Impact of Sulfadoxine-Pyrimethamine Resistance on Effectiveness of Intermittent Preventive Therapy for Malaria in Pregnancy at Clearing Infections and Preventing Low Birth Weight

Abstract

Background: Owing to increasing sulfadoxine-pyrimethamine (SP) resistance in sub-Saharan Africa, monitoring the effectiveness of intermittent preventive therapy in pregnancy (IPTp) with SP is crucial.

Methods: Between 2009 and 2013, both the efficacy of IPTp-SP at clearing existing peripheral malaria infections and the effectiveness of IPTp-SP at reducing low birth weight (LBW) were assessed among human immunodeficiency virus-uninfected participants in 8 sites in 6 countries. Sites were classified as high, medium, or low resistance after measuring parasite mutations conferring SP resistance. An individual-level prospective pooled analysis was conducted.

Results: Among 1222 parasitemic pregnant women, overall polymerase chain reaction-uncorrected and -corrected failure rates by day 42 were 21.3% and 10.0%, respectively (39.7% and 21.1% in high-resistance areas; 4.9% and 1.1% in low-resistance areas). Median time to recurrence decreased with increasing prevalence of Pfdhps-K540E. Among 6099 women at delivery, IPTp-SP was associated with a 22% reduction in the risk of LBW (prevalence ratio [PR], 0.78; 95% confidence interval [CI], .69-.88; P < .001). This association was not modified by insecticide-treated net use or gravidity, and remained significant in areas with high SP resistance (PR, 0.81; 95% CI, .67-.97; P = .02).

Conclusions: The efficacy of SP to clear peripheral parasites and prevent new infections during pregnancy is compromised in areas with >90% prevalence of Pfdhps-K540E. Nevertheless, in these high-resistance areas, IPTp-SP use remains associated with increases in birth weight and maternal hemoglobin. The effectiveness of IPTp in eastern and southern Africa is threatened by further increases in SP resistance and reinforces the need to evaluate alternative drugs and strategies for the control of malaria in pregnancy.

Keywords: effectiveness; intermittent preventive treatment; malaria in pregnancy; sulfadoxine-pyrimethamine resistance.

Conflict of interest statement

Potential conflicts of interests. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Published by Oxford University Press for the Infectious Diseases Society of America 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Figures

Figure 1

Parasitological failure rates among asymptomatic, parasitemic pregnant women receiving their first dose of intermittent preventive therapy in pregnancy with sulfadoxine-pyrimethamine (SP). The protocol in Zambia administered SP at 1 month and thus only contributes data through day 35 inclusive in this analysis. The therapeutic response was estimated using the Kaplan–Meier product limit formula [26]. In the polymerase chain reaction (PCR)–uncorrected analysis, recurrences were treated as treatment failures, and all other events (eg, withdrawal or protocol deviations) resulted in censoring at the time of that event, or at the time of their last follow-up visit in case of loss to follow-up. A similar strategy was used for the PCR-corrected analysis, except that patients with new Plasmodium falciparum infections (reinfections) were censored at the time of parasite reappearance [26]. To compare the failure risk across sites, hazard ratios (HRs) were estimated using Cox regression adjusting for gravidity and net use with a shared frailty component to account for the individual heterogeneity of the sites. Abbreviations: CI, confidence interval; ref, reference.

Figure 2

Median time to recurrence, recrudescence or reinfection of Plasmodium falciparum among women participating in the intermittent preventive therapy in pregnancy in vivo module. A, Median time to recurrence by frequency of pyrimethamine: dihydropteroate synthase (Pfdhps)-K540E. The circles represent the estimated median time to recurrence of P. falciparum infection at each site, sized according to the precision of each estimate (the inverse of its within-study variance, σ2). The line represents the linear prediction of the relationship between median time to recurrence and prevalence of Pfdhps-K540E. B, Median time in days by study site, ranked by resistance level. Abbreviations: CI, confidence interval; IPTp, intermittent preventive therapy in pregnancy.

Figure 3

Associations between each incremental dose of intermittent preventive therapy in pregnancy with sulfadoxine-pyrimethamine (SP) and mean birth weight and the prevalence of low birth weight, stratified by SP resistance, gravidity, and insecticide-treated net use. Abbreviations: CI, confidence interval; SD, standard deviation.

Figure 4

Meta-regression bubble plot of the prevalence of low birth weight (LBW) by the frequency of the pyrimethamine: dihydropteroate synthase (Pfdhps)-K540E mutation (8 sites, top panel) and in vivo failure rates in asymptomatic pregnant women (7 sites, bottom panel). The Tororo site in Uganda did not conduct an in vivo study and is missing from the bottom panel. The circles represent the estimated prevalence ratio of LBW, sized according to the sample size from each site. The gray area represents the 95% confidence interval, and the dotted line is the linear prediction. In the bottom panel, the prevalence ratio of LBW was regressed against the polymerase chain reaction (PCR)–corrected failure rate by day 35, as this was the latest standardized day available from all countries (in Zambia, the study was ended on day 35 rather than on day 42). The numbers under each site represent the prevalence ratio and its confidence limit.

Figure 5

Associations between each incremental dose of intermittent preventive therapy in pregnancy with sulfadoxine-pyrimethamine and all secondary outcomes. aGestational age, determined by Ballard score or where unavailable by last menstrual period, was missing from a variable number of individuals at each site; data completeness varied from 76% to 100%. bHemoglobin level (g/dL), assessed by HemoCue at delivery. cSmall for gestational age defined as birth weight for gestational age <10th percentile using an ultrasound-derived fetal size nomogram for a sub-Saharan African population [25]. dMalaria infection defined as either a positive peripheral smear (maternal malaria) or a positive placental impression smear (composite endpoint). eActive placental infection (acute or chronic) by placental histology, classified on a 5-point scale as described by Rogerson et al [30]. Placental histology was not done in the 3 sites in West Africa (low resistance strata). Abbreviations: CI, confidence interval; SD, standard deviation.