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

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Study Justification:
The study aimed to compare the efficacy of intermittent screening with malaria rapid diagnostic tests (RDTs) and treatment of RDT-positive women with artemisinin-based combination therapy (ISTp-ACT) versus intermittent preventive therapy in pregnancy with sulphadoxine-pyrimethamine (IPTp-SP) for malaria in pregnancy. This comparison was important because the efficacy of IPTp-SP is threatened by parasite resistance in sub-Saharan Africa. The study also aimed to understand the importance of subpatent infections in both treatment approaches.
Highlights:
– The study conducted an individual-participant data (IPD) meta-analysis, which included data from five trials conducted between 2007 and 2014.
– The analysis included a total of 10,821 pregnancies, with IPD data available for 10,362 pregnancies.
– At delivery, the prevalence of any malaria infection and patent infection was similar between the ISTp-ACT and IPTp-SP groups.
– Subpatent infections were more common in the ISTp-ACT group.
– There was no difference in adverse pregnancy outcomes between the two treatment approaches.
– Subpatent infections were associated with increased risk of low birthweight, lower mean birthweight, and preterm delivery.
Recommendations:
– The study suggests that ISTp-ACT is not superior to IPTp-SP and may result in more subpatent infections.
– More sensitive diagnostic tests are needed to detect and treat low-grade infections.
– The findings highlight the importance of addressing subpatent infections, as they are associated with adverse pregnancy outcomes.
Key Role Players:
– Researchers and scientists specializing in malaria and pregnancy
– Healthcare providers and clinicians
– Policy makers and government officials
– Non-governmental organizations (NGOs) working in the field of malaria prevention and treatment
Cost Items for Planning Recommendations:
– Research and data collection costs
– Diagnostic test development and procurement costs
– Training and capacity building for healthcare providers
– Implementation and monitoring costs for new diagnostic and treatment strategies
– Public awareness and education campaigns
– Infrastructure and logistics support for delivering interventions
– Collaboration and coordination costs among stakeholders

The strength of evidence for this abstract is 7 out of 10.
The evidence in the abstract is rated 7 because it provides a systematic review and individual participant data meta-analysis of randomized clinical trials. The study conducted an electronic literature search using appropriate search terms and databases. The authors followed PRISMA guidelines and applied a multi-concept Boolean search strategy. Two independent reviewers screened titles, abstracts, and full texts of all citations. The study included a sufficient number of trials and pregnancies, and the data analysis was conducted using appropriate statistical methods. However, the abstract does not provide information on the quality of the included trials, the risk of bias assessment, or the limitations of the study. To improve the evidence, the abstract could include a summary of the risk of bias assessment and limitations of the study.

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.

An electronic literature search, using the search terms: ((intermittent AND screening) AND malaria) AND pregnan* AND Clinical Trial[ptyp] AND Humans[Mesh]) was conducted on August 8, 2016, and updated on May 6, 2021, following PRISMA guidelines [20]. The following databases were searched: MEDLINE and the Malaria in Pregnancy Consortium (MiPc) Library, which includes references from Web of Knowledge, Scopus, CINAHL, Bioline, the Cochrane Library databases, WHO Global Health Library, as well as ‘grey literature’ and conference abstracts [21]. A multi-concept Boolean search strategy was applied using keywords and MeSH terms. Randomised controlled trials among pregnant women comparing ISTp-ACT versus IPTp-SP were eligible (Supplement 1, page 2). The search was conducted in English but without language or date restriction. Two independent reviewers (JRG and MM or CK) screened titles, abstracts, and full texts of all citations. For eligible studies, authors were contacted to request de-identified individual-level data. Three attempts were made to contact authors. Data were analysed using STATA/MP2 16.0 (StataCorp LP), according to an a priori defined statistical analysis plan. Reviewers were unblinded to the authors of the source study. Two reviewers (JRG and CK) independently assessed the risk of bias for the included trials using the Cochrane risk-of-bias tool for randomised trials version 2 (RoB2) [22] (Supplement 2, page 2). The study is registered in PROSPERO (CRD42016043789). The co-primary outcomes for the comparison of the effect of ISTp-ACT vs IPTp-SP were 1) maternal malaria infection at delivery, defined as any Plasmodium infection detected in peripheral or placental blood by PCR, microscopy, RDT, or histopathology (acute and/or chronic infection) and 2) adverse live-birth, defined as the composite of LBW (<2500 grams), small-for-gestational-age (SGA, <10th percentile relative to INTERGROWTH-21st gender-specific chart) [23], or preterm delivery (90% PfdhpsK540E) resistance [3]. Supportive secondary analyses using covariate adjusted and subgroup analyses were performed using the 2-stage model. Potential effect modifiers and confounding variables were pre-specified. In addition to the stratification factors study site and gravidity, these included the baseline factors maternal haemoglobin concentration, bed net use, and gestational age. Maternal socioeconomic status, maternal education, and malaria status at enrolment were excluded because they were missing in a large proportion of participants in at least one of the studies. Further sensitivity analyses to assess the robustness of the primary analysis were conducted using 1-stage models, with site and gravidity included as covariates, and random-effect models. The effect of exposure to subpatent malaria on pregnancy outcomes was examined using fixed-effect models with robust Poisson regression for binary outcomes and linear regression for continuous outcomes, accounting for study and the total number of malaria tests conducted, including the number of patent infections detected. In the binary models, risk ratios (RR) correspond to the change in the risk of the adverse outcome associated with one additional positive test (i.e. a patent or subpatent malaria infection) during pregnancy. In models with continuous outcomes, the mean difference in the outcome measure associated with each additional patent or subpatent infection was estimated. Both types of models included a robust estimator of variance. Crude models included study arm and the number of patent and subpatent infections as the two exposure variables of interest. Adjusted models (primary analysis) also included gestational age at enrolment, maternal age, gravidity (paucigravidae [G1-G2]/multigravidae), and the number of sick visits (Supplement 5, page 3). A sensitivity analysis was conducted to determine if the method used to assess gestational age influenced the conclusions for outcomes requiring gestational age at delivery (preterm delivery, SGA) (Supplement 6, page 4; Supplement 8, page 12; Table S5). Details of the performance of the RDTs to detect PCR-positive infections have been described previously [30]. The five original studies were approved by the relevant local and international partner ethical committees and institutional review boards. The protocol for the meta-analysis was reviewed by the US Centers for Disease Control and Prevention (CDC) Human Research Protection Office and deemed exempt from further review. Written consent was required from each patient for participation in each individual study. WWARN had no role in study design, data collection, data analysis, data interpretation, or writing of the report. CDC staff were involved in study design, data collection, data analysis, data interpretation, and writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

The study mentioned in the description is titled “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.” The study aimed to compare the efficacy of intermittent screening with malaria rapid diagnostic tests (RDTs) and treatment of RDT-positive women with artemisinin-based combination therapy (ISTp-ACT) versus intermittent preventive therapy in pregnancy with sulphadoxine-pyrimethamine (IPTp-SP) for malaria in pregnancy.

The study found that ISTp-ACT was not superior to IPTp-SP in terms of reducing malaria infection at delivery or adverse pregnancy outcomes. However, it did find that subpatent infections (PCR-positive, RDT/microscopy-negative) were more common in ISTp recipients and were associated with increased risk of low birthweight, lower mean birthweight, and preterm delivery.

The study highlights the need for more sensitive diagnostic tests to detect and treat low-grade infections. It also emphasizes the importance of addressing subpatent infections in order to improve maternal and fetal health outcomes.

Please note that this information is based on the study mentioned in the description and may not encompass all innovations or recommendations for improving access to maternal health.
AI Innovations Description
The recommendation based on the study is to consider implementing intermittent screening and treatment with artemisinin-combination therapy (ISTp-ACT) as an alternative to the current strategy of intermittent preventive therapy with sulphadoxine-pyrimethamine (IPTp-SP) for malaria in pregnancy. The study found that ISTp-ACT was not superior to IPTp-SP in terms of reducing maternal malaria infection at delivery or adverse pregnancy outcomes. However, it did highlight the importance of detecting and treating subpatent infections, which were more common in ISTp recipients. Subpatent infections were associated with increased risk of low birthweight and preterm delivery. Therefore, the recommendation is to develop more sensitive diagnostic tests to detect and treat low-grade infections, which could help improve access to maternal health and reduce the negative impact of malaria on pregnancy outcomes.
AI Innovations Methodology
Based on the provided description, it seems that the information you shared is related to a specific study on the efficacy of intermittent screening and treatment with artemisinin-combination therapy (ISTp-ACT) versus intermittent preventive treatment with sulphadoxine-pyrimethamine (IPTp-SP) for malaria in pregnancy. However, the request is to consider innovations for potential recommendations to improve access to maternal health and describe a methodology to simulate the impact of these recommendations.

To address this request, here are some potential innovations and a methodology to simulate their impact on improving access to maternal health:

1. Telemedicine and Mobile Health (mHealth) Solutions: Implementing telemedicine and mHealth solutions can improve access to maternal health by providing remote consultations, monitoring, and education to pregnant women in underserved areas. This innovation can be achieved through the use of mobile apps, text messaging, and video conferencing platforms.

Methodology: Conduct a pilot study in a specific region or community to assess the feasibility and effectiveness of implementing telemedicine and mHealth solutions for maternal health. Collect data on the number of pregnant women reached, the quality of care provided, and the impact on maternal and neonatal outcomes. Use this data to simulate the potential impact of scaling up the intervention to a larger population.

2. Community-Based Maternal Health Workers: Training and deploying community-based maternal health workers can improve access to essential maternal health services, especially in remote or rural areas. These workers can provide antenatal care, postnatal care, and health education to pregnant women within their communities.

Methodology: Select a target community or region and train a group of community-based maternal health workers. Monitor their activities and collect data on the number of women reached, the services provided, and the outcomes of maternal health interventions. Use this data to simulate the potential impact of scaling up the deployment of community-based maternal health workers to a larger population.

3. Mobile Clinics and Outreach Programs: Establishing mobile clinics and conducting outreach programs can bring essential maternal health services closer to communities with limited access to healthcare facilities. These mobile clinics can provide antenatal care, delivery services, and postnatal care in underserved areas.

Methodology: Set up mobile clinics in selected underserved areas and conduct regular outreach programs to provide maternal health services. Monitor the number of women served, the quality of care provided, and the outcomes of maternal health interventions. Use this data to simulate the potential impact of expanding mobile clinics and outreach programs to reach a larger population.

4. Health Information Systems and Data Analytics: Implementing robust health information systems and utilizing data analytics can improve the monitoring and evaluation of maternal health programs. This innovation can help identify gaps in access to care, track key maternal health indicators, and inform evidence-based decision-making.

Methodology: Enhance the existing health information systems in a specific region or country to capture comprehensive data on maternal health services, utilization, and outcomes. Analyze the collected data using data analytics techniques to identify trends, patterns, and areas for improvement. Use this analysis to simulate the potential impact of implementing targeted interventions based on the identified gaps and needs.

In summary, the innovations mentioned above, such as telemedicine and mHealth solutions, community-based maternal health workers, mobile clinics and outreach programs, and health information systems with data analytics, can improve access to maternal health. To simulate the impact of these recommendations, a methodology involving pilot studies, data collection, monitoring, and analysis can be employed to assess the feasibility, effectiveness, and potential scalability of these innovations in improving access to maternal health.

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