreover, positive associations between levels of antibody to VSA expressed by CSA-binding isolates at delivery and birth weight, gestation and maternal hemoglobin have been reported in certain subsets of women.56,57 The principal parasite ligand mediating CSA adhesion and believed to mediate placental sequestration, and the dominant VSA on the IE surface, is P. falciparum erythrocyte membrane protein 1 (PfEMP1), encoded by the var multigene family.5860 PfEMP1 and its encoding var genes have been the principal focus of studies into the basis of placental sequestration.61 After several false starts, compelling evidence has now emerged that one var gene, termed var2csa, is expressed by most CSA binding isolates.62,63 Deletion of var2csa largely or completely abolished CSA adhesion,64,65 placental isolates usually transcribe high levels of var2csa,66,67 and certain var2csa domains bind CSA in vitro.68 IE expressing the VAR2CSA protein, and var2csa domains expressed as recombinant proteins, are recognized in a gender- and parity-specific manner, characteristic of immunity to malaria in pregnancy,62 and levels of antibody to these proteins correlate with protection in some subgroups.69,70

Available data, then, suggest that var2csa may be a promising vaccine candidate (Table 1), but enthusiasm must be tempered somewhat. Sequence similarities among var2csa sequences vary, from 54–94%,67,71 and different CSA-binding isolates show distinct, as well as conserved epitopes.72 Protein studies of the erythrocyte surface suggest that other PfEMP1s are also expressed in placental malaria72,73; other pregnancy-specific parasite proteins may be expressed on the IE surface; and other receptors may be used for placental sequestration.74,75 Nevertheless, we must urgently pursue this promising target to identify sequences that might form part of a pregnancy-specific vaccine.

Cellular immunity to placental malaria.

Placental malaria disrupts the normal immune balance in the placenta,76 causing increased synthesis of inflammatory cytokines like TNF, interleukin (IL) 2, and interferon γ.7779 Levels of TNF have been associated with LBW and anemia,77,80 while IFN γ production in vitro by placental cells has been associated with decreased prevalence of placental malaria.78 Chemokines produced by monocytes and syncytiotrophoblast may be important in attracting monocytes to the placenta,81 and infiltrates also include increased numbers of neutrophils and T cells.82 Although peripheral blood T cell responses may be decreased in malaria,83 this may be due to trafficking of memory T cells out of the circulation. How T-cell responses relate to pregnancy outcomes is an important area for future study.

OTHER MALARIA VACCINES

Vaccines targeting pre-erythrocytic stages and merozoite antigens of P. falciparum and P. vivax are in advanced development.84 Of these, RTS,S/AS02 gave children 1–4 years old about 30% protection against clinical malaria, and is now entering wider studies.85 Earlier studies in adults showed modest protection in the context of pre-existing immunity.86 Some groups of pregnant women, such as young primi-gravidae and HIV-infected women, lack immunity to sporozoite and merozoite antigens87,88 (although it is unclear whether this translates into altered disease susceptibility), and levels of antibody to MSP119 may protect against placental malaria.89 It is critical to address pregnancy malaria in vaccine studies to determine whether, and under what circumstances, pregnant women and their babies may benefit from such vaccines.

MALARIA PREVENTION AND PROTECTIVE IMMUNITY

Protection from malaria in pregnancy includes use of ITNs and administration of regular doses of effective antimalarials through antenatal clinics, most recently as IPTp. In earlier studies, weekly chemoprophylaxis with pyrimethamine-dapsone in first pregnancy did not increase susceptibility to malaria in subsequent pregnancy, but treatment often commenced in the third trimester.90 More recently, primigravid women receiving SP IPTp developed less antibody to CSA binding isolates than did matched placebo recipients.91 ITN use throughout pregnancy was associated with decreased IgG antibody to Liver Stage Antigen 1 and MSP119, but increased antibody to CSP, although differences were modest; antibody to CSA binding isolates was not measured.92 Future studies should further explore the impact of ITNs and IPTp on development of protective immunity, and further investigate whether effective malaria prevention in first pregnancy increases subsequent susceptibility to placental malaria.

Timing of preventive therapy, infection, and susceptibility.

Currently, WHO recommends administration of two or more doses of a safe, effective antimalarial after the end of the first trimester to all pregnant women.93 HIV-infected women may require additional doses,7 and monthly administration may be operationally more effective.94 Recommendations are to start antimalarials after quickening (perception of fetal movements, usually at 16–18 weeks in primigravidae). However, the development of these regimens has been guided more by operational issues than pathogenesis.

Malaria may have important effects on the fetus before IPTp is usually administered. Susceptibility to malaria increases early in pregnancy, and parasitemias peak at 9–16 weeks,14,95 when few maternal blood cells are circulating through the placenta.96 Therefore, early susceptibility may be hormonal9799 or immunologic in origin, rather than due to selective advantages of placental variants. Prevention of placental sequestration (e.g., by vaccination against VAR2CSA) may not prevent these early infections, whereas pre-erythrocytic and merozoite-based vaccines might have an impact.

Malaria in early pregnancy, acting locally in the placenta or as a systemic illness, could disrupt the process of placentation and spiral artery remodeling, which continues until 20 weeks gestation.100 TNF, released during early malaria infection, may impair trophoblast invasion.77,101 If this process of placentation is impaired, this may lead to inadequate blood flow later in pregnancy, as in pre-eclampsia.102 Placental malaria has been associated with similar blood flow changes.103 Longitudinal studies relating Doppler and grey scale ultrasound to pregnancy malaria may clarify this relationship, and help us decide whether malaria prevention strategies should be commenced earlier in pregnancy. Our obligations to treat infected participants create logistic challenges for such studies.

Timing of IPTp administration in late pregnancy may be important, too. A 2-dose SP regimen is often begun at about 20–22 weeks,6,20 and repeated 4 weeks later,93 affording 2–3 weeks further prophylaxis.104 This timing may result in the pregnant woman being unprotected from about 30 weeks, when fetal growth peaks at about 200 g/week, before it declines to about 150 g/wk by term (Figure 1). Concerns regarding SP administration close to term, deriving from observations that parenteral sulfa drugs caused kernicterus in premature infants,105 have not been borne out in practice,7 and SP IPTp is not known to cause neonatal toxicity. As coverage with IPTp and ITNs is scaled up, it will be important to more closely evaluate timing of infection and duration of coverage with antimalarials as important variables.

Malaria in the puerperium needs study. On one hand, increased susceptibility to malaria continues into the puerperium,28,106 and IPTp should perhaps be continued after delivery. On the other hand, puerperal sepsis is a leading cause of maternal death in sub-Saharan Africa,107 and is frequently misdiagnosed as malaria.

PRE-TERM DELIVERY AND FETAL GROWTH RESTRICTION

In studies dissecting the causes of LBW due to malaria, acute infection and high parasitemia are associated with PTD, whereas chronic placental inflammatory infiltrates are especially associated with FGR.31 Timing differs, with PTD and FGR peaking at different times in the malaria season in The Gambia.108 The molecular mechanisms underlying PTD and FGR differ, with increases in inflammatory cytokines such as TNF and IL-8 in FGR but not PTD due to malaria (Figure 2).79,81 Chorioamnionitis is an important confounder in such studies, rarely taken into account.81

These outcomes are critically important for intervention studies. However, there are numerous problems associated with their measurement. To assess PTD, accurate gestational ages are necessary. However, women in developing countries rarely remember the date of their last menstrual period and neonatal assessment methods such as the Dubowitz and Ballard scores are inaccurate by up to 2 weeks.109 Studies using early fetal ultrasound for accurate gestational age assessments have only recently started and are in progress.

The definition of FGR is also quite difficult. Typically, FGR is defined as weight for gestational age in the lowest 10th percentile of a standard Western population. However, depending on the standard population used, the cut-offs can vary widely.110 Thus, better standardization of this definition is needed.

MATERNAL NUTRITION AND MALARIA

Maternal nutrition, especially protein and energy intake before and during pregnancy, is an important determinant of birth weight. Like malaria, maternal nutrition often shows marked seasonality, with food availability at its lowest when malaria incidence is rising108; under-nutrition and malaria are both diseases of the rural poor. Maternal macronutrient supplementation has been shown to improve birth weight,111 but the effects of under-nutrition on malaria susceptibility have not been explored. Future studies must take into account maternal nutritional status when evaluating malaria interventions. It may be that combining IPT and ITNs with nutritional intervention could result in additional benefits for infant and maternal health.

ANEMIA: ETIOLOGY AND PREVENTION

The etiology of maternal anemia is complex, and nutrient deficiencies, worm infestation, chronic inflammation, and HIV are important contributing factors.23,112 About half of pregnant women in sub-Saharan Africa have iron deficiency.113 Nevertheless, placental malaria also contributes significantly to maternal anemia, especially in the first pregnancy,19 and thus to maternal mortality.2 Placental inflammation has a central role, as placental TNF release and monocyte infiltrates are associated with maternal anemia.32,36,77,79

MALARIA AND THE NEONATE

Newborns in areas of high malaria transmission are relatively protected from malaria in early life, although the mechanisms are not fully understood.114,115 Cord blood infection is commonly detected, especially when molecular diagnosis is used,116,117 but symptomatic neonatal infection is rare in endemic areas.118 Contributing factors may include innate mechanisms (including fetal hemoglobin and PABA-deficient breast milk), cultural ones (swaddling of newborns, decreasing their exposure), transplacental transfer of protective antibody,119,120 and priming of neonatal responses by transplacental transfer of parasites or their products.121,122 In case reports from the U.S., newborns of non-immune women have developed severe febrile illness due to P. falciparum or P. vivax malaria.123 The apparent rareness of similar cases in babies of semi-immune women suggests a central protective role for transplacental antibody transfer. HIV infection interferes with this process.124,125 Whether this increases susceptibility of children of HIV-infected mothers to malaria is unknown.

ANTIMALARIALS IN PREGNANCY

The selection of drugs for malaria treatment and prevention in pregnancy has recently been reviewed in detail.126128 Three points are pertinent to this review: pharmacokinetics of antimalarials in pregnancy, timing of treatment (reviewed above), and drug resistance.

PHARMACOKINETICS

The distribution and metabolism, and thus the effective concentration of many drugs are altered in pregnancy. We have surprisingly little information on how these changes affect antimalarials, but we do know that levels of several important drugs are decreased, perhaps to the point where concentrations are subtherapeutic.127,129131 There are no published data on SP pharmacokinetics in pregnancy. Before we decide a drug is failing in pregnancy, we should first ensure it has been given in adequate dosages.

SP has a long half-life: 160 hrs for pyrimethamine and 8 days for sulfadoxine. IPT with SP not only clears parasites, but also results in prophylactic concentrations of the drug in the patient serum for several weeks; drug-resistant parasites may not be suppressed by these low concentrations.104 If the efficacy of SP as an IPTp agent is, in part, due to this prophylactic effect, this has implications both for how evolving drug resistance will affect its efficacy, and for the selection of future agents for IPTp.

DRUG RESISTANCE

Most IPTp regimes in Africa currently use SP. Resistance to SP arises through mutations in the genes encoding dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS), the targets of pyrimethamine and sulfadoxine, respectively. These decrease parasite drug sensitivity to a degree that depends on the number and pattern of mutations.104 “Quintuple mutant” parasites (with mutations at positions 51, 59, and 108 of DHFR and 437 and 540 of DHPS) are now common in Eastern and Southern Africa,132 and were present in > 90% of pregnant Malawian women.133 In the same study, I164L mutations in DHFR (which convey high-level resistance to SP) were found in 4 of 85 samples. The relationship between molecular markers of drug resistance and drug efficacy in pregnancy is presently unknown. In South East Asia, rapid spread of these mutations rendered SP rapidly useless.134

TOXICITY

The rapid development of the fetus makes it highly susceptible to many chemotherapeutic agents. Effects of IPTp agents on the fetus need to be carefully monitored. This is difficult for two reasons. First, pregnancies in poor countries have a high background frequency of poor birth outcomes (e.g., stillbirths, neonatal deaths), so a study must be well powered to distinguish a drug-related effect from this background. Second, loss to follow-up is a big problem, and women who abort may simply drop out of studies. Recently, groups in several African countries have begun to establish pharmacovigilance networks, which may allow the identification of important toxicities of antimalarials or other drugs.135

FUTURE DIRECTIONS

Table 2 outlines some important and unresolved research questions relating to the pathogenesis and immunity of malaria in pregnancy.

CONCLUSIONS

Our understanding of the pathogenesis of malaria in pregnancy has improved significantly in recent years, but important gaps remain. Emerging knowledge of the special characteristics of parasites that cause placental malaria or that cause severe and fatal malaria in pregnancy may lead to new remedies. First, we must discover whether we are using existing tools in the right way. Will earlier and more frequent administration of IPTp in association with ITNs be cost-effective, and will these interventions then impair development of immunity? How do malaria, HIV, anemia and nutritional factors interact to cause low birth weight, or to cause severe disease in pregnant women, and what is the best strategy to minimize the negative effects of each? We hope that increased funding support for this area in coming years will allow some of these questions to be answered, potentially changing the ways in which we design and implement interventions to decrease the present enormous burden of malaria in pregnancy.

Table 1

Characteristics of var2csa that make it a candidate for development of a vaccine to prevent placental malaria

PropertyReference
* Studies predating description of var2csa, some using isolates subsequently confirmed to express var2csa.
Gender-specific recognition*55
Parity-dependent recognition of isolates expressing var2csa*54,55
Parity-dependent recognition of var2csa recombinant proteins69,70
Expressed by CSA binding isolates62,63,69
Expressed by most placental isolates66,67
Relative (54–95%) amino acid conservation67,71,136
Antibodies to isolates expressing var2csa, or to var2csa recombinant proteins, associated with protection from malaria in pregnancy56,57,69,70
Var2csa knockout largely or completely loses CSA binding64,65
Table 2

Future research directions for pathogenesis and immunity of malaria in pregnancy

  1. Examining the importance, pathophysiological basis, and consequences of malaria infection in early pregnancy, especially the first trimester.

  2. Examining how IPTp affects evolution of natural immunity to malaria in pregnancy.

  3. Understanding interactions between malaria, HIV, maternal nutrition, and anemia in determining infant birth weight.

  4. Obtaining better data on the importance of malaria as a cause of maternal death, and of the burden of severe and cerebral malaria in pregnancy in areas of different transmission intensity.

  5. Longitudinal studies of effects of malaria in pregnancy on placental function, fetal growth, and pregnancy outcome.

  6. Discovering the mechanisms underlying the development of anemia associated with malaria in pregnancy.

  7. Mapping diversity of var2csa and mapping antibody responses to epitopes within var2csa.135

  8. Discovering the importance of specific antibody responses to var2csa in disease protection.

Figure 1.
Figure 1.

Relationship between timing of IPTp, fetal growth rates, and potential vulnerability of mother and fetus to deleterious effects of malaria. The fetal growth rate varies over the course of pregnancy, peaking at about 36 weeks (curve). In the context of moderate SP resistance, IPTp (vertical arrows) may or may not clear infection, and offers a shortened period of prophylaxis against reinfection (attached horizontal black arrows).104 Reinfection during the period of vulnerability may affect fetal growth (double-headed arrow). The effects of malaria early in pregnancy (dotted arrow) on fetal growth are less well understood.

Citation: The American Journal of Tropical Medicine and Hygiene 77, 6_Suppl

Figure 2.
Figure 2.

Some potential pathogenic mechanisms by which placental malaria affects placental function and results in IUGR or PTD. IRBC, infected red blood cell; CSA, chondroitin sulfate A; IUGR, intrauterine growth retardation; PTD, preterm delivery.

Citation: The American Journal of Tropical Medicine and Hygiene 77, 6_Suppl

*

Address correspondence to Stephen J. Rogerson, Department of Medicine (RMH/WH), Post Office Royal Melbourne Hospital, Parkville VIC 3050, Australia. E-mail: sroger@unimelb.edu.au

Authors’ addresses: Stephen J. Rogerson, Department of Medicine (RMH/WH), Post Office Royal Melbourne Hospital, Parkville VIC 3050 Australia, Tel: +61 3 8344 3259, Fax: +61 3 9347 1863. Victor Mwapasa, Department of Community Health, College of Medicine, University of Malawi, Blantyre, Malawi, Tel: +265 677 245, Fax: +265 674-700. Steven R. Meshnick, Departments of Epidemiology and of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC, Tel: +919 966 7414, Fax: +919 966 2089.

Acknowledgments: Sarah Landis drafted Figure 1. The authors thank Philippe Boeuf for critical reading of the manuscript.

Financial Support: SJR is supported by a Wellcome Trust Senior Research Fellowship ref 063215 and by the National Health and Medical Research Council of Australia.

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Author Notes

Reprint requests: Stephen J. Rogerson, Department of Medicine (RMH), University of Melbourne, Post Office, Royal Melbourne Hospital Victoria 3050, Australia. Tel: +61 3 8344 3259, Fax: +61 3 9347 1863, E-mail: sroger@unimelb.edu.au
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