Preventive Treatment for Malaria in Pregnant Women Living in an Area of High Drug Resistance

By Whitney Harrington, Pathobiology Graduate Program

Whitney Harrington

Malaria and pregnancy can be a dangerous combination, causing numerous problems for both the mother and the fetus. In an effort to prevent these problems, such as placental malaria, maternal anemia, and low birth weight, the World Health Organization recommends that pregnant women who live in malaria-endemic settings receive two doses of intermittent preventive treatment during pregnancy (IPTp) with the drug sulfadoxine-pyrimethamine (SP). When initially introduced, IPTp was effective at reducing malaria-related poor delivery outcomes among pregnant women and their newborns. Resistance to SP is rapidly increasing worldwide, however, causing concern about IPTp failure. I am working with Dr. Patrick Duffy, affiliate professor in the Department of Global Health, to understand the consequences of IPTp use in areas of high SP resistance, including changes in the population dynamics of parasites sequestered in the placenta and corresponding clinical outcomes.

My early work showed that in a cohort of pregnant women from Muheza, Tanzania, where resistance levels are extremely high, IPTp use was associated with selection for highly resistant placental infections, which were of increased parasite density and associated with increased inflammation, suggesting exacerbated disease. These findings are consistent with previous studies in mice describing a phenomenon known as parasite competitive facilitation: when mixed wild-type and resistant infections are treated with pyrimethamine, the wild-type parasites are killed while the resistant parasites experience a release, filling the niche and eventually over-growing.

Based on our findings, we examined clinical outcomes associated with IPTp use in this cohort and found that IPTp was associated with no benefit. In fact, IPTp was associated with worsening of some delivery outcomes, including decreased cord hemoglobin and birth weight.

Traditional models propose that as resistance to a particular drug increases, benefits will decrease in a linear fashion, eventually approaching zero. We found in this population, however, that the net effect of IPTp use was a combination of benefit and harm. We hypothesize that Muheza is at a “tipping point”—while the effect of IPTp is currently neutral, it appears to be shifting toward harm. We predict that in the event that either drug resistance or placental malaria rates increase in the population, the negative effects of disease exacerbation by IPTp in one part of the population will outweigh the positive effects of disease prevention in another part of the population.

These findings emphasize the need for continued evaluation of any accepted standard of care, as the effect of an intervention may change over time. We are currently working to replicate our findings at additional trial sites, with the goal of building a model that will predict the appropriate time to remove this failing drug regimen.