Antenatal receipt of sulfadoxine-pyrimethamine does not exacerbate pregnancy-associated malaria despite the expansion of drug-resistant Plasmodium falciparum: clinical outcomes from the QuEERPAM study

Abstract

Background: Antenatal intermittent preventive therapy with 2 doses of sulfadoxine-pyrimethamine (IPTp-SP) is the mainstay of efforts in sub-Saharan Africa to prevent pregnancy-associated malaria (PAM). Recent studies report that drug resistance may cause IPTp-SP to exacerbate PAM morbidity, raising fears that current policies will cause harm as resistance spreads.

Methods: We conducted a serial, cross-sectional analysis of the relationships between IPTp-SP receipt, SP-resistant Plasmodium falciparum, and PAM morbidity in delivering women during a period of 9 years at a single site in Malawi. PAM morbidity was assessed by parasite densities, placental histology, and birth outcomes.

Results: The prevalence of parasites with highly SP-resistant haplotypes increased from 17% to 100% (P < .001), and the proportion of women receiving full IPTp (≥2 doses) increased from 25% to 82% (P < .001). Women who received full IPTp with SP had lower peripheral (P = .018) and placental (P < .001) parasite densities than women who received suboptimal IPTp (<2 doses). This effect was not significantly modified by the presence of highly SP-resistant haplotypes. After adjustment for covariates, the receipt of SP in the presence of SP-resistant P. falciparum did not exacerbate any parasitologic, histologic, or clinical measures of PAM morbidity.

Conclusions: In this longitudinal study of malaria at delivery, the receipt of SP as IPTp did not potentiate PAM morbidity despite the increasing prevalence and fixation of SP-resistant P. falciparum haplotypes. Even when there is substantial resistance, SP may be used in modified IPTp regimens as a component of comprehensive antenatal care.

Figure 1.

Trends in sulfadoxine-pyrimethamine (SP) use and Plasmodium falciparum dhfr-dhps haplotypes over time. (A) Proportion of women receiving SP (gray bars) and the average number of doses received (black line); (B) the prevalence of dhfr-dhps haplotypes over time. Haplotypes assigned per Kublin et al [10].

Figure 2.

Parasitologic, histologic, and clinical delivery outcomes by intermittent preventive therapy with antimalarials during pregnancy (IPTp)–sulfadoxine-pyrimethamine use and stratified by Plasmodium falciparum dhfr-dhps haplotype. Gray boxes: suboptimal IPTp; white boxes: full IPTp. (A) Median (interquartile range [IQR]) maternal peripheral parasite densities; (B) median (IQR) maternal placental parasite densities; (C) median (IQR) percentage of placental parasitemia by histology; (D) median (IQR) percentage of mononuclear cells in the intervillous space; (E) mean (standard deviation) maternal hemoglobin (g/dL); (F) birth weight (g). Outcomes were compared between IPTp groups using the Student t test or the Kruskal-Wallis test. Δ indicates difference in median or mean of the full IPTp group relative to the suboptimal IPTp group.

Figure 3.

Pregnancy outcomes over time stratified by receipt of intermittent preventive therapy with antimalarials during pregnancy (IPTp)–sulfadoxine-pyrimethamine. Gray boxes: suboptimal IPTp; white boxes: full IPTp. (A) Median (interquartile range [IQR]) maternal peripheral parasite density; (B) median (IQR) placental parasite density; (C) median (IQR) percentage of parasitemia by histology; (D) median (IQR) percentage of mononuclear cells in the intervillous space; (E) mean (standard deviation [SD]) maternal hemoglobin; (F) mean (SD) birth weight. Neither birth weight nor placental outcomes were available for 1997.