The effects of childhood exposure to malaria on cognition and behavior: A systematic review protocol

Background: Malaria is one of the major contributing risk factor for poor development of children living in low-and middle-income countries (LMICs). However, little is known about the speci�c domains of cognition and behavior that are impacted by malaria, the extent of these de�cits, and the severity of malaria infection that is associated with these de�cits. The objective of this review is to determine the effect of malaria infection on cognition and behavior among children living in LMICs. Methods and analysis: We will systematically search online bibliographic databases including PubMed, EMBASE, Cochrane Collaborative Database, CINAHL and PsycINFO as well as Google Scholar and bibliographies of pertinent articles. We will include studies with a comparison group (e.g., clinical trials, cohort, cross-sectional and case–control studies) involving children under 18 years of age living in LMICs, as determined by World Bank Criteria, with either an active malaria infection or history of malaria. Included articles must also measure cognitive and behavioral outcomes using standardized instruments. Studies will be excluded if they are not in English, lack a control group, take place in a high-income country, or if a standardized instrument was not used. Two reviewers will independently review all articles to determine if they meet eligibility criteria. Any con�icts will be resolved after discussion with a third reviewer. When a list of included articles is �nalized, two reviewers will extract data to populate and then cross check within an electronic table. Risk of bias and the strength of evidence and recommendations will be assessed independently using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria, and a �nal score will be given upon consensus. For su�ciently homogeneous data on measured outcomes in multiple studies, we will investigate the possibility of pooling data to perform a meta-analysis. Discussion: This systematic review will evaluate the evidence of the effect of malaria on the cognitive and behavioral outcomes. Findings from this planned review will generate insight on the domains affected by the different forms malaria infection and may inform subsequent malaria interventions and future research in pediatric care.


Background
Malaria remains a public global health challenge that disproportionally affects children who already face multiple other risk factors for growth and development, such as poverty and malnutrition.Between 300-600 million people suffer from malaria each year, and 90% of these cases occur in young children in sub-Saharan Africa (1).Over 300,000 of children infected with malaria will die of the disease (2,3).Those who survive often suffer multiple morbidities, including increased risks of neurological, cognitive and behavioral de cits (4)(5)(6)(7)(8).With the prevalence of malaria infection worldwide, vast numbers of children are at increased risk of cognitive and behavioral impairments.By not reaching their full developmental potential, these children are estimated to have a 20% de cit in their adult incomes, which affects families, communities, and countries (9).
Only one review has evaluated the effects of Plasmodium falciparum on cognition, which found potential de cits in attention, memory, visuospatial skills, language, and executive functions after malaria infection (6).While this review brought attention to this critical issue, it was published over ten years ago and lacks differentiation regarding severity or different forms of malaria infection.A knowledge gap currently exists regarding what speci c domains of cognition and behavior may be negatively impacted by malaria infection and the extent of that impact.Furthermore, it is unclear how other potential factors, such as varying intensities of malaria infection, may impact cognition and behavior.
In recent years, cognitive and behavioral assessments are increasingly performed post-malaria infection, in both clinical and research settings.However, a succinct synthesis of these data has not been performed to describe the impact that various forms of malaria infection have on cognitive and behavioral outcomes in children, as well as other factors that may be contributing to cognitive and behavioral de cits in this population.This systematic review is necessary to help nd, appraise and summarize the current evidence on malaria infection effects on cognitive and behavioral performance and may provide evidence to inform clinical care and highlighting further areas for investigation.

Objectives
The objective of this systematic review is to determine the effect of malaria infection on cognition and behavior among children living in low-and middle-income countries (LMICs).We will achieve this objective by addressing the following research questions: a.) Which cognitive and behavioral domains are negatively impacted by malaria infection?b.)To what extend are these domains impacted?c.) Which forms of malaria are associated with speci c de cits in cognition and behavior?d.) What are other risk factors for cognitive and behavioral de cits?

Methods And Analysis
We developed our methods following the instructions of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines This systematic review will be also written in accordance with the PRISMA for systematic review protocols (PRISMA-P) statement (10,11) (See additional le 1).

Eligibility criteria
Quantitative studies investigating the association between malaria and cognitive and behavioral outcomes will be included.Studies will be selected according to the following eligibility (inclusion/exclusion) criteria (Table 1;  We will exclude reviews, opinion pieces and letters to the editor, commentaries, abstracts and case series including <5 individuals.

Participants
The target population for inclusion is children (≤18 years) with active or recent malaria (within 12 months) infection.Inclusion of longitudinal studies will allow us to evaluate the potential impact of malaria on cognition and behavior over time (12).

Exposure/ target condition
We will include any active malaria infection or any recent malaria infection that has occurred within 12 months of the cognitive and behavioral assessments.When possible, we will classify the malaria according to the following de nitions: Asymptomatic malaria is a form of Plasmodium malaria infection that lacks typical clinical symptoms, but has submicroscopic parasite densities detectable by microscopy, rapid diagnostic test (RDTs) or molecular methods (13).Asymptomatic malaria is commonly a submicroscopic infection (does not necessarily produce gametocytes chie y detectable by molecular methods than microscopy).
Uncomplicated malaria is a form of Plasmodium malaria infections that are accompanied by fever and/or other symptoms like nausea, vomiting, muscle aches, abdominal pains, chills and sweat that are indicative of malaria.These infections are, almost without exception, detectable by microscopy or rapid diagnostic test (13).
If the speci c form of malaria infection is not clear from the publication, it will be labeled as "general malaria infection."If the study cohort contains individuals with different forms of malaria infection, it will be labeled as "mixed malaria infection."

Outcome
We will include standardized methods of measuring cognition and behavior (questionnaire-based scales and or neurocognitive assessments).All instruments will be reviewed by a psychologist prior to nal inclusion.

Timing
Our search will not be restricted by earlier publication date and length of follow-up in order to compare outcomes across time.We will include studies published until the time of the search is performed.Note: Our preliminary scoping of the literature suggested no relevant citations would be retrieved prior to 1920.

Setting
Only studies undertaken in low-and middle-income countries will be eligible for inclusion, due to the high burden and receptivity of malaria infection in these settings.Income classi cation of countries will be according to the World Bank criteria (18).

Language
Studies published in English language and available in full text will be eligible for inclusion.Studies published in any language other than English will not be included.This criteria is due to the limited resources available in performing this review.

Information sources
We will systematically search MEDLINE (via PubMed), EMBASE, Cochrane Collaborative Database, CINAHL and PsycINFO.We will also search the reference lists of included studies to identify other studies.
We consulted a medical librarian at Indiana University to develop our search strategy.Our final search terms include text words; malaria (asymptomatic, uncomplicated and severe), cognitive, behavior, child development; MESH terms for cognition, behavior, child, malaria with the child lter (birth-18 years) (see Supplement 1).We will also hand-search the bibliographies of relevant studies and review articles, as well as search Google Scholar for additional potentially eligible articles.

Study screening, selection and data extraction
Studies will be included only if they meet the full inclusion criteria above and not met any exclusion criteria.The abstracts and full-text articles retrieved using the search strategy will be imported into Endnote software and duplicates will be removed.Two of the authors will independently screen studies for inclusion at two levels a) title/abstract and b) full text based on the eligibility criteria.We will screen full text articles of studies that meet eligibility at title and abstract screening.For any discrepancies, another author will serve as a third rater to create a consensus.Three authors will extract data from the full text articles of the included studies using an Excel spreadsheet screening and data extraction form developed a priori to capture study details (e.g., authors, year, country, setting, length of follow-up); sample characteristics (e.g.age, gender, number of participants included), study design (e.g.Randomized Controlled Trials (RCTs), case control, cohort, cross-sectional), descriptions of how malaria, cognition and behavior are assessed (tests and cut-off values used), and study outcomes (Table 2; See additional le 2).The Excel spreadsheet and Endnote library will be used to manage records and data throughout the review.

Assessment of risk of bias and grading strength of evidence
To evaluate the methodological quality and strength of evidence on the topic, we will use the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach (19,20).Two raters will independently assess the strength of evidence in five areas: study design, quality, consistency, directness and precision.The raters will add or subtract points for each of these categories in line with GRADE guidelines.By adding or subtracting points, GRADE helps us assess whether further evidence from newly published studies would change the conclusions of the review.The raters will resolve discrepancies through consensus and involvement of a third rater.

Data synthesis and statistical analysis
We will narratively synthesize the extracted data from all included studies.For subsets of studies that are sufficiently homogeneous in terms of sample characteristics, measures of cognition and behavior, and methods (e.g., design, setting, length of follow-up), a meta-analysis will be considered, for which a biostatistician will be asked to join the review team.A PRISMA ow chart will be developed to show each level of the review process.

Discussion And Outcomes
The systematic review will provide meaningful insights on the effects of malaria on cognition and behavior of children, including the adverse effects of post-malaria survival.Additionally, the review will inform strategies for the prevention and management of malaria and guide further research in addressing the current gaps in knowledge regarding cognitive and behavioral outcomes associated with malaria episodes.The review ndings will be presented at academic conferences and published in a peer reviewed journal.
This systematic review will be the rst to examine a full range of both cognitive and behavioral outcomes in children in malaria-endemic and LMICs, as well as explore of various forms of malaria infection may impact outcomes.Findings from this review may support clinicians, health experts and policy makers develop guidelines to minimize de cits and impairment due to malaria infection for children surviving malaria.
Ethics and dissemination: We will not seek for ethical approval as this is a systematic review protocol.We will synthesize literature on the cognitive and behavioral outcomes of children surviving malaria.The ndings of this review will be shared through peer-reviewed publications to provide information to scientists when developing guidelines for managing the outcomes in LMICs.

List Of Abbreviations
See additional le 2): Inclusion criteria Target population: Children below 18 years with malaria infection by laboratory diagnosis (i.e.microscopic diagnosis, molecular diagnosis, antigen detection, serology).Setting: LMICs, as determined by World Bank Criteria Primary outcome: cognitive and/or behavior score as determined by a psychological assessment.Exclusion criteria Studies repeating the cohort population reporting similar outcomes Malaria infection determined by clinical diagnosis only (patient symptoms and on physical examination) Human studies that do not assess cognitive and or behavioral function as an outcome Animal studies Studies without a control or comparison group Non-English studies Participants older than 18 years of age Studies in high income countries or not within LMICs, as determined by World Bank Criteria.
CM-Cerebral malaria GRADE -Grading of Recommendations Assessment, Development and Evaluation LMICs-Low and middle income countries P. falciparum-Plasmodium falciparum PRISMA -Preferred Reporting Items for Systematic Reviews and Meta-Analysis RCTs-Randomised Controlled Trials RDTs -Rapid diagnostic tests SMA-Severe Malaria Anaemia Declarations Ethics approval and consent to participate: Not applicable