title: 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.
authors.affiliation: Division of Parasitic Diseases and Malaria, Centers for Disease Control and Prevention, Atlanta, Georgia.
authors.forename: Julie
authors.initials: J
authors.lastname: Gutman
authors.affiliation: College of Medicine, University of Malawi Department of Community Health, College of Medicine, Blantyre.
authors.forename: Linda
authors.initials: L
authors.lastname: Kalilani
authors.affiliation: Duke University Medical Center, Durham University of North Carolina, Chapel Hill.
authors.forename: Steve
authors.initials: S
authors.lastname: Taylor
authors.affiliation: Division of Parasitic Diseases and Malaria, Centers for Disease Control and Prevention, Atlanta, Georgia.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Division of Parasitic Diseases and Malaria, Centers for Disease Control and Prevention, Atlanta, Georgia.
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Wiegand
authors.affiliation: Duke University Medical Center, Durham.
authors.forename: Kyaw L
authors.initials: KL
authors.lastname: Thwai
authors.affiliation: Malaria Alert Centre, University of Malawi College of Medicine.
authors.forename: Dyson
authors.initials: D
authors.lastname: Mwandama
authors.affiliation: Liverpool School of Tropical Medicine, United Kingdom.
authors.forename: Carole
authors.initials: C
authors.lastname: Khairallah
authors.affiliation: College of Medicine, University of Malawi Department of Community Health, College of Medicine, Blantyre.
authors.forename: Mwayi
authors.initials: M
authors.lastname: Madanitsa
authors.affiliation: College of Medicine, University of Malawi Department of Community Health, College of Medicine, Blantyre.
authors.forename: Ebbie
authors.initials: E
authors.lastname: Chaluluka
authors.affiliation: College of Medicine, University of Malawi Malaria Alert Centre, University of Malawi College of Medicine.
authors.forename: Fraction
authors.initials: F
authors.lastname: Dzinjalamala
authors.affiliation: National Malaria Control Program, Lilongwe, Malawi.
authors.forename: Doreen
authors.initials: D
authors.lastname: Ali
authors.affiliation: Malaria Alert Centre, University of Malawi College of Medicine Department of Community Health, College of Medicine, Blantyre.
authors.forename: Don P
authors.initials: DP
authors.lastname: Mathanga
authors.affiliation: Division of Parasitic Diseases and Malaria, Centers for Disease Control and Prevention, Atlanta, Georgia.
authors.forename: Jacek
authors.initials: J
authors.lastname: Skarbinski
authors.affiliation: Division of Parasitic Diseases and Malaria, Centers for Disease Control and Prevention, Atlanta, Georgia.
authors.forename: Ya Ping
authors.initials: YP
authors.lastname: Shi
authors.affiliation: Duke University Medical Center, Durham.
authors.forename: Steve
authors.initials: S
authors.lastname: Meshnick
authors.affiliation: Liverpool School of Tropical Medicine, United Kingdom.
authors.forename: Feiko O
authors.initials: FO
authors.lastname: ter Kuile
mesh_terms: D016054:DNA, Protozoan / Q000737:chemistry / Q000235:genetics; D004094:Dihydropteroate Synthase / Q000235:genetics*; D004338:Drug Combinations; D004351:Drug Resistance; D005260:Female; D005838:Genotype; D006801:Humans; D007231:Infant, Newborn; D016778:Malaria, Falciparum / Q000469:parasitology / Q000517:prevention & control*; D008295:Malawi; D020125:Mutation, Missense; D010963:Plasmodium falciparum / Q000201:enzymology* / Q000235:genetics / Q000302:isolation & purification; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D011739:Pyrimethamine / Q000494:pharmacology* / Q000627:therapeutic use*; D017422:Sequence Analysis, DNA; D013413:Sulfadoxine / Q000494:pharmacology* / Q000627:therapeutic use*; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D016054:DNA, Protozoan; D004338:Drug Combinations; C001205:fanasil, pyrimethamine drug combination; D013413:Sulfadoxine; D013762:Tetrahydrofolate Dehydrogenase; D004094:Dihydropteroate Synthase; D011739:Pyrimethamine
keywords: Malawi; Plasmodium falciparum; dihydropteroate synthase; intermittent preventive therapy; malaria; pregnancy; sulfadoxine-pyrimethamine