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

Pregnancy-associated malaria (PAM) is an important, preventable cause of poor birth outcomes in malaria-endemic areas in sub-Saharan Africa [1]. Intermittent preventive therapy with antimalarials during pregnancy (IPTp) is a critical tool for reducing the incidence of PAM-attributable adverse birth outcomes [2]. Sulfadoxine-pyrimethamine (SP) is the most commonly administered drug for IPTp owing to its long half-life, favorable side-effect profile, and safety during pregnancy. However, Plasmodium falciparum strains harboring mutations associated with SP resistance are increasingly prevalent throughout sub-Saharan Africa. The outcome of antimalarial therapy results from complex interactions between parasite pathogenicity, host immunity, drug characteristics, and parasite susceptibility to drug therapy. Recent in vitro studies have suggested that the removal of susceptible parasites from heterogeneous parasitemias by antimalarial therapy may facilitate the relative overgrowth of the remaining resistant parasites and therefore potentiate their pathogenicity [3]. A recent study in Tanzania documented increases in placental inflammation that were associated with SP receipt, suggesting that SP may potentiate placental pathology when applied to partially susceptible infections [4]. However, the effect of these placental findings upon birth outcomes was unclear. Given the prevalence of SP resistance and the current lack of appropriate, safe alternatives for use as IPTp, it is critical to explore the associations between IPTp-SP, SP resistance, and delivery outcomes in further contexts to inform malaria control policies. Malawi adopted a policy of IPTp with SP in 1993, and despite the subsequent development of widespread SP resistance [5], a sustained decline in the prevalence of PAM was observed from 1997 to 2005 [6]. In view of the evidence from Tanzania [4], we hypothesized that the emergence of SP-resistant parasites would modify the effect of IPTp-SP and thereby potentiate placental inflammation and parasite densities and worsen birth outcomes. The Queen Elizabeth Central Hospital Epidemiology of Resistance in Pregnancy-Associated Malaria (QuEERPAM) study [7] was a serial cross-sectional analysis in which we explored the relationships between IPTp-SP, the presence of resistant parasites at delivery, and multiple measures of adverse delivery outcome, including parasite densities, placental histology, maternal hemoglobin concentration, and birth weight.