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      Recent uptake of intermittent preventive treatment during pregnancy with sulfadoxine–pyrimethamine is associated with increased prevalence of Pfdhfr mutations in Bobo-Dioulasso, Burkina Faso

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          Abstract

          Background

          The impact of sulfadoxine–pyrimethamine (SP) used as intermittent preventive treatment during pregnancy (IPTp-SP) on mutant parasite selection has been poorly documented in Burkina Faso. This study sought first to explore the relationship between IPTp-SP and the presence of mutant parasites. Second, to assess the relationship between the mutant parasites and adverse pregnancy outcomes.

          Methods

          From September to December 2010, dried blood spots (DBS) were collected during antenatal care visits and at delivery from 109 pregnant women with microscopically confirmed falciparum malaria infection. DBS were analysed by PCR–restriction fragment length polymorphism (PCR–RFLP) for the polymorphisms at codons 51, 59, 108, and 164 of the Pfdhfr gene and codons 437 and 540 in the Pfdhps gene.

          Results

          Both the Pfdhfr and Pfdhps genes were successfully genotyped in 92.7% (101/109) of the samples. The prevalence of Pfdhfr mutations N51I, C59R and S108N was 71.3, 42.6 and 64.4%, respectively. Overall, 80.2% (81/101) of samples carried the Pfdhps A437G mutation. None of the samples had the Pfdhfr I164L and the Pfdhps K540E mutations. The prevalence of the triple mutation N51I + C59R + S108N was 25.7% (26/101). The use of IPTp-SP was associated with a threefold increased odds of Pfdhfr C59R mutation [crude OR 3.29; 95% CI (1.44–7.50)]. Pregnant women with recent uptake of IPTp-SP were at higher odds of both the Pfdhfr C59R mutation [adjusted OR 4.26; 95% CI (1.64–11.07)] and the Pfdhfr intermediate-to-high resistance, i.e., ≥ 2 Pfdhfr mutations [adjusted OR 3.45; 95% CI (1.18–10.07)]. There was no statistically significant association between the presence of the Pfdhfr intermediate-to-high resistance and parasite densities or both maternal haemoglobin level and anaemia.

          Conclusion

          The data indicate that despite the possibility that IPTp-SP contributes to the selection of resistant parasites, it did not potentiate pregnancy-associated malaria morbidity, suggesting the continuation of SP use as IPTp in Burkina Faso.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s12936-017-1695-1) contains supplementary material, which is available to authorized users.

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          Most cited references27

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          The burden of malaria in pregnancy in malaria-endemic areas.

          Pregnant women in malarious areas may experience a variety of adverse consequences from malaria infection including maternal anemia, placental accumulation of parasites, low birth weight (LBW) from prematurity and intrauterine growth retardation (IUGR), fetal parasite exposure and congenital infection, and infant mortality (IM) linked to preterm-LBW and IUGR-LBW. We reviewed studies between 1985 and 2000 and summarized the malaria population attributable risk (PAR) that accounts for both the prevalence of the risk factors in the population and the magnitude of the associated risk for anemia, LBW, and IM. Consequences from anemia and human immunodeficiency virus infection in these studies were also considered. Population attributable risks were substantial: malaria was associated with anemia (PAR range = 3-15%), LBW (8-14%), preterm-LBW (8-36%), IUGR-LBW (13-70%), and IM (3-8%). Human immunodeficiency virus was associated with anemia (PAR range = 12-14%), LBW (11-38%), and direct transmission in 20-40% of newborns, with direct mortality consequences. Maternal anemia was associated with LBW (PAR range = 7-18%), and fetal anemia was associated with increased IM (PAR not available). We estimate that each year 75,000 to 200,000 infant deaths are associated with malaria infection in pregnancy. The failure to apply known effective antimalarial interventions through antenatal programs continues to contribute substantially to infant deaths globally.
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            Competitive facilitation of drug-resistant Plasmodium falciparum malaria parasites in pregnant women who receive preventive treatment.

            Intermittent preventive treatment in pregnancy (IPTp) is used to prevent Plasmodium falciparum malaria. However, parasites resistant to the IPTp drug sulfadoxine-pyrimethamine (SP) have emerged worldwide, and infections with mixed resistant and susceptible parasites are exacerbated by pyrimethamine in mice. In a prospective delivery cohort in Muheza, Tanzania, we examined the effects of SP IPTp on parasite resistance alleles, parasite diversity, level of parasitemia, and inflammation in the placenta. IPTp use was associated with an increased fraction of parasites carrying the resistance allele at DHPS codon 581, an increase in the level of parasitemia, and more intense placental inflammation. The lowest mean level of parasite diversity and highest mean level of parasitemia occurred in women after recent IPTp use. These findings support a model of parasite release and facilitation, whereby the most highly resistant parasites out-compete less fit parasite populations and overgrow under drug pressure. Use of partially effective anti-malarial agents for IPTp may exacerbate malaria infections in the setting of widespread drug resistance.
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              Evidence that a point mutation in dihydrofolate reductase-thymidylate synthase confers resistance to pyrimethamine in falciparum malaria.

              Analysis of a genetic cross of Plasmodium falciparum and of independent parasite isolates from Southeast Asia, Africa, and South America indicates that resistance to pyrimethamine, an antifolate used in the treatment of malaria, results from point mutations in the gene encoding dihydrofolate reductase-thymidylate synthase (EC 1.5.1.3 and EC 2.1.1.45, respectively). Parasites having a mutation from Thr-108/Ser-108 to Asn-108 in DHFR-TS are resistant to the drug. The Asn-108 mutation occurs in a region analogous to the C alpha-helix bordering the active site cavity of bacterial, avian, and mammalian enzymes. Additional point mutations (Asn-51 to Ile-51 and Cys-59 to Arg-59) are associated with increased pyrimethamine resistance and also occur at sites expected to border the active site cavity. Analogies with known inhibitor/enzyme structures from other organisms suggest that the point mutations occur where pyrimethamine contacts the enzyme and may act by inhibiting binding of the drug.
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                Author and article information

                Contributors
                cisse_m@yahoo.fr
                gawandare@ug.edu.gh
                alamissas@yahoo.fr
                tintohalidou@yahoo.fr
                mphayette@chu.ulg.ac.be
                rguiguemde@yahoo.fr
                Journal
                Malar J
                Malar. J
                Malaria Journal
                BioMed Central (London )
                1475-2875
                23 January 2017
                23 January 2017
                2017
                : 16
                : 38
                Affiliations
                [1 ]ISNI 0000 0004 0564 1122, GRID grid.418128.6, Laboratory of Parasitology and Entomology, , Centre MURAZ, ; 01 BP 390, Bobo-Dioulasso, Burkina Faso
                [2 ]ISNI 0000 0004 1937 1485, GRID grid.8652.9, West African Centre for Cell Biology of Infectious Pathogens, College of Basic and Applied Sciences, , University of Ghana, ; Accra, Ghana
                [3 ]ISNI 0000 0004 0564 1122, GRID grid.418128.6, Department of Clinical Research, , Centre MURAZ, ; Bobo-Dioulasso, Burkina Faso
                [4 ]ISNI 0000 0000 8607 6858, GRID grid.411374.4, Laboratory of Clinical Microbiology, , University Hospital of Liège, ; Liège, Belgium
                Author information
                http://orcid.org/0000-0001-8512-8561
                Article
                1695
                10.1186/s12936-017-1695-1
                5259838
                28114990
                9184659d-ac59-4a92-8f3f-6b131a1d053b
                © The Author(s) 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 23 November 2016
                : 13 January 2017
                Funding
                Funded by: World Bank African Centers of Excellence grant
                Award ID: ACE02-WACCBIP
                Award Recipient :
                Funded by: Wellcome Trust DELTAS grant
                Award ID: 107755/Z/15/Z
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2017

                Infectious disease & Microbiology
                malaria,pregnancy,sulfadoxine–pyrimethamine,drug resistance,burkina faso

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