Rapid Diagnostic Test Performance Assessed Using Latent Class Analysis for the Diagnosis of Plasmodium falciparum Placental Malaria.

Placental malaria causes low birth weight and neonatal mortality in malaria-endemic areas. The diagnosis of placental malaria is important for program evaluation and clinical care, but is compromised by the suboptimal performance of current diagnostics. Using placental and peripheral blood specimens collected from delivering women in Malawi, we compared estimation of the operating characteristics of microscopy, rapid diagnostic test (RDT), polymerase chain reaction, and histopathology using both a traditional contingency table and a latent class analysis (LCA) approach. The prevalence of placental malaria by histopathology was 13.8%; concordance between tests was generally poor. Relative to histopathology, RDT sensitivity was 79.5% in peripheral and 66.2% in placental blood; using LCA, RDT sensitivities increased to 93.7% and 80.2%, respectively. Our results, if replicated in other cohorts, indicate that RDT testing of peripheral or placental blood may be suitable approaches to detect placental malaria for surveillance programs, including areas where intermittent preventive therapy in pregnancy is not used

Interactions between antenatal sulfadoxine-pyrimethamine, drug-resistant Plasmodium falciparum parasites and delivery outcomes in Malawi.

BACKGROUND Sulfadoxine-pyrimethamine (SP) is used as intermittent preventive therapy in pregnancy (IPTp) for malaria in sub-Saharan Africa. The resistance marker dhps A581G has been associated with reduced IPTp-SP efficacy and enhanced morbidity in SP-recipients. METHODS We measured SP-resistance allele frequencies in Malawian women participating in a trial (www.isrctn.com/ISRCTN69800930) comparing IPTp with SP against intermittent screening by rapid diagnostic tests (ISTp). We genotyped PCR-detected parasites using deep sequencing of SP-resistance alleles. RESULTS Among 125 placental infections, A581G-bearing parasites were associated with reduced birthweight (mean difference[MD]:252g, 95% CI:46,457, p=0.017). Relative to ISTp, IPTp-SP was associated with higher birthweights in women with wildtype parasites (MD:116g, 95% CI:-40,272; p=0.142) and lower birthweights in women with A581G-bearing parasites (MD:192g, 95% CI:-264,648; p=0.385) (pinteraction=0.033). Similar associations were noted on gestational age (pinteraction=0.075). Amongst only IPTp-SP recipients, relative to women who last received SP >4 weeks before delivery, recent SP receipt was associated with lower birthweight in women with wildtype parasites (MD:118g, 95% CI:-376,139; p=0.361) and higher birthweight in women with A581G-bearing parasites (MD:783g, 95% CI:-20,1586; p=0.054) (pinteraction=0.005). CONCLUSIONS The effectiveness on birthweight of IPTp-SP is compromised by A581G-bearing parasites, but there was no evidence that the adverse effects of these parasites are exacerbated by antenatal SP

Post-discharge Malaria Chemoprevention in Children Admitted with Severe Anaemia in Malaria-Endemic Settings in Africa: A systematic review and Individual Patient Data meta-analysis of randomised controlled trials

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 an individual patient data (IPD) meta-analysis to determine the efficacy of monthly post-discharge malaria chemoprevention (PDMC) in children recovering from severe anaemia. Methods: Following PRISMA-IPD guidelines, we searched multiple databases, without time or language restrictions, for randomised controlled trials comparing monthly PDMC with placebo or standard-of-care among children admitted with severe anaemia in malaria-endemic Africa. Trials using daily or weekly malaria prophylaxis were not eligible. Fixed-effects two-stage meta-analysis of risk ratios (RR) was used to generate pooled effect estimates for mortality. Recurrent time-to-event data 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: Three double-blind placebo-controlled trials involving 3,663 children with severe anaemia fulfilled the eligibility criteria; 3,507 (95.7%) contributed to the modified intention-to-treat analysis. They received either monthly sulfadoxine-pyrimethamine until the end of the malaria transmission season (average 3.1 courses/child) (N=1,085, the Gambia), monthly artemether-lumefantrine given at the end of the 4th and 8th week post-discharge (N=1,373, Malawi), or monthly dihydroartemisinin-piperaquine given at the end of the 2nd, 6th, and 10th week post-discharge (N=1,049, Uganda and Kenya). During the period of chemoprevention, PDMC was associated with a 77% reduction in mortality (RR=0.23 [95% CI 0.08-0.70], p=0.0094, I2=0%) and a 55% reduction in all-cause readmissions (HR=0.45 [0.36-0.56], p<0.0001). The reductions were not sustained after protective drug levels had waned. The small number of trials limited our ability to assess heterogeneity, its sources and publication bias. Interpretation: In malaria-endemic Africa, PDMC reduces mortality and readmissions in recently discharged children recovering from severe anaemia. PDMC can be a valuable strategy for the post-discharge management of this high-risk group. Future research should focus on methods of PDMC delivery, options to prolong the protection duration, other hospitalised special risk groups, and interventions targeting non-malarial causes of post-discharge morbidity

Cost-effectiveness of intermittent preventive treatment with dihydroartemisinin-piperaquine versus single screening and treatment for the control of malaria in pregnancy in Papua, Indonesia: a provider perspective analysis from a cluster-randomised trial.

BACKGROUND: Malaria infection during pregnancy is associated with serious adverse maternal and birth outcomes. A randomised controlled trial in Papua, Indonesia, comparing the efficacy of intermittent preventive treatment with dihydroartemisinin-piperaquine with the current strategy of single screening and treatment showed that intermittent preventive treatment is a promising alternative treatment for the reduction of malaria in pregnancy. We aimed to estimate the incremental cost-effectiveness of intermittent preventive treatment with dihydroartemisinin-piperaquine compared with single screening and treatment with dihydroartemisinin-piperaquine. METHODS: We did a provider perspective analysis. A decision tree model was analysed from a health provider perspective over a lifetime horizon. Model parameters were used in deterministic and probabilistic sensitivity analyses. Simulations were run in hypothetical cohorts of 1000 women who received intermittent preventive treatment or single screening and treatment. Disability-adjusted life-years (DALYs) for fetal loss or neonatal death, low birthweight, moderate or severe maternal anaemia, and clinical malaria were calculated from trial data and cost estimates in 2016 US dollars from observational studies, health facility costings and public procurement databases. The main outcome measure was the incremental cost per DALY averted. FINDINGS: Relative to single screening and treatment, intermittent preventive treatment resulted in an incremental cost of US$5657 (95$53 per DALY averted. INTERPRETATION: Intermittent preventive treatment with dihydroartemisinin-piperaquine offers a cost-effective alternative to single screening and treatment for the prevention of the adverse effects of malaria infection in pregnancy in the context of the moderate malaria transmission setting of Papua. The higher cost of intermittent preventive treatment was driven by monthly administration, as compared with single-administration single screening and treatment. However, acceptability and feasibility considerations will also be needed to inform decision making. FUNDING: Medical Research Council, Department for International Development, and Wellcome Trust

Intermittent screening and treatment with artemisinin-combination therapy versus intermittent preventive treatment with sulphadoxine-pyrimethamine for malaria in pregnancy: a systematic review and individual participant data meta-analysis of randomised clinical trials.

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, I2=67.0 %) and patent infection (RR=1.02, 0.61-1.16, I2=0.0%) were similar. Subpatent infections were more common in ISTp recipients (RR=1.31, 1.05-1.62, I2=0.0%). There was no difference in adverse pregnancy outcome (RR=1.00, 0.96-1.05; studies=4, N=9,191, I2=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

Neurocognitive outcomes in Malawian children exposed to malaria during pregnancy: An observational birth cohort study

BACKGROUND Annually 125 million pregnancies are at risk of malaria infection. However, the impact of exposure to malaria in pregnancy on neurodevelopment in children is not well understood. We hypothesized that malaria in pregnancy and associated maternal immune activation result in neurodevelopmental delay in exposed offspring. METHODS AND FINDINGS Between April 2014 and April 2015, we followed 421 Malawian mother-baby dyads (median [IQR] maternal age: 21 [19, 28] years) who were previously enrolled (median [IQR] gestational age at enrollment: 19.7 [17.9, 22.1] weeks) in a randomized controlled malaria prevention trial with 5 or 6 scheduled assessments of antenatal malaria infection by PCR. Children were evaluated at 12, 18, and/or 24 months of age with cognitive tests previously validated in Malawi: the Malawi Developmental Assessment Tool (MDAT) and the MacArthur-Bates Communicative Development Inventories (MCAB-CDI). We assessed the impact of antenatal malaria (n [%] positive: 240 [57.3]), placental malaria (n [%] positive: 112 [29.6]), and maternal immune activation on neurocognitive development in children. Linear mixed-effects analysis showed that children exposed to antenatal malaria between 33 and 37 weeks gestation had delayed language development across the 2-year follow-up, as measured by MCAB-CDI (adjusted beta estimate [95% CI], -7.53 [-13.04, -2.02], p = 0.008). Maternal immune activation, characterized by increased maternal sTNFRII concentration, between 33 and 37 weeks was associated with lower MCAB-CDI language score (adjusted beta estimate [95% CI], -8.57 [-13.09, -4.06], p < 0.001). Main limitations of this study include a relatively short length of follow-up and a potential for residual confounding that is characteristic of observational studies. CONCLUSIONS This mother-baby cohort presents evidence of a relationship between malaria in pregnancy and neurodevelopmental delay in offspring. Malaria in pregnancy may be a modifiable risk factor for neurodevelopmental injury independent of birth weight or prematurity. Successful interventions to prevent malaria during pregnancy may reduce the risk of neurocognitive delay in children

The Angiopoietin-Tie2 axis contributes to placental vascular disruption and adverse birth outcomes in malaria in pregnancy

BACKGROUND Malaria during pregnancy is a major contributor to the global burden of adverse birth outcomes including fetal growth restriction, preterm birth, and fetal loss. Recent evidence supports a role for angiogenic dysregulation and perturbations to placental vascular development in the pathobiology of malaria in pregnancy. The Angiopoietin-Tie2 axis is critical for placental vascularization and remodeling. We hypothesized that disruption of this pathway would contribute to malaria-induced adverse birth outcomes. METHODS Using samples from a previously conducted prospective cohort study of pregnant women in Malawi, we measured circulating levels of angiopoietin-1 (Angpt-1) and Angpt-2 by Luminex (n=1392). We used a preclinical model of malaria in pregnancy (Plasmodium berghei ANKA [PbA] in pregnant BALB/c mice), genetic disruption of Angpt-1 (Angpt1 mice), and micro-CT analysis of placental vasculature to test the hypothesis that disruptions to the Angpt-Tie2 axis by malaria during pregnancy would result in aberrant placental vasculature and adverse birth outcomes. FINDINGS Decreased circulating levels of Angpt-1 and an increased ratio of Angpt-2/Angpt-1 across pregnancy were associated with malaria in pregnancy. In the preclinical model, PbA infection recapitulated disruptions to the Angiopoietin-Tie2 axis resulting in reduced fetal growth and viability. Malaria decreased placental Angpt-1 and Tie2 expression and acted synergistically with reduced Angpt-1 in heterozygous dams (Angpt1), to worsen birth outcomes by impeding vascular remodeling required for placental function. INTERPRETATION Collectively, these data support a mechanistic role for the Angpt-Tie2 axis in malaria in pregnancy, including a potential protective role for Angpt-1 in mitigating infection-associated adverse birth outcomes. FUNDING This work was supported by the Canadian Institutes of Health Research (CIHR), Canada Research Chair, and Toronto General Research Institute Postdoctoral Fellowship Award. The parent trial was supported by the European & Developing Countries Clinical Trials Partnership and the Malaria in Pregnancy Consortium, which was funded by the Bill & Melinda Gates Foundation. The funders had no role in design, analysis, or reporting of these studies

Implementation of post-discharge malaria chemoprevention (PDMC) in Benin, Kenya, Malawi, and Uganda: stakeholder engagement meeting report

A Stakeholder engagement meeting on the implementation of post-discharge malaria chemoprevention (PDMC) in Benin, Kenya, Malawi, and Uganda was held in Nairobi, Kenya, on 27 September 2023. Representatives from the respective National Malaria Control Programmes, the World Health Organization (WHO) Geneva, Africa Regional and Kenya offices, research partners, non-governmental rganizations, and the Medicines for Malaria Venture participated. PDMC was recommended by the WHO in June 2022 and involves provision of a full anti-malarial treatment course at regular intervals during the post-discharge period in children hospitalized with severe anaemia in areas of moderate-to-high malaria transmission. The WHO recommendation followed evidence from a meta-analysis of three clinical trials and from acceptability, delivery, cost-ffectiveness, and modelling studies. The trials were conducted in The Gambia using monthly sulfadoxine-pyrimethamine during the transmission season, in Malawi using monthly artemether-lumefantrine, and in Kenya and Uganda using monthly dihydroartemisinin-piperaquine, showing a significant reduction in all-cause mortality by 77% (95% CI 30–98) and a 55% (95% CI 44–64) reduction in all-cause hospital readmissions 6 months post-discharge. The recommendation has not yet been implemented in sub-Saharan Africa. There is no established platform for PDMC delivery. The objectives of the meeting were for the participating countries to share country contexts, plans and experiences regarding the adoption and implementation of PDMC and to explore potential delivery platforms in each setting. The meeting served as the beginning of stakeholder engagement within the PDMC Saves Lives project and will be followed by formative and implementation research to evaluate alternative delivery strategies in selected countries. Meeting highlights included country consensus on use of dihydroartemisinin-piperaquine for PDMC and expansion of the target group to "severe anaemia or severe malaria", in addition to identifying country-specific options for PDMC delivery for evaluation in implementation research. Further exploration is needed on whether the age group should be extended to school-age children

Projected health impact of post-discharge malaria chemoprevention among children with severe malarial anaemia in Africa.

Children recovering from severe malarial anaemia (SMA) remain at high risk of readmission and death after discharge from hospital. However, a recent trial found that post-discharge malaria chemoprevention (PDMC) with dihydroartemisinin-piperaquine reduces this risk. We developed a mathematical model describing the daily incidence of uncomplicated and severe malaria requiring readmission among 0-5-year old children after hospitalised SMA. We fitted the model to a multicentre clinical PDMC trial using Bayesian methods and modelled the potential impact of PDMC across malaria-endemic African countries. In the 20 highest-burden countries, we estimate that only 2-5 children need to be given PDMC to prevent one hospitalised malaria episode, and less than 100 to prevent one death. If all hospitalised SMA cases access PDMC in moderate-to-high transmission areas, 38,600 (range 16,900-88,400) malaria-associated readmissions could be prevented annually, depending on access to hospital care. We estimate that recurrent SMA post-discharge constitutes 19% of all SMA episodes in moderate-to-high transmission settings