Abstract and Introduction
Abstract
Despite increased malaria control efforts, recent reports indicate that over 1.2 million deaths due to malaria occurred in 2010. Pregnant women represent a particularly vulnerable risk group as malaria infection can lead to life-threatening disease for the mother and fetus. With 125 million women at risk of malaria in pregnancy every year, better diagnostic tools are needed for timely identification and treatment of malaria infection. Diagnostic surveillance tools are also needed to estimate disease burden and inform public health policies. In this review, the authors focus on malaria diagnostics in pregnancy and discuss considerations for different Plasmodium species and geographic regions. The authors also look at promising diagnostic modalities to monitor fetal and maternal health in pregnancy and discuss implementation barriers for low resource settings.
Introduction
An estimated 125 million women become pregnant every year in malaria endemic regions.[1] Despite renewed global malaria control efforts, pregnant women and their unborn children face a disproportionately high burden of disease. Pregnant women are more likely to be infected with malaria than their nonpregnant counterparts and are at increased risk of adverse clinical outcomes including anemia and death.[2,3] Pregnancies exposed to malaria are at increased risk of miscarriage, stillbirth, preterm delivery and fetal growth restriction.[3] Malaria is estimated to contribute to 200,000 infant deaths annually as a result of low birthweight (LBW) deliveries.[4] Accurate diagnosis of malaria infection during pregnancy is critical for timely and appropriate clinical management. Limitations of current diagnostic tools combined with inadequate access to antenatal care result in missed diagnoses, delayed treatment and serious health implications for mother and child.
Malaria diagnostics cannot be discussed without first highlighting the complex interplay between the host and parasite. While all pregnant women are at increased risk of malaria, a woman's level of immunity prior to pregnancy is a critical determinant of outcome.[5] In areas of high malaria transmission, pregnant women are often paucisymptomatic or asymptomatic during infection, making clinical diagnosis challenging. Primigravidae are at the highest risk of infection and adverse pregnancy outcomes because they lack immunity to 'pregnancy-specific' variants of Plasmodium falciparum that selectively accumulate in the placental intervillous space leading to placental malaria (malaria parasites detected in the placenta) and occult placental malaria (malaria detected in the placental blood and not in the peripheral blood). Several lines of evidence indicate that the parasitized erythrocytes infiltrating the placenta are functionally and antigenically distinct from those observed in nonpregnant individuals.[6] Placental parasite isolates express novel variable surface antigens on the parasitized erythrocyte surface that confer a distinctive adhesive phenotype allowing them to sequester in the placenta. Whereas almost all nonplacental isolates of P. falciparum bind to the scavenger receptor CD36, placental isolates preferentially bind to glycosaminoglycans such as chondroitin sulfate A expressed on placental syncytiotrophoblast, and uniquely do not adhere to CD36.[6,7] Immunity to placental malaria is acquired over subsequent pregnancies as women develop antibodies to prevent P. falciparum sequestration and enhance opsonic clearance of parasitizes erythrocytes.[6–8]
Immunocompromised women (i.e., HIV positive) fail to develop this protective immune response and thus women of all gravidae are susceptible to malaria and its associated consequences.[8] This scenario is common in sub-Saharan Africa where P. falciparum is the dominant species and on average 26% of women are infected with malaria at delivery[9] (African region; AFRO, Figure 1). In hyperendemic areas such as Cameroon, up to 100% of primigravidae and over 90% of multigravidae may test positive for malaria at least once during pregnancy.[10]
Figure 1.
Risk distribution for malaria in pregnancy. A map depicting the spatial distribution of malaria globally with the number of pregnancies at risk of Plasmodium falciparum and Plasmodium vivax by region with the associated public-health policies for malaria prevention and treatment. The colors represent the mean point estimates of the age-standardized annual mean P. falciparum parasite rate in children aged 2–10 years (PfPR2-10) within the spatial limits of stable transmission [74. (A) The distribution of P. vivax is similar to that of falciparum but with slightly wider distribution in the Asia–Pacific region [1]. The distribution of P. vivax in the African region is restricted to Madagascar and eastern Africa around the Horn of Africa (for full details see [1]).
AFRO: Africa region; AMRO: American region; PfAPI: Annual parasite incidence for P. falciparum; PfPR2–10: The estimated proportion of 2–10-year-olds in the general population that are infected with P. falciparum at any one time, averaged over the 12 months of 2010; SP: Sulfadoxine–pyrimethamine.
In areas of low or unstable malaria transmission (e.g., Asia–Pacific region), on average 11% of women are infected with malaria at delivery and 35% or more will have malaria at some point during pregnancy.[11] Women in areas of low transmission lack immunity to malaria and are more likely to be symptomatic and develop severe and life-threatening disease including hypoglycemia and coma.[5] This is typified by transmission in the Asia–Pacific region where malaria transmission is highly heterogeneous and mixed-species infections complicate diagnosis and treatment. In such areas, frequent screening is used to identify and treat infections, before women become symptomatic and pregnancies are at risk.[12] In the American Region, another 4 million women are at risk of malaria in pregnancy where there is roughly an equal distribution between Plasmodium vivax and P. falciparum malaria.[1] However, there is a paucity of population estimates on malaria prevalence from central and South America. Although there are policies in place recommending malaria screening of pregnant women through antenatal care, there are indications that this may not be practiced.[13]
Generally, areas of unstable transmission coincide with P. vivax transmission. Although P. vivax does not seem to accumulate in the placenta to the same degree as P. falciparum, recent evidence suggests that it can adhere of placental glycosaminoglycans and does cause maternal anemia and fever, which contribute to both preterm delivery[14,15] and fetal growth restriction.[16,17] The majority of P. vivax transmission globally occurs in the Asia–Pacific region (>80%, 76 million pregnancies at risk), which is also home to considerable numbers of women at risk of P. falciparum both in areas of stable and unstable malaria transmission.[1]
To reduce the deleterious impact of malaria on pregnancy, a multifaceted prevention-focused approach is required.[18] This involves the use of long-lasting insecticidal nets among pregnant women, indoor residual spraying and intermittent preventive treatment of malaria in pregnancy (IPTp) in areas of high malaria transmission. Prompt recognition and treatment of malaria infections (symptomatic and asymptomatic) are necessary to prevent maternal anemia and LBW. Microscopy or rapid diagnostic tests (RDTs) are currently used for the diagnosis of malaria in pregnancy but are insensitive to sequestration or low-level parasite burdens, complicating malaria diagnosis. As a result, healthcare workers may miss other causes of fever in pregnancy due, in part, to a lack of suitable field appropriate diagnostics.
Current policies across endemic regions recommend the use of IPTp, which involves the administration of at least two curative doses sulfadoxine–pyrimethamine (SP) following quickening (first perceived fetal movements). SP is attractive for treatment of malaria in pregnancy as it consists of a single treatment dose that has long-lasting prophylactic (~4 weeks) protection and is safe for use in pregnancy.[18] However, drug-resistant parasites threaten SP-IPTp programs in some regions and make it obsolete in others.[19,20] To date, there are no suitable drugs to replace SP in IPTp programs. Mefloquine is effective for chemoprophylaxis in pregnancy,[19] but has not been implemented as an alternative drug for IPTp because of a perceived risk of adverse effects when given at treatment doses (three- to five-times the chemoprophylaxis dose). Currently, a multisite trial is underway to assess the efficacy, safety and tolerability of different dosing regimens (MIPPAD Trial, NOD 00811421). Intermittent screening and treatment (IST) is an alternative clinical management approach that has been implemented in parts of Asia and is proposed for use in Africa, with field trials currently underway. As the name suggests, IST relies on active case detection of malaria.[21] With a proposed shift from passive to active case detection, it is time to consider alternative diagnostic methods with the potential to improve identification of malaria in pregnancy. Technologies are needed that are appropriate for field use in resource-limited settings and may be scaled up for population-wide case detection.
While appropriate diagnosis and treatment of malaria in pregnancy is paramount, diagnostic tools capable of assessing fetal risk are also important. The association between malaria infection in pregnancy and LBW, through fetal growth restriction or preterm delivery, is well established. Diagnostic tools, which can identify pregnancies at risk of poor birth outcomes, are important to ensure high-risk pregnancies are closely monitored. In this review, the authors discuss the current diagnostic tools used to identify malaria in pregnancy and highlight emerging technologies with the potential for scale-up in malaria endemic areas. The authors will also focus on biomarkers as objective measures that can be used as surrogate markers of infection (parasite antigen, hemozoin) or to assess fetal risk (host biomarkers). Studies included in this review were identified using an English language PubMed search and selected following abstract review by Andrea Conroy or Chloe Macdonald. Additional references were identified by reviewing references in the selected manuscripts. This review is intended to be an overview of malaria diagnostics in pregnancy: for a more detailed review of malaria diagnostics refer to a recent review by Erdman and Kain.[22]
Expert Rev Anti Infect Ther. 2012;10(11):1331-1342. © 2012 Expert Reviews Ltd.
