BACKGROUND: Resistance of Plasmodium falciparum to sulfadoxine-pyrimethamine threatens the antimalarial effectiveness of intermittent preventive treatment during pregnancy (IPTp) with sulfadoxine-pyrimethamine (ITPp-SP) in sub-Saharan Africa. We updated an aggregated-data meta-analysis to assess the associations between sulfadoxine-pyrimethamine resistance and the effectiveness of IPTp-SP to inform policy. METHODS: We searched databases (Jan 1, 1990, to June 8, 2024) for observational studies or trials reporting data on malaria, low birthweight (<2500 g), anaemia, and other outcomes by IPTp-SP dose and matched these by year and location with studies that reported on molecular markers of sulfadoxine-pyrimethamine resistance. Studies including only women with HIV or combined interventions were excluded. We evaluated how sulfadoxine-pyrimethamine resistance influenced the adjusted risk ratio (aRR) between three and two doses of IPTp-SP for various outcomes using Poisson mixed-effects models that allowed for non-linear relationships. Initially, we performed a threshold analysis, stratified by region, to identify the resistance levels most predictive of altered effect of IPTp-SP doses on malaria parasitaemia at delivery (peripheral or placental parasitaemia by any test), our primary outcome. These resistance strata were then used in all subsequent models for other outcomes. All analyses were adjusted for malaria transmission intensity, HIV infection, percentage of paucigravidae, and insecticide-treated net use. Performance of models was evaluated using cross-validation. The trial was registered with PROSPERO (CRD42021250359). FINDINGS: Overall, 122 studies involving 148 693 participants were included. For west and central Africa (69 studies comprising 63 745 participants), very low resistance was categorised as a prevalence of the dihydropteroate synthase (dhps) Lys540Glu mutation in the parasite population of less than 4%, and low resistance as a prevalence of Lys540Glu of 4% or higher. In east and southern Africa (53 studies comprising 84 948 participants), moderate resistance was categorised as a prevalence of the Lys540Glu mutation of less than 60% combined with a prevalence of the Ala581Gly mutation of less than 5%, high resistance as a prevalence of Lys540Glu of 60% or higher combined with a prevalence of Ala581Gly of less than 5%, and very high resistance as a prevalence of the Lys540Glu mutation of 60% or higher combined with a prevalence of Ala581Gly of 5% or higher. There was a marked trend towards lower efficacy of IPTp-SP on reducing malaria infection with increasing resistance levels. In west and central Africa, when comparing three versus two doses, the aRR was 0·71 (95% CI 0·65-0·78) in areas with very low resistance and 0·83 (0·72-0·95) in areas with low resistance (p=0·0144 for the difference between dose-response curves in very low vs low resistance). For east and southern Africa, the same trend was observed: the aRR was 0·63 (95% CI 0·57-0·69) in areas with moderate resistance, 0·89 (0·82-0·96) in areas with high resistance, and 0·93 (0·85-1·01) in areas with very high resistance (p<0·0001 for dose-response curves differences between moderate vs high and moderate vs very high resistance). This pattern was not seen for low birthweight. When comparing three versus two doses in west and central Africa, the aRR was 0·58 (95% CI 0·48-0·68) in areas with very low resistance and 0·56 (0·44-0·68) in areas with low resistance (p=0·72 for dose-response curves very low vs low resistance). For east and southern Africa, the aRR was 0·75 (95% CI 0·52-0·98) in areas with moderate resistance, 0·73 (0·69-0·78) in areas with high resistance, and 0·75 (0·63-0·87) in areas with very high resistance (p=0·80 for dose-response curves moderate vs high resistance; p=0·90 for moderate vs very high resistance). Dose comparisons in some resistance strata were limited by sample size. INTERPRETATION: IPTp-SP antimalarial efficacy is greatly reduced in very high resistance areas. However, it remains effective at reducing low birthweight in these areas, possibly through non-malaria effects on fetal growth. While IPTp-SP use should continue in high SP-resistance areas, alternative malaria preventive strategies are urgently needed in these areas. FUNDING: WHO and WorldWide-Antimalarial-Resistance-Network.

BACKGROUND: Severe anaemia is associated with high in-hospital mortality among young children. In malaria-endemic areas, surviving children also have an increased risk of mortality or readmission after hospital discharge. We conducted a systematic review and individual patient data meta-analysis to determine the efficacy of monthly post-discharge malaria chemoprevention in children recovering from severe anaemia. METHODS: This analysis was conducted according to PRISMA-IPD guidelines. We searched multiple databases on Aug 28, 2023, without date or language restrictions, for randomised controlled trials comparing monthly post-discharge malaria chemoprevention with placebo or standard of care among children (aged <15 years) admitted with severe anaemia in malaria-endemic Africa. Trials using daily or weekly malaria prophylaxis were not eligible. The investigators from all eligible trials shared pseudonymised datasets, which were standardised and merged for analysis. The primary outcome was all-cause mortality during the intervention period. Analyses were performed in the modified intention-to-treat population, including all randomly assigned participants who contributed to the endpoint. Fixed-effects two-stage meta-analysis of risk ratios (RRs) was used to generate pooled effect estimates for mortality. Recurrent time-to-event data (readmissions or clinic visits) were analysed using one-stage mixed-effects Prentice-Williams-Peterson total-time models to obtain hazard ratios (HRs). This study is registered with PROSPERO, CRD42022308791. FINDINGS: Our search identified 91 articles, of which 78 were excluded by title and abstract, and a further ten did not meet eligibility criteria. Three double-blind, placebo-controlled trials, including 3663 children with severe anaemia, were included in the systematic review and meta-analysis; 3507 (95·7%) contributed to the modified intention-to-treat analysis. Participants received monthly sulfadoxine-pyrimethamine until the end of the malaria transmission season (mean 3·1 courses per child [range 1-6]; n=1085; The Gambia), monthly artemether-lumefantrine given at the end of weeks 4 and 8 post discharge (n=1373; Malawi), or monthly dihydroartemisinin-piperaquine given at the end of weeks 2, 6, and 10 post discharge (n=1049; Uganda and Kenya). During the intervention period, post-discharge malaria chemoprevention was associated with a 77% reduction in mortality (RR 0·23 [95% CI 0·08-0·70], p=0·0094, I(2)=0%) and a 55% reduction in all-cause readmissions (HR 0·45 [95% CI 0·36-0·56], p<0·0001) compared with placebo. The protective effect was restricted to the intervention period and was not sustained after the direct pharmacodynamic effect of the drugs had waned. The small number of trials limited our ability to assess heterogeneity, its sources, and publication bias. INTERPRETATION: In malaria-endemic Africa, post-discharge malaria chemoprevention reduces mortality and readmissions in recently discharged children recovering from severe anaemia. Post-discharge malaria chemoprevention could be a valuable strategy for the management of this group at high risk. Future research should focus on methods of delivery, options to prolong the protection duration, other hospitalised groups at high risk, and interventions targeting non-malarial causes of post-discharge morbidity. FUNDING: The Research-Council of Norway and the Bill-&-Melinda-Gates-Foundation through the Worldwide-Antimalarial-Research-Network.

BACKGROUND: Resistance of Plasmodium falciparum to sulfadoxine-pyrimethamine threatens the antimalarial effectiveness of intermittent preventive treatment during pregnancy (IPTp) in sub-Saharan Africa. We aimed to assess the associations between markers of sulfadoxine-pyrimethamine resistance in P falciparum and the effectiveness of sulfadoxine-pyrimethamine IPTp for malaria-associated outcomes. METHODS: For this systematic review and meta-analysis, we searched databases (from Jan 1, 1990 to March 1, 2018) for clinical studies (aggregated data) or surveys (individual participant data) that reported data on low birthweight (primary outcome) and malaria by sulfadoxine-pyrimethamine IPTp dose, and for studies that reported on molecular markers of sulfadoxine-pyrimethamine resistance. Studies that involved only HIV-infected women or combined interventions were excluded. We did a random-effects meta-analysis (clinical studies) or multivariate log-binomial regression (surveys) to obtain summarised dose-response data (relative risk reduction [RRR]) and multivariate meta-regression to explore the modifying effects of sulfadoxine-pyrimethamine resistance (as indicated by Ala437Gly, Lys540Glu, and Ala581Gly substitutions in the dhps gene). This study is registered with PROSPERO, number 42016035540. FINDINGS: Of 1097 records screened, 57 studies were included in the aggregated-data meta-analysis (including 59 457 births). The RRR for low birthweight declined with increasing prevalence of dhps Lys540Glu (p(trend)=0·0060) but not Ala437Gly (p(trend)=0·35). The RRR was 7% (95% CI 0 to 13) in areas of high resistance to sulfadoxine-pyrimethamine (Lys540Glu ≥90% in east and southern Africa; n=11), 21% (14 to 29) in moderate-resistance areas (Ala437Gly ≥90% [central and west Africa], or Lys540Glu ≥30% to <90% [east and southern Africa]; n=16), and 27% (21 to 33) in low-resistance areas (Ala437Gly <90% [central and west Africa], or Lys540Glu <30% [east and southern Africa]; n=30; p(trend)=0·0054 [univariate], I(2)=69·5%). The overall RRR in all resistance strata was 21% (17 to 25). In the analysis of individual participant data from 13 surveys (42 394 births), sulfadoxine-pyrimethamine IPTp was associated with reduced prevalence of low birthweight in areas with a Lys540Glu prevalence of more than 90% and Ala581Gly prevalence of less than 10% (RRR 10% [7 to 12]), but not in those with an Ala581Gly prevalence of 10% or higher (pooled Ala581Gly prevalence 37% [range 29 to 46]; RRR 0·5% [-16 to 14]; 2326 births). INTERPRETATION: The effectiveness of sulfadoxine-pyrimethamine IPTp is reduced in areas with high resistance to sulfadoxine-pyrimethamine among P falciparum parasites, but remains associated with reductions in low birthweight even in areas where dhps Lys540Glu prevalence exceeds 90% but where the sextuple-mutant parasite (harbouring the additional dhps Ala581Gly mutation) is uncommon. Therapeutic alternatives to sulfadoxine-pyrimethamine IPTp are needed in areas where the prevalence of the sextuple-mutant parasite exceeds 37%. FUNDING: US Centers for Disease Control and Prevention, the Malaria in Pregnancy Consortium (funded through a grant from the Bill & Melinda Gates Foundation to the Liverpool School of Tropical Medicine), Worldwide Antimalarial Resistance Network, European and Developing Countries Clinical Trials Partnership.

BACKGROUND: In sub-Saharan Africa, the efficacy of intermittent preventive therapy in pregnancy with sulphadoxine-pyrimethamine (IPTp-SP) for malaria in pregnancy is threatened by parasite resistance. We conducted an individual-participant data (IPD) meta-analysis to assess the efficacy of intermittent screening with malaria rapid diagnostic tests (RDTs) and treatment of RDT-positive women with artemisinin-based combination therapy (ISTp-ACT) compared to IPTp-SP, and understand the importance of subpatent infections. METHODS: We searched MEDLINE and the Malaria-in-Pregnancy Library on May 6, 2021 for trials comparing ISTp-ACT and IPTp-SP. Generalised linear regression was used to compare adverse pregnancy outcomes (composite of small-for-gestational-age, low birthweight (LBW), or preterm delivery) and peripheral or placental Plasmodium falciparum at delivery. The effects of subpatent (PCR-positive, RDT/microscopy-negative) infections were assessed in both arms pooled using multi-variable fixed-effect models adjusting for the number of patent infections. PROSPERO registration: CRD42016043789. FINDINGS: Five trials conducted between 2007 and 2014 contributed (10,821 pregnancies), two from high SP-resistance areas where dhfr/dhps quintuple mutant parasites are saturated, but sextuple mutants are still rare (Kenya and Malawi), and three from low-resistance areas (West-Africa). Four trials contributed IPD data (N=10,362). At delivery, the prevalence of any malaria infection (relative risk [RR]=1.08, 95% CI 1.00-1.16, I(2)=67.0 %) and patent infection (RR=1.02, 0.61-1.16, I(2)=0.0%) were similar. Subpatent infections were more common in ISTp recipients (RR=1.31, 1.05-1.62, I(2)=0.0%). There was no difference in adverse pregnancy outcome (RR=1.00, 0.96-1.05; studies=4, N=9,191, I(2)=54.5%). Subpatent infections were associated with LBW (adjusted RR=1.13, 1.07-1.19), lower mean birthweight (adjusted mean difference=32g, 15-49), and preterm delivery (aRR=1.35, 1.15-1.57). INTERPRETATION: ISTp-ACT was not superior to IPTp-SP and may result in more subpatent infections than the existing IPTp-SP policy. Subpatent infections were associated with increased LBW and preterm delivery. More sensitive diagnostic tests are needed to detect and treat low-grade infections. FUNDING: Centers for Disease Control and Prevention and Worldwide Antimalarial Resistance Network.

Background: Dihydroartemisinin-piperaquine (DP) is a long-acting artemisinin combination treatment that provides effective chemoprevention and has been proposed as an alternative antimalarial drug for intermittent-preventive therapy in pregnancy (IPTp). Several pharmacokinetic studies have shown that dose adjustment may not be needed for the treatment of malaria in pregnancy with DP. However, there are limited data on the optimal dosing for IPTp. Objective: This study aimed to evaluate the population pharmacokinetics of piperaquine given as IPTp in pregnant women. Methods: Pregnant women were enrolled in clinical trials conducted in Kenya and Indonesia and treated with standard 3-day courses of DP, administered in 4-8 weeks intervals from the second trimester until delivery. Pharmacokinetic blood samples were collected for piperaquine drug measurements before each treatment round, time of breakthrough symptomatic malaria, and at delivery. Piperaquine population pharmacokinetic properties were investigated using nonlinear mixed-effects modelling with a prior approach. Results: In total data from 366 Kenyan and 101 Indonesian women were analysed. The pharmacokinetic properties of piperaquine were adequately described using a flexible transit absorption (n=5) followed by a three-compartment disposition model. Gestational age did not affect the pharmacokinetic parameters of piperaquine. After three rounds of monthly IPTp, 9.45% (95% CI: 1.8-26.5) of pregnant women had trough piperaquine concentrations below the suggested target concentration (10.3 ng/mL). Translational simulations suggest that providing the full treatment dose of DP at monthly intervals provides sufficient protection to prevent malaria infection. Conclusions: Monthly administration of a DP has the potential to offer optimal prevention of malaria during pregnancy.

Plasmodium falciparum in pregnancy is a major cause of adverse pregnancy outcomes. We combine performance estimates of standard rapid diagnostic tests (RDT) from trials of intermittent screening and treatment in pregnancy (ISTp) with modelling to assess whether screening at antenatal visits improves upon current intermittent preventative therapy with sulphadoxine-pyrimethamine (IPTp-SP). We estimate that RDTs in primigravidae at first antenatal visit are substantially more sensitive than in non-pregnant adults (OR = 17.2, 95% Cr.I. 13.8-21.6), and that sensitivity declines in subsequent visits and with gravidity, likely driven by declining susceptibility to placental infection. Monthly ISTp with standard RDTs, even with highly effective drugs, is not superior to monthly IPTp-SP. However, a hybrid strategy, recently adopted in Tanzania, combining testing and treatment at first visit with IPTp-SP may offer benefit, especially in areas with high-grade SP resistance. Screening and treatment in the first trimester, when IPTp-SP is contraindicated, could substantially improve pregnancy outcomes.

Pregnancy associated malaria (PAM) causes adverse pregnancy and birth outcomes owing to Plasmodium falciparum accumulation in the placenta. Placental accumulation is mediated by P. falciparum protein VAR2CSA, a leading PAM-specific vaccine target. The extent of its antigen diversity and impact on clinical outcomes remain poorly understood. Through amplicon deep-sequencing placental malaria samples from women in Malawi and Benin, we assessed sequence diversity of VAR2CSA's ID1-DBL2x region, containing putative vaccine targets and estimated associations of specific clades with adverse birth outcomes. Overall, var2csa diversity was high and haplotypes subdivided into five clades, the largest two defined by homology to parasites strains, 3D7 or FCR3. Across both cohorts, compared to women infected with only FCR3-like variants, women infected with only 3D7-like variants delivered infants with lower birthweight (difference: -267.99 g; 95% Confidence Interval [CI]: -466.43 g,-69.55 g) and higher odds of low birthweight (<2500 g) (Odds Ratio [OR] 5.41; 95% CI:0.99,29.52) and small-for-gestational-age (OR: 3.65; 95% CI: 1.01,13.38). In two distinct malaria-endemic African settings, parasites harboring 3D7-like variants of VAR2CSA were associated with worse birth outcomes, supporting differential effects of infection with specific parasite strains. The immense diversity coupled with differential clinical effects of this diversity suggest that an effective VAR2CSA-based vaccine may require multivalent activity.

BACKGROUND: Monitoring the effectiveness of intermittent preventive therapy in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is crucial owing to increasing SP resistance in sub-Saharan Africa. 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 birthweight (LBW) were assessed among HIV-negative participants in 8 sites in 6 countries. Sites were classified as high, medium or low resistance after measuring mutations conferring SP resistance. An individual-level prospective pooled analysis was conducted. RESULTS: Among 1,222 parasitaemic pregnant women, overall PCR-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 6,099 women at delivery, each incremental dose of IPTp-SP was associated with a 22% reduction in the risk of LBW (prevalence ratio [PR]=0.78 [95% CI 0.69-0.88], p<0.001). This association was not modified by insecticide-treated net use or gravidity, and remained significant in areas with SP resistance (PR=0.81 [0.67-0.97], p=0.02). 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 birthweight and maternal haemoglobin. 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.

BACKGROUND: The Plasmodium falciparum dihydropteroate synthase (Pfdhps) A581 G: mutation in combination with the dhfr/dhps quintuple mutant (the "sextuple" mutant) has been associated with increased placental inflammation and decreased birthweight among women receiving intermittent preventive treatment in pregnancy with sulphadoxine-pyrimethamine (IPTp-SP). METHODS: Between 2009-2011, HIV-uninfected delivering women were enrolled in an observational study of IPTp-SP effectiveness in Malawi. Parasites were detected by polymerase chain reaction (PCR); positive samples were sequenced to genotype at dhfr and dhps loci. Presence of Pfdhps-K540 E: was used as a marker for the quintuple mutant. RESULTS: Samples from 1809 women were analysed by PCR; 220 (12%) were positive for P.falciparum. A total of 202 specimens were genotyped at codon Pfdhps-581; 17 (8.4%) harbored the sextuple mutant. The sextuple mutant was associated with higher risks of patent infection in peripheral (adjusted prevalence ratio [aPR] 2.76; 95% confidence interval 1.82-4.18) and placental blood (aPR 3.28 [1.88-5.78]), and higher parasite densities. Recent SP was not associated with increased parasite densities or placental pathology, overall and among women with dhps-A581 G: mutant parasites. CONCLUSIONS: IPTp-SP failed to inhibit parasite growth but did not exacerbate pathology among women infected with sextuple mutant parasites. New interventions to prevent malaria in pregnancy are needed urgently.