Abstract
BackgroundResistance 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.MethodsTemporal 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.ResultsThe 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.ConclusionsThere 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.
Highlights
Resistance to sulphadoxine-pyrimethamine (SP) in Plasmodium falciparum parasites is associated with mutations in the dihydrofolate reductase and dihydropteroate synthase genes and has spread worldwide
There was a difference in the proportion of Human immunodeficiency virus (HIV) sero-positive samples that were used in this study, with a greater proportion of HIV positive samples used in 1996–2000 compared to in 2008–2009
The key observations from this study were: 1) a noticeable background level of SP mutations in pregnant women prior to IPTp policy adoption, 2) a significant rise in the prevalence of the drug resistance markers after IPTp adoption seemingly in parallel with an increase in the percentage of SP use in pregnancy, and 3) an association between more single-nucleotide polymorphisms (SNPs) mutations and SP use during pregnancy only in the 1996–2000 study in univariable analysis but not in 2002–2008 and 2008–2009 study periods. These results suggest that the increase in drug-resistant parasites in the pregnant women over time could be influenced by other major factors in addition to the minor role of IPTp adoption and SP use in pregnancy
Summary
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. In Africa, an estimated 30 million women are at risk of Plasmodium falciparum infection during pregnancy annually [2]. More SP doses are recommended for women with HIV who are not taking daily cotrimoxazole (CTX, sulphamethoxazoletrimethoprim) for the prevention of opportunistic infections [4]. For HIV-infected women taking CTX, WHO does not recommend IPTp-SP, as CTX inhibits the same enzymes as SP in the folic acid biosynthetic pathway, presumably acting as an anti-malarial, and the excess of adverse events were observed in the SP and CTX comedication [4]
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