Abstract
Intermittent preventive treatment during pregnancy with sulfadoxine–pyrimethamine (IPTp-SP) is a key strategy in the control of pregnancy-associated malaria. However, this strategy is compromised by widespread drug resistance from single-nucleotide polymorphisms in the Plasmodium falciparum dihydrofolate reductase and dihydropteroate synthetase genes. During September 2008–October 2010, we monitored a cohort of 924 pregnant women in an area of Tanzania with declining malaria transmission. P. falciparum parasites were genotyped, and the effect of infecting haplotypes on birthweight was assessed. Of the genotyped parasites, 9.3%, 46.3%, and 44.4% had quadruple or less, quintuple, and sextuple mutated haplotypes, respectively. Mutant haplotypes were unrelated to SP doses. Compared with infections with the less-mutated haplotypes, infections with the sextuple haplotype mutation were associated with lower (359 g) birthweights. Continued use of the suboptimal IPTp-SP regimen should be reevaluated, and alternative strategies (e.g., intermittent screening and treatment or intermittent treatment with safe and effective alternative drugs) should be evaluated.
Highlights
Intermittent preventive treatment during pregnancy with sulfadoxine–pyrimethamine (IPTp-SP) is a key strategy in the control of pregnancy-associated malaria
There is sufficient evidence to support that the triple Pfdhfr mutation asparagine 51 to isoleucine (N51I), cysteine 59 to arginine (C59R), and serine 108 to asparagine (S108N) in combination with double Pfdhps mutant alanine 437 to glycine (A437G) and lysine 540 to glutamic acid (K540E)—forming quintuple mutant haplotypes—confer a high risk for treatment failure in malaria-infected children and nonpregnant adults who receive SP treatment [14]
A total of 91 samples from women with rapid diagnostic test (RDT) parasitepositive results were examined by P. falciparum–specific PCR, and 65 (71.4%) were positive
Summary
Intermittent preventive treatment during pregnancy with sulfadoxine–pyrimethamine (IPTp-SP) is a key strategy in the control of pregnancy-associated malaria. This strategy is compromised by widespread drug resistance from single-nucleotide polymorphisms in the Plasmodium falciparum dihydrofolate reductase and dihydropteroate synthetase genes. Because P. falciparum parasite resistance to SP is high, most likely because of the high prevalence of quintuple mutant haplotypes, use of the drug to treat uncomplicated malaria has been abandoned in many parts of eastern Africa. The high prevalence (>50%) of the K540E mutation, which is found almost exclusively as the quintuple mutant haplotype, has resulted in poor SP efficacy when used as intermittent preventive treatment in infants [16]. With increased P. falciparum resistance, the usefulness of IPTp-SP might be compromised [18,19,20]
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