Prevention of malaria in pregnancy: The threat of sulfadoxine-pyrimethamine resistance

Abstract

Malaria infection in pregnancy can lead to adverse outcomes for both the pregnant person and fetus. The administration of intermittent preventative therapy (IPTp) with sulfadoxine-pyrimethamine (SP) during pregnancy (IPTp-SP) improves outcomes, including severe maternal anemia, placental malaria infection, and low infant birth weight. The WHO recommends IPTp-SP for pregnant individuals living in areas of moderate or high malaria transmission in Africa. The current regimen consists of two or more doses of SP starting as early as possible in the second trimester, at least 1 month apart. Unfortunately, rising Plasmodium falciparum SP resistance throughout Africa threatens to erode the benefits of SP. Recent studies have shown a decrease in IPTp-SP efficacy in areas with high SP resistance. Thus, there is an urgent need to identify new drug regimens that can be used for intermittent preventative therapy in pregnancy. In this review, we discuss recent data on P. falciparum SP resistance in Africa, the effect of resistance on IPTp-SP, and studies of alternative IPTp regimens. Finally, we present a framework for the ideal pharmacokinetic and pharmacodynamic properties for future IPTp regimens.

Keywords: IPTp; antimalarial; drug resistance; low birth weight; malaria.

Figure 1

Mutations in dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) that confer resistance to sulfadoxine pyrimethamine. Mutations found in the highly resistant “quintuple mutant” are shown in orange. Additional mutations, that are increasing in prevalence in Africa, are shown in black. Figures generated in Biorender.

Figure 2

Idealized IPTp regimen. A treatment dose of a drug that meets MMV TPP-1 (management, orange line) eradicates existing asexual and placental infection (dotted blue line). A drug that meets TPP-2 (chemoprevention, black line) provides long-term protection against re-infection until the next prenatal visit.