The A581G Mutation in the Gene Encoding Plasmodium falciparum Dihydropteroate Synthetase Reduces the Effectiveness of Sulfadoxine-Pyrimethamine Preventive Therapy in Malawian Pregnant Women

Abstract

Background: The A581 G: mutation in the gene encoding Plasmodium falciparum dihydropteroate synthase (dhps), in combination with the quintuple mutant involving mutations in both dhps and the gene encoding dihydrofolate reductase (dhfr), the so-called sextuple mutant, has been associated with increased placental inflammation and decreased infant birth weight among women receiving intermittent preventive treatment with sulfadoxine-pyrimethamine (IPTp-SP) during pregnancy.

Methods: Between 2009 and 2011, delivering women without human immunodeficiency virus infection were enrolled in an observational study of IPTp-SP effectiveness in Malawi. Parasites were detected by polymerase chain reaction (PCR); positive samples were sequenced to genotype the dhfr and dhps loci. The presence of K540 E: in dhps was used as a marker for the quintuple mutant.

Results: Samples from 1809 women were analyzed by PCR; 220 (12%) were positive for P. falciparum. A total of 202 specimens were genotyped at codon 581 of dhps; 17 (8.4%) harbored the sextuple mutant. The sextuple mutant was associated with higher risks of patent infection in peripheral blood (adjusted prevalence ratio [aPR], 2.76; 95% confidence interval [CI], 1.82-4.18) and placental blood (aPR 3.28; 95% CI, 1.88-5.78) and higher parasite densities. Recent SP use was not associated with increased parasite densities or placental pathology overall and among women with parasites carrying dhps A581 G: .

Conclusions: IPTp-SP failed to inhibit parasite growth but did not exacerbate pathology among women infected with sextuple-mutant parasites. New interventions to prevent malaria during pregnancy are needed urgently.

Keywords: Malawi; Plasmodium falciparum; dihydropteroate synthase; intermittent preventive therapy; malaria; pregnancy; sulfadoxine-pyrimethamine.

Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Figures

Figure 1.

Flow of selection of women with infection due to Plasmodium falciparum with and without the A581G mutation in the gene encoding dihydropteroate synthase (dhps). Abbreviations: PCR, polymerase chain reaction; WT, wild type.

Figure 2.

Associations between binomial variables (A) and continuous variables (B) and parasitologic and morbidity end points, by time since last dose of sulfadoxine-pyrimethamine (SP), among 202 women who tested positive for Plasmodium falciparum by polymerase chain reaction. Abbreviations: CI, confidence interval; dhps, dihydropteroate synthase; Hb, hemoglobin; SD, standard deviation; SGA, small for gestational age; WT, wild type.

Figure 2.

Associations between binomial variables (A) and continuous variables (B) and parasitologic and morbidity end points, by time since last dose of sulfadoxine-pyrimethamine (SP), among 202 women who tested positive for Plasmodium falciparum by polymerase chain reaction. Abbreviations: CI, confidence interval; dhps, dihydropteroate synthase; Hb, hemoglobin; SD, standard deviation; SGA, small for gestational age; WT, wild type.