Volume 94, Issue 5
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645



Heterozygous hemoglobin S (HbAS), or sickle trait, protects children from life-threatening falciparum malaria, potentially by attenuating binding of -infected red blood cells (iRBCs) to extracellular ligands. Such binding is central to the pathogenesis of placental malaria (PM). We hypothesized that HbAS would be associated with reduced risks of PM and low birth weight (LBW). We tested this hypothesis in 850 delivering women in southern Malawi. Parasites were detected by polymerase chain reaction in placental and peripheral blood, and placentae were scored histologically for PM. The prevalence of HbAS was 3.7%, and 11.2% of infants were LBW (< 2,500 g). The prevalence of was 12.7% in placental and 8.5% in peripheral blood; 24.4% of placentae demonstrated histological evidence of . HbAS was not associated with reduced prevalence of in placental (odds ratio [OR]: 1.27, 95% confidence interval [CI]: 0.50–3.23, = 0.61) or peripheral blood (OR: 2.53, 95% CI: 1.08–2.54, = 0.03), prevalence of histological PM (OR: 0.97, 95% CI: 0.40–2.34, = 0.95), or prevalence of LBW (OR: 0.82, 95% CI: 0.24–2.73, = 0.74). Mean (standard deviation) birth weights of infants born to HbAS (2,947 g [563]) and, homozygous hemoglobin A (2,991 g [465]) mothers were similar. Across a range of parasitologic, clinical, and histologic outcomes, HbAS did not confer protection from PM or its adverse effects.


Article metrics loading...

The graphs shown below represent data from March 2017
Loading full text...

Full text loading...



  1. Taylor SM, Cerami C, Fairhurst RM, , 2013. Hemoglobinopathies: slicing the Gordian knot of Plasmodium falciparum malaria pathogenesis. PLoS Pathog 9: e1003327.[Crossref] [Google Scholar]
  2. Taylor SM, Parobek CM, Fairhurst RM, , 2012. Haemoglobinopathies and the clinical epidemiology of malaria: a systematic review and meta-analysis. Lancet Infect Dis 12: 457468.[Crossref] [Google Scholar]
  3. Williams TN, Obaro SK, , 2011. Sickle cell disease and malaria morbidity: a tale with two tails. Trends Parasitol 27: 315320.[Crossref] [Google Scholar]
  4. Aidoo M, Terlouw DJ, Kolczak MS, McElroy PD, ter Kuile FO, Kariuki S, Nahlen BL, Lal AA, Udhayakumar V, , 2002. Protective effects of the sickle cell gene against malaria morbidity and mortality. Lancet 359: 13111312.[Crossref] [Google Scholar]
  5. Bunn HF, , 2013. The triumph of good over evil: protection by the sickle gene against malaria. Blood 121: 2025.[Crossref] [Google Scholar]
  6. Ayi K, Turrini F, Piga A, Arese P, , 2004. Enhanced phagocytosis of ring-parasitized mutant erythrocytes: a common mechanism that may explain protection against falciparum malaria in sickle trait and beta-thalassemia trait. Blood 104: 33643371.[Crossref] [Google Scholar]
  7. Cabrera G, Cot M, Migot-Nabias F, Kremsner PG, Deloron P, Luty AJ, , 2005. The sickle cell trait is associated with enhanced immunoglobulin G antibody responses to Plasmodium falciparum variant surface antigens. J Infect Dis 191: 16311638.[Crossref] [Google Scholar]
  8. Brabin BJ, Romagosa C, Abdelgalil S, Menéndez C, Verhoeff FH, McGready R, Fletcher KA, Owens S, d'Alessandro U, Nosten F, Fischer PR, Ordi J, , 2004. The sick placenta—the role of malaria. Placenta 25: 359378.[Crossref] [Google Scholar]
  9. Rogerson SJ, Hviid L, Duffy PE, Leke RF, Taylor DW, , 2007. Malaria in pregnancy: pathogenesis and immunity. Lancet Infect Dis 7: 105117.[Crossref] [Google Scholar]
  10. Salanti A, Staalsoe T, Lavstsen T, Jensen AT, Sowa MP, Arnot DE, Hviid L, Theander TG, , 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: 179191.[Crossref] [Google Scholar]
  11. Sander AF, Salanti A, Lavstsen T, Nielsen MA, Theander TG, Leke RG, Lo YY, Bobbili N, Arnot DE, Taylor DW, , 2011. Positive selection of Plasmodium falciparum parasites with multiple var2csa-type PfEMP1 genes during the course of infection in pregnant women. J Infect Dis 203: 16791685.[Crossref] [Google Scholar]
  12. Rogerson SJ, Mwapasa V, Meshnick SR, , 2007. Malaria in pregnancy: linking immunity and pathogenesis to prevention. Am J Trop Med Hyg 77: 1422. [Google Scholar]
  13. Plowe CV, Djimde A, Bouare M, Doumbo O, Wellems TE, , 1995. Pyrimethamine and proguanil resistance-conferring mutations in Plasmodium falciparum dihydrofolate reductase: polymerase chain reaction methods for surveillance in Africa. Am J Trop Med Hyg 52: 565568. [Google Scholar]
  14. Rogerson SJ, Pollina E, Getachew A, Tadesse E, Lema VM, Molyneux ME, , 2003. Placental monocyte infiltrates in response to Plasmodium falciparum malaria infection and their association with adverse pregnancy outcomes. Am J Trop Med Hyg 68: 115119. [Google Scholar]
  15. Taylor SM, Messina JP, Hand CC, Juliano JJ, Muwonga J, Tshefu AK, Atua B, Emch M, Meshnick SR, , 2011. Molecular malaria epidemiology: mapping and burden estimates for the Democratic Republic of the Congo, 2007. PLoS One 6: e16420.[Crossref] [Google Scholar]
  16. Rantala AM, Taylor SM, Trottman PA, Luntamo M, Mbewe B, Maleta K, Kulmala T, Ashorn P, Meshnick SR, , 2010. Comparison of real-time PCR and microscopy for malaria parasite detection in Malawian pregnant women. Malar J 9: 269.[Crossref] [Google Scholar]
  17. Modiano D, Luoni G, Sirima BS, Simpore J, Verra F, Konate A, Rastrelli E, Olivieri A, Calissano C, Paganotti GM, D'Urbano L, Sanou I, Sawadogo A, Modiano G, Coluzzi M, , 2001. Haemoglobin C protects against clinical Plasmodium falciparum malaria. Nature 414: 305308.[Crossref] [Google Scholar]
  18. Fairhurst RM, Fujioka H, Hayton K, Collins KF, Wellems TE, , 2003. Aberrant development of Plasmodium falciparum in hemoglobin CC red cells: implications for the malaria protective effect of the homozygous state. Blood 101: 33093315.[Crossref] [Google Scholar]
  19. Fairhurst RM, Baruch DI, Brittain NJ, Ostera GR, Wallach JS, Hoang HL, Hayton K, Guindo A, Makobongo MO, Schwartz OM, Tounkara A, Doumbo OK, Diallo DA, Fujioka H, Ho M, Wellems TE, , 2005. Abnormal display of PfEMP-1 on erythrocytes carrying haemoglobin C may protect against malaria. Nature 435: 11171121.[Crossref] [Google Scholar]
  20. Cholera R, Brittain NJ, Gillrie MR, Lopera-Mesa TM, Diakite SA, Arie T, Krause MA, Guindo A, Tubman A, Fujioka H, Diallo DA, Doumbo OK, Ho M, Wellems TE, Fairhurst RM, , 2008. Impaired cytoadherence of Plasmodium falciparum-infected erythrocytes containing sickle hemoglobin. Proc Natl Acad Sci USA 105: 991996.[Crossref] [Google Scholar]
  21. Wang Y, Zhao S, , 2010. Vascular Biology of the Placenta. Integrated Systems Physiology: From Molecules to Function to Disease. San Rafael, CA: Morgan and Claypool Life Sciences. [Google Scholar]
  22. Srivastava A, Gangnard S, Round A, Dechavanne S, Juillerat A, Raynal B, Faure G, Baron B, Ramboarina S, Singh SK, Belrhali H, England P, Lewit-Bentley A, Scherf A, Bentley GA, Gamain B, , 2010. Full-length extracellular region of the var2CSA variant of PfEMP1 is required for specific, high-affinity binding to CSA. Proc Natl Acad Sci USA 107: 48844889.[Crossref] [Google Scholar]
  23. Elsworth B, Matthews K, Nie CQ, Kalanon M, Charnaud SC, Sanders PR, Chisholm SA, Counihan NA, Shaw PJ, Pino P, Chan JA, Azevedo MF, Rogerson SJ, Beeson JG, Crabb BS, Gilson PR, de Koning-Ward TF, , 2014. PTEX is an essential nexus for protein export in malaria parasites. Nature 511: 587591.[Crossref] [Google Scholar]
  24. Larrabee KD, Monga M, , 1997. Women with sickle cell trait are at increased risk for preeclampsia. Am J Obstet Gynecol 177: 425428.[Crossref] [Google Scholar]
  25. Roopnarinesingh S, Ramsewak S, , 1986. Decreased birth weight and femur length in fetuses of patients with the sickle-cell trait. Obstet Gynecol 68: 4648. [Google Scholar]
  26. Brown S, Merkow A, Wiener M, Khajezadeh J, , 1972. Low birth weight in babies born to mothers with sickle cell trait. JAMA 221: 14041405.[Crossref] [Google Scholar]
  27. Baill IC, Witter FR, , 1990. Sickle trait and its association with birthweight and urinary tract infections in pregnancy. Int J Gynaecol Obstet 33: 1921.[Crossref] [Google Scholar]
  28. Blattner P, Dar H, Nitowsky HM, , 1977. Pregnancy outcome in women with sickle cell trait. JAMA 238: 13921394.[Crossref] [Google Scholar]
  29. Stamilio DM, Sehdev HM, Macones GA, , 2003. Pregnant women with the sickle cell trait are not at increased risk for developing preeclampsia. Am J Perinatol 20: 4148.[Crossref] [Google Scholar]
  30. Tan TL, Seed P, Oteng-Ntim E, , 2008. Birthweights in sickle cell trait pregnancies. BJOG 115: 11161121.[Crossref] [Google Scholar]
  31. Tuck SM, Studd JW, White JM, , 1983. Pregnancy in women with sickle cell trait. Br J Obstet Gynaecol 90: 108111.[Crossref] [Google Scholar]
  32. Adeyemi AB, Adediran IA, Kuti O, Owolabi AT, Durosimi MA, , 2006. Outcome of pregnancy in a population of Nigerian women with sickle cell trait. J Obstet Gynaecol 26: 133137.[Crossref] [Google Scholar]
  33. Okonofua FE, Odutayo R, Onwudiegwu U, , 1990. Maternal sickle cell trait is not a cause of low birthweight in Nigerian neonates. Int J Gynaecol Obstet 32: 331333.[Crossref] [Google Scholar]
  34. Desai M, ter Kuile FO, Nosten F, McGready R, Asamoa K, Brabin B, Newman RD, , 2007. Epidemiology and burden of malaria in pregnancy. Lancet Infect Dis 7: 93104.[Crossref] [Google Scholar]

Data & Media loading...

  • Received : 14 Sep 2015
  • Accepted : 29 Jan 2016
  • Published online : 04 May 2016

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error