06/11/2023
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.
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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.5–9 Unfortunately, high-level coverage with SP IPTp and ITNs has not yet been achieved.10–13
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.
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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.32–36 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.58–60 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.
