Prevalence and factors associated with malaria among under-ve children in Ethiopia: A Systematic review and Meta-analysis Protocol

Background: The Sub-Saharan African countries have been carried 80% of the global burden of malaria. Consequently, malaria is still the leading cause of under-ve mortality in developing nations. In Ethiopia, studies conducted regarding prevalence and associated factors of malaria among under ve children are inconsistently reported and highly variable. Objective: to determine the pooled prevalence and associated factors of malaria among under ve children in Ethiopia. Methods: The protocol for this review is registered at PROSPERO with registration number: CRD42020157886. A comprehensive search of the following electronic databases were made using: MEDLINE, EMBASE, CINAHL, Scopus, web science, HINARI, Cochrane library, Google Scholar and maternity & infant care databases as well as grey literature uploaded at Ethiopian Health Development Journal were searched until May 2020. The quality of studies will be assessed using Joanna Briggs Institute (JBI) checklist. All identied observational studies reporting the prevalence of malaria and associated factors among under ve children in Ethiopia will be considered. Three reviewers will screen all retrieved articles, conduct data extraction, and then critically appraise all identied studies. The analysis of data will be done using STATA 14.0 statistical software. We will determine the pooled prevalence and determinants of malaria among under ve children using random effect model with effect size and 95% condence interval. Heterogeneity among the included studies will be assessed through the Cochrane Q-test statistics and I2 test. Furthermore, publication bias will be checked using funnel plot and egger’s test. Finally, statistical signicance level will be declared at a p-value less than 0.05. Discussion: The result from this systematic review will inform and guide health policy planners and researchers on the burden, and determinants of under ve children malaria in Ethiopia. To our knowledge, this is the rst systematic review in Ethiopia. We will synthesize the ndings to generate up-to-date knowledge on malaria among under ve children in Ethiopia.


Background
Globally, malaria causes more than 216 million (95% CI: 196-263 million) cases per year. Of these cases, more than 90% are found concentrated in sub-Sahara African countries including Ethiopia [1]. Moreover, nearly half a million (429 000) deaths were caused by malaria, and more than 92% 0f these deaths have been happened in sub-Sahara African countries [2]. Consequently, malaria is still the leading public health problem in developing nations and it predominately affects pregnant mothers and under-ve children [3].
In Ethiopia, three-fourth of the areas are malaria endemic, and more than two-thirds of its population (more than 55 million people) are at risk for malaria [4,5]. According to the 2013 health and health related indicator report of the Ministry of Health (MOH), malaria was one of the leading causes of morbidity and mortality in the country [6]. Several strategies, policies and malaria elimination programs had been tried at global, regional and national levels in the last decades [7][8][9][10]. Consequently, over 6.2 million malaria deaths were averted between 2000 and 2015 in sub-Saharan African countries [11]. However, Ethiopia was not met the 2015 target of MDG (reduce the incidence rate by 50%) [12]. Thus, despite the signi cant decline in the burden of malaria, the disease is still one of the major public health concern in the country [13]. Furthermore, the prevalence of malaria among under ve children is unacceptably high which is between 16% and 54% in the country [4,[14][15][16][17].
Previous studies conducted across sub-Saharan African countries have been identi ed many factors associated with malaria endemic among under-ve children. These includes; sex of the child, age of the child, number of bed nets available for the household members, presence of forest cover, altitude of the residence, household density (family size), living near to dam, seasonal variation and housing conditions [4,5,15,16,18,19]. According to the 2016 Ethiopian Demographic and Health Survey (EDHS) report, the magnitude of under-ve mortality rate varies across the nine regions and the lowest in … and the highest (125 deaths per 1000 live births) in Afar region [20]. Unfortunately, in Ethiopia, only 33% of children under the age of ve were sleeping under insecticide treated nets [21]. Consequently, the high under ve mortality rate should be attributed to malaria.

Objective
The objectives of this systematic review and meta-analysis are; 1) to determine the pooled prevalence of malaria among under ve children in Ethiopia and 2) to identify factors associated malaria among under ve children in Ethiopia.

Reporting of the review findings
The protocol for this review is registered at PROSPERO with registration number: CRD42020157886. We will use the Preferred Reporting Items for Systematic review and Meta-analyses (PRISMA-2009) [22] (additional le 3) and (PRISMA-P 2015) [23] (Additional le 1) statements to report the ndings. Moreover, we have used the guideline of the Prospero for registration.

Study design
A systematic review and meta-analysis will be conducted to determine the pooled prevalence of birth asphyxia and its determinants among newborns in Ethiopia. Outcome: We will include studies those assess prevalence of malaria and its determinants among under ve children in Ethiopia.

Searching strategy
This meta-analysis will be prepared and presented according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis [PRISMA, 2009]. We will develop an appropriate and comprehensive search strategy with relevant search terms and pilot test it before the nal search. We will search PubMed, MEDLINE, Google Scholar, and Cochrane electronic Databases. We will include articles published from start of indexing until December 30, 2019. We will use Medical Subject Heading (Mesh), keywords, and free text search terms. As the search terms, we will include alternative terms for malaria parasite, and will combine them using Boolean operators. To ensure the comprehensiveness, we will consult an expert librarian. The search strategy for PubMed is supplemented with this protocol (Additional le 2). We will utilize snowballing to screen the references of identi ed articles for potentially relevant studies. Furthermore, we will contact experts, researchers, and relevant organizations for suggestions on other existing relevant studies. Studies identi ed by our database searching strategy will be retrieved and managed using Endnote X8 (Thomson Reuters, Philadelphia, PA, USA) software.
Search terms: search ((("under-ve children" OR "0-59 months old children" OR infants OR neonates)AND ( malaria OR "plasmodium falciparum" OR "plasmodium vivax" OR "mixed malaria" OR "plasmodium species") AND (Prevalence OR incidence OR magnitude OR burden) AND (determinants OR "risk Factors" OR predictors OR causes OR associated factors") AND (Ethiopia OR Ethio OR Etiopia))

Outcome measurement
This systematic review and meta-analysis will have two main outcomes. The rst outcome is estimating the pooled prevalence of malaria among under-ve children. Malaria is de ned as children with con rmed malaria parasite infection. Pooled prevalence will be calculated by dividing the number of under-ve children with malaria to the total number of children who have been included in the study (total sample size) multiplied by 100. The second outcome of the study is to identify maternal and child factors associated with malaria among under-ve children. The predictors will be determined in the form of the log odds ratio.

selection of studies
Two authors (AW, and SB) will review the studies, based on inclusion and exclusion criteria. The review will follow three stages. In the rst stage, reviewers will assess the titles of the studies identi ed from the search. In the second stage, abstracts of these selected titles will be included for the nal stage of fulltext screening. In the third stage, full-text screening, we will screen the full texts selected in the previous stage. If the articles are not open access, we will contact the corresponding author at least for three times.
If the authors are not willing to provide the full text, we will exclude that speci c article.
In the review, we will only include those studies approved by both authors. The authors will resolve disagreements through discussion or consultation with a third reviewer (KU). We will provide reason for exclusion for all excluded studies. Finally, we will prepare a nal list of articles for data extraction

Data extraction and management
Three authors (AW, SB and MD) will independently extracted all necessary data using a standardized data extraction format, which is adapted from the JBI data extraction format for observational studies [24]. We will pretest the data extraction form on three studies of each type, to ensure that it adequately facilitates the collection of all necessary data required for an effective systematic review and meta-analysis. Discrepancies between data extractors will be discussed to reach consensus. If a consensus cannot be reached, the authors will consult a third reviewer (KU). For each included articles, we will record the rst author's last name, year of publication, the setting where the study was conducted, study design, study period, sample size, the response rate, the population, outcome de nition, comparison groups, and the effect estimate.

Quality assessments
Four authors (AW, SB, KU and MD) will independently conduct quality assessment of included studies, by using the checklist of the JBI appraisal tool for cross-sectional, cohort and case-control studies (Additional le 3). In customising the scale to t this study, we will took into account the study sampling methods and similarities between the study groups regarding adjustment for confounding factors, the ascertainment of exposure and outcomes, and study design. The abstracting tool will include different questions based on the study designs. The four investigators independently will perform the quality assessment while abstracting the data for the meta-analysis. The quality scores of the four abstractors will be averaged. Finally, the studies with higher scores (>50%) will be included into meta-analysis.

Data synthesis and analysis
The extracted data will be entered into a Microsoft Excel Database and then imported into STATA version 14.0 (Stata Corp LLC, Texas, USA) software with packages of Meta-analysis for further analysis. The researchers will perform a narrative description of the study population, the studies included, the risk factors identi ed, and the cause for malaria infection as well as the outcome characteristics. We will use tables and gures to summarize the selected studies and results.
The pooled prevalence of malaria among children under ve in Ethiopia will be demonstrated using the random effect model [25]. The Freeman Tuckey variant of the arcsine square root transformation of proportions will be tted to avoid variance instability when handling proportions close to one [26]. We will assess heterogeneity by using chi-squared test on Cochran's Q statistic with a 5% level of statistical signi cance [26] and I 2 statistic test [27], assuming that I 2 value of 25%, 50%, and 75% being representative of low, moderate, and high heterogeneity, respectively [27]. If the heterogeneity is signi cant (I 2 > 75%), then, we will conduct subgroup analyses and meta-regression to investigate sources of heterogeneity.
Publication bias will be examined by the visual inspection of funnel plots [28] and Egger's test [29]. A p value < 0.10 will be considered indicative of statistically signi cant publication bias. Thus, if there is evidence of publication bias, we will use Duval and Tweedie's trim-and-ll method [30].
For factors associated with malaria among under-ve children; two-by-two tables will be constructed (if possible), the odds ratio with 95% con dence interval will be calculated. Then, the statistically signi cance level will be declared at a p-value less than 0.05. However, if the meta-analysis is not possible, we will conduct narrative synthesis.

Subgroup and sensitivity analyses
Sub-group analysis will be performed based on study design, sample size, regions or state, year of publication, quality of studies, and study settings of included studies. by years of publication, study setting, study design, and sample size of the studies. Finally, to conduct sensitivity analysis, we will assess the stability or robustness of the pooled estimates to outliers and the impact of individual studies [30].

Discussion
This review will provide a detailed summary of the evidence on prevalence and factors of malaria among children in Ethiopia. This review will be the rst to synthesis available data on malaria among children. Findings of the review will ll an evidence gap in understanding the burden, risk factors, and causes of malaria in the country. The result from this review will inform health policy planners and researchers upto-date data on malaria among children and provide direction in which risk factors the policy should focus to reduce burden of malaria among children in the country.

Dissemination plan
The results of this systematic review and meta-analysis will be published in a peer-reviewed journal and presented at national and international research conferences. Outcomes and prioritization 13 List and de ne all outcomes for which data will be sought, including prioritization of main and additional outcomes, with rationale 7 Risk of bias in individual studies 14 Describe anticipated methods for assessing risk of bias of individual studies, including whether this will be done at the outcome or study level, or both; state how this information will be used in data synthesis 9 Data synthesis 15a Describe criteria under which study data will be quantitatively synthesized 9 15b If data are appropriate for quantitative synthesis, describe planned summary measures, methods of handling data and methods of combining data from studies, including any planned exploration of consistency (such as I 2 , Kendall's τ) 15c Describe any proposed additional analyses (such as sensitivity or subgroup analyses, meta-regression) 9 15d If quantitative synthesis is not appropriate, describe the type of summary planned 9 Meta-bias(es) 16 Specify any planned assessment of meta-bias(es) (such as publication bias across studies, selective reporting within studies) 6.2 Additional file 2: PubMed search string