Defending the Use of Sulfadoxine-Pyrimethamine for Intermittent Preventive Treatment for Malaria in Pregnancy: A Short-Sighted Strategy

To the Editor—We read with interest the recent article by Gutman et al that described an observational study of sulfadoxine-pyrimethamine for intermittent preventive treatment for malaria in pregnancy (SP-IPTp) in Malawi [1]. Because the article heavily cited work from our group [2], we are compelled to call attention to what we feel is a misunderstanding of competitive facilitation, as well as a mischaracterization of our work.

Our original article, from 2009, described associations between SP-IPTp use, selection for the DHPS c581 drug resistance mutation, and increased parasite density and inflammation during placental malarial parasite infections [2]. To explain our findings, we proposed a mechanism of competitive facilitation [3], whereby drug pressure applied to a mixed infection eliminates susceptible parasites and allows resistant parasites to overgrow. Such a model requires (1) a mixture of susceptible and resistant parasites in competition, and (2) the application of drug pressure that selects for the resistant parasites. Although Gutman et al argue that they replicated our design, unfortunately, they failed to meet the basic criteria of this model: they neither convinced us that mixed infections are common in their population nor demonstrated that there was a differential selection by their treatment conditions (SP-IPTp dose or timing of SP-IPTp). Of greatest concern, the study included only 4 women in the control group (no SP-IPTp), preventing meaningful conclusions about the effect of SP-IPTp relative to no SP-IPTp, the essential element of our work. If the authors truly wished to assess whether SP-IPTp is harmful, then they must design a study in which a sufficient number of subjects have not been exposed to the drug.

In addition, the authors state that our original article found “a strong association between parasitologic outcomes and timing of SP dose” and “the highest densities  …  among women who had received SP in the last few weeks before [sic] pregnancy or had received multiple doses of SP.” To the contrary, the only outcome we described to be independently associated with SP timing was a reduction of parasite diversity by msp-2 typing, and we did not examine a dose response in our study. Using this false construct, Gutman et al erroneously combined women who had not received SP-IPTp with women whose last dose was received >4 weeks prior and compared this group to women who had received SP-IPTp in the last 4 weeks. This comparison has no biologic or clinical relevance, as women who have not received SP-IPTp are entirely different from those who received SP-IPTp early in the pregnancy, nor does it replicate our own comparisons.

All of this, however, distracts from what is perhaps the most important point—SP-IPTp is failing in East Africa. Numerous reports now describe a lack of benefit with SP-IPTp [4–6], including a lack of efficacy in Malawi as early as 2006 [7]. This failure is at least partially attributable to the emerging c581 mutation, and the present study, which concluded 4 years ago (2009–2011), found an 8.4% prevalence of parasites harboring this resistance marker, heralding an era of certain SP-IPTp failure. Without clear evidence of benefit, why continue to expose millions of pregnant women and their offspring to a failing drug regimen? Rather than defend this short-sighted strategy while pregnant women and their offspring suffer the consequences, we should invest in alternatives. A paradigm shift is clearly needed.