Pregnancy-associated malaria (PAM) or placental malaria is a presentation of the common illness that is particularly life-threatening to both mother and developing fetus. PAM is caused primarily by infection with Plasmodium falciparum, the most dangerous of the four species of malaria-causing parasites that infect humans. During pregnancy, a woman faces a much higher risk of contracting malaria and of associated complications. Prevention and treatment of malaria are essential components of prenatal care in areas where the parasite is endemic.
While the average adult citizen of an endemic region possesses some immunity to the parasite, pregnancy causes complications that leave the woman and fetus extremely vulnerable. The parasite interferes with transmission of vital substances through the fetal placenta, often resulting in stillbirth, spontaneous abortion, or dangerously low birth weight. The tragedy of malaria in developing countries receives abundant attention from the international health community, but until recently PAM and its unique complications were not adequately addressed.
Signs and Symptoms
Women experiencing PAM may exhibit normal symptoms of malaria, but may also be asymptomatic or present with more mild symptoms, including a lack of the characteristic fever. This may prevent a woman from seeking treatment despite the danger to herself and her unborn child.
The disease results from the aggregation of erythrocytes infected by Plasmodium falciparum which have been shown to adhere to chondroitin sulfate A (CSA) on placental proteoglycans causing them to accumulate in the intervillous spaces of the placenta, blocking the crucial flow of nutrients from mother to embryo.
Globally, an estimated 125 million or more pregnant women per year risk contracting PAM. Pregnancy-related malaria causes around 100,000 infant deaths each year, due in large part to low birth weight.
P. falciparum expresses proteins on the surface of parasite-infected erythrocytes (IE) helping them bind to an unusually low-sulfated form of chondroitin sulfate A (CSA) in the placental intervillous space. By this process, the parasite avoids being filtered through the spleen where it would be cleared from the bloodstream and killed. When selected in vitro for CSA-binding, the only upregulated gene expressed in the P. falciparum parasites was the var2csa gene. Parasite clones where the var2csa gene was disrupted lost the ability to adhere to CSA by blocking the binding of IE. Its protein, VAR2CSA (Variant Surface antigen 2-CSA), belongs to the P. falciparum Erythrocyte Membrane Protein 1 (PfEMP1) family and contains six Duffy binding-like (DBL) domains. The regions that mediate binding to CSA have not been defined, but DBL2, DBL3, and DBL6 have shown the highest affinity for CSA binding when testing with recombinant single-domains.
Each VAR2CSA domain has a potential affinity to CSA, but there are large areas not exposed to the immune system and appear to be buried in the quaternary structure. Data has indicated that these domains interact, forming a binding site that is specific for low-sulfated CSA found in the placenta. The binding of antibodies to one of these domains would prevent adhesion of parasitic IE in the placenta.
Moreover, studies have shown that women acquire immunity to PAM through antibody recognition of the VAR2CSA domain, also known as VSAPAM, after exposure during their first pregnancy. By measuring circulating levels of IgG antibodies that presumably target VAR2SCA, the study demonstrated that subsequent pregnancies confer progressively greater protection to PAM. Thus, PfEMP1 proteins such as the VAR2CSA domain could prove attractive as potential candidates for vaccine targets.
- Srivastava, Anand; Gangnard, Stéphane; Round, Adam; Dechavanne, Sébastien; Juillerat, Alexandre; Raynal, Bertrand; Faure, Grazyna; Baron, Bruno; et al. (2010). "Full-length extracellular region of the var2CSA variant of PfEMP1 is required for specific, high-affinity binding to CSA". Proceedings of the National Academy of Sciences 107 (11): 4884–9. doi:10.1073/pnas.1000951107. PMC 2841952. PMID 20194779. Lay summary – ScienceDaily (March 12, 2010).
- "CDC-Malaria-Malaria Parasites". Centers for Disease Control and Prevention.
- Perlmann, P; Troye-Blomberg, M (2000). "Malaria blood-stage infection and its control by the immune system". Folia biologica 46 (6): 210–8. PMID 11140853.
- "Lives at Risk: Malaria in Pregnancy". WHO. Retrieved March 30, 2011.
- Duffy, P. E.; M. Fried (2005). "Malaria in the Pregnant Woman". Current Topics in Microbiology and Immunology 295: 169–200. doi:10.1007/3-540-29088-5_7. PMID 16265891.
- Doolan, Denise L.; Dobano, Carlota; Baird, J. Kevin (2009). "Acquired Immunity to Malaria". Clinical Microbiology Reviews 22 (1): 13–36, Table of Contents. doi:10.1128/CMR.00025-08. PMC 2620631. PMID 19136431.
- Matteelli, BY; Caligaris, S; Castelli, F; Carosi, G (1997). "The placenta and malaria". Annals of Tropical Medicine and Parasitology 91 (7): 803–10. doi:10.1080/00034989760563. PMID 9625937.
- "Roll Back Malaria: Malaria in Pregnancy". WHO. Retrieved 18 April 2011.
- Desai, Meghna; et al. (22 January 2007). "Epidemiology and burden of malaria in pregnancy". The Lancet 7 (2): 93–104. doi:10.1016/S1473-3099(07)70021-X. Retrieved April 14, 2011.
- "Burden of Malaria in Pregnancy in Latin America Not Known". Centers for Disease Control and Prevention. Retrieved April 14, 2011.
- "New study finds 125 million pregnancies globally at risk from malaria every year". Malaria in Pregnancy Consortium. Retrieved April 14, 2011.
- Fried, M., and P. E. Duffy. 1996. Adherence of Plasmodium falciparum to chondroitin sulfate A in the human placenta. Science 272:1502-1504.
- Nielsen, M.A., Pinto, V.V., Resende, M., Dahlback, M., Ditlev, S.B., Theander, T.G. and Salanti, A. (2009). Induction of Adhesion-Inhibitory Antibodies against Placental Plasmodium falciparum Parasites by Using Single Domains of VAR2CSA. Infection and Immunity. 23:2482-2487.
- David, P.H., Hommel, H., Miller, L.H., Udeinya, I.J. And Oligino, L.D. (1983). Parasite sequestration in Plasmodium falciparum malaria: spleen and antibody modulation of cytoadherence of infected erythrocytes. Proc. Natl. Acad. Sci. 80: 5075-5079.
- Resende, M., Ditlev, S.B., Nielsen, M.A., Bodevin, S., Bruun, S., Pinto, V.V., Clausen, H., Turner, L., Theander, T.G., Salanti, A. and Dahlback, M. (2009). Chondroitin sulphate A (CSA)-binding of single recombinant Duffy-binding-like domains is not restricted to Plasmodium falciparum Erythrocyte Membrane Protein 1 expressed by CSA-binding parasites. International Journal for Parasitology. 39 (11), 1195-1204.
- Salanti, A., T. Staalsoe, T. Lavstsen, A. T. R. Jensen, M. P. K. Sowa, D. E. Arnot, L. Hviid, and T. G. Theander. 2003. Selective upregulation of a single distinctly structured var gene in chondroitin sulphate A-adhering Plasmodium falciparum involved in pregnancy-associated malaria. Mol. Microbiol. 49:179-191.
- Duffy, P. E., and M. Fried. 2003. Antibodies that inhibit Plasmodium falciparum adhesion to chondroitin sulfate A are associated with increased birth weight and the gestational age of newborns. Infect. Immun. 71:6620-6623.
- Viebig, N. K., B. Gamain, C. Scheidig, C. Lepolard, J. Przyborski, M. Lanzer, J. Gysin, and A. Scherf. 2005. A single member of the Plasmodium falciparum var multigene family determines cytoadhesion to the placental receptor chondroitin sulphate A. EMBO Rep. 6:775-781.
- Gamain, B., A. R. Trimnell, C. Scheidig, A. Scherf, L. H. Miller, and J. D. Smith. 2005. Identification of multiple chondroitin sulfate A (CSA)-binding domains in the var2CSA gene transcribed in CSA-binding parasites. J. Infect. Dis. 191(6):1010-1013.
- Andersen, P., Nielsen, M.A., Resende, M., Rask, T.S., Dahlback, M., Theander, T. Lund, O. and Salanti, A. (2008). Structural insight into epitopes in the pregnancy-associated malaria protein VAR2CSA. PLoS. Pathog. 4:e42
- Avril, M., Gamain, B., Lepolard, C., Viaud, N., Scherf, A. And Gysin, J. (2006). Characterization of anti-var2CSA-PfEMP1 cytoadhesion inhibitory mouse monoclonal antibodies. Microbes Infect. 8:2863-2871.
- Fernandez, P., Kviebig, N., Decchavanne, S., Lepolard, C., Gysin, J., Scherf, A. And Gamain, B. (2008). Var2CSA DBL6-epsilon domain expressed in HEK293 induces limited cross-reactive and blocking antibodies to CSA binding parasites. Malar. J., 7: 170
- Brabin, BJ (1983). "An analysis of malaria in pregnancy in Africa.". Bulletin of the World Health Organization 61 (6): 1005–16. PMC 2536236. PMID 6370484.
- "Prevention and Treatment of Malaria in Pregnancy in Sub-Saharan Africa" (PDF). United States Agency for International Development. February 2007.
- "Malaria in Pregnancy Resource Package". Jhpiego.