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The Cochrane Database of Systematic... Feb 2022Description of the condition Malaria, an infectious disease transmitted by the bite of female mosquitoes from several Anopheles species, occurs in 87 countries with... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Description of the condition Malaria, an infectious disease transmitted by the bite of female mosquitoes from several Anopheles species, occurs in 87 countries with ongoing transmission (WHO 2020). The World Health Organization (WHO) estimated that, in 2019, approximately 229 million cases of malaria occurred worldwide, with 94% occurring in the WHO's African region (WHO 2020). Of these malaria cases, an estimated 409,000 deaths occurred globally, with 67% occurring in children under five years of age (WHO 2020). Malaria also negatively impacts the health of women during pregnancy, childbirth, and the postnatal period (WHO 2020). Sulfadoxine/pyrimethamine (SP), an antifolate antimalarial, has been widely used across sub-Saharan Africa as the first-line treatment for uncomplicated malaria since it was first introduced in Malawi in 1993 (Filler 2006). Due to increasing resistance to SP, in 2000 the WHO recommended that one of several artemisinin-based combination therapies (ACTs) be used instead of SP for the treatment of uncomplicated malaria caused by Plasmodium falciparum (Global Partnership to Roll Back Malaria 2001). However, despite these recommendations, SP continues to be advised for intermittent preventive treatment in pregnancy (IPTp) and intermittent preventive treatment in infants (IPTi), whether the person has malaria or not (WHO 2013). Description of the intervention Folate (vitamin B9) includes both naturally occurring folates and folic acid, the fully oxidized monoglutamic form of the vitamin, used in dietary supplements and fortified food. Folate deficiency (e.g. red blood cell (RBC) folate concentrations of less than 305 nanomoles per litre (nmol/L); serum or plasma concentrations of less than 7 nmol/L) is common in many parts of the world and often presents as megaloblastic anaemia, resulting from inadequate intake, increased requirements, reduced absorption, or abnormal metabolism of folate (Bailey 2015; WHO 2015a). Pregnant women have greater folate requirements; inadequate folate intake (evidenced by RBC folate concentrations of less than 400 nanograms per millilitre (ng/mL), or 906 nmol/L) prior to and during the first month of pregnancy increases the risk of neural tube defects, preterm delivery, low birthweight, and fetal growth restriction (Bourassa 2019). The WHO recommends that all women who are trying to conceive consume 400 micrograms (µg) of folic acid daily from the time they begin trying to conceive through to 12 weeks of gestation (WHO 2017). In 2015, the WHO added the dosage of 0.4 mg of folic acid to the essential drug list (WHO 2015c). Alongside daily oral iron (30 mg to 60 mg elemental iron), folic acid supplementation is recommended for pregnant women to prevent neural tube defects, maternal anaemia, puerperal sepsis, low birthweight, and preterm birth in settings where anaemia in pregnant women is a severe public health problem (i.e. where at least 40% of pregnant women have a blood haemoglobin (Hb) concentration of less than 110 g/L). How the intervention might work Potential interactions between folate status and malaria infection The malaria parasite requires folate for survival and growth; this has led to the hypothesis that folate status may influence malaria risk and severity. In rhesus monkeys, folate deficiency has been found to be protective against Plasmodium cynomolgi malaria infection, compared to folate-replete animals (Metz 2007). Alternatively, malaria may induce or exacerbate folate deficiency due to increased folate utilization from haemolysis and fever. Further, folate status measured via RBC folate is not an appropriate biomarker of folate status in malaria-infected individuals since RBC folate values in these individuals are indicative of both the person's stores and the parasite's folate synthesis. A study in Nigeria found that children with malaria infection had significantly higher RBC folate concentrations compared to children without malaria infection, but plasma folate levels were similar (Bradley-Moore 1985). Why it is important to do this review The malaria parasite needs folate for survival and growth in humans. For individuals, adequate folate levels are critical for health and well-being, and for the prevention of anaemia and neural tube defects. Many countries rely on folic acid supplementation to ensure adequate folate status in at-risk populations. Different formulations for folic acid supplements are available in many international settings, with dosages ranging from 400 µg to 5 mg. Evaluating folic acid dosage levels used in supplementation efforts may increase public health understanding of its potential impacts on malaria risk and severity and on treatment failures. Examining folic acid interactions with antifolate antimalarial medications and with malaria disease progression may help countries in malaria-endemic areas determine what are the most appropriate lower dose folic acid formulations for at-risk populations. The WHO has highlighted the limited evidence available and has indicated the need for further research on biomarkers of folate status, particularly interactions between RBC folate concentrations and tuberculosis, human immunodeficiency virus (HIV), and antifolate antimalarial drugs (WHO 2015b). An earlier Cochrane Review assessed the effects and safety of iron supplementation, with or without folic acid, in children living in hyperendemic or holoendemic malaria areas; it demonstrated that iron supplementation did not increase the risk of malaria, as indicated by fever and the presence of parasites in the blood (Neuberger 2016). Further, this review stated that folic acid may interfere with the efficacy of SP; however, the efficacy and safety of folic acid supplementation on these outcomes has not been established. This review will provide evidence on the effectiveness of daily folic acid supplementation in healthy and malaria-infected individuals living in malaria-endemic areas. Additionally, it will contribute to achieving both the WHO Global Technical Strategy for Malaria 2016-2030 (WHO 2015d), and United Nations Sustainable Development Goal 3 (to ensure healthy lives and to promote well-being for all of all ages) (United Nations 2021), and evaluating whether the potential effects of folic acid supplementation, at different doses (e.g. 0.4 mg, 1 mg, 5 mg daily), interferes with the effect of drugs used for prevention or treatment of malaria.
OBJECTIVES
To examine the effects of folic acid supplementation, at various doses, on malaria susceptibility (risk of infection) and severity among people living in areas with various degrees of malaria endemicity. We will examine the interaction between folic acid supplements and antifolate antimalarial drugs. Specifically, we will aim to answer the following. Among uninfected people living in malaria endemic areas, who are taking or not taking antifolate antimalarials for malaria prophylaxis, does taking a folic acid-containing supplement increase susceptibility to or severity of malaria infection? Among people with malaria infection who are being treated with antifolate antimalarials, does folic acid supplementation increase the risk of treatment failure?
METHODS
Criteria for considering studies for this review Types of studies Inclusion criteria Randomized controlled trials (RCTs) Quasi-RCTs with randomization at the individual or cluster level conducted in malaria-endemic areas (areas with ongoing, local malaria transmission, including areas approaching elimination, as listed in the World Malaria Report 2020) (WHO 2020) Exclusion criteria Ecological studies Observational studies In vivo/in vitro studies Economic studies Systematic literature reviews and meta-analyses (relevant systematic literature reviews and meta-analyses will be excluded but flagged for grey literature screening) Types of participants Inclusion criteria Individuals of any age or gender, living in a malaria endemic area, who are taking antifolate antimalarial medications (including but not limited to sulfadoxine/pyrimethamine (SP), pyrimethamine-dapsone, pyrimethamine, chloroquine and proguanil, cotrimoxazole) for the prevention or treatment of malaria (studies will be included if more than 70% of the participants live in malaria-endemic regions) Studies assessing participants with or without anaemia and with or without malaria parasitaemia at baseline will be included Exclusion criteria Individuals not taking antifolate antimalarial medications for prevention or treatment of malaria Individuals living in non-malaria endemic areas Types of interventions Inclusion criteria Folic acid supplementation Form: in tablet, capsule, dispersible tablet at any dose, during administration, or periodically Timing: during, before, or after (within a period of four to six weeks) administration of antifolate antimalarials Iron-folic acid supplementation Folic acid supplementation in combination with co-interventions that are identical between the intervention and control groups. Co-interventions include: anthelminthic treatment; multivitamin or multiple micronutrient supplementation; 5-methyltetrahydrofolate supplementation. Exclusion criteria Folate through folate-fortified water Folic acid administered through large-scale fortification of rice, wheat, or maize Comparators Placebo No treatment No folic acid/different doses of folic acid Iron Types of outcome measures Primary outcomes Uncomplicated malaria (defined as a history of fever with parasitological confirmation; acceptable parasitological confirmation will include rapid diagnostic tests (RDTs), malaria smears, or nucleic acid detection (i.e. polymerase chain reaction (PCR), loop-mediated isothermal amplification (LAMP), etc.)) (WHO 2010). This outcome is relevant for patients without malaria, given antifolate antimalarials for malaria prophylaxis. Severe malaria (defined as any case with cerebral malaria or acute P. falciparum malaria, with signs of severity or evidence of vital organ dysfunction, or both) (WHO 2010). This outcome is relevant for patients without malaria, given antifolate antimalarials for malaria prophylaxis. Parasite clearance (any Plasmodium species), defined as the time it takes for a patient who tests positive at enrolment and is treated to become smear-negative or PCR negative. This outcome is relevant for patients with malaria, treated with antifolate antimalarials. Treatment failure (defined as the inability to clear malaria parasitaemia or prevent recrudescence after administration of antimalarial medicine, regardless of whether clinical symptoms are resolved) (WHO 2019). This outcome is relevant for patients with malaria, treated with antifolate antimalarials. Secondary outcomes Duration of parasitaemia Parasite density Haemoglobin (Hb) concentrations (g/L) Anaemia: severe anaemia (defined as Hb less than 70 g/L in pregnant women and children aged six to 59 months; and Hb less than 80 g/L in other populations); moderate anaemia (defined as Hb less than 100 g/L in pregnant women and children aged six to 59 months; and less than 110 g/L in others) Death from any cause Among pregnant women: stillbirth (at less than 28 weeks gestation); low birthweight (less than 2500 g); active placental malaria (defined as Plasmodium detected in placental blood by smear or PCR, or by Plasmodium detected on impression smear or placental histology). Search methods for identification of studies A search will be conducted to identify completed and ongoing studies, without date or language restrictions. Electronic searches A search strategy will be designed to include the appropriate subject headings and text word terms related to each intervention of interest and study design of interest (see Appendix 1). Searches will be broken down by these two criteria (intervention of interest and study design of interest) to allow for ease of prioritization, if necessary. The study design filters recommended by the Scottish Intercollegiate Guidelines Network (SIGN), and those designed by Cochrane for identifying clinical trials for MEDLINE and Embase, will be used (SIGN 2020). There will be no date or language restrictions. Non-English articles identified for inclusion will be translated into English. If translations are not possible, advice will be requested from the Cochrane Infectious Diseases Group and the record will be stored in the "Awaiting assessment" section of the review until a translation is available. The following electronic databases will be searched for primary studies. Cochrane Central Register of Controlled Trials. Cumulative Index to Nursing and Allied Health Literature (CINAHL). Embase. MEDLINE. Scopus. Web of Science (both the Social Science Citation Index and the Science Citation Index). We will conduct manual searches of ClinicalTrials.gov, the International Clinical Trials Registry Platform (ICTRP), and the United Nations Children's Fund (UNICEF) Evaluation and Research Database (ERD), in order to identify relevant ongoing or planned trials, abstracts, and full-text reports of evaluations, studies, and surveys related to programmes on folic acid supplementation in malaria-endemic areas. Additionally, manual searches of grey literature to identify RCTs that have not yet been published but are potentially eligible for inclusion will be conducted in the following sources. Global Index Medicus (GIM). African Index Medicus (AIM). Index Medicus for the Eastern Mediterranean Region (IMEMR). Latin American & Caribbean Health Sciences Literature (LILACS). Pan American Health Organization (PAHO). Western Pacific Region Index Medicus (WPRO). Index Medicus for the South-East Asian Region (IMSEAR). The Spanish Bibliographic Index in Health Sciences (IBECS) (ibecs.isciii.es/). Indian Journal of Medical Research (IJMR) (journals.lww.com/ijmr/pages/default.aspx). Native Health Database (nativehealthdatabase.net/). Scielo (www.scielo.br/). Searching other resources Handsearches of the five journals with the highest number of included studies in the last 12 months will be conducted to capture any relevant articles that may not have been indexed in the databases at the time of the search. We will contact the authors of included studies and will check reference lists of included papers for the identification of additional records. For assistance in identifying ongoing or unpublished studies, we will contact the Division of Nutrition, Physical Activity, and Obesity (DNPAO) and the Division of Parasitic Diseases and Malaria (DPDM) of the CDC, the United Nations World Food Programme (WFP), Nutrition International (NI), Global Alliance for Improved Nutrition (GAIN), and Hellen Keller International (HKI). Data collection and analysis Selection of studies Two review authors will independently screen the titles and abstracts of articles retrieved by each search to assess eligibility, as determined by the inclusion and exclusion criteria. Studies deemed eligible for inclusion by both review authors in the abstract screening phase will advance to the full-text screening phase, and full-text copies of all eligible papers will be retrieved. If full articles cannot be obtained, we will attempt to contact the authors to obtain further details of the studies. If such information is not obtained, we will classify the study as "awaiting assessment" until further information is published or made available to us. The same two review authors will independently assess the eligibility of full-text articles for inclusion in the systematic review. If any discrepancies occur between the studies selected by the two review authors, a third review author will provide arbitration. Each trial will be scrutinized to identify multiple publications from the same data set, and the justification for excluded trials will be documented. A PRISMA flow diagram of the study selection process will be presented to provide information on the number of records identified in the literature searches, the number of studies included and excluded, and the reasons for exclusion (Moher 2009). The list of excluded studies, along with their reasons for exclusion at the full-text screening phase, will also be created. Data extraction and management Two review authors will independently extract data for the final list of included studies using a standardized data specification form. Discrepancies observed between the data extracted by the two authors will be resolved by involving a third review author and reaching a consensus. Information will be extracted on study design components, baseline participant characteristics, intervention characteristics, and outcomes. For individually randomized trials, we will record the number of participants experiencing the event and the number analyzed in each treatment group or the effect estimate reported (e.g. risk ratio (RR)) for dichotomous outcome measures. For count data, we will record the number of events and the number of person-months of follow-up in each group. If the number of person-months is not reported, the product of the duration of follow-up and the number of children evaluated will be used to estimate this figure. We will calculate the rate ratio and standard error (SE) for each study. Zero events will be replaced by 0.5. We will extract both adjusted and unadjusted covariate incidence rate ratios if they are reported in the original studies. For continuous data, we will extract means (arithmetic or geometric) and a measure of variance (standard deviation (SD), SE, or confidence interval (CI)), percentage or mean change from baseline, and the numbers analyzed in each group. SDs will be computed from SEs or 95% CIs, assuming a normal distribution of the values. Haemoglobin values in g/dL will be calculated by multiplying haematocrit or packed cell volume values by 0.34, and studies reporting haemoglobin values in g/dL will be converted to g/L. In cluster-randomized trials, we will record the unit of randomization (e.g. household, compound, sector, or village), the number of clusters in the trial, and the average cluster size. The statistical methods used to analyze the trials will be documented, along with details describing whether these methods adjusted for clustering or other covariates. We plan to extract estimates of the intra-cluster correlation coefficient (ICC) for each outcome. Where results are adjusted for clustering, we will extract the treatment effect estimate and the SD or CI. If the results are not adjusted for clustering, we will extract the data reported. Assessment of risk of bias in included studies Two review authors (KSC, LFY) will independently assess the risk of bias for each included trial using the Cochrane 'Risk of bias 2' tool (RoB 2) for randomized studies (Sterne 2019). Judgements about the risk of bias of included studies will be made according to the recommendations outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021). Disagreements will be resolved by discussion, or by involving a third review author. The interest of our review will be to assess the effect of assignment to the interventions at baseline. We will evaluate each primary outcome using the RoB2 tool. The five domains of the Cochrane RoB2 tool include the following. Bias arising from the randomization process. Bias due to deviations from intended interventions. Bias due to missing outcome data. Bias in measurement of the outcome. Bias in selection of the reported result. Each domain of the RoB2 tool comprises the following. A series of 'signalling' questions. A judgement about the risk of bias for the domain, facilitated by an algorithm that maps responses to the signalling questions to a proposed judgement. Free-text boxes to justify responses to the signalling questions and 'Risk of bias' judgements. An option to predict (and explain) the likely direction of bias. Responses to signalling questions elicit information relevant to an assessment of the risk of bias. These response options are as follows. Yes (may indicate either low or high risk of bias, depending on the most natural way to ask the question). Probably yes. Probably no. No. No information (may indicate no evidence of that problem or an absence of information leading to concerns about there being a problem). Based on the answer to the signalling question, a 'Risk of bias' judgement is assigned to each domain. These judgements include one of the following. High risk of bias Low risk of bias Some concerns To generate the risk of bias judgement for each domain in the randomized studies, we will use the Excel template, available at www.riskofbias.info/welcome/rob-2-0-tool/current-version-of-rob-2. This file will be stored on a scientific data website, available to readers. Risk of bias in cluster randomized controlled trials For the cluster randomized trials, we will be using the RoB2 tool to analyze the five standard domains listed above along with Domain 1b (bias arising from the timing of identification or recruitment of participants) and its related signalling questions. To generate the risk of bias judgement for each domain in the cluster RCTs, we will use the Excel template available at https://sites.google.com/site/riskofbiastool/welcome/rob-2-0-tool/rob-2-for-cluster-randomized-trials. This file will be stored on a scientific data website, available to readers. Risk of bias in cross-over randomized controlled trials For cross-over randomized trials, we will be using the RoB2 tool to analyze the five standard domains listed above along with Domain 2 (bias due to deviations from intended interventions), and Domain 3 (bias due to missing outcome data), and their respective signalling questions. To generate the risk of bias judgement for each domain in the cross-over RCTs, we will use the Excel template, available at https://sites.google.com/site/riskofbiastool/welcome/rob-2-0-tool/rob-2-for-crossover-trials, for each risk of bias judgement of cross-over randomized studies. This file will be stored on a scientific data website, available to readers. Overall risk of bias The overall 'Risk of bias' judgement for each specific trial being assessed will be based on each domain-level judgement. The overall judgements include the following. Low risk of bias (the trial is judged to be at low risk of bias for all domains). Some concerns (the trial is judged to raise some concerns in at least one domain but is not judged to be at high risk of bias for any domain). High risk of bias (the trial is judged to be at high risk of bias in at least one domain, or is judged to have some concerns for multiple domains in a way that substantially lowers confidence in the result). The 'risk of bias' assessments will inform our GRADE evaluations of the certainty of evidence for our primary outcomes presented in the 'Summary of findings' tables and will also be used to inform the sensitivity analyses; (see Sensitivity analysis). If there is insufficient information in study reports to enable an assessment of the risk of bias, studies will be classified as "awaiting assessment" until further information is published or made available to us. Measures of treatment effect Dichotomous data For dichotomous data, we will present proportions and, for two-group comparisons, results as average RR or odds ratio (OR) with 95% CIs. Ordered categorical data Continuous data We will report results for continuous outcomes as the mean difference (MD) with 95% CIs, if outcomes are measured in the same way between trials. Where some studies have reported endpoint data and others have reported change-from-baseline data (with errors), we will combine these in the meta-analysis, if the outcomes were reported using the same scale. We will use the standardized mean difference (SMD), with 95% CIs, to combine trials that measured the same outcome but used different methods. If we do not find three or more studies for a pooled analysis, we will summarize the results in a narrative form. Unit of analysis issues Cluster-randomized trials We plan to combine results from both cluster-randomized and individually randomized studies, providing there is little heterogeneity between the studies. If the authors of cluster-randomized trials conducted their analyses at a different level from that of allocation, and they have not appropriately accounted for the cluster design in their analyses, we will calculate the trials' effective sample sizes to account for the effect of clustering in data. When one or more cluster-RCT reports RRs adjusted for clustering, we will compute cluster-adjusted SEs for the other trials. When none of the cluster-RCTs provide cluster-adjusted RRs, we will adjust the sample size for clustering. We will divide, by the estimated design effects (DE), the number of events and number evaluated for dichotomous outcomes and the number evaluated for continuous outcomes, where DE = 1 + ((average cluster size 1) * ICC). The derivation of the estimated ICCs and DEs will be reported. We will utilize the intra-cluster correlation coefficient (ICC), derived from the trial (if available), or from another source (e.g., using the ICCs derived from other, similar trials) and then calculate the design effect with the formula provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021). If this approach is used, we will report it and undertake sensitivity analysis to investigate the effect of variations in ICC. Studies with more than two treatment groups If we identify studies with more than two intervention groups (multi-arm studies), where possible we will combine groups to create a single pair-wise comparison or use the methods set out in the Cochrane Handbook to avoid double counting study participants (Higgins 2021). For the subgroup analyses, when the control group was shared by two or more study arms, we will divide the control group (events and total population) over the number of relevant subgroups to avoid double counting the participants. Trials with several study arms can be included more than once for different comparisons. Cross-over trials From cross-over trials, we will consider the first period of measurement only and will analyze the results together with parallel-group studies. Multiple outcome events In several outcomes, a participant might experience more than one outcome event during the trial period. For all outcomes, we will extract the number of participants with at least one event. Dealing with missing data We will contact the trial authors if the available data are unclear, missing, or reported in a format that is different from the format needed. We aim to perform a 'per protocol' or 'as observed' analysis; otherwise, we will perform a complete case analysis. This means that for treatment failure, we will base the analyses on the participants who received treatment and the number of participants for which there was an inability to clear malarial parasitaemia or prevent recrudescence after administration of an antimalarial medicine reported in the studies. Assessment of heterogeneity Heterogeneity in the results of the trials will be assessed by visually examining the forest plot to detect non-overlapping CIs, using the Chi2 test of heterogeneity (where a P value of less than 0.1 indicates statistical significance) and the I2 statistic of inconsistency (with a value of greater than 50% denoting moderate levels of heterogeneity). When statistical heterogeneity is present, we will investigate the reasons for it, using subgroup analysis. Assessment of reporting biases We will construct a funnel plot to assess the effect of small studies for the main outcome (when including more than 10 trials). Data synthesis The primary analysis will include all eligible studies that provide data regardless of the overall risk of bias as assessed by the RoB2 tool. Analyses will be conducted using Review Manager 5.4 (Review Manager 2020). Cluster-RCTs will be included in the main analysis after adjustment for clustering (see the previous section on cluster-RCTs). The meta-analysis will be performed using the Mantel-Haenszel random-effects model or the generic inverse variance method (when adjustment for clustering is performed by adjusting SEs), as appropriate. Subgroup analysis and investigation of heterogeneity The overall risk of bias will not be used as the basis in conducting our subgroup analyses. However, where data are available, we plan to conduct the following subgroup analyses, independent of heterogeneity. Dose of folic acid supplementation: higher doses (4 mg or more, daily) versus lower doses (less than 4 mg, daily). Moderate-severe anaemia at baseline (mean haemoglobin of participants in a trial at baseline below 100 g/L for pregnant women and children aged six to 59 months, and below 110 g/L for other populations) versus normal at baseline (mean haemoglobin above 100 g/L for pregnant women and children aged six to 59 months, and above 110 g/L for other populations). Antimalarial drug resistance to parasite: known resistance versus no resistance versus unknown/mixed/unreported parasite resistance. Folate status at baseline: Deficient (e.g. RBC folate concentration of less than 305 nmol/L, or serum folate concentration of less than 7nmol/L) and Insufficient (e.g. RBC folate concentration from 305 to less than 906 nmol/L, or serum folate concentration from 7 to less than 25 nmol/L) versus Sufficient (e.g. RBC folate concentration above 906 nmol/L, or serum folate concentration above 25 nmol/L). Presence of anaemia at baseline: yes versus no. Mandatory fortification status: yes, versus no (voluntary or none). We will only use the primary outcomes in any subgroup analyses, and we will limit subgroup analyses to those outcomes for which three or more trials contributed data. Comparisons between subgroups will be performed using Review Manager 5.4 (Review Manager 2020). Sensitivity analysis We will perform a sensitivity analysis, using the risk of bias as a variable to explore the robustness of the findings in our primary outcomes. We will verify the behaviour of our estimators by adding and removing studies with a high risk of bias overall from the analysis. That is, studies with a low risk of bias versus studies with a high risk of bias. Summary of findings and assessment of the certainty of the evidence For the assessment across studies, we will use the GRADE approach, as outlined in (Schünemann 2021). We will use the five GRADE considerations (study limitations based on RoB2 judgements, consistency of effect, imprecision, indirectness, and publication bias) to assess the certainty of the body of evidence as it relates to the studies which contribute data to the meta-analyses for the primary outcomes. The GRADEpro Guideline Development Tool (GRADEpro) will be used to import data from Review Manager 5.4 (Review Manager 2020) to create 'Summary of Findings' tables. The primary outcomes for the main comparison will be listed with estimates of relative effects, along with the number of participants and studies contributing data for those outcomes. These tables will provide outcome-specific information concerning the overall certainty of evidence from studies included in the comparison, the magnitude of the effect of the interventions examined, and the sum of available data on the outcomes we considered. We will include only primary outcomes in the summary of findings tables. For each individual outcome, two review authors (KSC, LFY) will independently assess the certainty of the evidence using the GRADE approach (Balshem 2011). For assessments of the overall certainty of evidence for each outcome that includes pooled data from included trials, we will downgrade the evidence from 'high certainty' by one level for serious (or by two for very serious) study limitations (risk of bias, indirectness of evidence, serious inconsistency, imprecision of effect estimates, or potential publication bias).
Topics: Child; Infant; Pregnancy; Infant, Newborn; Female; Humans; Child, Preschool; Antimalarials; Sulfadoxine; Pyrimethamine; Folic Acid Antagonists; Birth Weight; Parasitemia; Vitamins; Folic Acid; Anemia; Neural Tube Defects; Dietary Supplements; Iron; Recurrence
PubMed: 36321557
DOI: 10.1002/14651858.CD014217 -
The Cochrane Database of Systematic... Jul 2022Many nations require child-serving professionals to report known or suspected cases of significant child abuse and neglect to statutory child protection or safeguarding... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Many nations require child-serving professionals to report known or suspected cases of significant child abuse and neglect to statutory child protection or safeguarding authorities. Considered globally, there are millions of professionals who fulfil these roles, and many more who will do so in future. Ensuring they are trained in reporting child abuse and neglect is a key priority for nations and organisations if efforts to address violence against children are to succeed.
OBJECTIVES
To assess the effectiveness of training aimed at improving reporting of child abuse and neglect by professionals and to investigate possible components of effective training interventions.
SEARCH METHODS
We searched CENTRAL, MEDLINE, Embase, 18 other databases, and one trials register up to 4 June 2021. We also handsearched reference lists, selected journals, and websites, and circulated a request for studies to researchers via an email discussion list.
SELECTION CRITERIA
All randomised controlled trials (RCTs), quasi-RCTs, and controlled before-and-after studies examining the effects of training interventions for qualified professionals (e.g. teachers, childcare professionals, doctors, nurses, and mental health professionals) to improve reporting of child abuse and neglect, compared with no training, waitlist control, or alternative training (not related to child abuse and neglect).
DATA COLLECTION AND ANALYSIS
We used methodological procedures described in the Cochrane Handbook for Systematic Reviews of Interventions. We synthesised training effects in meta-analysis where possible and summarised findings for primary outcomes (number of reported cases of child abuse and neglect, quality of reported cases, adverse events) and secondary outcomes (knowledge, skills, and attitudes towards the reporting duty). We used the GRADE approach to rate the certainty of the evidence.
MAIN RESULTS
We included 11 trials (1484 participants), using data from 9 of the 11 trials in quantitative synthesis. Trials took place in high-income countries, including the USA, Canada, and the Netherlands, with qualified professionals. In 8 of the 11 trials, interventions were delivered in face-to-face workshops or seminars, and in 3 trials interventions were delivered as self-paced e-learning modules. Interventions were developed by experts and delivered by specialist facilitators, content area experts, or interdisciplinary teams. Only 3 of the 11 included studies were conducted in the past 10 years. Primary outcomes Three studies measured the number of cases of child abuse and neglect via participants' self-report of actual cases reported, three months after training. The results of one study (42 participants) favoured the intervention over waitlist, but the evidence is very uncertain (standardised mean difference (SMD) 0.81, 95% confidence interval (CI) 0.18 to 1.43; very low-certainty evidence). Three studies measured the number of cases of child abuse and neglect via participants' responses to hypothetical case vignettes immediately after training. A meta-analysis of two studies (87 participants) favoured training over no training or waitlist for training, but the evidence is very uncertain (SMD 1.81, 95% CI 1.30 to 2.32; very low-certainty evidence). We identified no studies that measured the number of cases of child abuse and neglect via official records of reports made to child protection authorities, or adverse effects of training. Secondary outcomes Four studies measured professionals' knowledge of reporting duty, processes, and procedures postintervention. The results of one study (744 participants) may favour the intervention over waitlist for training (SMD 1.06, 95% CI 0.90 to 1.21; low-certainty evidence). Four studies measured professionals' knowledge of core concepts in all forms of child abuse and neglect postintervention. A meta-analysis of two studies (154 participants) favoured training over no training, but the evidence is very uncertain (SMD 0.68, 95% CI 0.35 to 1.01; very low-certainty evidence). Three studies measured professionals' knowledge of core concepts in child sexual abuse postintervention. A meta-analysis of these three studies (238 participants) favoured training over no training or waitlist for training, but the evidence is very uncertain (SMD 1.44, 95% CI 0.43 to 2.45; very low-certainty evidence). One study (25 participants) measured professionals' skill in distinguishing reportable and non-reportable cases postintervention. The results favoured the intervention over no training, but the evidence is very uncertain (SMD 0.94, 95% CI 0.11 to 1.77; very low-certainty evidence). Two studies measured professionals' attitudes towards the duty to report child abuse and neglect postintervention. The results of one study (741 participants) favoured the intervention over waitlist, but the evidence is very uncertain (SMD 0.61, 95% CI 0.47 to 0.76; very low-certainty evidence).
AUTHORS' CONCLUSIONS
The studies included in this review suggest there may be evidence of improvements in training outcomes for professionals exposed to training compared with those who are not exposed. However, the evidence is very uncertain. We rated the certainty of evidence as low to very low, downgrading due to study design and reporting limitations. Our findings rest on a small number of largely older studies, confined to single professional groups. Whether similar effects would be seen for a wider range of professionals remains unknown. Considering the many professional groups with reporting duties, we strongly recommend further research to assess the effectiveness of training interventions, with a wider range of child-serving professionals. There is a need for larger trials that use appropriate methods for group allocation, and statistical methods to account for the delivery of training to professionals in workplace groups.
Topics: Child; Child Abuse; Family; Health Personnel; Humans; Mandatory Reporting; Systematic Reviews as Topic
PubMed: 35788913
DOI: 10.1002/14651858.CD011775.pub2 -
The British Journal of Nutrition Nov 2023Vegan and vegetarian diets are widely supported and adopted, but individuals following such diets remain at greater risk of iodine deficiency. This systematic review and... (Meta-Analysis)
Meta-Analysis Review
Vegan and vegetarian diets are widely supported and adopted, but individuals following such diets remain at greater risk of iodine deficiency. This systematic review and meta-analysis was conducted to assess the iodine intake and status in adults following a vegan or vegetarian diet in the modern day. A systematic review and quality assessment were conducted from October 2020 to December 2022 according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidance. Studies were identified in Ovid MEDLINE, Web of Science, PubMed, and Scopus. Eleven articles were eligible for review containing 4421 adults (aged ≥ 18 years). Vegan groups had the lowest median urinary iodine concentration (mUIC) (12·2/l). None of the dietary groups had mUIC within the optimal range for iodine status (100-200 µg/l) (WHO). Vegan diets had the poorest iodine intake (17·3 µg/d) and were strongly associated with lower iodine intake ( = < 0·001) compared with omnivorous diets. Lower intake in vegan diets was influenced by sex ( = 0·007), the presence of voluntary or absence of Universal Salt Iodisation (USI) programmes ( = 0·01 & = < 0·001), and living in a country with adequate iodine nutrition ( = < 0·001). Vegetarians and particularly vegans living in countries with no current USI programme continue to have increased risk of low iodine status, iodine deficiency and inadequate iodine intake. Further research into the usefulness of mandatory fortification of vegan appropriate foods is required.
Topics: Adult; Humans; Diet, Vegan; Vegans; Iodine; Diet, Vegetarian; Nutritional Status; Vegetarians
PubMed: 36912094
DOI: 10.1017/S000711452300051X -
European Journal of Physical and... Apr 2023One of the most common disabling complications in breast cancer (BC) patients is breast cancer-related lymphedema (BCRL), a pathological condition affecting both...
INTRODUCTION
One of the most common disabling complications in breast cancer (BC) patients is breast cancer-related lymphedema (BCRL), a pathological condition affecting both physical and psychological function, with detrimental consequences on health-related quality of life (HR-QoL). Rehabilitation has a key role in the comprehensive management of this condition with several studies reporting positive results after performing complex decongestive therapies (CDT) in these women. Kinesio taping (KT) is a rather recent therapeutic approach to treat BCRL, however, evidence in literature regarding its effectiveness is far from being fully characterized. Therefore, this systematic review aimed at assessing the role of KT among the CDT to treat BCRL.
EVIDENCE ACQUISITION
PubMed, Scopus, and Web of Science were systematically searched from inception until May 5, 2022 to determine randomized control trials (RCTs) reporting patients with BCRL; KT as intervention; limb volume as outcome (PROSPERO number: CRD42022349720).
EVIDENCE SYNTHESIS
Out of the documents identified, 123 were eligible for data screening, and only 7 RCTs satisfied the eligibility criteria and were included. We found that KT might have a positive effect on limb volume reduction in patients with BCRL, albeit there is little evidence for low quality of the included studies.
CONCLUSIONS
Taken together, this systematic review showed that KT did not significantly reduce the upper limb volume in BCRL women, albeit it seemed to increase the flow rate during the passive exercise. Further high-quality-studies are mandatory to improve the knowledge in order to include the KT might into a multidisciplinary rehabilitative approach for the management of BC survivors affected by lymphedema.
Topics: Female; Humans; Randomized Controlled Trials as Topic; Breast Neoplasms; Lymphedema; Upper Extremity; Athletic Tape
PubMed: 36847633
DOI: 10.23736/S1973-9087.23.07752-3 -
Campbell Systematic Reviews Mar 2021The Campbell Collaboration undertakes systematic reviews of the effects of social and economic policies (interventions) to help policymakers, practitioners, and the... (Review)
Review
BACKGROUND
The Campbell Collaboration undertakes systematic reviews of the effects of social and economic policies (interventions) to help policymakers, practitioners, and the public to make well-informed decisions about policy interventions. In 2010, the Cochrane Collaboration and the Campbell Collaboration developed a voluntary co-registration policy under the rationale to make full use of the shared interests and diverse expertise from different review groups within these two organizations. In order to promote the methodological quality and transparency of Campbell intervention reviews, the Methodological Expectations of Campbell Collaboration Intervention Reviews (MECCIR) were introduced in 2014 to guide Campbell reviewers. However, there has not been a comprehensive review of the methodological quality and reporting characteristics of Campbell reviews.
OBJECTIVES
This review aimed to assess the methodological and reporting characteristics of Campbell intervention reviews and to compare the methodological quality and reporting completeness of Campbell reviews published before and after the implementation of MECCIR. A secondary aim was to compare the methodological quality and reporting completeness of reviews registered with Campbell only versus those co-registered with Cochrane and Campbell.
SEARCH METHODS
We searched the Campbell Library to identify all the completed intervention reviews published between 1 January 2011 to 31 January 2018.
SELECTION CRITERIA
One researcher downloaded and screened all the records to exclude non-intervention reviews based on reviews' title and abstract. A second researcher checked the full text of all the excluded records to confirm the exclusion. In case of discrepancies, the two researchers jointly agreed on the final decision.
DATA COLLECTION AND ANALYSIS
We developed the abstraction form based on mandatory reporting items for methods, results, and discussion from the MECCIR reporting standards Version 1.1; and additional epidemiological characteristics identified in a similar study of systematic reviews in health. Additionally, we judged the methodological quality and completeness of reporting of each included review. For methodological quality, we used the AMSTAR 2 (A MeaSurement Tool to Assess systematic Reviews 2) instrument; for reporting completeness we used the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) checklist. We rated reporting as either complete/partial or not reported. We described characteristics of the included reviews with frequencies and percentages, and median with interquartile ranges (IQRs). We used Stata version 12.0 to conduct multiple linear regressions for continuous data and the ordered logistic regressions for ordered data to investigate associations between prespecified factors and both methodological quality and completeness of reporting.
MAIN RESULTS
We included 96 Campbell reviews, 46 were published between January 2011 and September 2014 (pre-MECCIR) and 50 between October 2014 and January 2018 (post-MECCIR). Twenty-two of 96 (23%) reviews were co-registered with Cochrane. For overall methodological quality, 16 (17%) reviews were rated as high, 40 (42%) as moderate, 24 (25%) as low and 16 (17%) as critical low using AMSTAR 2. Reviews published after the release of MECCIR had better methodological quality ratings than those published before MECCIR (odds ratio [OR] =6.61, 95% confidence interval [CI] [2.86, 15.27], < .001). The percentages of reviews of high or moderate quality were 76% (post-MECCIR) and 39% (pre-MECCIR). Reviews co-registered with Cochrane were rated as having better methodological quality than those registered only with Campbell (OR = 5.57, 95% CI [2.13, 14.58], < .001). The percentages of reviews of high or moderate quality were 77% versus 53% between co-registered and Campbell registered only reviews. Twenty-five of 96 reviews (26%) completely or partially reported all 27 PRISMA checklist items. The median number of items reported across reviews was 25 (IQR, 22-26). Reviews published after the release of MECCIR reported 2.80 more items than those published before MECCIR (95% CI [1.74, 3.88], < .001); reviews co-registered on Campbell and Cochrane reported 1.98 more items than reviews only registered in Campbell (95% CI [0.72, 3.24], = .003). An increasing trend over time was observed for both the percentage of high and moderate methodological quality of reviews and the median number of PRISMA items reported.
AUTHORS' CONCLUSIONS
Many features expected in systematic reviews were present in Campbell reviews most of the time. Methodological quality and reporting completeness were both significantly higher in reviews published after the introduction of MECCIR in 2014 compared with those published before. However, this may also reflect general improvement in the reporting the methodology of systematic reviews over time or associations with other characteristics which were not assessed such as funding or experience of teams. Reviews co-registered with Cochrane were of higher methodological quality and more complete reporting than reviews only registered in Campbell.
PubMed: 37133262
DOI: 10.1002/cl2.1134 -
The Journal of Investigative Dermatology Jan 2021We sought to assess the quality of dermatological systematic reviews (SRs) and identify factors that predict high methodological quality. We searched for all SRs... (Meta-Analysis)
Meta-Analysis
We sought to assess the quality of dermatological systematic reviews (SRs) and identify factors that predict high methodological quality. We searched for all SRs published in 2017 using PubMed, Epistemonikos, and the Cochrane Database of SRs. We included studies identified as SRs or meta-analysis in the title or abstract and dealing with a dermatological topic. Study selection and data extraction were carried out and Preferred Reporting Items for SRs and Meta-Analyses and rating by A MeaSurement Tool to Assess SRs 2 were used independently by two authors. On the basis of A MeaSurement Tool to Assess SRs 2, confidence in SRs results was classified as high, moderate, low, or very low. We included 732 studies. We described a random sample of 140. The overall rating of confidence in the results according to a tool called A MeaSurement Tool to Assess SRs 2 was high or moderate for nine reviews (6%). A total of 20 reviews (15%) had a registered protocol. Independent factors associated with moderate or high rating of A MeaSurement Tool to Assess SRs 2 were publication in a journal where Preferred Reporting Items for SRs and Meta-Analyses was mandatory (OR [95% confidence interval] = 27.0 [1.4-528]) and journal impact factor (OR of 1.9 [1.3-3]) for each increase in one more point. The observation that 90% of published dermatology SRs are of very low quality is alarming. Review registration in the International Prospective Register of SRs and full reporting according to Preferred Items for SRs and Meta-Analyses should be mandatory for publication. This study is registered in the International Prospective Register of SRs (CRD42018093856).
Topics: Databases, Factual; Dermatology; Humans; Quality Improvement
PubMed: 32603750
DOI: 10.1016/j.jid.2020.05.109 -
Frontiers in Public Health 2022To perform a systematic review to describe the available findings on clinical outcomes in HIV-1 and HTLV-1/HTLV-2 co-infected individuals since 1995.
AIM
To perform a systematic review to describe the available findings on clinical outcomes in HIV-1 and HTLV-1/HTLV-2 co-infected individuals since 1995.
DESIGN
This Systematic Review used PECO criteria follow by PRISMA reporting guidelines and registered as CRD42021279062 (Prospero database). The Newcastle-Ottawa Scale assessed the methodological quality of included studies.
DATA COLLECTION AND ANALYSIS
A systematical search in PubMed/MEDLINE, Embase, Web of Sciences databases for cross-sectional, case-control, or cohort studies design to identify clinical and laboratorial outcomes related to HIV-1 and HTLV-1/2 coinfection. Search strategy: [("HIV-1" AND "HTLV-1" OR "HTLV-2") AND ("Coinfection") AND (1990/01/01:2021/12/31[Date- Publication])].
RESULTS
A total of 15 articles were included on this systematic review describing data of 2,566 mono and coinfected patients, 58% male, with mean age was 35.7 ± 5.7 years. HIV-1 and HTLV-1 coinfected patients were more likely to had shorter survival and faster progression to death or mortality than monoinfected ones. Coinfected had higher CD4 cell counts and less likelihood of ART use. In addition, higher frequency of diseases like ichthyosis (22.2 vs. 6.8%), scabies (18.6 vs. 0%), candidiasis (42 vs. 12%), Strongyloidiasis (15.4 vs. 2%) and neurological manifestations like encephalopathy, peripheral neuropathy and HAM/TSP were more frequently reported in coinfected patients.
CONCLUSIONS
HIV-1 and HTLV-1 coinfection and HIV-1 and HTLV-1 /2 triple coinfection were related to shorter survival, higher mortality rate, and faster progression to death, while coinfection by HIV-1/HTLV-2 seems to have neutral association with longer survival, slower AIDS progression, and lower mortality rate. The available evidence indicates an urgent need for prevention and control measures, including screening, diagnosis, and treatment of HIV-1 and HTLV-1/2 coinfected patients. Test-and-treat strategy for patients living with HIV in areas endemic for HTLV infection is mandatory, to avoid the risks of delayed therapy and death for coinfected patients.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/, identifier: CRD42021279062.
Topics: Adult; Coinfection; Cross-Sectional Studies; Female; HIV Infections; HIV-1; HTLV-I Infections; HTLV-II Infections; Human T-lymphotropic virus 1; Human T-lymphotropic virus 2; Humans; Male
PubMed: 35359787
DOI: 10.3389/fpubh.2022.820727 -
Hepatology (Baltimore, Md.) Apr 2023Immunotherapy-based regimes have changed the management of HCC. However, evidence of efficacy in patients with impaired liver function is unknown. This systematic review... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND AIMS
Immunotherapy-based regimes have changed the management of HCC. However, evidence of efficacy in patients with impaired liver function is unknown. This systematic review and meta-analysis assesses survival of HCC patients and liver dysfunction treated with immunotherapy-based regimens.
METHODS
Systematic review and meta-analysis of original articles or abstracts reporting survival of HCC patients treated with immunotherapy according to liver function between 2017 and 2022. Overal survival (OS) according to restricted mean survival time (RMST) and median OS, and hazard ratio (HR) of Child-Pugh B or B/C versus Child-Pugh A were assessed while considering the line of treatment.
RESULTS
Of the 2218 articles considered, 15 articles recruiting 2311 patients were included. Of these, 639 (27.7%) were Child-Pugh B and 34 (1.5%) C. RMST was 8.36 (95% CI, 6.15-10.57; I2 =93%) months, estimated from 8 studies. The HR was reported in 8 studies for survival between Child-Pugh B versus Child-Pugh A and metanalysis disclosed a 1.65 HR (95% CI,1.45-1.84; I2 =0% heterogeneity; p = 0.45). Treatment line data were available for 47% of the patients and 3 studies included patients treated with atezolizumab-bevacizumab in the first line.
CONCLUSIONS
The high heterogeneity across studies reflects the incapacity of the current evidence to support the indication of immunotherapy in HCC patients with relevant liver dysfunction. It is mandatory to report complementary information to Child-Pugh classification such as prior liver decompensation, use of concomitant medication to control ascites, or signs of clinically significant portal hypertension to allow better patient stratification in future studies.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Immunotherapy
PubMed: 36632997
DOI: 10.1097/HEP.0000000000000030 -
Vaccine Mar 2022Invasive meningococcal disease (IMD) is a notifiable disease in Germany and other European countries. Due to the high lethality of the disease and the risk of long-term... (Review)
Review
INTRODUCTION
Invasive meningococcal disease (IMD) is a notifiable disease in Germany and other European countries. Due to the high lethality of the disease and the risk of long-term consequences, IMD prevention is of high public health relevance despite the low number of cases in the population. This study aims to describe key epidemiological and economic parameters of IMD in Germany to support national decision-making processes for implementing enhanced prevention measures.
METHODS
Based on a systematic literature review in PubMed and EMBASE, all publications on the burden of disease and costs of IMD published up to May 2020 were evaluated. Additionally, notification data were used to report the annual case numbers and incidence of IMD in Germany until the end of 2019.
RESULTS
Thirty-six studies were included, of which 35 reported data on the epidemiological burden of disease and three reported data on economic aspects of IMD. The type of reported endpoints and results on the incidence of IMD differed widely by reporting year, population, and data source used. Most of the data are reported without specific information about a serogroup. Data on the economic burden of disease and healthcare resource use are scarce. Based on mandatory notification data, a decrease in the incidence of notified IMD cases has been observed since 2004. Currently, the nationwide annual incidence in Germany is at 0.3 cases per 100,000 persons and has gradually decreased. While the overall decline is mainly attributable to MenB, cases with MenY and MenW are the only ones that have increased on a low level in recent years.
CONCLUSION
While IMD is a rare disease, high direct and indirect costs illustrate the relevance of the disease for patients, caregivers, as well as for the health care system. Future research should concentrate on quantifying the long-term economic burden and indirect costs of meningococcal disease. Integrated IMD surveillance with isolate characterisation remains crucial to inform public health policies.
Topics: Financial Stress; Germany; Humans; Incidence; Meningococcal Infections; Meningococcal Vaccines; Neisseria meningitidis; Serogroup
PubMed: 35227520
DOI: 10.1016/j.vaccine.2022.02.043 -
Seizure Jul 2023Catamenial epilepsy (CE) is defined as an increase in seizure frequency during specific phases of the menstrual cycle in women with epilepsy. The treatment usually... (Review)
Review
OBJECTIVE
Catamenial epilepsy (CE) is defined as an increase in seizure frequency during specific phases of the menstrual cycle in women with epilepsy. The treatment usually includes a combination of non-hormonal and hormonal therapies. This systematic review summarizes the available data on the efficacy of progesterone and its derivates to treat CE.
METHODS
We performed a systematic search of the literature to identify studies reporting data on the use of progesterone and its derivatives (any type and dose) for the treatment of CE. The main outcome included the efficacy of progesterone and its derivatives on seizure frequency.
RESULTS
Nineteen articles (457 patients) were included; four were randomized controlled trials (two comparing progesterone vs placebo and two comparing norethisterone vs placebo). Progesterone was generally administered during the luteal phase (from day 15 to 25) or during perimenstrual exacerbations (from day 23 to 25), with an average dose of 10-30 mg/day to a maximum of 300 mg/day. The therapy, usually well tolerated, was ineffective in the randomized controlled trials; conversely, it was associated with an overall reduction in seizure frequency in case reports and uncontrolled studies.
CONCLUSIONS
Although data from uncontrolled studies suggest that hormone therapy with progesterone may be useful in the treatment of CE, its efficacy has not been demonstrated in controlled trials. The possible antiseizure effect of progesterone could be mediated by its active metabolite allopregnanolone, making the plasmatic measurement of these hormones mandatory to evaluate efficacy. Further randomized controlled trials should investigate the efficacy of progesterone and its derivatives, addressing these pharmacological issues.
Topics: Humans; Female; Progesterone; Anticonvulsants; Menstrual Cycle; Epilepsy, Reflex; Seizures; Randomized Controlled Trials as Topic
PubMed: 37229848
DOI: 10.1016/j.seizure.2023.05.004