The online version of this article (doi:10.1186/1475-2875-11-134) contains supplementary material, which is available to authorized users.
The authors declare that they have no competing interests.
NCI, MS, WG, SK, AAL and YOO carried out genotyping work for the current study. AME, JA, FOK, BN (first period), JM, SOO (second period), MD, MJH, PO, and LS (third period) implemented the observational malaria in pregnancy studies from 1996 to 2009 including enrolment of patients and collection of clinical and epidemiological data and samples. YPS conceived, designed and supervised the current study. NCI, MS and JVE did the statistical analysis. NCI, MS and YPS wrote the paper. All authors contributed to the interpretation of results and critical discussion of the conclusion and approved the final manuscript.
Resistance to sulphadoxine-pyrimethamine (SP) in Plasmodium falciparum parasites is associated with mutations in the dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) genes and has spread worldwide. SP remains the recommended drug for intermittent preventive treatment for malaria in pregnancy (IPTp) and information on population prevalence of the SP resistance molecular markers in pregnant women is limited.
Temporal trends of SP resistance molecular markers were investigated in 489 parasite samples collected from pregnant women at delivery from three different observational studies between 1996 and 2009 in Kenya, where SP was adopted for both IPTp and case treatment policies in 1998. Using real-time polymerase chain reaction, pyrosequencing and direct sequencing, 10 single-nucleotide polymorphisms (SNPs) of SP resistance molecular markers were assayed.
The prevalence of quintuple mutant (dhfr N51I/C59R/S108N and dhps A437G/K540E combined genotype) increased from 7 % in the first study (1996–2000) to 88 % in the third study (2008–2009). When further stratified by sample collection year and adoption of IPTp policy, the prevalence of the quintuple mutant increased from 2.4 % in 1998 to 44.4 % three years after IPTp policy adoption, seemingly in parallel with the increase in percentage of SP use in pregnancy. However, in the 1996–2000 study, more mutations in the combined dhfr/dhps genotype were associated with SP use during pregnancy only in univariable analysis and no associations were detected in the 2002–2008 and 2008–2009 studies. In addition, in the 2008–2009 study, 5.3 % of the parasite samples carried the dhps triple mutant (A437G/K540E/A581G). There were no differences in the prevalence of SP mutant genotypes between the parasite samples from HIV + and HIV- women over time and between paired peripheral and placental samples.
There was a significant increase in dhfr/dhps quintuple mutant and the emergence of new genotype containing dhps 581 in the parasites from pregnant women in western Kenya over 13 years. IPTp adoption and SP use in pregnancy only played a minor role in the increased drug-resistant parasites in the pregnant women over time. Most likely, other major factors, such as the high prevalence of resistant parasites selected by the use of SP for case management in large non-pregnant population, might have contributed to the temporally increased prevalence of SP resistant parasites in pregnant women. Further investigations are needed to determine the linkage between SP drug resistance markers and efficacy of IPTp-SP.
Additional file 1: Statistical procedure. The file described the statistical methods used for the descriptive and association analysis. (DOC 47 KB)12936_2012_2106_MOESM1_ESM.doc
Additional file 2: Proportion of SP drug resistant genotypes by HIV status and by study period. A, dhfr genotypes. B, dhps genotypes. C, combined dhfr/dhps genotypes. The figures described the prevalence of dhfr, dhps and the combined dhfr/dhps genotypes between HIV + and HIV- women. (TIFF 361 KB)12936_2012_2106_MOESM2_ESM.tiff
Authors’ original file for figure 112936_2012_2106_MOESM3_ESM.tiff
Authors’ original file for figure 212936_2012_2106_MOESM4_ESM.tiff
Authors’ original file for figure 312936_2012_2106_MOESM5_ESM.tiff
Authors’ original file for figure 412936_2012_2106_MOESM6_ESM.tiff
Authors’ original file for figure 512936_2012_2106_MOESM7_ESM.doc
WHO: Lives at risk: malaria in pregnancy. 2003, [ http://www.who.int/features/2003/04b/en/] (Accessed 14 December 2010)
WHO: World Malaria Report 2008. 2008, WHO Press, Geneva, Switzerland
WHO: A strategic framework for malaria prevention and control during pregnancy in the Africa region. 2004, WHO Regional Office for Africa, Brazzaville, Congo, AFR/MAL/04/01
Maiga OM, Kayentao K, Traore BT, Djimde A, Traore B, Traore M, Ongoiba A, Doumtabe D, Doumbo S, Traore MS, Dara A, Guindo O, Karim DM, Coulibaly S, Bougoudogo F, Ter Kuile FO, Danis M, Doumbo OK: Superiority of 3 over 2 doses of intermittent preventive treatment with sulphadoxine-pyrimethamine for the prevention of malaria during pregnancy in mali: a randomized controlled trial. Clin Infect Dis. 2011, 53: 215-223. 10.1093/cid/cir374. CrossRefPubMed
Goodman CA, Coleman PG, Mills AJ: The cost-effectiveness of antenatal malaria prevention in sub-Saharan Africa. AmJTrop Med Hyg. 2001, 64: 45-56.
Parise ME, Ayisi JG, Nahlen BL, Schultz LJ, Roberts JM, Misore A, Muga R, Oloo AJ, Steketee RW: Efficacy of sulphadoxine-pyrimethamine for prevention of placental malaria in an area of Kenya with a high prevalence of malaria and human immunodeficiency virus infection. AmJTrop Med Hyg. 1998, 59: 813-822.
Kayentao K, Kodio M, Newman RD, Maiga H, Doumtabe D, Ongoiba A, Coulibaly D, Keita AS, Maiga B, Mungai M, Parise ME, Doumbo O: Comparison of intermittent preventive treatment with chemoprophylaxis for the prevention of malaria during pregnancy in Mali. J Infect Dis. 2005, 191: 109-116. 10.1086/426400. CrossRefPubMed
Sirima SB, Cotte AH, Konate A, Moran AC, Asamoa K, Bougouma EC, Diarra A, Ouedraogo A, Parise ME, Newman RD: Malaria prevention during pregnancy: assessing the disease burden one year after implementing a program of intermittent preventive treatment in Koupela District, Burkina Faso. AmJTrop Med Hyg. 2006, 75: 205-211.
Hamel MJ, Poe A, Bloland P, McCollum A, Zhou Z, Shi YP, Ouma P, Otieno K, Vulule J, Escalante A, Udhayakumar V, Slutsker L: Dihydrofolate reductase I164L mutations in Plasmodium falciparum isolates: clinical outcome of 14 Kenyan adults infected with parasites harbouring the I164L mutation. Trans R Soc Trop Med Hyg. 2008, 102: 338-345. 10.1016/j.trstmh.2008.01.018. CrossRefPubMed
Nzila AM, Mberu EK, Sulo J, Dayo H, Winstanley PA, Sibley CH, Watkins WM: Towards an understanding of the mechanism of pyrimethamine-sulphadoxine resistance in Plasmodium falciparum: genotyping of dihydrofolate reductase and dihydropteroate synthase of Kenyan parasites. Antimicrob Agents Chemother. 2000, 44: 991-996. 10.1128/AAC.44.4.991-996.2000. PubMedCentralCrossRefPubMed
Gesase S, Gosling RD, Hashim R, Ord R, Naidoo I, Madebe R, Mosha JF, Joho A, Mandia V, Mrema H, Mapunda E, Savael Z, Lemnge M, Mosha FW, Greenwood B, Roper C, Chandramohan D: High resistance of Plasmodium falciparum to sulphadoxine/pyrimethamine in northern Tanzania and the emergence of dhps resistance mutation at Codon 581. PLoS One. 2009, 4: e4569-10.1371/journal.pone.0004569. PubMedCentralCrossRefPubMed
Alifrangis M, Lusingu JP, Mmbando B, Dalgaard MB, Vestergaard LS, Ishengoma D, Khalil IF, Theander TG, Lemnge MM, Bygbjerg IC: Five-year surveillance of molecular markers of Plasmodium falciparum antimalarial drug resistance in Korogwe District, Tanzania: accumulation of the 581G mutation in the P. falciparum dihydropteroate synthase gene. AmJTrop Med Hyg. 2009, 80: 523-527.
Kublin JG, Dzinjalamala FK, Kamwendo DD, Malkin EM, Cortese JF, Martino LM, Mukadam RA, Rogerson SJ, Lescano AG, Molyneux ME, Winstanley PA, Chimpeni P, Taylor TE, Plowe CV: Molecular markers for failure of sulphadoxine-pyrimethamine and chlorproguanil-dapsone treatment of Plasmodium falciparum malaria. J Infect Dis. 2002, 185: 380-388. 10.1086/338566. CrossRefPubMed
Happi CT, Gbotosho GO, Folarin OA, Akinboye DO, Yusuf BO, Ebong OO, Sowunmi A, Kyle DE, Milhous W, Wirth DF, Oduola AM: Polymorphisms in Plasmodium falciparum dhfr and dhps genes and age related in vivo sulphadoxine-pyrimethamine resistance in malaria-infected patients from Nigeria. Acta Trop. 2005, 95: 183-193. 10.1016/j.actatropica.2005.06.015. CrossRefPubMed
Sridaran S, McClintock SK, Syphard LM, Herman KM, Barnwell JW, Udhayakumar V: Anti-folate drug resistance in Africa: meta-analysis of reported dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) mutant genotype frequencies in African Plasmodium falciparum parasite populations. Malar J. 2010, 9: 247-10.1186/1475-2875-9-247. PubMedCentralCrossRefPubMed
WHO: Report of the technical expert group meeting on intermittent preventive treatment in pregnancy (IPTp). 2008, World Health Organization, Geneva, Geneva, 2007 July 11–13
Harrington WE, Mutabingwa TK, Muehlenbachs A, Sorensen B, Bolla MC, Fried M, Duffy PE: Competitive facilitation of drug-resistant Plasmodium falciparum malaria parasites in pregnant women who receive preventive treatment. Proc Natl Acad Sci U S A. 2009, 106: 9027-9032. 10.1073/pnas.0901415106. PubMedCentralCrossRefPubMed
Menendez C, Serra-Casas E, Scahill MD, Sanz S, Nhabomba A, Bardaji A, Sigauque B, Cistero P, Mandomando I, Dobano C, Alonso PL, Mayor A: HIV and placental infection modulate the appearance of drug-resistant Plasmodium falciparum in pregnant women who receive intermittent preventive treatment. Clin Infect Dis. 2011, 52: 41-48. 10.1093/cid/ciq049. CrossRefPubMed
Perrault SD, Hajek J, Zhong K, Owino SO, Sichangi M, Smith G, Shi YP, Moore JM, Kain KC: Human immunodeficiency virus co-infection increases placental parasite density and transplacental malaria transmission in Western Kenya. AmJTrop Med Hyg. 2009, 80: 119-125.
van Eijk AM, Blokland IE, Slutsker L, Odhiambo F, Ayisi JG, Bles HM, Rosen DH, Adazu K, Lindblade KA: Use of intermittent preventive treatment for malaria in pregnancy in a rural area of western Kenya with high coverage of insecticide-treated bed nets. Trop Med Int Health. 2005, 10: 1134-1140. 10.1111/j.1365-3156.2005.01497.x. CrossRefPubMed
Watsierah CA, Jura WG, Oyugi H: Abong'o B. Ouma C: Factors determining anti-malarial drug use in a peri-urban population from malaria holoendemic region of western Kenya. Malar J. 2010, 9: 295-
Shah M, Kariuki S, Vanden Eng J, Blackstock AJ, Garner K, Gatei W, Gimnig JE, Lindblade K, Terlouw D, ter Kuile F, Hawley WA, Phillips-Howard P, Nahlen B, Walker E, Hamel MJ, Slutsker L, Shi YP: Effect of transmission reduction by insecticide-treated bednets (ITNs) on antimalarial drug resistance in western Kenya. PLoS One. 2011, 6: e26746-10.1371/journal.pone.0026746. PubMedCentralCrossRefPubMed
Pearce RJ, Drakeley C, Chandramohan D, Mosha F, Roper C: Molecular determination of point mutation haplotypes in the dihydrofolate reductase and dihydropteroate synthase of Plasmodium falciparum in three districts of northern Tanzania. Antimicrob Agents Chemother. 2003, 47: 1347-1354. 10.1128/AAC.47.4.1347-1354.2003. PubMedCentralCrossRefPubMed
Zhou Z, Poe AC, Limor J, Grady KK, Goldman I, McCollum AM, Escalante AA, Barnwell JW, Udhayakumar V: Pyrosequencing, a high-throughput method for detecting single nucleotide polymorphisms in the dihydrofolate reductase and dihydropteroate synthetase genes of Plasmodium falciparum. J Clin Microbiol. 2006, 44: 3900-3910. 10.1128/JCM.01209-06. PubMedCentralCrossRefPubMed
Alam MT, de Souza DK, Vinayak S, Griffing SM, Poe AC, Duah NO, Ghansah A, Asamoa K, Slutsker L, Wilson MD, Barnwell JW, Udhayakumar V, Koram KA: Selective sweeps and genetic lineages of Plasmodium falciparum drug-resistant alleles in Ghana. J Infect Dis. 2011, 203: 220-227. 10.1093/infdis/jiq038. PubMedCentralCrossRefPubMed
WHO: Recommended genotyping procedures (RGPs) to indentify parasite populations. Developed after an informal consultation organized by the Medicines for Malaria Venture and cosponsored by the World Health Organization, 29–31 May 2007. 2008, WHO, Amsterdam, The Netherlands, 1-44.
Farnert A, Arez AP, Babiker HA, Beck HP, Benito A, Bjorkman A, Bruce MC, Conway DJ, Day KP, Henning L, Mercereau-Puijalon O, Ranford-Cartwright LC, Rubio JM, Snounou G, Walliker D, Zwetyenga J, do Rosario VE: Genotyping of Plasmodium falciparum infections by PCR: a comparative multicentre study. Trans R Soc Trop Med Hyg. 2001, 95: 225-232. 10.1016/S0035-9203(01)90175-0. CrossRefPubMed
Alifrangis M, Lemnge MM, Ronn AM, Segeja MD, Magesa SM, Khalil IF, Bygbjerg IC: Increasing prevalence of wildtypes in the dihydrofolate reductase gene of Plasmodium falciparum in an area with high levels of sulphadoxine/pyrimethamine resistance after introduction of treated bed nets. AmJTrop Med Hyg. 2003, 69: 238-243.
Vinayak S, Alam MT, Mixson-Hayden T, McCollum AM, Sem R, Shah NK, Lim P, Muth S, Rogers WO, Fandeur T, Barnwell JW, Escalante AA, Wongsrichanalai C, Ariey F, Meshnick SR, Udhayakumar V: Origin and evolution of sulphadoxine resistant Plasmodium falciparum. PLoS Pathog. 2010, 6: e1000830-10.1371/journal.ppat.1000830. PubMedCentralCrossRefPubMed
Alker AP, Mwapasa V, Purfield A, Rogerson SJ, Molyneux ME, Kamwendo DD, Tadesse E, Chaluluka E, Meshnick SR: Mutations associated with sulphadoxine-pyrimethamine and chlorproguanil resistance in Plasmodium falciparum isolates from Blantyre, Malawi. Antimicrob Agents Chemother. 2005, 49: 3919-3921. 10.1128/AAC.49.9.3919-3921.2005. PubMedCentralCrossRefPubMed
Gebru-Woldearegai T, Hailu A, Grobusch MP, Kun JF: Molecular surveillance of mutations in dihydrofolate reductase and dihydropteroate synthase genes of Plasmodium falciparum in Ethiopia. AmJTrop Med Hyg. 2005, 73: 1131-1134.
A-Elbasit IE, Alifrangis M, Khalil IF, Bygbjerg IC, Masuadi EM, Elbashir MI, Giha HA: The implication of dihydrofolate reductase and dihydropteroate synthetase gene mutations in modification of Plasmodium falciparum characteristics. Malar J. 2007, 6: 108-10.1186/1475-2875-6-108. PubMedCentralCrossRefPubMed
Wang P, Lee CS, Bayoumi R, Djimde A, Doumbo O, Swedberg G, Dao LD, Mshinda H, Tanner M, Watkins WM, Sims PF, Hyde JE: Resistance to antifolates in Plasmodium falciparum monitored by sequence analysis of dihydropteroate synthetase and dihydrofolate reductase alleles in a large number of field samples of diverse origins. Mol Biochem Parasitol. 1997, 89: 161-177. 10.1016/S0166-6851(97)00114-X. CrossRefPubMed
Kiwanuka GN: Genetic diversity in Plasmodium falciparum merozoite surface protein 1 and 2 coding genes and its implications in malaria epidemiology: a review of published studies from 1997–2007. J Vector Borne Dis. 2009, 46: 1-12. PubMed
- Temporal trends of sulphadoxine-pyrimethamine (SP) drug-resistance molecular markers in Plasmodium falciparum parasites from pregnant women in western Kenya
Nnaemeka C Iriemenam
Anna M van Eijk
Jodi Vanden Eng
Simon O Owino
Ashima A Lal
Yusuf O Omosun
Feiko O ter Kuile
Mary J Hamel
Ya Ping Shi
- BioMed Central
Neu im Fachgebiet Innere Medizin
Meistgelesene Bücher aus der Inneren Medizin
e.Med Kampagnen-Visual, Mail Icon II