Impact of Plasmodium falciparum Sulphadoxine-Pyrimethamine Resistance on the Effectiveness of Intermittent Preventive Therapy for Malaria in Pregnancy in Africa: A Systematic Review and Meta-Analysis

Background Plasmodium falciparum resistance to sulphadoxine-pyrimethamine (SP) threatens the efficacy of intermittent preventive treatment (IPTp) for malaria in pregnancy in Africa. We conducted a meta-analysis to assess the impact of SP resistance on IPTp-SP effectiveness. Methods We searched databases (1990 to March-01-2018) for clinical studies (aggregated data) or surveys (individual-participant data) containing information on low birthweight (LBW, primary outcome) and malaria by IPTp-SP dose, and for studies reporting SP-resistance molecular markers. We performed random-effects meta-analysis (clinical studies) or multivariate log-binomial regression (surveys) to obtain summarized dose-response data (Relative-Risk-Reduction:RRR) and multivariate meta-regression to explore modifying effects of SP-resistance (dhps substitutions A437G, K540E, A581G). Findings Of 1097 records, 57 studies were included in the aggregated-data meta-analysis (59,457 births). The RRR for LBW declined with increasing prevalence of Pfdhps-K540E (P-trend=0.0060) but not with Pfdhps-A437G (P-trend=0.35). The RRR in areas of high (Pfdhps-K540E >90%, n=11), moderate (Central/West Africa:Pfdhps-A437G≥90% or East/southern Africa:Pfdhps-K540E 30-90%, n=16) and low SP-resistances (n=30) were 7% (95% CI 0-13), 21% (14-29) and 27% (21-33) respectively (P-trend=0.0054, I2=69.5%). In the individual-participant analysis of 13 surveys (42,394 births), IPTp-SP was associated with reduced LBW in areas with Pfdhps-K540E>90% & Pfdhps-A581G=10% (pooled Pfdhps-A581G prevalence:37%, range 29-46) (RRR=0.5%, -16-14, n=3). Interpretation The effectiveness of IPTp-SP is reduced in areas with high SP-resistance, but IPTp-SP remains associated with reduced LBW in areas where Pfdhps-K540E prevalence exceeds 90%. IPTp-SP is not effective in areas with ≥37% prevalence of the highly-resistant sextuple Pfdhps-A581G-containing genotype