Frequency of markers of resistance to antifolates used as preventive therapy for placental malaria in pregnant women, Tororo District

Abstract

Antifolates are currently being used in Africa as intermittent preventive therapy (IPT) to prevent malaria in pregnant women. It is recommended that HIV-uninfected pregnant women receive at least two doses of sulfadoxine-pyrimethamine (SP) during pregnancy to prevent malaria and that HIV-infected women take trimethoprim-sulfamethoxazole (TS) prophylaxis daily during pregnancy in order to prevent malaria, as well as opportunistic infections. SP and TS decrease the incidence of malaria, but they share mechanisms of action and resistance, and their widespread use might select for resistant parasites, raising concerns about continued preventive efficacy of SP and TS. This study assessed the frequency of known markers of resistance to antifolates in pregnant women who received SP or TS at Tororo District Hospital. A cross-sectional study was carried out in Tororo District, Eastern Uganda, where HIV and malaria prevalences are high. A total of 573 placentas were obtained from women delivering at Tororo District Hospital. Polymorphisms of the dhfr and dhps genes known to play a role in resistance to antifolates were analyzed by PCR and restriction fragment length polymorphism (PCR-RFLP) and prevalences of polymorphism were then compared between women without (receiving SP IPT) and with (receiving daily TS) HIV infection. The prevalence of placental malaria, as determined by PCR, was 19.4% and 25.5% among HIV-infected and HIV-uninfected women, respectively. Primigravidae were at higher risk for placental malaria than multigravidae among HIV-uninfected women but not among HIV-infected women. The prevalences of the common markers of resistance to antifolates were very high in placentas in Tororo: dhfr C59R (92.3%), dhps A437G (98.5%) and dhps K540E (96.9%). There was no difference in the frequency of these markers between HIV-infected women and HIV-uninfected women. An additional marker of high-level antifolate resistance, (dhfr I164L) was identified in only one sample (0.8%). This study also showed no relationship between the presence of known markers of resistance and maternal age, gravidity, or low birth weight. It was concluded that there were high frequency (over 90%) of dhfr C59R, dhps A437G and K540E mutaions in placental malaria samples from both HIV-uninfected and HIV-infected women in Tororo District so need for the alternative drugs to be studied as a replacement of SP as a preventive therapy against placental malaria.