clinical research review article

JAY SIWEK, M.D., MARGARET L. GOURLAY, M.D., DAVID C. SLAWSON, M.D., AND ALLEN F. SHAUGHNESSY, PHARM.D.

Am Fam Physician. 2002;65(2):251-258

Traditional clinical review articles, also known as updates, differ from systematic reviews and meta-analyses. Updates selectively review the medical literature while discussing a topic broadly. Nonquantitative systematic reviews comprehensively examine the medical literature, seeking to identify and synthesize all relevant information to formulate the best approach to diagnosis or treatment. Meta-analyses (quantitative systematic reviews) seek to answer a focused clinical question, using rigorous statistical analysis of pooled research studies. This article presents guidelines for writing an evidence-based clinical review article for American Family Physician . First, the topic should be of common interest and relevance to family practice. Include a table of the continuing medical education objectives of the review. State how the literature search was done and include several sources of evidence-based reviews, such as the Cochrane Collaboration, BMJ's Clinical Evidence , or the InfoRetriever Web site. Where possible, use evidence based on clinical outcomes relating to morbidity, mortality, or quality of life, and studies of primary care populations. In articles submitted to American Family Physician , rate the level of evidence for key recommendations according to the following scale: level A (randomized controlled trial [RCT], meta-analysis); level B (other evidence); level C (consensus/expert opinion). Finally, provide a table of key summary points.

American Family Physician is particularly interested in receiving clinical review articles that follow an evidence-based format. Clinical review articles, also known as updates, differ from systematic reviews and meta-analyses in important ways. 1 Updates selectively review the medical literature while discussing a topic broadly. An example of such a topic is, “The diagnosis and treatment of myocardial ischemia.” Systematic reviews comprehensively examine the medical literature, seeking to identify and synthesize all relevant information to formulate the best approach to diagnosis or treatment. Examples are many of the systematic reviews of the Cochrane Collaboration or BMJ's Clinical Evidence compendium. Meta-analyses are a special type of systematic review. They use quantitative methods to analyze the literature and seek to answer a focused clinical question, using rigorous statistical analysis of pooled research studies. An example is, “Do beta blockers reduce mortality following myocardial infarction?”

The best clinical review articles base the discussion on existing systematic reviews and meta-analyses, and incorporate all relevant research findings about the management of a given disorder. Such evidence-based updates provide readers with powerful summaries and sound clinical guidance.

In this article, we present guidelines for writing an evidence-based clinical review article, especially one designed for continuing medical education (CME) and incorporating CME objectives into its format. This article may be read as a companion piece to a previous article and accompanying editorial about reading and evaluating clinical review articles. 1 , 2 Some articles may not be appropriate for an evidence-based format because of the nature of the topic, the slant of the article, a lack of sufficient supporting evidence, or other factors. We encourage authors to review the literature and, wherever possible, rate key points of evidence. This process will help emphasize the summary points of the article and strengthen its teaching value.

Topic Selection

Choose a common clinical problem and avoid topics that are rarities or unusual manifestations of disease or that have curiosity value only. Whenever possible, choose common problems for which there is new information about diagnosis or treatment. Emphasize new information that, if valid, should prompt a change in clinical practice, such as the recent evidence that spironolactone therapy improves survival in patients who have severe congestive heart failure. 3 Similarly, new evidence showing that a standard treatment is no longer helpful, but may be harmful, would also be important to report. For example, patching most traumatic corneal abrasions may actually cause more symptoms and delay healing compared with no patching. 4

Searching the Literature

When searching the literature on your topic, please consult several sources of evidence-based reviews ( Table 1 ) . Look for pertinent guidelines on the diagnosis, treatment, or prevention of the disorder being discussed. Incorporate all high-quality recommendations that are relevant to the topic. When reviewing the first draft, look for all key recommendations about diagnosis and, especially, treatment. Try to ensure that all recommendations are based on the highest level of evidence available. If you are not sure about the source or strength of the recommendation, return to the literature, seeking out the basis for the recommendation.

In particular, try to find the answer in an authoritative compendium of evidence-based reviews, or at least try to find a meta-analysis or well-designed randomized controlled trial (RCT) to support it. If none appears to be available, try to cite an authoritative consensus statement or clinical guideline, such as a National Institutes of Health Consensus Development Conference statement or a clinical guideline published by a major medical organization. If no strong evidence exists to support the conventional approach to managing a given clinical situation, point this out in the text, especially for key recommendations. Keep in mind that much of traditional medical practice has not yet undergone rigorous scientific study, and high-quality evidence may not exist to support conventional knowledge or practice.

Patient-Oriented vs. Disease-Oriented Evidence

With regard to types of evidence, Shaughnessy and Slawson 5 – 7 developed the concept of Patient-Oriented Evidence that Matters (POEM), in distinction to Disease-Oriented Evidence (DOE). POEM deals with outcomes of importance to patients, such as changes in morbidity, mortality, or quality of life. DOE deals with surrogate end points, such as changes in laboratory values or other measures of response. Although the results of DOE sometimes parallel the results of POEM, they do not always correspond ( Table 2 ) . 2 When possible, use POEM-type evidence rather than DOE. When DOE is the only guidance available, indicate that key clinical recommendations lack the support of outcomes evidence. Here is an example of how the latter situation might appear in the text: “Although prostate-specific antigen (PSA) testing identifies prostate cancer at an early stage, it has not yet been proved that PSA screening improves patient survival.” (Note: PSA testing is an example of DOE, a surrogate marker for the true outcomes of importance—improved survival, decreased morbidity, and improved quality of life.)

Evaluating the Literature

Evaluate the strength and validity of the literature that supports the discussion (see the following section, Levels of Evidence). Look for meta-analyses, high-quality, randomized clinical trials with important outcomes (POEM), or well-designed, nonrandomized clinical trials, clinical cohort studies, or case-controlled studies with consistent findings. In some cases, high-quality, historical, uncontrolled studies are appropriate (e.g., the evidence supporting the efficacy of Papanicolaou smear screening). Avoid anecdotal reports or repeating the hearsay of conventional wisdom, which may not stand up to the scrutiny of scientific study (e.g., prescribing prolonged bed rest for low back pain).

Look for studies that describe patient populations that are likely to be seen in primary care rather than subspecialty referral populations. Shaughnessy and Slawson's guide for writers of clinical review articles includes a section on information and validity traps to avoid. 2

Levels of Evidence

Readers need to know the strength of the evidence supporting the key clinical recommendations on diagnosis and treatment. Many different rating systems of varying complexity and clinical relevance are described in the medical literature. Recently, the third U.S. Preventive Services Task Force (USPSTF) emphasized the importance of rating not only the study type (RCT, cohort study, case-control study, etc.), but also the study quality as measured by internal validity and the quality of the entire body of evidence on a topic. 8

While it is important to appreciate these evolving concepts, we find that a simplified grading system is more useful in AFP . We have adopted the following convention, using an ABC rating scale. Criteria for high-quality studies are discussed in several sources. 8 , 9 See the AFP Web site ( www.aafp.org/afp/authors ) for additional information about levels of evidence and see the accompanying editorial in this issue discussing the potential pitfalls and limitations of any rating system.

Level A (randomized controlled trial/meta-analysis): High-quality randomized controlled trial (RCT) that considers all important outcomes. High-quality meta-analysis (quantitative systematic review) using comprehensive search strategies.

Level B (other evidence): A well-designed, nonrandomized clinical trial. A nonquantitative systematic review with appropriate search strategies and well-substantiated conclusions. Includes lower quality RCTs, clinical cohort studies, and case-controlled studies with non-biased selection of study participants and consistent findings. Other evidence, such as high-quality, historical, uncontrolled studies, or well-designed epidemiologic studies with compelling findings, is also included.

Level C (consensus/expert opinion): Consensus viewpoint or expert opinion.

Each rating is applied to a single reference in the article, not to the entire body of evidence that exists on a topic. Each label should include the letter rating (A, B, C), followed by the specific type of study for that reference. For example, following a level B rating, include one of these descriptors: (1) nonrandomized clinical trial; (2) nonquantitative systematic review; (3) lower quality RCT; (4) clinical cohort study; (5) case-controlled study; (6) historical uncontrolled study; (7) epidemiologic study.

Here are some examples of the way evidence ratings should appear in the text:

“To improve morbidity and mortality, most patients in congestive heart failure should be treated with an angiotensin-converting enzyme inhibitor. [Evidence level A, RCT]”

“The USPSTF recommends that clinicians routinely screen asymptomatic pregnant women 25 years and younger for chlamydial infection. [Evidence level B, non-randomized clinical trial]”

“The American Diabetes Association recommends screening for diabetes every three years in all patients at high risk of the disease, including all adults 45 years and older. [Evidence level C, expert opinion]”

When scientifically strong evidence does not exist to support a given clinical recommendation, you can point this out in the following way:

“Physical therapy is traditionally prescribed for the treatment of adhesive capsulitis (frozen shoulder), although there are no randomized outcomes studies of this approach.”

Format of the Review

Introduction.

The introduction should define the topic and purpose of the review and describe its relevance to family practice. The traditional way of doing this is to discuss the epidemiology of the condition, stating how many people have it at one point in time (prevalence) or what percentage of the population is expected to develop it over a given period of time (incidence). A more engaging way of doing this is to indicate how often a typical family physician is likely to encounter this problem during a week, month, year, or career. Emphasize the key CME objectives of the review and summarize them in a separate table entitled “CME Objectives.”

The methods section should briefly indicate how the literature search was conducted and what major sources of evidence were used. Ideally, indicate what predetermined criteria were used to include or exclude studies (e.g., studies had to be independently rated as being high quality by an established evaluation process, such as the Cochrane Collaboration). Be comprehensive in trying to identify all major relevant research. Critically evaluate the quality of research reviewed. Avoid selective referencing of only information that supports your conclusions. If there is controversy on a topic, address the full scope of the controversy.

The discussion can then follow the typical format of a clinical review article. It should touch on one or more of the following subtopics: etiology, pathophysiology, clinical presentation (signs and symptoms), diagnostic evaluation (history, physical examination, laboratory evaluation, and diagnostic imaging), differential diagnosis, treatment (goals, medical/surgical therapy, laboratory testing, patient education, and follow-up), prognosis, prevention, and future directions.

The review will be comprehensive and balanced if it acknowledges controversies, unresolved questions, recent developments, other viewpoints, and any apparent conflicts of interest or instances of bias that might affect the strength of the evidence presented. Emphasize an evidence-supported approach or, where little evidence exists, a consensus viewpoint. In the absence of a consensus viewpoint, you may describe generally accepted practices or discuss one or more reasoned approaches, but acknowledge that solid support for these recommendations is lacking.

In some cases, cost-effectiveness analyses may be important in deciding how to implement health care services, especially preventive services. 10 When relevant, mention high-quality cost-effectiveness analyses to help clarify the costs and health benefits associated with alternative interventions to achieve a given health outcome. Highlight key points about diagnosis and treatment in the discussion and include a summary table of the key take-home points. These points are not necessarily the same as the key recommendations, whose level of evidence is rated, although some of them will be.

Use tables, figures, and illustrations to highlight key points, and present a step-wise, algorithmic approach to diagnosis or treatment when possible.

Rate the evidence for key statements, especially treatment recommendations. We expect that most articles will have at most two to four key statements; some will have none. Rate only those statements that have corresponding references and base the rating on the quality and level of evidence presented in the supporting citations. Use primary sources (original research, RCTs, meta-analyses, and systematic reviews) as the basis for determining the level of evidence. In other words, the supporting citation should be a primary research source of the information, not a secondary source (such as a nonsystematic review article or a textbook) that simply cites the original source. Systematic reviews that analyze multiple RCTs are good sources for determining ratings of evidence.

The references should include the most current and important sources of support for key statements (i.e., studies referred to, new information, controversial material, specific quantitative data, and information that would not usually be found in most general reference textbooks). Generally, these references will be key evidence-based recommendations, meta-analyses, or landmark articles. Although some journals publish exhaustive lists of reference citations, AFP prefers to include a succinct list of key references. (We will make more extensive reference lists available on our Web site or provide links to your personal reference list.)

You may use the following checklist to ensure the completeness of your evidence-based review article; use the source list of reviews to identify important sources of evidence-based medicine materials.

Checklist for an Evidence-Based Clinical Review Article

The topic is common in family practice, especially topics in which there is new, important information about diagnosis or treatment.

The introduction defines the topic and the purpose of the review, and describes its relevance to family practice.

A table of CME objectives for the review is included.

The review states how you did your literature search and indicates what sources you checked to ensure a comprehensive assessment of relevant studies (e.g., MEDLINE, the Cochrane Collaboration Database, the Center for Research Support, TRIP Database).

Several sources of evidence-based reviews on the topic are evaluated ( Table 1 ) .

Where possible, POEM (dealing with changes in morbidity, mortality, or quality of life) rather than DOE (dealing with mechanistic explanations or surrogate end points, such as changes in laboratory tests) is used to support key clinical recommendations ( Table 2 ) .

Studies of patients likely to be representative of those in primary care practices, rather than subspecialty referral centers, are emphasized.

Studies that are not only statistically significant but also clinically significant are emphasized; e.g., interventions with meaningful changes in absolute risk reduction and low numbers needed to treat. (See http://www.cebm.net/index.aspx?o=1116 .) 11

The level of evidence for key clinical recommendations is labeled using the following rating scale: level A (RCT/meta-analysis), level B (other evidence), and level C (consensus/expert opinion).

Acknowledge controversies, recent developments, other viewpoints, and any apparent conflicts of interest or instances of bias that might affect the strength of the evidence presented.

Highlight key points about diagnosis and treatment in the discussion and include a summary table of key take-home points.

Use tables, figures, and illustrations to highlight key points and present a step-wise, algorithmic approach to diagnosis or treatment when possible.

Emphasize evidence-based guidelines and primary research studies, rather than other review articles, unless they are systematic reviews.

The essential elements of this checklist are summarized in Table 3 .

Siwek J. Reading and evaluating clinical review articles. Am Fam Physician. 1997;55:2064-2069.

Shaughnessy AF, Slawson DC. Getting the most from review articles: a guide for readers and writers. Am Fam Physician. 1997;55:2155-60.

Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med. 1999;341:709-17.

Flynn CA, D'Amico F, Smith G. Should we patch corneal abrasions? A meta-analysis. J Fam Pract. 1998;47:264-70.

Slawson DC, Shaughnessy AF, Bennett JH. Becoming a medical information master: feeling good about not knowing everything. J Fam Pract. 1994;38:505-13.

Shaughnessy AF, Slawson DC, Bennett JH. Becoming an information master: a guidebook to the medical information jungle. J Fam Pract. 1994;39:489-99.

Slawson DC, Shaughnessy AF. Becoming an information master: using POEMs to change practice with confidence. Patient-oriented evidence that matters. J Fam Pract. 2000;49:63-7.

Harris RP, Helfand M, Woolf SH, Lohr KN, Mulrow CD, Teutsch SM, et al. Methods Work Group, Third U.S. Preventive Services Task Force. Current methods of the U.S. Preventive Services Task Force. A review of the process. Am J Prev Med. 2001;20(3 suppl):21-35.

CATbank topics: levels of evidence and grades of recommendations. Retrieved November 2001, from: http://www.cebm.net/ .

Saha S, Hoerger TJ, Pignone MP, Teutsch SM, Helfand M, Mandelblatt JS. for the Cost Work Group of the Third U.S. Preventive Services Task Force. The art and science of incorporating cost effectiveness into evidence-based recommendations for clinical preventive services. Am J Prev Med. 2001;20(3 suppl):36-43.

Evidence-based medicine glossary. Retrieved November 2001, from: http://www.cebm.net/index.aspx?o=1116 .

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• Open access
• Published: 10 October 2023

Clinical systematic reviews – a brief overview

• Mayura Thilanka Iddagoda 1 , 2 &
• Leon Flicker 1 , 2  

BMC Medical Research Methodology volume  23 , Article number:  226 ( 2023 ) Cite this article

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Systematic reviews answer research questions through a defined methodology. It is a complex task and multiple articles need to be referred to acquire wide range of required knowledge to conduct a systematic review. The aim of this article is to bring the process into a single paper.

The statistical concepts and sequence of steps to conduct a systematic review or a meta-analysis are examined by authors.

The process of conducting a clinical systematic review is described in seven manageable steps in this article. Each step is explained with examples to understand the method evidently.

A complex process of conducting a systematic review is presented simply in a single article.

Peer Review reports

Systematic reviews are a structured approach to answer a research question based on all suitable available empirical evidence. The statistical methodology used to synthesize results in such a review is called ‘meta-analysis’. There are five types of clinical systematic reviews described in this article (see Fig. 1 ), including intervention, diagnostic test accuracy, prognostic, methodological and qualitative. This review will provide a very brief overview in a narrative fashion. This article does not cover systematic reviews of more epidemiologically based studies. The recommended process undertaken in a systematic review is described under seven steps in this paper [ 1 ].

Types of systematic reviews

There are resources for those who are moving from the beginning stage and gaining more expertise (See Table 1 ). Cochrane conducts online interactive master classes on systematic reviews throughout the year and there are web tutorials in the form of e-learning modules. Some groups in Cochrane commission limited number of systematic reviews and can be contacted directly for support ([email protected]). Some institutions have systematic review training programs including John Hopkins (Coursea), Joanna Briggs Institute (JBI education), Yale University (Search strategy), University of York (Centre for Reviews) and Mayo Clinic Libraries. BMC systematic reviews group also introduced “Peer review mentoring” program to support early researchers in systematic reviews. The local University/Hospital librarian is usually a good point of first reference for searches and is able to direct reviewers to other support.

Research question and study protocol

A clearly defined study question is vital and will direct the following steps in a systematic review. The question should have some novelty (e.g. there should be no existing review without new primary studies) and be of interest to the reviewers. Major conflicts of interest can be problematic (e.g. employment by a company that manufactures the intervention). Primary components of a research question should include inclusion criteria, search strategy, analysis or outcome measures and interpretation. Types of reviews will determine the categories of research questions such as intervention, prognostic, diagnostic, etc. [ 1 ].

Study protocol elaborates the research question. The language of the study protocol is important. It is usually written in future tense, accessible language, active voice and full sentences [ 2 ]. Structure of the review protocol is described in Fig. 2 .

Structure of the review protocol

Searching studies

The comprehensive search for eligible studies is the most defining step in a systematic review. The guidance by an information specialist, or an experienced librarian, is a key requirement for designing a thorough search strategy [ 3 , 4 ].

The search strategy should explore multiple sources rigorously and it should be reproducible. It is important to balance sensitivity and precision in designing a search plan. A sensitive approach will provide a large number of studies, which lowers the risk of missing relevant studies but may produce a large workload. On the other hand, a focused search (precision) will give a more manageable number of studies but increases the risk of missing studies.

There are multiple sources to search for eligible studies in a systematic review or a meta-analysis. The key databases are Central (Cochrane register of clinical trials), MEDLINE (PubMed) and Embase. There are many other databases, published reviews and reference lists that may be used. Forward citation tracking can be done for searched studies using citation indices like Google Scholar, Scopus or Web of Science. There may be studies presented to different levels of governmental and non-governmental organizations which are not recognized as commercial publishers. These studies are called ‘grey literature’. Extensive investigations in different sources are required to identify grey literature. Information specialists are helpful in finding these studies [ 2 ].

Designing the search strategy requires a structured approach. Again, assistance from a librarian or an information specialist is recommended. PICOS, PICO and PICOTS elements are used to design key concepts. Participants and study design are relevant elements used in all reviews. Intervention reviews require specification of the intervention’s exact nature. Outcomes are important for both intervention and prognostic reviews.

Search terms are then developed using key concepts. There are two main search terms (text words and index terms). Text words or natural language terms appear in most publications. Different authors may use different text words for the same pathology. For an example, words such as injury, wound, trauma are used to describe physical damage to the body. Index terms, on the other hand, are controlled vocabularies defined by database indexers [ 4 ]. Common terms are MeSH (Medical Subject Headings) by MEDLINE and Emtree in Embase. The index terms do not change with the interface (eg. the term ‘wound and injuries’ is used for all types of damage to the body from external causes) [ 5 ].

Search filters are used to identify search terms. The choice of filters depends on the study design, database and interface. There are specific words used to combine search terms called ‘Boolean operators’. The main Boolean operators are ‘OR’ which broaden the search (accidents OR falls will include all studies with both terms) and ‘AND’ which narrow the search (accidents AND falls will select studies with both terms). In standard search strategy all terms within a key concept are combined with ‘OR’ and in-between concepts using ‘AND’.

Limits and restrictions are used in search strategy to improve precision. The common restrictions are language selections, publication date limits and format boundaries. These limits may result in missing relevant studies. It is good practice to explain the reason for restrictions in the search strategy. It is also important to be aware of errors and retractions in selected studies. Information specialists can add terms to remove such studies in the search process. The final step is piloting the search strategy. It will give an opportunity to adjust the search strategy for optimal sensitivity and precision [ 6 ].

All systematic reviews require consistent management of the search studies. It is challenging to manage a large number of studies manually. Reference management software can merge all search results, remove duplicates, record number of studies selected in each step, store methodology and selection criteria, and support exporting selected studies to analysis software. Specific platforms and software packages are extremely useful and can save time and effort in navigating the search and compiling the appropriate data. There are many software packages available for systematic review reference management, including Covidence, Abstracker, CADIMA, SUMARI and DistillerSR.

Throughout the search process, documentation is crucial. Search criteria and strategy, total number of studies in each step, searched databases and non-databases and copies of internet results are important records. In a situation where the search was more than 12 months old, it is advisable to re-run the search to minimize missing novel studies [ 2 , 6 ].

Selecting studies

All the searched studies are selected for quantitative synthesis. Numbers of studies marked in each selection process needs to be documented. The PRISMA flow maps (Fig. 3 ) can be used to report the selection process [ 7 ].

PRISMA flow diagram map for systematic review study selection process

During the selection process, it is important to minimize bias. This can be achieved by measures such as having a pre-planned written review protocol with inclusion and exclusion criteria, adding study design as an inclusion criteria and independent study selection by at least 2 researchers. Items to consider in collecting data are source, eligibility, methods, outcomes, and results. Outcomes should be based on what is important to patients, not what researchers have decided to measure. Other items of interest are bibliographic information and references of other relevant studies. The most important decisions for the entire review are whether individual studies will be included or excluded for consideration in subsequent analyses. This may be the major determinant of the final composite results of the review. It is important to resolve any discrepancies in individual judgements by reviewers as objectively as possible, always remembering that individuals may be nature by “lumpers” or "splitters”. Ref (Darwin, Charles (1 August 1857). "Letter no. 2130". Darwin Correspondence Project).

Once the items to collect are decided, data extraction forms can be used to collect data for the review. The extraction form can be set up as paper, soft copy (word, excel or pdf format) or by using a database from specific software (eg: Covidence, EPPI-Reviewer, etc). All recordable outcome measures are collected for optimal analysis. It is nearly always a problem that some included studies may not provide usable data for extraction. These challenges are managed as shown in Table 2 .

It is important to be polite and clear when contacting authors. Imputing missing data carries a risk of error and it is best to get as much possible information from relevant authors. There are different data categories used to report outcomes in research studies. Table 3 summarizes common data types with some examples [ 2 ].

Study quality and bias

The results will not represent accurate evidence when there is bias in a study. These poor-quality studies introduce bias into a systematic review. Risk of bias is decreased, and the study’s quality improved by clearcut randomization, outcome data on all participants (i.e. complete follow-up) and blinding (for both participant and outcome assessor) [ 2 , 8 ].

The Cochrane Risk of bias tool (RoB) [ 9 ] can be used to assess risk of bias in Randomized Control Trials (RCTs). However, in Non-Randomized Studies of Interventions (NRSI), tools such as The Newcastle-Ottawa Scale [ 10 ], ROBINS-I [ 11 ], The DOWNS-Black [ 12 ] can be used to assess risk of bias. Please see bias domains in RCT and NRSI in Table 4 .

Blinding and masking can minimize the bias secondary to deviation from intended interventions. Missing outcome data or attrition due to various issues such as participant withdrawal, loss to follow up and lost data are also common causes for bias in studies. Researchers use imputation to address missing data which could lead to over or underestimation of intervention effects. Sensitivity analysis can be conducted to investigate the effect of such assumptions. Selective reporting is another problem, and it is difficult to identify and sources such as clinical trial registries or published trial protocols can be used to minimize such discrepancies.

Data analysis

Analysis of data is crucial in a systematic review and important aspect of this step are described below [ 2 , 13 ].

• Effect measure

Outcome data for each selected study will be in different measures. It is important to select a comparable effect measure for all studies for the particular outcome to facilitate synthesis of overall effect measure. Common effect measures for dichotomous outcomes are risk ratios (RR), odds ratios (OR) and risk differences (absolute risk reduction - ARR). These measures are selected for the analysis based on their consistency, mathematical properties, and communication effect For DTA reviews sensitivity and specificity are commonly used.

The mean difference (MD) is the commonest effect measure of continuous outcome data. When interpreting MD, report as many details such as the size of the difference, nature of the outcome (good or bad), characteristics of the scale for better understanding of the results. However, studies in the review may not use the same scales and standardization of results may be required. The standardized mean difference (SMD) can be calculated in such situations if the same concept or measures are used. The SMD is expressed in units of Standard Deviation (SD). It is important to correct the direction of the scale before combining them. All outcome data should be reported along with a measure of uncertainty such as confidence interval (CI).

There are endpoints and changes from baseline data in studies. Endpoint scores are usually reported in standard deviations (SD) and change from baseline data present in MD. Although it is possible to combine two types of data, SMD calculations are inaccurate in such situations. It is also good practice to conduct sensitivity analyses to assess the acceptability of the choices made.

Meta analysis

There are many advantages to performing a meta-analysis. It combines samples and provides more precise quantitative answers to the study objective. Study quality, comparability of data and data formats affect the output of the meta-analysis. The acceptable steps in meta-analysis are described in Table 5 .

• Heterogeneity

Variation across studies, more than expected by chance, is called heterogeneity. Although there are several types of heterogeneity such as clinical (variations in population and interventions), methodological (differences in designs and outcomes) and statistical (variable measure of effects), statistical heterogeneity is the most important type to discuss in meta-analysis [ 2 , 14 , 15 ].

The heterogeneity assumptions affect data analysis. There are two models as described in Fig. 4 , used to assess heterogeneity. If the heterogeneity is minimal, then the Tau 2 is close to zero and weight estimates are similar from both methods. Tau is the standard deviation of true effect between studies and Tau 2 is the variance.

Heterogeneity assumption methods

There are a few tools to assess heterogeneity. These are Q test, I 2 statistics and visual inspection of forest plot. The easiest method is visual inspection of forest plot. Studies without overlap in confidence intervals are not homogenous. At the same time studies spread over null effect line, the heterogeneity is more relevant in analysis to guide the direction of the effect. The chi-squared or Q test believes all studies measure the same effect and a low p value suggests high heterogeneity. However, reliability of the Q test is low in extreme number of studies as the p value becomes less sensitive or too sensitive, thus under- or over-diagnosing heterogeneity respectively. The other tool to diagnose heterogeneity is I 2 statistic, which presents heterogeneity in a percentage value. Low values, below 30%, suggest minimal heterogeneity.

The next step is to deal with heterogeneity by exploring possible causes. Errors in data collection or analysis and true variations in population or intervention are common reasons for outlying results. These identified reasons should be presented cautiously in subgroup analysis. If no cause is identified, mention this in (GRADE approach– described later) the review as unexplained heterogeneity. In each subgroup, the heterogeneity and effect modification should be reported. It is also important to have a logical basis for each factor reported in the subgroup analysis, as too many factors may confuse readers. It is equally important to make sure there is meaningful clinical relevance in these subgroups.

Different study designs and missing data

Some studies may have more than one intervention. It is reasonable to ignore intervention arms of no interest in the review. But if all treatment arms need to be included, the control group could be divided uniformly amongst intervention arms, or all arms could be analyzed together or separately. The unit of analysis error is common in cluster randomized trial analysis, since clusters are considered as units. Similarly, correlation should be considered in crossover trials to minimize over or under weighting the study in analysis. There will be high risk of bias and heterogeneity in analyzing nonrandomized studies (NRS). However, normal effect measures can be used in relatively homogenous NRS meta-analysis.

Sometimes, missing statistics are found, and it is reasonable to calculate means and SDs from available data. Imputation of data should be done cautiously and reported in sensitive analysis.

Reporting and interpretation of results

It is important to report results in depth and not merely statistical values. The main measures used to report meta-analysis are Confidence interval (CI) and SMD [ 2 ].

The CI is the range where the true value probably sits. A narrow CI suggests more precise effects. The CI is usually presented as 95% interval (Corresponding to p value of 0.05) and rarely in 90% interval (P of 0.1). It is statistically significant when CI is away from the line of zero effect. However even statistically significant effects may not have clinical value if it does not meet minimally important change. On the other effects that are not statistically significant may still have clinical importance and raises question regarding the overall power of the meta-analysis to detect clinically important effects.

The SMD is defined above (“ Data analysis ” section) as an effect measure. The value more than zero means significant change of the intervention. However, interpretation of the size of significance is difficult in SMD as it reports units of standard deviation (SD). The Cohen’s rule of thumb (SMD <0.4 small effect, >0.7 large effect and moderate in between), transformation to OR (assuming equal SDs in both control and intervention arms) or calculating estimate MDs in a familiar scale are reasonable methods to report SMD results.

Reporting bias and certainty of evidence

The risk of missing information in a systematic review in the process from writing study protocol to publication is called reporting bias. Many factors such as author beliefs, word limitations, editorial and reviewers’ approvals can cause reporting bias. Funnel plots are a recommended statistical method to detect reporting bias in systematic reviews and meta-analysis.

Reporting the certainty of the results is another important step at the end of study analysis. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) is a recommended structured approach to report certainty of data. Table 6 describe topics used to rate up or down the certainty according to GRADE system [ 16 ]. Another important aspect of a systematic review is to categorize and present research studies based on the quality of the study.

The final rating of certainty in a meta-analysis is based on combination of all domains in each and overall studies. This information should be mentioned in the result section using numbers and explained in text in the discussion. The same system can be used in narrative synthesis of results in systematic reviews. It is important to remember rate up is only relevant for non-randomized studies and randomized studies starts with higher certainty.

Reporting the review

The last step of a systematic review or meta-analysis is report writing. Here, all parts are merged to write the review in structured format, using the protocol as the starting point. All systematic reviews should have a protocol to begin with as shown in Fig. 5 [ 2 ].

Structure for report writing

Summary of finding table

The ‘summary of finding’ table is a useful step in the writing. All the outcomes with a list of studies are recorded in this table. Then the relative / absolute effect (import from forest plots), certainty of evidence (based on GRADE) and comments are included in separate columns. Footnotes can be included for explanation of decisions. There are softwares to develop summary of tables, such as GRADEpro, which is compatible with RevMan [ 17 ].

Presenting results

The first paragraph of the results is the search process. The PRISMA flow (described in Fig. 1 ) is recommended to report the search summary [ 7 ]. The second section is the summary of risk of bias assessment for included studies. This will be only a narrative writing of significant differences, as individual study risk of bias will be presented in data tables in detail. Following this, review findings are presented in structured format.

The effects of interventions are presented in forest plots and data tables/figures. It is important to remember that this is not the section to interpret or infer results. All outcomes planned in the protocol should be reported, including the outcomes without evidence. Consistency of outcomes order should be maintained throughout the review. Present intervention vs no intervention before one vs other intervention. Primary outcomes are compared first, followed by secondary outcomes. Throughout the writing, check the reliability of results among plots, tables, figures, and texts. However, it may not be feasible to publish all plots and tables in the main document. Supplementary materials or appendices are available in journals for less important analyses.

There may be situations where selected studies are too diverse to conduct a meta-analysis. Narrative synthesis is an option in such situations to analyze results. It is easy to examine data by grouping studies in a narrative synthesis. Avoid vote counting of positive and negative studies in narrative reviews.

The first paragraph in the discussion should summarize the main (both positive and negative) findings along with certainty of evidence. The summary of the finding table can be used to identify the most important outcomes. Then describe whether the results address the study questions in the format of PICOS.

The quality of the review evidence is discussed afterwards. All domains of GRADE assessment including inconsistency, indirectness, imprecision, publication bias should be discussed in relation to the conclusions. Selection bias of studies can be included in the strengths/limitations section along with other assumptions made during the review. It is reasonable to mention agreements/disagreements with other reviews at the end in the context of past reviews.

The conclusion is the summary of review findings which guide readers to make decisions in policy making or clinical practice. It is important to mention both positive and negative salient results of the review in the conclusion. Make sure only your study findings are presented, and do not comment on outside sources. At the end of presenting results, recommendations can be mentioned to fill the gaps in evidence. The primary value of systematic reviews is to drive improvements in evidence-based practice, based on the needs of patients.

There are often other versions of the summaries from reviews presenting the major findings in plain language for the benefit of consumers and general public. It is advisable to use bullet points, and subheadings can be phrased as questions (What is the intervention? Whys it is important? What did we find? What are limitations? What is the conclusion?). It is better to write in first person active voice to directly address readers.

All types of summaries should provide consistent information to the main text. When describing uncertainty, be clear with the study limitations. As the summary is painting the study report, focus on the main results and quality of evidence.

Availability of data and materials

Not applicable.

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Iddagoda, M.T., Flicker, L. Clinical systematic reviews – a brief overview. BMC Med Res Methodol 23 , 226 (2023). https://doi.org/10.1186/s12874-023-02047-8

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Transforming Clinical Research to Meet Health Challenges

• 1 Office of the Director, National Institutes of Health, Bethesda, Maryland

The COVID-19 pandemic made “clinical trials” a household phrase, highlighting the critical value of clinical research in creating vaccines and treatments and demonstrating the need for large-scale, well-designed, and rapidly deployed clinical trials to address the public health emergency. As the largest public funder of clinical trials, the National Institutes of Health (NIH) launched a high-level effort to absorb the lessons of the pandemic and to assess and build on ongoing initiatives to improve efficiency, accountability, and transparency in clinical research.

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Wolinetz CD , Tabak LA. Transforming Clinical Research to Meet Health Challenges. JAMA. 2023;329(20):1740–1741. doi:10.1001/jama.2023.3964

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Clinical Trials and Clinical Research: A Comprehensive Review

Affiliations.

• 1 Clinical Microbiology, Prathima Institute of Medical Sciences, Karimnagar, IND.
• 2 Biochemistry, Prathima Institute of Medical Sciences, Karimnagar, IND.
• PMID: 36938261
• PMCID: PMC10023071
• DOI: 10.7759/cureus.35077

Clinical research is an alternative terminology used to describe medical research. Clinical research involves people, and it is generally carried out to evaluate the efficacy of a therapeutic drug, a medical/surgical procedure, or a device as a part of treatment and patient management. Moreover, any research that evaluates the aspects of a disease like the symptoms, risk factors, and pathophysiology, among others may be termed clinical research. However, clinical trials are those studies that assess the potential of a therapeutic drug/device in the management, control, and prevention of disease. In view of the increasing incidences of both communicable and non-communicable diseases, and especially after the effects that Coronavirus Disease-19 (COVID-19) had on public health worldwide, the emphasis on clinical research assumes extremely essential. The knowledge of clinical research will facilitate the discovery of drugs, devices, and vaccines, thereby improving preparedness during public health emergencies. Therefore, in this review, we comprehensively describe the critical elements of clinical research that include clinical trial phases, types, and designs of clinical trials, operations of trial, audit, and management, and ethical concerns.

Keywords: audit; clinical research; clinical trials; efficacy; ethical concerns; medical research; therapeutic drug.

Copyright © 2023, Kandi et al.

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• Review article
• Open access
• Published: 09 November 2023

Male contraception: narrative review of ongoing research

• Eli J. Louwagie   ORCID: orcid.org/0000-0001-8741-2240 1 ,
• Garrett F.L. Quinn 1 ,
• Kristi L. Pond 1 &
• Keith A. Hansen 2  

Basic and Clinical Andrology volume  33 , Article number:  30 ( 2023 ) Cite this article

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Metrics details

Since the release of the combined oral contraceptive pill in 1960, women have shouldered the burden of contraception and family planning. Over 60 years later, this is still the case as the only practical, effective contraceptive options available to men are condoms and vasectomy. However, there are now a variety of promising hormonal and non-hormonal male contraceptive options being studied. The purpose of this narrative review is to provide clinicians and laypeople with focused, up-to-date descriptions of novel strategies and targets for male contraception. We include a cautiously optimistic discussion of benefits and potential drawbacks, highlighting several methods in preclinical and clinical stages of development.

As of June 2023, two hormonal male contraceptive methods are undergoing phase II clinical trials for safety and efficacy. A large-scale, international phase IIb trial investigating efficacy of transdermal segesterone acetate (Nestorone) plus testosterone gel has enrolled over 460 couples with completion estimated for late 2024. A second hormonal method, dimethandrolone undecanoate, is in two clinical trials focusing on safety, pharmacodynamics, suppression of spermatogenesis and hormones; the first of these two is estimated for completion in December 2024. There are also several non-hormonal methods with strong potential in preclinical stages of development.

Conclusions

There exist several hurdles to novel male contraception. Therapeutic development takes decades of time, meticulous work, and financial investment, but with so many strong candidates it is our hope that there will soon be several safe, effective, and reversible contraceptive options available to male patients.

Depuis la sortie de la pilule contraceptive orale combinée en 1960, les femmes ont assumé le fardeau de la contraception et de la planification familiale. Plus de 60 ans plus tard, c’est toujours le cas, car les seules options contraceptives pratiques et efficaces disponibles pour les hommes sont les préservatifs et la vasectomie. Cependant, il existe maintenant une variété d’options contraceptives masculines hormonales et non hormonales prometteuses qui sont à l’étude. Le but de cette revue narrative est de fournir aux cliniciens et aux profanes des descriptions ciblées et à jour de nouvelles stratégies et cibles pour la contraception masculine. Nous incluons une discussion prudemment optimiste sur les avantages et les inconvénients potentiels, en soulignant plusieurs méthodes aux stades précliniques et cliniques du développement.

En juin 2023, deux méthodes contraceptives masculines hormonales faisaient l’objet d’essais cliniques de phase II pour leur innocuité et leur efficacité. Un essai international de phase IIb à grande échelle, portant sur l’efficacité de l’acétate de ségestérone transdermique (Nestorone) et du gel de testostérone, a recruté plus de 460 couples et devrait être achevé pour la fin de 2024. Une seconde méthode hormonale, l’undécanoate de diméthandrolone, fait l’objet de deux essais cliniques axés sur l’innocuité, la pharmacodynamique, la suppression de la spermatogenèse et des hormones; le premier de ces deux essais devrait être achevé en décembre 2024. Il existe également plusieurs méthodes non hormonales à fort potentiel aux stades précliniques de développement.

Il existe plusieurs obstacles à la nouvelle contraception masculine. Le développement thérapeutique nécessite des décennies de temps, un travail méticuleux et un investissement financier ; mais avec autant de candidats solides, nous espérons qu’il y aura bientôt plusieurs options contraceptives sûres, efficaces et réversibles, disponibles pour les hommes.

Introduction

In the wake of the Dobbs v. Jackson Women’s Health Organization 2022 decision, the resultant “trigger laws” in 13 U.S. states, and the lingering retraction of reproductive rights in many more [ 1 , 2 ], the need for novel contraceptive options has gained urgency across the United States. Unfortunately, due to a complex combination of medical challenges and societal beliefs [ 3 , 4 , 5 , 6 ], the burden of contraception has fallen almost entirely on women, and the only practical effective options available to males are condoms and vasectomy. Even with ‘perfect use’, the failure rate of condoms is still over 10% [ 7 ], and vasectomy is largely irreversible. Further, many of the contraceptive options currently available have high discontinuation rates [ 8 ], contributing to high rates of unintended pregnancy in the United States [ 9 , 10 ]. With that in mind, there is a growing demand for safe, effective, and reversible male contraception that would allow men to share the burden of family planning [ 11 , 12 ].

Male fertility is dependent on production of an adequate number of viable, motile sperm capable of moving through the female reproductive tract and fertilizing oocytes. Fertile males generally have seminal sperm concentrations greater than 15 million sperm/mL [ 13 ], and adequate sperm suppression for contraception requires sperm levels ≤ 1 million/mL [ 14 ]. The process of sperm production is termed spermatogenesis and is controlled by the hypothalamic-pituitary-testicular (HPT) axis (Fig. 1 ) [ 15 ]. Briefly, the hypothalamus produces gonadotropin-releasing hormone (GnRH) in a pulsatile fashion, which stimulates the anterior pituitary to secrete the gonadotrophic hormones luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH stimulates androgen production by testicular Leydig cells, and FSH, along with high levels of intratesticular T, enables spermatogenesis within the seminiferous tubules [ 16 ]. T exerts negative feedback on GnRH release and therefore suppresses LH and FSH secretion; the same effect is seen with exogenous androgens. Similarly, natural and synthetic progesterone, the latter termed progestins, exert negative feedback on the HPT axis to suppress LH and FSH release [ 16 ]. These concepts underlie the mechanisms of hormonal contraceptives discussed in this review, which generally target spermatogenesis, sperm motility, or transport through the vas deferens (Fig. 1 ).

Overview of the hypothalamic-pituitary-testicular (HPT) axis and targets of male contraception. The HPT axis consists of the hypothalamus, pituitary gland, and testes. The hypothalamus releases gonadotropin-releasing hormone (GnRH) in a pulsatile fashion which signals for release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary. LH and FSH drive testosterone (T) production and spermatogenesis in the testes. T and the hormonal contraceptives exert negative feedback on the hypothalamus to inhibit GnRH, LH, and FSH release, therefore suppressing spermatogenesis. Non-hormonal methods focus on distinct targets to inhibit spermatogenesis, sperm motility, or transit through the vas deferens. Pointed arrows indicate activation; red broad-tipped arrows indicate inhibition. NES/T, Nestorone/testosterone; DMAU, dimethandrolone undecanoate; 11β-MNTDC, 11β-methyl-19-nortestosterone dodecylcarbonate; RARA, retinoic acid receptor alpha; BRDT, bromodomain testis-specific protein; TSSK, testis-specific serine/threonine kinase; sAC, soluble adenylyl cyclase; CatSper, cation channel of sperm; SLO3, slowpoke homolog 3; RISUG, reversible inhibition of sperm under guidance. Figure created by EJL using BioRender.com

There are several promising male contraceptive options in development, and they can be broadly categorized as either hormonal or non-hormonal. The purpose of this review is to provide an overview of the most promising male contraceptive methods under study, including how they work, their current state in research and development, and potential side effects or barriers to marketability. We will also briefly discuss some methods in preclinical stages of development to demonstrate that men may soon have access to a variety of safe, effective, and reversible contraceptive options.

Materials and methods

For this narrative review, authors searched the online databases MEDLINE (via PubMed.gov), Cochrane Reviews, CENTRAL (via CochraneLibrary.com), ClinicalTrials.gov, and the World Health Organization’s International Clinical Trials Registry Platform for publications and ongoing clinical trials through 20 June 2023. Search terms included “contraception”, “male contraception”, “hormonal contraception”, “spermatogenesis inhibition”, “vas deferens occlusion”, and terms related to methods discussed below. Authors considered all identified ongoing studies related to male contraception, but we excluded from discussion those evaluating 7α-Methyl-19-nortestosterone (MENT) [ 17 , 18 , 19 ] or T combined with GnRH antagonists [ 20 , 21 ], estradiol [ 22 ], or progestins (medroxyprogesterone acetate [ 23 , 24 ] or norethisterone enanthate [ 25 , 26 , 27 , 28 ]) as these treatments ultimately failed to progress in clinical trials. Several past trials evaluating T injection alone [ 29 , 30 , 31 , 32 , 33 , 34 , 35 ] were also excluded as ongoing trials use T as a supplemental rather than primary compound. Authors EJL, GFLQ, and KLP completed literature search and assessed methodology of ongoing trials with particular focus on sample size ( n ), primary and secondary outcomes, and inclusion and exclusion criteria; none of the studies were excluded due to grossly unsound methodology.

Hormonal methods

Three hormonal methods show great promise in male contraception: segesterone acetate (Nestorone; NES), dimethandrolone undecanoate (DMAU), and 11β-methyl-19-nortestosterone dodecylcarbonate (11β-MNTDC). NES and DMAU are currently in phase II clinical trials, and 11β-MNTDC has completed one phase II trial. Each method will be discussed separately below, and the clinical trials investigating these three compounds are summarized in Table 1 .

Segesterone acetate + testosterone (NES/T)

Segesterone acetate, most often identified by its trade name Nestorone (NES), is a potent progestin with virtually no affinity for androgen receptors (AR) or estrogen receptors (ER) and minimal glucocorticoid activity [ 49 , 50 , 51 ]. NES shows low bioavailability when taken orally but is readily absorbed by transdermal application [ 52 ]; it has been available with ethinyl estradiol in the ANNOVERA vaginal ring (Mayne Pharma, Raleigh, NC) since 2018 and is a well-tolerated female contraceptive with > 97% efficacy [ 53 , 54 , 55 ]. NES is now compounded with T in a transdermal gel (NES/T) in a phase II clinical trial evaluating efficacy [ 36 , 37 ]. T is added to improve suppression of spermatogenesis and minimize potential symptoms of androgen deficiency [ 56 ].

Phase I trials of NES/T daily gel (approximately 8.3 mg/62.5 mg) have demonstrated gonadotropin suppression adequate to suppress spermatogenesis in nearly 90% of participants [ 38 , 39 ], suggesting that NES/T will be an effective form of male birth control [ 57 ]. Importantly, in these same studies there were no severe side effects with treatment. The main adverse effects were similar to the combined estrogen-progestin contraceptive pills used by women [ 58 ] and included minor mood symptoms, acne, and likely transient gastrointestinal symptoms [ 38 , 39 , 40 ]. From the most recent Phase I trial and a survey on attitudes towards NES/T, the majority of participants (79% and 56%, respectively) were satisfied or very satisfied with the treatments, and 50–51% reported that they would use NES/T daily gel as a sole form of contraception [ 38 , 59 ].

A phase IIb trial investigating NES/T efficacy is currently underway at 17 medical centers across 8 U.S. states and 7 other countries [ 36 , 37 ]; it is sponsored by the Population Council and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). Participants are self-administering the transdermal gel with one of two T doses (both compounded as NES/T; 8 mg/62 mg or 8 mg/74 mg), and participants showing low serum T with symptoms of hypogonadism will be offered additional T [ 37 ]. The trial is broken down into phases. There is an initial screening phase, after which participants begin daily NES/T. Within 20 weeks of beginning treatment, participants must show sperm suppression to levels ≤ 1 million sperm/mL before entering the 52-week efficacy phase. The recovery phase is intended to assess sperm production after ceasing NES/T application and continue symptom surveillance of both males and their female partners [ 37 ]. Enrollment was completed in November 2022 with 462 couples having started treatment. Completion of the primary endpoint, contraceptive efficacy, is estimated for late 2024, with full study results likely available in early 2025 [ 36 , 37 ].

Dimethandrolone undecanoate (DMAU)

DMAU is a testosterone-derived pro-drug, metabolized to active form dimethandrolone (DMA), with high affinity for AR and, to a lesser degree, progesterone receptors (PR) [ 60 ]. DMAU and DMA are not aromatized and therefore lack estrogenic effects [ 61 ], but DMAU is highly lipophilic and experiences first-pass metabolism by the liver [ 62 ], requiring study of a variety of formulations to determine the optimal delivery method. In preclinical animal studies including non-human primates, DMAU was shown to effectively, reversibly suppress gonadotropins and spermatogenesis while maintaining physiologic androgenic effects without serious side effects [ 63 , 64 , 65 ]; importantly, there were no signs of liver toxicity, a well-characterized side effect of many exogenous androgens [ 66 ]. DMAU has been studied in several clinical trials for safety, pharmacodynamics, and gonadotropin suppression to evaluate its potential in male contraception, and phase I and phase II clinical trials are currently underway.

Early human trials of DMAU evaluated safety and absorption with doses up to 800 mg. In 2014, the first clinical trial orally dosed DMAU in a powder formulation from 25 to 800 mg, fasting or following high-fat meal (50% calories as fat). With a high-fat meal, authors found considerable, dose-escalating absorption of DMAU and suppression of gonadotropins (12 h later) from 200 mg upwards [ 45 ]. In a follow-up 2017 study, authors evaluated daily DMAU absorption at doses up to 400 mg daily and effects on estrogen and T levels [ 44 ]. Similarly, they found improved absorption with high-fat meals and suppression of estrogen and T in the absence of any serious side effects [ 44 ].

In a placebo-controlled, double-blinded, randomized phase I trial, Thirumalai et al. 2019 [ 43 ] investigated safety, tolerability, and adverse events associated with oral DMAU over 28 days of treatment, as well as pharmacokinetics, pharmacodynamics, hormonal changes, and sperm counts. The study found suppression of T at even the lowest dose of DMAU and dose-dependent suppression of LH and FSH, theoretically sufficient to suppress spermatogenesis with treatment for 10 weeks [ 57 ]. No serious side effects were observed; several participants reported decreased libido or erectile dysfunction, particularly at the highest tested dose, but participants did not report this affecting their sexual or erectile satisfaction [ 43 ]. Of note, DMAU was taken after a meal containing 25–30 g of fat, reflecting a typical Western diet but approximately half the fat content of the Ayoub et al. 2017 study [ 44 ]. In a secondary analysis of this trial’s samples and data, Thirumalai et al. 2021 found dose-dependent suppression of T and estrogen as well as an increase in a marker for bone formation over 28 days [ 67 ]. In another secondary analysis comparing metabolic effects of DMAU and 11β-MNTDC (discussed below), Yuen et al. 2021 found that DMAU caused a mean weight gain of 1.2 or 2.0 kg with 200 or 400 mg daily dosing, respectively, and mild lipid changes, but there were no serious adverse effects or signs of overt insulin resistance [ 46 ]. Collectively, these analyses indicate that orally dosed DMAU is well-tolerated and shows promise as a male contraceptive.

Today, there are two ongoing trials with DMAU, run by Drs. Christina Wang, MD, out of the University of California Los Angeles and Stephanie Page, MD, PhD, out of the University of Washington [ 41 , 42 ]. Per ClinicalTrials.gov, both are reportedly still recruiting. The first is a phase I trial comparing a single injection of intramuscular (80-800 mg) vs. subcutaneous (50-200 mg) DMAU and is primarily assessing safety, pharmacodynamics, and hormonal suppression in healthy males [ 41 ]. Completion is estimated for December 2024. The second is a phase II trial primarily investigating the ability of orally dosed DMAU with or without a low dose of levonorgestrel (a progestin) to suppress spermatogenesis after 12 weeks treatment; secondary outcomes include hormonal suppression, serious adverse events, systemic symptoms, and tolerability [ 42 ]. Ideally, these ongoing studies will shed further light on the optimal route and dose of DMAU administration to guide efficacy trials.

11β-methyl-19-nortestosterone dodecylcarbonate (11β-MNTDC)

11β-MNTDC is a testosterone derivative active at both AR and PR; it does not undergo aromatization and therefore lacks estrogenic effects [ 48 , 61 , 65 ]. Like DMAU, 11β-MNTDC is a pro-drug and is converted to 11β-methyl-19-nortestosterone (11β-MNT), which is structurally similar to DMA [ 68 ]. However, 11β-MNT’s affinity for AR and PR is more balanced than that of DMA (which favors AR), so side effect profiles may vary [ 48 ]. In preclinical animal studies, 11β-MNTDC was shown to effectively suppress serum gonadotropins [ 65 ] and exert even less liver toxicity than other androgens, including DMAU [ 63 ].

Several clinical trials have investigated 11β-MNTDC. The first major human trial was directed by Drs. Wang and Page and published in 2019 [ 48 ]. Twelve healthy adult males were given a single oral dose of 100-800 mg 11β-MNTDC with a high-fat meal or fasting, then assessed for pharmacokinetics, adverse effects, serum gonadotropins, and T levels. Like DMAU, 11β-MNTDC absorption was improved with high-fat meal, treatment was overall well-tolerated, and T was suppressed in a dose-dependent manner from 200 mg upwards [ 48 ]. Gonadotropin levels were not significantly reduced with a single dose, but this was addressed in a follow-up study published in 2020 [ 47 ]. This randomized, placebo-controlled phase II trial was again directed by Drs. Wang and Page, and participants received a daily oral dose of 200 or 400 mg 11β-MNTDC for 28 consecutive days. 11β-MNTDC was taken after a meal containing 25–30 g of fat [ 47 ], a more typical fat content per meal than in the previous trial [ 48 ]. Ultimately, 11β-MNTDC was well-tolerated; participants reported no serious adverse events, no one discontinued the trial due to side effects, and all reported side effects were mild or moderate. The most common sides effects were headache, acne, and decreased libido in 16% of participants [ 47 ]. Mood symptoms were reported, but they were comparable to those seen with currently available female estrogen-containing contraceptives [ 69 , 70 , 71 ]. 11β-MNTDC caused dose-dependent suppression of LH and FSH, and more participants in the 400 mg group had suppression to LH and FSH levels < 1.0 IU/L, the threshold at which spermatogenesis will be suppressed in nearly 90% of participants [ 57 ].

Efficacy trials are still needed for 11β-MNTDC, but between the two clinical trials and a secondary analysis comparing metabolic effects of DMAU and 11β-MNTDC (DMAU discussed above), 11β-MNTDC demonstrated acceptable safety profiles. Levels of T, estradiol, and sex hormone binding globulin (SHBG) were all suppressed, but these changes did not correlate with side effects or changes in serum chemistries [ 46 , 47 , 48 ]. 11β-MNTDC slightly increased participant weight and serum low-density lipoprotein (LDL) cholesterol levels, but there were no serious adverse events or signs of overt insulin resistance [ 46 ]. Results-to-date warrant clinical trials evaluating efficacy and safety using a larger number of participants.

Non-hormonal methods

Several non-hormonal methods show promise in the field of male contraception, and two are either near human study or recently began human trials. In theory, these methods lack hormonal side effects, such as acne or mood symptoms, as well as the societal stigmas and false beliefs associated with hormonal contraception in the United States [ 6 , 72 ]. The non-hormonal methods showing the most potential or closest to market, particularly those that inhibit spermatogenesis, motility, or vas deferens passage, will be discussed in greatest depth.

• Spermatogenesis

All-trans retinoic acid (RA), also known as tretinoin, is derived from vitamin A and plays global roles in cell growth and development. RA plays essential roles in spermatogenesis and acts through binding the retinoic acid receptor alpha (RARA) located in the testes [ 73 , 74 ]. The first human trial targeting RARA was conducted over 60 years ago with the non-selective RA biosynthesis inhibitor WIN 18,446 [ 75 ]. Sixty men were treated for one year, and spermatogenesis was suppressed in all participants throughout. However, off-target effects including inhibition of aldehyde dehydrogenase 2 in the liver unfortunately lead to a severe disulfiram-like reaction, effectively making the drug unmarketable [ 75 ]. Since then, the pharmaceutical company Bristol-Myers Squibb (BMS) designed and, with other labs, demonstrated effective, reversible suppression of spermatogenesis in mice with the pan-antagonist BMS-189,453 [ 76 , 77 , 78 ]. Theoretically, reversible alpha-selective agents would effectively and safely suppress sperm production without the systemic side effects of pan-antagonists. In other words, this would be an ideal method of contraception. Early attempts, most notably BMS-189,532 and BMS-189,614, lacked the efficacy of the pan-antagonist (WIN 18,446) by oral, intravenous, or intraperitoneal routes [ 79 ], but RARA remains a strong potential target for male contraception.

Bromodomains are amino acid segments in proteins that facilitate specific protein-protein interactions and a wide variety of cellular functions [ 80 , 81 ]. One of these bromodomains, bromodomain testis-specific protein (BRDT), is required for spermatogenesis, and males with BRDT gene mutations are infertile with abnormal sperm morphology and impaired motility [ 82 , 83 ]. Like RARA inhibition, specific inhibition of BRDT would theoretically suppress sperm production without the systemic effects of pan-inhibitors or hormonal methods. Indeed, inhibition of BRDT has been shown to effectively suppress spermatogenesis in male rodents using the small molecule JQ1 [ 84 ]. In this study, JQ1 was safe, reversible, and lacked obvious transgenerational effects, but authors noted potential off-target binding that could be reduced or prevented through design of more specific molecular inhibitors [ 84 ]. Progress has been made in the search for more specific BRDT inhibitors [ 85 , 86 , 87 , 88 ], but the compounds have yet to be tested in vivo and are therefore far from human trials.

Males express distinct testis-specific serine/threonine kinases (TSSK) that play spermatogenic roles in spermatids [ 89 ]. Mice with TSSK1 and TSSK2, TSSK3, or TSSK 6 deletions and human males with TSSK2 mutations are infertile, suggesting potential non-hormonal targets for contraception [ 90 , 91 , 92 , 93 ]. Of these, research into TSSK2 has shown the most progress. Since generation of enzymatically active, isolated TSSK2 [ 94 ], several inhibitors have demonstrated potent in vitro inhibition of TSSK2 [ 95 ]. To our knowledge, these inhibitors have yet to undergo in vivo study.

In order to reach and fertilize oocytes, sperm must travel through the female reproductive tract. This quality is termed motility , and immotile sperm are a major contributor to male-factor infertility [ 96 ]. Theoretically, by targeting enzymes or receptors that play essential roles in motility and are present only in sperm, one may reversibly immobilize sperm without systemic side effects. Eppin is an enzyme made in the testes that binds to the surface of sperm to play essential roles in motility [ 97 ]. Both immunization against eppin and molecular inhibition using the inhibitor EP055 has been shown to significantly, transiently reduce sperm motility [ 98 , 99 ]. Although these studies were both done with small sample sizes and much work is needed before eppin inhibition may see clinical trials, no severe side effects were noted in these animal studies, suggesting that eppin may hold promise as a non-hormonal target [ 100 ].

In a similar vein as eppin, soluble adenylyl cyclase (sAC) is an intracellular signaling molecule needed for sperm capacitation, motility, and acrosome formation [ 101 , 102 , 103 ]. Several compounds have been tested in preclinical in vitro studies and shown to effectively inhibit sAC in mouse and human sperm [ 101 , 104 ]. Indeed, sAC inhibition stands as a strong candidate for male contraception, and two recent studies have been conducted by Drs. Lonny Levin, PhD, and Jochen Buck, MD, PhD, out of Weill Cornell Medicine.

The first study by the Levin-Buck lab intricately compared capacitation and motility of sperm from sAC null mice and from healthy, wild type mice [ 105 ]. In vitro, they demonstrated that sAC plays essential roles in capacitation. In vivo, sAC null mice mated similarly to wild type mice, but their sperm were unable to migrate through the female reproductive tract. Essentially, these sperm were immotile [ 105 ]. Improving on the inhibitors mentioned above [ 102 ], a recent, well-designed study by the Levin-Buck lab investigated the new compound TDI-11,861; they demonstrated that a single oral or intraperitoneal dose of TDI-11,861 acutely inhibits sAC in mice, impairing capacitation and motility [ 103 ]. Importantly, the mice in this study had no changes in behavior, no obvious toxicity, and no pregnancies when treated within 2.5 h of mating [ 103 ]. With completion of this proof-of-concept study, authors anticipate additional safety and transgenerational studies to follow.

Calcium plays several signaling roles in sperm, including modulation of motility through activating sAC [ 96 ]. Extracellular calcium enters sperm flagella, the organelle that propels sperm, primarily through the cell type-specific cation channel of sperm (CatSper) [ 106 ]. Studies nearly 15 years ago demonstrated that immunologic inhibition of CatSper significantly suppresses sperm motility [ 107 ]; since, several compounds (RU1968 and HC-056456) have demonstrated effective inhibition of CatSper in vitro [ 108 , 109 ] and preliminarily in vivo [ 110 ]. Several new compounds have been identified, synthesized, and tested on human sperm in vitro with excellent efficacy and safety profiles, at least on a cellular level [ 111 ]. Additional in vivo animal studies are anticipated.

Slowpoke homolog 3 (SLO3) is the main potassium channel in sperm and has functions directly related to calcium signaling and the CatSper channel [ 112 , 113 ]. Like CatSper, SLO3 is specific to sperm and has functions essential for male fertility, making it an ideal target for male contraception [ 114 , 115 , 116 ]. A highly specific inhibitor of SLO3, VU0546110, has been identified and shown in vitro to inhibit sperm motility and acrosome reactions [ 117 ]. Better yet, at least one compound (termed “7 a” by Carlson et al. 2022) has been identified that blocks both SLO3 and CatSper, indicating potential for synergistic inhibition of sperm motility [ 111 ].

Vas deferens occlusion

The final target we wish readers to know about is physical obstruction of the vas deferens, termed ‘vas occlusion’, via gel injection to physically disrupt sperm during passage through the vas deferens. The benefits of this approach include fast installation (i.e. a quick injection at an outpatient visit) and relatively fast onset of action. A major barrier has been reversibility, but once overcome this approach may hold strong potential in male contraception. Several distinct polymers have been studied, including two styrene compounds termed “reversible inhibition of sperm under guidance” (RISUG) in India [ 118 , 119 , 120 ] and Valsalgel in the United States [ 121 , 122 , 123 ], and silicone and polyurethane compounds in the People’s Republic of China [ 124 , 125 ]. The most recent trial of RISUG showed high contraceptive efficacy and a favorable safety profile [ 120 ], but human trials demonstrating reversibility of RISUG are needed. Despite these setbacks, one newer compound is being investigated in an ongoing clinical trial [ 126 ]. This new compound is a proprietary hydrogel, named ADAM by its founding company, Contraline Inc. of Charlottesville, Virginia. The trial started enrolling in late 2022 with a planned 25 total male participants through June 2025; ADAM injections will be done at the Epworth Freemasons Hospital in Melbourne, Australia. The primary outcome is adverse events, and secondary outcomes include percentage of participants achieving azoospermia and any serious adverse events [ 126 ].

Limitations of the study

This review is subject to several limitations. The clinical trials discussed above are ongoing, and results have yet to be peer-reviewed and published. This does not yet allow for data-driven conclusions. Although this narrative review focuses on the most recent and ongoing studies of male contraception, authors recognize that it is not comprehensive. As mentioned above in Materials and Methods, several compounds were excluded because they failed to progress to human trials, failed after reaching human trials, or are in early preclinical stages. For these, we advise readers to explore several well-written reviews by Thirumalai and Amory [ 127 ], Long et al. [ 128 ], or the University of California San Diego urology department [ 129 ] that include many of these discontinued approaches.

It is long overdue that male partners share the burden of family planning, and it is the authors’ hope that this will soon be a possibility. Ultimately, we feel that two of the methods discussed above—NES/T and DMAU—show the greatest potential for male contraception in the next decade. However, as clinical trials range from early planning stages to data collection stages, it may be several years before we see the efficacy and safety data needed to apply for FDA approval. In particular, the ongoing phase IIb NES/T trial results will not be published before 2025, and this is the method farthest along ‘the pipeline.’

Despite their many theoretical advantages to hormonal contraception, the non-hormonal targets are further from practical application. Authors recognize that there are many obstacles to reaching human studies, let alone late-stage clinical trials. Clinical trials require years of time, meticulous study, and financial support, and many compounds that perform well in pre-clinical animal studies fall short in human trials. The tools needed to efficiently design and study these non-hormonal targets are relatively young. However, they are already being employed to design and test strong drug candidates. As a society we now possess not only the scientific knowledge, technology, and clinical infrastructure needed to overcome these challenges, but also the social drive. With so many strong candidates, it is our hope that there will soon be several safe, effective, and reversible contraceptive options available to male patients.

Availability of data and materials

Not applicable.

Abbreviations

11β-methyl-19-nortestosterone

11β-methyl-19-nortestosterone dodecylcarbonate

Androgen receptor

Bristol-Myers Squibb

Bromodomain testis-specific protein

Cation channel of sperm

Dimethandrolone

Dimethandrolone undecanoate

Follicle-stimulating hormone

Gonadotropin-releasing hormone

Hypothalamic-pituitary-testicular

Intramuscular

Low-density lipoprotein

Luteinizing hormone

Levonorgestrel

7α-Methyl-19-nortestosterone

Nestorone/testosterone transdermal gel

Eunice Kennedy Shriver National Institute of Child Health and Human Development

Progesterone receptor

All-trans retinoic acid

Retinoic acid receptor alpha

Randomized controlled trial

Soluble adenylyl cyclase

Subcutaneous

Sex hormone binding globulin

Slowpoke homolog 3

Testosterone

Testis-specific serine/threonine kinase

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This manuscript was supported by the University of South Dakota Sanford School of Medicine Department of Obstetrics and Gynecology.

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Louwagie, E.J., Quinn, G.F., Pond, K.L. et al. Male contraception: narrative review of ongoing research. Basic Clin. Androl. 33 , 30 (2023). https://doi.org/10.1186/s12610-023-00204-z

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Acute care models for older people living with frailty: a systematic review and taxonomy

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The need to improve the acute care pathway to meet the care needs of older people living with frailty is a strategic priority for many healthcare systems. The optimal care model for this patient group is unclear.

A systematic review was conducted to derive a taxonomy of acute care models for older people with acute medical illness and describe the outcomes used to assess their effectiveness. Care models providing time-limited episodes of care (up to 14 days) within 48 h of presentation to patients over the age of 65 with acute medical illness were included. Care models based in hospital and community settings were eligible.

Searches were undertaken in Medline, Embase, CINAHL and Cochrane databases. Interventions were described and classified in detail using a modified version of the TIDIeR checklist for complex interventions. Outcomes were described and classified using the Core Outcome Measures in Effectiveness Trials (COMET) taxonomy. Risk of bias was assessed using RoB2 and ROBINS-I.

The inclusion criteria were met by 103 articles. Four classes of acute care model were identified, acute-bed based care, hospital at home, emergency department in-reach and care home models. The field is dominated by small single centre randomised and non-randomised studies. Most studies were judged to be at risk of bias. A range of outcome measures were reported with little consistency between studies. Evidence of effectiveness was limited.

Acute care models for older people living with frailty are heterogenous. The clinical effectiveness of these models cannot be conclusively established from the available evidence.

Trial registration

PROSPERO registration (CRD42021279131).

Peer Review reports

Introduction

Population ageing and the increasing prevalence of long-term health conditions represent a significant challenge to many advanced health care systems [ 1 ]. Older people, particularly those living with frailty and multimorbidity, are at high risk of sudden health crisis necessitating urgent assessment to identify and treat causative conditions. The acute care pathway collectively defines the clinical processes employed to achieve this function. It typically comprises sequential assessment in community and hospital settings and culminates in emergency hospital admission when necessary.

Older people living with frailty are at high risk of adverse outcomes such as mortality [ 2 ] and have longer average lengths of hospital stay when accessing the acute care pathway [ 3 ]. The conversion rate from ED attendance to emergency admission is 3 times higher in people aged over 85 relative to people under 65 [ 4 ]. As older people represent a growing proportion of ED attendances the demand for hospital bed-based care is likely to rise [ 4 ]. This must be reconciled with downward trends in the number of acute hospital beds at the population level [ 5 ]. Improved integration between health and social care may help mitigate the impact of these changes to some degree but will not abrogate the need for hospital assessment and inpatient bed-based care in the context of sudden deterioration or severe illness [ 6 ]. Adaptations to the acute care pathway may improve the quality of care for older people while simultaneously reducing pressure on an increasingly congested acute care system.

These factors have collectively driven a rapid expansion of studies investigating models of care intended to mitigate the risk of hospital admission or avoid bed-based hospital care entirely [ 7 ]. Previous systematic reviews of acute care models for older people have focused on interventions located at specific points along the acute care pathway [ 8 , 9 , 10 ]. There has been a tendency to group interventions with different eligibility criteria and clinical processes. Differentiating models of care able to manage acute illness from those primarily engaged with rehabilitation and the functional consequence of resolving acute illness is not straightforward. This distinction is important as policy makers and commissioners look to maximise the efficiency of acute hospital bed use and find credible alternatives to acute inpatient care in the community.

It is possible that a more granular classification of the interventions may foster a greater understanding of which elements of the model drive effectiveness and highlight areas of best practice.

A systematic review was undertaken to describe and classify the range of acute care models designed to manage acute medical illness in older people with the objective of deriving a taxonomy of care models. The review also aimed to describe and classify the outcome measures used in studies investigating these models. A secondary objective was to determine whether the proposed taxonomy was useful in understanding any differences in observed outcomes between studies. We took the novel approach of including acute care models operating in hospital and community settings.

Study design

The systematic review was conducted using a two-step process. The first step was undertaken to describe and classify acute care models for older people and the outcome measures used to demonstrate their clinical effectiveness within the current literature. This information was used to create a taxonomy of care models accompanied by a narrative summary. No restrictions were placed on study design at this stage of the process.

The second step looked to describe the effectiveness of each model and restricted analysis to randomised controlled trials or observational studies with an experimental design (including non-randomised trials, cohort studies with comparator groups, before and after longitudinal studies). Previous systematic reviews and meta-analyses were not used to inform the taxonomy. Primary studies from relevant systematic reviews were included if they met the inclusion criteria. The systematic review was undertaken in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. The study protocol was registered with PROSPERO (CRD42021279131).

Eligibility criteria and study selection

Inclusion and exclusion criteria were designed to incorporate interventions operating within the hospital and the community. An age threshold of 65 years was used to define care models for older people (mean age of study participants > 65 years. Mean age as opposed to a strict age threshold was employed to ensure care models accepting younger patients with frailty identified using alternative measures, such as validated frailty scores or multi-morbidity were not excluded.

The intervention needed to target acute medical illness or acute exacerbation of chronic disease. There is no consensus definition of acute care. To ensure a focus on acute care, study participants needed to be recruited within 48 h of presentation and the care model had to provide time limited episodes of care (up to 14 days). The requirement for time limited episodes of care was used as a criterion to exclude care models delivering ongoing chronic disease management after resolution of acute illness which were felt likely to employ different care processes and focus on different clinical outcomes. Recruitment direct from the ED was used as a proxy for recruitment within 48 h in studies where this metric was not reported. Community interventions were only included if they were able to provide a credible alternative to hospital bed-based care. This was defined as the capability to provide face-to-face review alongside access to hospital level treatments (eg intravenous treatments) and hospital level diagnostics (eg blood tests, imaging) at home.

A full list of inclusion and exclusion criteria is provided in Table 1 .

Data sources and searches

The search strategy comprised both MeSH terms and keyword text and was performed on 30 th September 2021 with no date restrictions. The search strategy is provided in Supplementary Table 1 . The search was undertaken in 5 electronic databases (Ovid MEDLINE, Ovid Embase, Cumulative Index to Nursing and Allied Health Literature, Cochrane Database of systematic reviews, Cochrane Central Register of Controlled Trials). Hand reference list screening was carried out of all included articles. Systematic reviews were not included directly. All individual studies meeting the inclusion criteria contained within systematic reviews identified by the search were included.

Titles and abstracts were reviewed by two reviewers. (TK reviewed each and at-least one further review from CA, VK, CG, JR). Full-text records were obtained and reviewed against the eligibility criteria. Disagreements were resolved by a third reviewer (DL). Data extraction was undertaken by 1 reviewer (TK). A bespoke data extraction tool was adapted from the TIDIeR checklist to characterise each intervention [ 11 ]. Outcome measurements were classified using the Core Outcome Measures in Effectiveness Trials (COMET) taxonomy [ 12 ].

Data extraction and quality assessment

Risk of bias was assessed using criteria from the Cochrane Handbook. Randomised controlled trials were assessed using RoB-2 tool [ 13 ] and observational studies were assessed using the ROBINS-I tool [ 14 ]. Risk of bias was assessed by 1 reviewer (TK).

Data synthesis

Finding from included articles were grouped and summarised. Due to clinical heterogeneity between studies meta-analysis was not appropriate. A narrative synthesis of the results was undertaken. Visualisations were created using R statistical software (Version 1.3.1093, Vienna. Austria). The geographical location of included studies was mapped using the ggmap package. Source maps were obtained from © Stamen Design, under a Creative Commons Attribution (CC BY 3.0) license. Outcome areas and domains were plotted using the treemap package.

The initial search returned 13,102 relevant articles. Title and abstract screening identified 340 relevant articles for full text review. A total of 90 articles met the eligibility criteria. Hand searching of references identified 13 further articles. Therefore, 103 articles were included in the analysis (see Fig.  1 ). Identified articles were published between April 1991 and April 2021. This comprised 20 randomised controlled trials reported across 26 articles), 6 study protocols (results for 2 had been reported and were included), 38 observational studies with a comparator group reported across 51 articles, and 20 descriptive studies without a comparator group. The search identified 101 conference abstracts which did not contain sufficient information to adequately describe the model of care delivered. These abstracts were not used to inform the taxonomy.

A PRISMA flow diagram for the studies screened and included in the systematic review. Legend: Studies were screened against the inclusion and exclusion criteria described in Table 1 . Reasons for exclusion are provided

The articles could be broadly categorised into four groups based on the model of care they described. These included: bedded acute frailty units (AFU), Hospital at Home models (HaH), ED based in-reach models and acute care home models, see Fig.  2 . A detailed description of the interventions described in each individual study is provided in Supplementary Table 2 . The geographical location of included studies is provided in Fig.  3 .

The Proposed taxonomy of acute care models for older people. Legend: The taxonomy was defined using key features of the care models; Care models were initially differentiated based on location. Acute bedded frailty units operated from a fixed bed base or offering consultation to general medical wards. Hospital at home models were differentiated based on their use of telemedicine. Physician intensive models used face to face review at home as standard. Remote oversight models were primarily delivered by specialist nurses with care supported provided remotely by physicians on a selective basis. Emergency Department in reach models could be differentiated by their staffing model. Nurse led care coordination without direct input from a dedicated geriatrician or care delivered by geriatricians within the Emergency Department. Care home models were differentiated by their primary location of activity, either services offered within the care home or adaptations to the care pathway following transfer to the Emergency Department

A map identifying the countries where the included studies were based. Legend. The map shows the location of included studies identifying: Colours to denote the care model type as defined by the taxonomy. Brown dots represent Hospital at Home models, Violet dots represents bedded Acute Frailty Units. Purple dots Emergency Department in-reach models. Green dots care models. Source maps were obtained from © Stamen Design, under a Creative Commons Attribution (CC BY 3.0) license

Bedded acute frailty units models

The provision of tailored bed-based in-patient care for frail adults as a direct alternative to treatment on a general medical ward was described in 32 articles derived from 24 studies. This included 8 articles [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ] reporting results from 6 randomised controlled trials, 1 trial protocol without results [ 23 ], 11 observational studies with a comparator group reported across 15 articles [ 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ] and 8 descriptive studies without a comparator [ 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ]. A detailed description of the care models is provided in Supplementary Table 2 A.

The AFU care model has a strong focus on maintaining and restoring function, but in contrast to a rehabilitation ward intervenes prior to full resolution of acute illness. A range of names were used to identify care models with similar underlying approaches, including Acute Frailty units (AFU), Acute Care for Elders (ACE) units and CGA units. Generic descriptions of the model frequently reference four core components, patient centred care, specifically designed environments, review of medical care and early discharge planning as key characteristics of the model. There was considerable variation in how these shared high-level objectives were operationalised within individual care models.

Treatment was delivered within a geographically distinct bedded unit in 20 studies [ 15 , 16 , 17 , 18 , 19 , 21 , 22 , 23 , 24 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 34 , 35 , 38 , 39 , 42 , 44 , 45 , 46 ], of which 7 specifically reported adaptations to optimise the environment for older people [ 15 , 17 , 18 , 23 , 24 , 39 , 41 ]. The mean number of beds in each unit was 18 (SD 8). The number of beds was not reported in 3 studies [ 25 , 41 , 46 ]. A mobile model providing specialist consultations to patients within general medical bed was described in 3 studies [ 20 , 33 , 36 ] (and an integrated service with variable bed capacity operating within an acute medical unit in 1 study [ 45 ].

Eligibility criteria were heterogenous. Age criteria were reported in studies describing 20 care models [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 35 , 36 , 37 , 38 , 39 , 41 , 42 , 44 , 45 ]. Descriptions of the process of patient referral and how eligibility criteria were implemented in practice were uncommon. The presence of additional criteria such as functional impairment or specific geriatric conditions were frequently reported, but it was not possible to establish how these criteria were operationalised. The use of validated frailty assessment tools to define eligible patients were reported in 1 study (reported across 5 articles) [ 26 , 28 , 29 , 30 , 31 ]. Patients from residential care homes were excluded in 2 studies [ 18 , 21 ]. Bed availability was cited as a common determinant of receiving treatment on the AFU.

Hospital at home models

Hospital at home (HaH) models describe the provision of acute medical care within a person’s usual place of residence. The care model aims to replicate acute bed-based care and operate under the assumption that care would be delivered in an acute hospital setting if the model were absent. HaH models were described in 37 articles derived from 27 studies. This included 16 articles [ 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 ] reporting results from 12 randomised controlled, 2 protocols (of which 1 had reported results and was included) [ 63 , 64 ], 9 observational studies with a comparator group reported across 15 articles [ 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 ] and 4 descriptive studies without a comparator group [ 79 , 80 , 81 , 82 ]. A detailed description of the care models is provided in Supplementary Table 2 B.

There was significant clinical heterogeneity between included HaH models. The model accommodated patients with unselected acute medical illness in 31 studies and specific disease groups in 7 studies (decompensated heart failure = 3 [ 57 , 58 , 62 ], COPD = 4 [ 47 , 51 , 52 , 70 , 79 ]).

Eligibility criteria to define suitability for HaH care were heterogenous. All included studies made the intention to act as an alternative to hospital bed-based care explicit. Clinical discretion exercised by the HaH team was the arbiter of the appropriateness and safety of HaH care in all the identified studies. No standardised approach to assessment was identified and it was not possible to reliably determine the acuity of included patients from the reported data. The majority of HaH studies specifically targeted adults over the age of 65. In models open to adults of all ages, the mean age of participants was over 65 in all cases. Care home residents were excluded in 9 studies [ 53 , 58 , 59 , 63 , 67 , 73 , 74 , 75 , 80 ].

Care was led by a geriatrician in 6 studies, [ 47 , 59 , 61 , 62 , 73 , 78 ] by a general internal medicine physician in 29 studies and a primary care physician in 2 studies [ 60 , 83 ]. The intensity of physician and nursing involvement varied substantially. Physician involvement ranged from multiple daily physical home visits to remote oversight without direct physical assessment. Specific out-of-hours arrangements were reported in 12 studies reported across 19 articles [ 47 , 53 , 54 , 55 , 61 , 62 , 65 , 67 , 68 , 69 , 71 , 72 , 74 , 75 , 76 , 77 , 81 , 82 , 83 ]. The use of telemedicine was described in 5 studies reported across 11 articles [ 47 , 65 , 66 , 68 , 69 , 71 , 72 , 74 , 75 , 76 , 77 ]. Reporting of the study intervention was often restricted to a description of standardised operating procedure. The frequency of assessment achieved in practice was reported in 6 studies [ 52 , 53 , 58 , 74 , 75 , 81 ] and the proportion of patients receiving specific treatments was reported in 3 studies [ 47 , 53 , 80 ].

ED in-reach models

ED in-reach models aim to optimise processes of care for older people in the ED. The care models typically provide care coordination and elements of CGA to reduce the likelihood of admission to acute-bed based care. ED in-reach models were described in 28 studies describing 27 care models. This included 2 randomised controlled trials, [ 84 , 85 ] 1 randomised controlled trial protocol without results [ 86 ], 12 observational studies with a comparator group [ 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 ] and 13 descriptive studies without a comparator group [ 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 ]. A detailed description of the care models is provided in Supplementary Table 2 C.

Two distinct approaches to the operational design of services were evident. One approach, described in 11 studies, involved the use of bedded areas located within ED clinical decision units (alternatively referred to as ED short stay units) to provide elements of CGA to older patients who required additional assessment and investigation before a decision regarding acute medical admission could be reached [ 87 , 89 , 90 , 91 , 94 , 96 , 104 , 105 , 107 , 109 , 111 ].

An alternative approach, described in 20 studies, involved the provision of elements of CGA directly within the ED. CGA was undertaken by a geriatrician in 10 care models [ 84 , 88 , 97 , 100 , 101 , 102 , 103 , 108 , 110 ] and by specially trained nurses in 7 care models [ 85 , 86 , 92 , 93 , 95 , 98 , 99 , 106 ]. Studies of this care model frequently cited a reduction in the number of avoidable medical admissions as the primary motivation for the service. The distinction between avoidable and unavoidable admissions was poorly defined.

Eligibility criteria were heterogenous. Age criteria were reported in 13 care models [ 84 , 88 , 91 , 93 , 94 , 95 , 98 , 99 , 102 , 103 , 104 , 106 , 108 , 112 ]. The use of validated frailty assessment tools to define eligible patients were reported in 5 care models [ 84 , 86 , 92 , 99 , 106 ]. Care home residents were excluded in 3 studies [ 86 , 91 , 94 ]. Eligibility criteria were not reported in 5 studies [ 87 , 89 , 91 , 109 , 110 ]. A variety of approaches were adopted to identifying potentially eligible patients in the ED. Screening of all patients attending the ED was reported in 3 studies [ 84 , 88 , 93 ]. The service was accessed by a referral from the ED team in 11 care models [ 89 , 90 , 92 , 95 , 98 , 99 , 100 , 101 , 104 , 109 , 110 ]. The process of referral and patient selection were not consistently reported.

Acute care home models

Models targeting care home residents were reported in 5 studies. All 5 studies had an observational design [ 113 , 114 , 115 , 116 , 117 ]. Two categories of intervention were described. The first involved the presence of dedicated staff trained in acute care present with the care home [ 113 , 117 ]. These staff had the ability to deliver acute interventions in the care home. Privileged access was given to the on-call ED physician in both models (augmented by telemedicine in one study) [ 117 ]. The process which triggered assessment by the on-site team were not defined. A detailed description of the care models is provided in Supplementary Table 2 D.

An alternative model involved a hospital-based team providing out-reach to care homes and early assessment of care home resident presenting to ED. Both care models in this category also had the capability to provide ongoing acute care in the care home when required. This was achieved by a geriatrician-led team with the option to provide daily visits in one model [ 116 ] and a specialist ED nursing team in the other [ 114 , 115 ].

Outcome measurements

Outcomes were classified using the COMET taxonomy. Outcomes were reported across 6 core areas and 15 domains. Mortality was reported (in isolation or as part of a composite outcome) in 35 studies, the reporting time horizon ranged from in-hospital mortality to 1 year. Life impact was reported 27 studies, this included measurement of physical function in 21 studies and cognitive function in 6 studies. The tools used to measure physical function and the time horizons of assessment varied.

Resource use was the most reported core outcome measure. Studies frequently described multiple outcome domains related to resource use. The average length of stay was reported in 34 studies and re-admission rate in 39 studies. Readmission rates were reported over a range of time horizons 30 days to 1 year. Care home admission were reported (in isolation of as part of a composite outcome) in 14 studies over a time horizon of 30 days to 6 months. Economic analysis was reported in 19 studies. Adverse events were reported in 22 studies. A detailed summary of the outcome domains, methods of measurement and associated time horizons is provided in Supplementary Table 3 .

The relative frequency with which the outcome domains were reported across all studies is provided in Fig.  4 A and stratified by care model in Fig.  4 B. Outcomes reported by bedded AFU and HaH were broadly similar, although AFU more commonly reported outcomes related to physical function. Economic analysis was less prevalent in studies investigating ED in-reach models. A focus on aspects of care delivery, such as disposition from the ED and analysis of clinical processes relevant to the quality and adequacy of intervention were more common in studies evaluating ED in-reach.

Tree diagrams: A tree diagrams representing the relative proportion of outcomes reported in all studies. B Tree diagrams representing the relative proportion of studies by study group. Legend. * Treemap representing hierarchical outcome data using nested rectangles. Large rectangle represent core outcome areas, smaller rectangular tiles within each core outcome area represent outcome domains. Each rectangle has an area proportional to the frequency reported within included studies. All studies n  = 103, Bedded acute frailty unit n  = 32, Hospital at Home n  = 38, ED in reach models n  = 28, Care home n  = 5

Effectiveness

Clinical heterogeneity amongst the care models identified and disparity in the outcomes measured used to evaluate the care models precluded meta-analysis. Risk of bias was assessed for each study. Aggregated results of the domain-based risk of bias assessment tools are provided in Fig.  5 and the results of individual study assessments are provided in Supplementary Table 4 .

Summary of bias assessments. A Summary of randomised controlled studies using RoB2 tool. B Summary of non-randomised studies using ROBINS-I tool

The nature of the intervention precluded blinding of participants or personnel to group allocation in all included randomised controlled trials. Partial blinding of outcome assessment was reported in one study investigating the effectiveness of bedded AFUs [ 17 ] and assessment was unblinded in the remainder. Blinding during outcome assessment was reported in 4 randomised controlled trials investigating HaH [ 47 , 52 , 59 , 60 ]. Outcome assessment was unblinded in both randomised controlled trials investigating ED in-reach models [ 84 , 85 ]. All the studies investigating bedded AFUs were undertaken in single sites which may have led to contamination of the control arm. This would be anticipated to favour the null hypothesis [ 15 , 16 , 18 , 19 , 20 , 21 , 22 ]. Contamination of the control arm was less likely in HaH models delivered by distinct clinical teams.

All included observational studies were at serious or critical risk of confounding. The decision to manage patients in the intervention arm is likely to have been selective, based on clinical judgment informed by pre-intervention clinical characteristics. Only 5 studies employed robust statistical techniques to control for confounding [ 65 , 67 , 69 , 78 , 92 ]. Residual confounding from unmeasured prognostic factors posed at risk of bias all included observational studies.

Effectiveness of acute care models

Bedded acute frailty unit models.

No statistical difference in primary outcome was observed in 2 randomised controlled trials (reported across 3 articles) of specialist bed-based care for unselected older medical patients, 1 study measured the composite outcome of death, severe dependence and psychological well-being [ 15 ] and the other physical function at 3 months following discharge [ 19 ]. A planned cost-analysis demonstrated no difference in the total cost of admission between groups [ 16 ]. A single centre randomised controlled trial comparing a specialist unit for acutely unwell patients with cognitive impairment with usual care demonstrated no statistical difference in the composite outcome of days at home [ 17 ]. All included observational studies were judged to be at critical or serious risk of bias.

The largest randomised controlled trial included 1055 participants [ 59 ]. The study was designed to recruit to the HaH intervention at a ratio of 2:1. A significant number of participants moved from the control to the intervention arm due to operational pressures within the hospital. The study found no difference in the primary outcome of living at home at 6 months (the inverse of death or long-term residential care) [ 59 ]. The remaining 11 trials (reported across 15 articles) had smaller sample sizes (mean 81 participants, SD 33). One randomised controlled trial (2 articles) reported a statistically significant reduction in the rate of adverse events [ 50 ] and favourable functional outcomes in the group allocated to HaH care [ 49 ].

HaH care for older people with decompensated heart failure was investigated in 2 randomised controlled trials, 1 reported no difference in mortality or readmission at 6 months [ 62 ] and 1 no difference in mortality or readmission at 12 months [ 57 ]. HaH care for older people with an acute exacerbation of COPD was investigated in 2 randomised controlled trials, 1 reported a statistically significant reduction in readmissions at 6 months and no difference in mortality at 6 months [ 47 ] and 1 reported lower costs at 90 days, driven by shorted length of stay in the HaH group, with no difference in mortality or readmission rate at 90 days [ 52 ]. Economic analysis determined HaH was associated with lower costs in 1 randomised controlled trial of participants with unselected medical-illness [ 53 ]. Nested analysis of patient and carer satisfaction was included in 5 trials [ 47 , 52 , 53 , 59 , 62 ] in 3 trials the findings were reported in separate articles [ 51 , 55 , 66 ]. All showed an increase in measures of patient satisfaction in the HaH intervention group.

One randomised trial compared two contrasting models of HaH. The study arms compared HaH care led by primary care physicians with care led by hospital specialists [ 60 ]. Those in the hospital specialist arm were initially assessed in the ED and discharged within 4 h of assessment with a home-based care plan. The hospital specialist team did not undertake home visits. Those in the primary care physician arm received care exclusively at home. In both arms the plan care was delivered by a dedicated HaH nursing team. The primary care physician model was a associated with a statistically significant reduction in hospital admission at 7 days. A series of articles published as part of a non-randomised controlled trial [ 75 ] reported a reduction in length of admission, [ 75 ] reduced levels of carer stress [ 71 ] and no difference in physical function [ 72 ] in the HaH group.

ED in reach models

No statistical difference in the primary outcome measure was observed in 2 randomised controlled trials investigating ED in-reach models. In one study the provision of geriatrician lead CGA to patients aged over 75 with a clinical frailty scale (CFS) of 4 or above did not affect cumulative length of stay over a 1 year follow up period [ 84 ]. A randomised controlled trial investigating provision of nurse-led care coordination in the ED found no significant effect on the rate of hospital admission [ 85 ]. Uncontrolled before and after studies were a common methodological approach to the assessment of ED in-reach models, employed in 5 studies. All included observational studies were judged to be at serious risk of bias.

This systematic review provides a summary and classification of acute care models for older people living with frailty and an assessment of effectiveness based on current published evidence. The care models identified could be broadly differentiated by the location within the acute care pathway at which they operate. This generic classification provides a degree of structure to a large and complicated field of research, sensitive to the fact that relevant interventions have emerged across hospital and community settings. The spectrum of outcomes reported and differing approaches to measurement suggest consensus on how best to determine the effectiveness of these care models has yet to emerge.

The clinical effectiveness of acute care models for older people was difficult to determine from the available studies. The number of participants within each trial was small. The risk of confounding by indication was pervasive amongst observational studies and statistical techniques to control for cofounding were generally absent or inadequate. These methodological limitations prevented meaningful comparisons of the impact on outcomes between care models. There is a paucity of contemporary data on the effectiveness of acute care models for older people. Some of the most influential studies were conducted over two decades ago. This raises the concern that the clinical processes employed may now be obsolete.

Complex interventions, such as acute care models for older people are often difficult to characterise. The detailed summary of individual interventions provided within this review highlights the contrasting approaches adopted by services under the same umbrella.

Few studies adopted a structured approach to defining the intervention under investigation and the descriptions provided varied in depth and quality. The nature of care provided in the usual care arm of comparative studies was equally difficult to define. The absence of consistent inclusion and exclusion criteria or knowledge of how criteria were operationalised makes it difficult to discern the population targeted by each intervention. Assignment often incorporated a subjective assessment by an individual clinician acting as gatekeeper. Thresholds for admission and discharge are not standardised and risk tolerance may vary at the individual, hospital and system level. This is particularly pertinent to studies investigating the role of HaH and ED in-reach models, predicated on the assumption that care would inevitably require in-patient bed-based care if the intervention was absent. This assumption is inherently difficult to substantiate. All the HaH models included in this systematic review had access to hospital level diagnostics and interventions but the proportion of patients receiving these interventions were inconsistently reported. This obfuscates an objective assessment of acuity and whether hospital admission was warranted.

Comparison with previous literature

Clinical heterogeneity in the studies included in previous systematic reviews and the absence of universally accepted definitions for the care models investigated cloud interpretation of the existing literature. The diverse range of approaches to patient selection, operational design and outcome measurement highlighted in this review suggests caution is warranted when pooling studies in this subject area.

Several systematic reviews investigating acute care models for older people have focused the delivery of comprehensive geriatric assessment (CGA) [ 8 ]. CGA involves multidimensional assessment with particular attention on the functional consequences of illness [ 118 ]. CGA has been shown to increase the likelihood of being alive or returning to home at 3 to 12 months follow up amongst older patients admitted to hospital with acute illness [ 8 ]. Meta-analysis of CGA delivered in bed-based frailty units found a lower risk of functional decline, a higher likelihood of living at home after discharge and no differences in mortality [ 119 ]. CGA delivered in bed-based frailty units may also reduce the incidence of adverse events such as falls, delirium and pressure sores at discharge [ 10 ]. The inclusion of interventions delivered on rehabilitation wards, and patients with surgical and orthopaedic presentations in previous systematic reviews limits generalisation to care models employed at earlier time points in the acute care pathway. The available literature suggests alternatives to usual bed-based care incorporating CGA may be of benefit but offers little to guide how these services should be designed and implemented. When inclusion is limited to interventions employed within 48 h of presentation the evidence of effectiveness is less compelling. This is important given the benefit of CGA is cited as the primary motivation for operational models located upstream in the acute care pathway [ 120 ].

HaH models have also been the subject of systematic review and meta-analysis. A Cochrane review of admission avoidance HaH identified ten randomised controlled trials including 1333 participants of which 850 were included in individual patient level meta-analysis [ 121 ]. The analysis demonstrated a significant reduction in mortality at 6 months (adjusted HR 0.62, 95% CI 0.45–0.87). A more recent systematic review and meta-analysis found patients managed in HaH following discharge from the ED had a lower risk of admission to institutional care (RR 0.16 95% CI 0.03–0.74) and no difference in mortality (RR 0.84 95% CI 0.6–1.2) [ 122 ]. These systematic reviews pooled results from studies investigating HaH in the context of a diverse range of conditions including stroke, cellulitis, fractures and respiratory illness which would be expected to employ very different clinical processes. Applying a more restrictive approach to study inclusion, by only including HaH models with access to hospital level diagnostics and treatments allows greater confidence in the assertion that the HaH models included in the current review offered a true alternative to hospital admission.

Implications for policy and future research

The provision of acute care models for older people are predicated on a logic model rather than empirical evidence of benefit. Further large and rigorously constructed randomised controlled trials may strengthen the evidence base but may not be the most effectual method of influencing local decisions on service provision or the direction of policy.

Research in acute care delivery is complicated by a need to maintain operational performance. Amongst the studies identified, bed availability and restricted operational hours frequently resulted in a large differential between the number of potentially eligible participants and the number of patients ultimately included. Practical considerations aside, the outcomes of interventional studies are likely to be highly dependent on local context and external factors which influence generalisability.

Knowledge in this subject area may be enhanced by developing a consistent approach to outcome reporting and measurement, ideally incorporating the priorities and preferences of patients. Mortality may not be the most appropriate metric of effectiveness given a significant proportion of older people living with frailty requiring acute care for medical illness are entering the last 12 months of life [ 123 ]. Current models of acute care infrequently establish and record individual preferences in relation to location of care in the event of acute medical illness or preferred location of death amongst older people [ 124 ]. A narrow focus on clinical and operational outcomes may simplify study design, facilitate comparisons and provide reassurance around safety but risks ignoring other aspects of care, such as quality of life, which may be more meaningful from the patient perspective.

Given the complexity of the intervention, an understanding of the processes and behaviours which drive successful models may be best approached from a qualitative research paradigm.

Strength and limitations

The primary objective of this systematic review was to describe and categorise acute care models for older people and highlight variation in the outcome measures used to assess them. An extensive search strategy inclusive of the grey literature and indifferent to methodological design was purposefully employed in order to capture a comprehensive representation of the range of models in operation. Every acute hospital encounters older people living with frailty and the potential for variation in approach is vast. Only a small fraction of care models delivered in practice are reported in the literature. The practice of publishing multiple articles from the same original study was relatively common, particularly in literature pertaining to acute bed-based care and HaH models. The account provided is therefore susceptible to both publication and outcome reporting bias.

Availability of data and materials

The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

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DSL is funded by National Institute for Health Research (NIHR) Applied Research Collaboration (ARC) West Midlands, NIHR Community Healthcare MedTech and IVD Cooperative and NIHR Oxford Biomedical Research Centre (BRC). The views expressed are those of the authors and not necessarily those of the NIHR or Department of Health and Social Care.

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Knight, T., Kamwa, V., Atkin, C. et al. Acute care models for older people living with frailty: a systematic review and taxonomy. BMC Geriatr 23 , 809 (2023). https://doi.org/10.1186/s12877-023-04373-4

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Alternative routes into clinical research: a guide for early career doctors

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• Peer review
• Phillip LR Nicolson , consultant haematologist and associate professor of cardiovascular science 1 2 3 ,
• Martha Belete , registrar in anaesthetics 4 5 ,
• Rebecca Hawes , clinical fellow in anaesthetics 5 6 ,
• Nicole Fowler , haematology clinical research fellow 7 ,
• Cheng Hock Toh , professor of haematology and consultant haematologist 8 9
• 1 Institute of Cardiovascular Sciences, University of Birmingham, UK
• 2 Department of Haemostasis, Liaison Haematology and Transfusion, University Hospitals Birmingham NHS Foundation Trust, Birmingham
• 3 HaemSTAR, UK
• 4 Department of Anaesthesia, Plymouth Hospitals NHS Trust, Plymouth, UK
• 5 Research and Audit Federation of Trainees, UK
• 6 Department of Anaesthesia, The Rotherham NHS Foundation Trust, Rotherham Hospital, Rotherham
• 7 Department of Haematology, Royal Cornwall Hospitals NHS Trust, Treliske, Truro
• 8 Liverpool University Hospitals NHS Foundation Trust, Prescott Street, Liverpool
• 9 Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool
• Correspondence to P Nicolson, C H Toh p.nicolson{at}bham.ac.uk ; c.h.toh{at}liverpool.ac.uk

Working in clinical research alongside clinical practice can make for a rewarding and worthwhile career. 1 2 3 Building research into a clinical career starts with research training for early and mid-career doctors. Traditional research training typically involves a dedicated period within an integrated clinical academic training programme or as part of an externally funded MD or PhD degree. Informal training opportunities, such as journal clubs and principal investigator (PI)-mentorship are available ( box 1 ), but in recent years several other initiatives have launched in the UK, meaning there are more ways to obtain research experience and embark on a career in clinical research.

Examples of in-person and online research training opportunities

These are available either informally or formally, free of charge or paid, and via local employing hospital trusts, allied health organisations, royal colleges, or universities

Acute medicine

No national trainee research network

Anaesthesia

Research and Audit Federation of Trainees (RAFT). www.raftrainees.org

Cardiothoracic surgery

No national trainee-specific research network. National research network does exist: Cardiothoracic Interdisciplinary Research Network (CIRN). www.scts.org/professionals/research/cirn.aspx

Emergency medicine

Trainee Emergency Medicine Research Network (TERN). www.ternresearch.co.uk

Ear, nose, and throat

UK ENT Trainee Research Network (INTEGRATE). www.entintegrate.co.uk

Gastroenterology

No national trainee research network. Many regional trainee research networks

General practice

No national trainee-specific research network, although national research networks exist: Society for Academic Primary Care (SAPC) and Primary Care Academic Collaborative (PACT). www.sapc.ac.uk ; www.gppact.org

General surgery

Student Audit and Research in Surgery (STARSurg). www.starsurg.org . Many regional trainee research networks

Geriatric Medicine Research Collaborative (GeMRC). www.gemresearchuk.com

Haematology (non-malignant)

Haematology Specialty Training Audit and Research (HaemSTAR). www.haemstar.org

Haematology (malignant)

Trainee Collaborative for Research and Audit in Hepatology UK (ToRcH-UK). www.twitter.com/uk_torch

Histopathology

Pathsoc Research Trainee Initiative (PARTI). www.pathsoc.org/parti.aspx

Intensive care medicine

Trainee Research in Intensive Care Network (TRIC). www.tricnetwork.co.uk

Internal medicine

No trainee-led research network. www.rcp.ac.uk/trainee-research-collaboratives

Interventional radiology

UK National Interventional Radiology Trainee Research (UNITE) Collaborative. https://www.unitecollaborative.com

Maxillofacial surgery

Maxillofacial Trainee Research Collaborative (MTReC). www.maxfaxtrainee.co.uk/

UK & Ireland Renal Trainee Network (NEPHwork). www.ukkidney.org/audit-research/projects/nephwork

Neurosurgery

British Neurosurgical Trainee Research Collaborative (BNTRC). www.bntrc.org.uk

Obstetrics and gynaecology

UK Audit and Research Collaborative in Obstetrics and Gynaecology (UKAROG). www.ukarcog.org

The National Oncology Trainee Collaborative for Healthcare Research (NOTCH). www.uknotch.com

Breast Cancer Trainee Research Collaborative Group (BCTRCG). https://bctrcguk.wixsite.com/bctrcg

Ophthalmology

The Ophthalmology Clinical Trials Network (OCTN). www.ophthalmologytrials.net

Paediatrics

RCPCH Trainee Research Network. www.rcpch.ac.uk/resources/rcpch-trainee-research-network

Paediatric anaesthesia

Paediatric Anaesthesia Trainee Research Network (PATRN). www.apagbi.org.uk/education-and-training/trainee-information/research-network-patrn

Paediatric haematology

Paediatric Haematology Trainee Research Network (PHTN). No website

Paediatric surgery

Paediatric Surgical Trainees Research Network (PSTRN). www.pstrnuk.org

Pain medicine

Network of Pain Trainees Interested in Research & Audit (PAIN-TRAIN). www.paintrainuk.com

Palliative care

UK Palliative Care Trainee Research Collaborative (UKPRC). www.twitter.com/uk_prc

Plastic surgery

Reconstructive Surgery Trials Network (RSTN). www.reconstructivesurgerytrials.net/trainees/

Pre-hospital medicine

Pre-Hospital Trainee Operated Research Network (PHOTON). www.facebook.com/PHOTONPHEM

Information from Royal College of Psychiatrists. www.rcpsych.ac.uk/members/your-faculties/academic-psychiatry/research

Radiology Academic Network for Trainees (RADIANT). www.radiantuk.com

Respiratory

Integrated Respiratory Research collaborative (INSPIRE). www.inspirerespiratory.co.uk

British Urology Researchers in Surgical Training (BURST). www.bursturology.com

Vascular surgery

Vascular & Endovascular Research Network (VERN). www.vascular-research.net

This article outlines these formal but “non-traditional” routes available to early and mid-career doctors that can successfully increase research involvement and enable research-active careers.

Trainee research networks

Trainee research networks are a recent phenomenon within most medical specialties. They are formalised regional or national groups led by early and mid-career doctors who work together to perform clinical research and create research training opportunities. The first of these groups started in the early 2010s within anaesthetics but now represent nearly every specialty ( box 2 ). 4 Trainee research networks provide research training with the aim of increasing doctors’ future research involvement. 5

A non-exhaustive list of UK national trainee led research networks*

Research training opportunities.

Mentorship by PIs at local hospital

Taking on formal role as sub-investigator

Journal clubs

Trainee representation on regional/national NIHR specialty group

API Scheme: https://www.nihr.ac.uk/health-and-care-professionals/training/associate-principal-investigator-scheme.htm .

eLearning courses available at https://learn.nihr.ac.uk (free): Good clinical practice, fundamentals of clinical research delivery, informed consent, leadership, future of health, central portfolio management system.

eLearning courses available from the Royal College of Physicians. Research in Practice programme (free). www.rcplondon.ac.uk

eLearning courses available from the Medical Research Council (free). https://bygsystems.net/mrcrsc-lms/

eLearning courses available from Nature (both free and for variable cost via employing institution): many and varied including research integrity and publication ethics, persuasive grant writing, publishing a research paper. https://masterclasses.nature.com

University courses. Examples include novel clinical trial design in translational medicine from the University of Cambridge ( https://advanceonline.cam.ac.uk/courses/ ) or introduction to randomised controlled trials in healthcare from the University of Birmingham ( https://www.birmingham.ac.uk/university/colleges/mds/cpd/ )

*limited to those with formal websites and/or active twitter accounts. Correct as of 5 January 2024. For regional trainee-led specialty research networks, see www.rcp.ac.uk/trainee-research-collaboratives for medical specialties, www.asit.org/resources/trainee-research-collaboratives/national-trainee-research-collaboratives/res1137 for surgical specialties, and www.rcoa.ac.uk/research/research-bodies/trainee-research-networks for anaesthetics.

Networks vary widely in structure and function. Most have senior mentorship to guide personal development and career trajectory. Projects are usually highly collaborative and include doctors and allied healthcare professionals working together.

Observational studies and large scale audits are common projects as their feasibility makes them deliverable rapidly with minimal funding. Some networks do, however, carry out interventional research. The benefits of increasing interventional research studies are self-evident, but observational projects are also important as they provide data useful for hypothesis generation and defining clinical equipoise and incidence/event rates, all of which are necessary steps in the development of randomised controlled studies.

These networks offer a supportive learning environment and research experience, and can match experience with expectations and responsibilities. Early and mid-career doctors are given opportunities to be involved and receive training in research at every phase from inception to publication. This develops experience in research methodology such as statistics, scientific writing, and peer review. As well as research skills training, an important reward for involvement in a study is manuscript authorship. Many groups give “citable collaborator” status to all project contributors, whatever their input. 6 7 This recognises the essential role everyone plays in the delivery of whole projects, counts towards publication metrics, and is important for future job applications.

Case study—Pip Nicolson (HaemSTAR)

Haematology Specialist Training, Audit and Research (HaemSTAR) is a trainee research network founded because of a lack of principal investigator training and clinical trial activity in non-malignant haematology. It has led and supported national audits and research projects in various subspecialty areas such as immune thrombocytopenia, thrombotic thrombocytopenic purpura, venous thrombosis, and transfusion. 8 9 10 Through involvement in this network as a registrar, I have acted as a sub-investigator and supported the principal investigator on observational and interventional portfolio-adopted studies by the National Institute for Health and Care Research. These experiences gave me valuable insight into the national and local processes involved in research delivery. I was introduced to national leaders in non-malignant haematology who not only provided mentorship and advice on career development, but also gave me opportunities to lead national audits and become involved in HaemSTAR’s committee. 10 11 These experiences in leadership have increased my confidence in management situations as I have transitioned to being a consultant, and have given me skills in balancing clinical and academic roles. Importantly, I have also developed long term friendships with peers across the country as a result of my involvement in HaemSTAR.

Associate Principal Investigator scheme

The Associate Principal Investigator (API) scheme is a training programme run by NIHR to develop research skills and contribute to clinical study delivery at a local level. It is available throughout England, Scotland, Wales, and Northern Ireland for NIHR portfolio-adopted studies. The programme runs for six months and, upon completion, APIs receive formal recognition endorsed by the NIHR and a large number of royal colleges. The scheme is free and open to medical and allied healthcare professionals at all career grades. It is designed to allow those who would not normally take part in clinical research to do so under the mentorship of a local PI. Currently there are more than 1500 accredited APIs and over 600 affiliated studies across 28 specialties. 12 It is a good way to show evidence of training and involvement in research and get more involved in research conduct. APIs have been shown to increase patient recruitment and most people completing the scheme continue to be involved in research. 12 13

Case study—Rebecca Hawes

I completed the API scheme as a senior house officer in 2021. A local PI introduced me to the Quality of Recovery after Obstetric Anaesthesia NIHR portfolio study, 14 which I saw as a training opportunity and useful experience ahead of specialist training applications. It was easy to apply for and straightforward to navigate. I was guided through the six month process in a step-by-step manner and completed eLearning modules and video based training on fundamental aspects of running research projects. All this training was evidenced on the online API platform and I had monthly supervision meetings with the PI and wider research team. As well as the experience of patient recruitment and data collection, other important aspects of training were study set-up and sponsor communications. Key to my successful API scheme was having a supportive and enthusiastic PI and developing good organisational skills. I really enjoyed the experience, and I have since done more research and have become a committee member on a national trainee research network in anaesthesia called RAFT (Research and Audit Federation of Trainees). I’ve seen great enthusiasm among anaesthetists to take part in the API scheme, with over 150 signing up to the most recent RAFT national research project.

Clinical research posts

Dedicated clinical research posts (sometimes termed “clinical research fellow” posts) allow clinicians to explore and develop research skills without committing to a formal academic pathway. They can be undertaken at any stage during a medical career but are generally performed between training posts, or during them by receiving permission from local training committees to temporarily go “out of programme.” These positions are extremely varied in how they are advertised, funded, and the balance between research and clinical time. Look out for opportunities with royal colleges, local and national research networks, and on the NHS Jobs website. Research fellowships are a good way to broaden skills that will have long term impact across one’s clinical career.

Case study—Nicole Fowler

After completing the Foundation Programme, I took up a 12 month clinical trials fellow position. This gave me early career exposure to clinical research and allowed me to act as a sub-investigator in a range of clinical trials. I received practical experience in all stages of clinical research while retaining a patient facing role, which included obtaining consent and reviewing patients at all subsequent visits until study completion. Many of the skills I developed in this post, such as good organisation and effective teamwork, are transferable to all areas of medicine. I have thoroughly enjoyed the experience and it is something I hope to talk about at interview as it is an effective way of showing commitment to a specialty. Furthermore, having a dedicated research doctor has been beneficial to my department in increasing patient involvement in research.

Acknowledgments

We would like to thank Holly Speight and Clare Shaw from the NIHR for information on the API scheme.

*These authors contributed equally to this work

Patient and public involvement: No patients were directly involved in the creation of this article.

PLRN, MB, and CHT conceived the article and are guarantors. All authors wrote and edited the manuscript.

Competing interests: PLRN was the chair of HaemSTAR from 2017 to 2023. MB is the current chair of the Research and Audit Federation of Trainees (RAFT). RH is the current secretary of RAFT. CHT conceived HaemSTAR.

Provenance and peer review: Commissioned; externally peer reviewed.

• Downing A ,
• Morris EJ ,
• Corrigan N ,
• Bracewell M ,
• Medical Academic Staff Committee of the British Medical Association
• ↵ RAFT. The start of RAFT. https://www.raftrainees.org/about
• Jamjoom AAB ,
• Hutchinson PJ ,
• Bradbury CA ,
• McCulloch R ,
• Nicolson PLR ,
• HaemSTAR Collaborators
• Collaborators H ,
• ↵ National Institute for Health and Care Research. Associate Principal Investigator (PI) Scheme. 2023. https://www.nihr.ac.uk/health-and-care-professionals/career-development/associate-principal-investigator-scheme.htm
• Fairhurst C ,
• Torgerson D
• O’Carroll JE ,
• Warwick E ,
• ObsQoR Collaborators

• Open access
• Published: 28 February 2023

Complex and alternate consent pathways in clinical trials: methodological and ethical challenges encountered by underserved groups and a call to action

• Amy M. Russell 1   na1 ,
• Victoria Shepherd   ORCID: orcid.org/0000-0002-7687-0817 2   na1 ,
• Kerry Woolfall 3 ,
• Bridget Young 3 ,
• Katie Gillies 4 ,
• Anna Volkmer 5 ,
• Mark Jayes 6 ,
• Richard Huxtable 7 ,
• Alexander Perkins 8 ,
• Nurulamin M. Noor 9 ,
• Beverley Nickolls 10 &
• Julia Wade 11  

Trials volume  24 , Article number:  151 ( 2023 ) Cite this article

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Informed consent is considered a fundamental requirement for participation in trials, yet obtaining consent is challenging in a number of populations and settings. This may be due to participants having communication or other disabilities, their capacity to consent fluctuates or they lack capacity, or in emergency situations where their medical condition or the urgent nature of the treatment precludes seeking consent from either the participant or a representative. These challenges, and the subsequent complexity of designing and conducting trials where alternative consent pathways are required, contribute to these populations being underserved in research. Recognising and addressing these challenges is essential to support trials involving these populations and ensure that they have an equitable opportunity to participate in, and benefit from, research. Given the complex nature of these challenges, which are encountered by both adults and children, a cross-disciplinary approach is required.

A UK-wide collaboration, a sub-group of the Trial Conduct Working Group in the MRC-NIHR Trial Methodology Research Partnership, was formed to collectively address these challenges. Members are drawn from disciplines including bioethics, qualitative research, trials methodology, healthcare professions, and social sciences. This commentary draws on our collective expertise to identify key populations where particular methodological and ethical challenges around consent are encountered, articulate the specific issues arising in each population, summarise ongoing and completed research, and identify targets for future research. Key populations include people with communication or other disabilities, people whose capacity to consent fluctuates, adults who lack the capacity to consent, and adults and children in emergency and urgent care settings. Work is ongoing by the sub-group to create a database of resources, to update NIHR guidance, and to develop proposals to address identified research gaps.

Collaboration across disciplines, sectors, organisations, and countries is essential if the ethical and methodological challenges surrounding trials involving complex and alternate consent pathways are to be addressed. Explicating these challenges, sharing resources, and identifying gaps for future research is an essential first step. We hope that doing so will serve as a call to action for others seeking ways to address the current consent-based exclusion of underserved populations from trials.

Peer Review reports

Informed consent is seen as a cornerstone in the ethical conduct of clinical trials. However, in populations or settings where there are challenges to seeking or providing consent, alternative consent arrangements may be required. These challenges may arise due to communication barriers, where a participant’s capacity to provide consent fluctuates over time, where capacity is lost during a trial, or they are deemed to lack the capacity to consent at the outset. These challenges may be particularly pronounced in emergency settings where the urgent nature of the condition and the need for immediate action preclude the ability to seek prior consent for either adults or children. Populations where consent may pose a challenge have historically been excluded from trials and are recognised as being underserved by research as a result [ 1 ]. For example, one in three patients with hip fractures have a concomitant cognitive impairment, yet eight out of ten hip fracture trials exclude this population despite evidence that those with cognitive impairment are likely to experience different outcomes [ 2 ]. Even trials in conditions associated with cognitive impairment frequently exclude people with impaired capacity to consent [ 3 ]. This exclusion of relevant subgroups of patients risks presenting biased estimates of treatment effects [ 4 , 5 ] and limits the ability to provide evidence-based care for these groups.

For many of these populations, research inequity contributes to the health disparities that they already encounter [ 6 ]. For example, adults with intellectual disabilities die on average 10–15 years earlier than those without intellectual disabilities in the UK and the USA [ 7 , 8 ], yet 90% of clinical trials are designed in a way that automatically excludes them from participating [ 9 ]. The importance of widening opportunities for the participation of underserved populations in research has received recognition both in the UK and beyond, resulting in national and international initiatives to improve inclusivity and diversity in the design, conduct, and reporting of clinical trials [ 1 , 10 , 11 , 12 ]. Research funders increasingly require researchers to address issues around inclusivity and representativeness in their funding applications [ 13 ]. However, the challenges of conducting trials where consent is complex, and where consent-based exclusion denies populations the opportunity to participate in and benefit from research, have received less attention [ 14 ].

The ethical and methodological issues surrounding trials involving complex and alternative consent pathways have led to the formation of a new UK multi-institutional collaboration to collectively address some of these challenges. This collaboration forms a sub-group of the Trial Conduct Working Group in the MRC-NIHR Trial Methodology Research Partnership, consisting of members from disciplines including trials methodology, qualitative research, healthcare, bioethics, and social sciences. This paper summarises and discusses contexts where researchers may encounter particular methodological and ethical challenges around consent. The focus is on trials where the process of consent is challenging and alternative consent pathways are required, rather than where the informational content required for consent to be valid is complex [ 15 ], or where the trial design is complex such as a multistage randomised controlled trial [ 16 ].

Drawing on our experiences as an interdisciplinary group of researchers with an interest in complex and alternate consent pathways in trials, we will focus on key populations where consent-based challenges contribute to their exclusion: adults with communication or other disabilities [ 17 ], adults who lack the capacity to consent [ 18 ], adults whose capacity to consent fluctuates or is lost during a trial [ 19 ], and adults and children requiring emergency and urgent care [ 20 ]. The question of alternative consent pathways for children in non-emergency research will not be addressed in this article as it requires specific attention [ 21 ]. For each population, we articulate the challenges around inclusion in trials, summarise current evidence and ongoing work, and identify areas for future research. We hope that this will serve as a cri de cœur for others seeking ways to address the consent-based exclusion of underserved populations from trials.

Trials involving adults with communication, hearing, and sight disabilities

Despite the fact that the majority of legislation delineating consent processes urges professionals to make adjustments for people with communication, hearing, and visual impairments, they may be excluded from research simply due to the fact that obtaining informed consent is more challenging [ 22 ]. Communication disabilities can comprise a range of difficulties that impact a person’s ability to understand spoken or written information (sounds, words, or sentences) and express themselves verbally or non-verbally (articulate sounds/letters, select words, or use relevant grammar and sentence forms) in spoken, written, or picture form. Difficulties in accessing and comprehension of information are one of the most common barriers in consent scenarios across several diagnoses including dementia [ 23 ], stroke [ 24 ], and brain injury [ 25 ], as well as developmental disorders such as autism and learning/intellectual disabilities [ 26 ]. Other difficulties that can impede a person’s ability to access spoken or written information include hearing or visual impairments, which may or may not be associated with an underlying condition. The use of British Sign Language interpreters or translation of written materials to other languages including Braille is extremely important for those with hearing or visual impairment [ 27 ]. Beyond this, the heterogeneity amongst people with communication disabilities requires adaptations to be tailored to individual needs based on knowledge of the person’s communication strengths and difficulties. People with stroke-related language impairments (aphasia), for example, may benefit from the information being presented using active language, shorter sentences, or written keywords [ 28 ].

The challenges

Making changes to support communication needs is complex. Some researchers find current guidance such as the Mental Capacity Act Code of Practice [ 27 ] and Health Research Authority guidance [ 29 ] difficult to interpret and implement [ 30 , 31 ]. Researchers acknowledge a lack of skills, knowledge, and confidence in being able to adapt their language and communication to meet the needs of people with communication disabilities [ 31 ]. Other barriers identified include the lack of specific training, tools, time and access to ethically approved materials [ 31 , 32 , 33 ].

There is limited evidence relating to the inclusion of people with communication disabilities in the informed consent process. This is in part because people with communication disabilities often have been excluded from study recruitment processes [ 17 , 30 , 31 , 33 , 34 , 35 ], and because studies that have included them have tended not to report the recruitment and consent methods used [ 32 ].

Current research and guidance

People with communication disabilities may not be included in the informed consent process for different reasons: this group is frequently defined as ineligible for inclusion in studies per se, solely due to their communication disabilities [ 31 ]; even where included, researchers may consult proxies (e.g. family members) because they assume that people with communication disabilities lack the mental capacity to provide informed consent [ 17 , 31 , 33 ]; researchers may find the consent process for this group too challenging and time-consuming [ 31 ]. Reluctance to include people with communication disabilities in the consent process may follow challenges involving people with significant communication disabilities in patient and public involvement and engagement activity, and current involvement guidance does not provide specific information about how to include this group [ 36 ]. Recent UK studies have helped to contextualise these findings, by examining the legal, policy, and governance frameworks that apply to the recruitment of people with communication disabilities [ 30 , 37 , 38 ]. Whilst not specific to trials, these frameworks provide guidance for facilitating the inclusion of this group in the informed consent process. This includes recommendations to co-produce information materials with people with communication disabilities and to adapt communication environments and processes to improve their accessibility. These recommendations are supported by research that has developed and tested communication methods to support decision-making during the informed consent process for people with post-stroke aphasia [ 22 , 32 , 39 ] and intellectual disability [ 33 , 40 ].

In recent examples, researchers have been able to create and use accessible consent materials and implement these within stroke trials [ 41 , 42 , 43 ] using practical, evidence-based resources [ 22 , 44 , 45 ]. These have been co-produced to ensure the language is accessible, readable, and accompanied by transparent visual representations and alternative mediums (video for example). Furthermore, the recent ASSENT [ 46 ] and CONSULT [ 47 ] projects have developed inclusive consent guidance and resources to aid researchers.

Future research

More research is required to explore the inclusion of people with communication disabilities in the informed consent process in trials, in terms of current practice and professional and participant experience. Most existing research appears to have focused on two main groups: people with post-stroke aphasia and people with intellectual disabilities. Future research should explore the experiences and needs of people with different types of communication disabilities, for example, people living with dementia or with other progressive neurological conditions.

Further research is required to develop and evaluate additional tools, resources, and training interventions to support researchers to work with people with communication disabilities more easily and effectively during the informed consent process [ 37 ]. Evaluation should include the exploration of usability, acceptability to professionals and participants, and cost-effectiveness. In addition, studies should explore how researchers can form successful and equitable collaborations with people with communication disabilities as part of trial public involvement and engagement activity in order to co-produce inclusive consent processes and materials [ 48 ].

Trials involving adults whose capacity fluctuates or is lost during a trial

Informed consent can only be obtained from individuals who have the capacity to give consent. Fluctuating capacity can refer to situations where a person’s condition is cyclical (moving from an acute phase to a recovery phase) [ 49 ] or where their capacity is influenced by other factors including but not limited to health or environment [ 50 , 51 ]. It can also relate to capacity that is task-specific, where an individual may have the capacity to consent to certain aspects of a trial but may struggle to give informed consent to all aspects or understand long-term follow-up processes.

Fluctuating capacity raises three main challenges: (1) the potential exclusion of those believed to have fluctuating capacity where no clear assessment process is in place, (2) the need for a process of consent-taking at each data collection time point, and (3) the need to incorporate planning for a loss of capacity, temporary or otherwise, when creating trial processes, patient information and consent materials. Without forward planning, unanticipated lost capacity during data collection may lead to withdrawal and/or missing data and the unnecessary exclusion of participants [ 52 ].

Capacity is often framed (and commonly understood and implemented by recruiting staff) in binary terms as something a person has or does not have [ 53 , 54 ], which has been critiqued in certain populations and cultural contexts [ 55 ]. In England and Wales, the Mental Capacity Act 2005 makes it clear that capacity is task-specific. Once assessed, capacity is not an end point but an ongoing process of engagement with a participant.

An intention to carry out capacity assessments is often alluded to in trial protocols without further detail being given on why certain individuals will be assessed, who will conduct assessments, and what criteria they will use [ 9 ]. The Mental Capacity Act 2005 and the Code of Practice (2007) exist to protect individuals, but not to impede their right to participate in research, something researchers should acknowledge. However, there is a lack of practical guidance in these documents which results in uncertainty about how researchers should best assess capacity. This can lead to inconsistent approaches to assessment. Capacity should be assumed in individuals, and capacity assessments should also only take place after the individual has been given clear information, appropriate to their needs, and there is a question raised about their ability to provide informed consent. This again raises challenges for trials where standard information is required that can be complex, lengthy, and difficult to adapt to the needs of different groups (for example, people with communication disabilities) [ 56 , 57 ].

Suggestions for alternative forms of consent that may support those whose capacity fluctuates have been developed by researchers working with specific populations [ 58 ], including process consent in dementia research [ 59 ]. These distinguish between time and task-specific capacity and the capacity to take a longitudinal view, implying an understanding of future risks and benefits [ 49 ]. However, research to date often focuses on distinct populations, e.g. people receiving palliative care [ 60 ], people living with dementia, and stroke survivors. Attention to managing fluctuations in capacity is less often seen in population-wide trials. To reduce blanket exclusions for certain populations, and misuse of lack of capacity being used as an exclusion criterion, further research resulting in clear guidance is required.

Standardised tools for capacity assessment have been developed, but there is no gold standard for the assessment of capacity in clinic or in research, nor is there an agreement that any one tool can sufficiently capture the complexity of capacity assessment [ 61 ]. Current Mental Capacity Act-compliant tools remain difficult to adapt to the heterogeneity of the populations for whom capacity fluctuates [ 62 , 63 , 64 ]. Capacity assessment processes are also often only employed in certain trials which anticipate that their target population will require them.

Consent needs to be understood as task- and time-specific and requiring accessible information. Research is needed to generate guidance on what to do if capacity is lost during follow up and it must be based on a defined process of establishing the wishes of participants at the initial consent stages. More evidence is required on the best methods for capacity assessment and how to support researchers to assess capacity. Trials need to build protocols for how to prevent exclusion of those who may fluctuate in capacity to consent and on how to manage data collection from those whose capacity does fluctuate.

Trials involving adults who lack the capacity to consent

Even with support, some people will be unable to provide their own consent to take part in a trial. The exclusion of adults who lack the capacity to consent has been widely documented [ 18 , 65 , 66 ] and is due to a range of intersecting methodological and systemic barriers to their inclusion [ 34 ]. Specific consent-based challenges include the complexity of the patchwork of legal frameworks that govern trials involving adults lacking capacity both within the UK [ 67 ] and internationally [ 68 ], and the uncertainties of applying them in practice [ 69 ]. In the UK, clinical trials of an investigational medicinal product involving adults lacking capacity are governed by the Medicines for Human Use (Clinical Trials) Regulations [ 70 ], with other types of trials covered by mental capacity legislation such as the Mental Capacity Act in England and Wales [ 71 ]. In both cases, there are provisions for an alternative decision-maker to be involved in enrolment decisions, usually a family member or close friend, or someone acting in a professional capacity who is not involved in the research if no one is able or willing to act in a personal capacity [ 70 , 71 ]. For clinical trials, the alternative decision-maker is termed a legal representative and provides consent based on the person’s presumed will [ 70 ], and for other types of research, they act as a consultee and are asked to provide advice about participation based on the person’s wishes and preferences [ 29 ]. However, little guidance is available to families and health and social care professionals about their role in making decisions about trial participation, nor the legal basis for their decision [ 72 ].

Due in part to this legal complexity, a lack of knowledge about research involving adults who lack capacity, and paternalistic attitudes generally, may result in gatekeeping practices by researchers and health and social care professionals towards this population [ 73 , 74 ]. Involving health and social care professionals as a consultee or legal representative relies on them having the time and willingness to be involved. Some may be concerned about being unable to determine or represent the wishes and preferences that a person may hold and so may decline to become involved [ 38 ]. Other challenges arise due to the difficulties in identifying and contacting consultees and legal representatives [ 75 ]. Even when they have been identified, family members are less likely to agree to research participation on the person’s behalf than patients themselves [ 76 ]. This may be due to families’ difficulties in knowing what that person’s wishes and preferences would be about participation [ 77 ]. People rarely discuss their research preferences in the event that they might lose capacity, and there is no current mechanism in the UK for prospectively appointing a consultee or legal representative to make decisions about research [ 78 ].

Procedures for identifying and approaching consultees and legal representatives are one of the issues that research ethics committees (RECs) consider when reviewing applications for trials involving adults who lack capacity, alongside arrangements for assessing capacity to consent where required [ 29 ]. However, RECs’ resistance to the inclusion of adults who lack capacity in a trial, and whether there is sufficient justification to do so, is cited as one of the greatest barriers to their inclusion [ 79 , 80 ]. RECs do not interpret the legal frameworks consistently or, at times, correctly, with inaccurate terminology and requirements being cited [ 37 , 72 , 81 ]. There have been calls for greater explicitness and accuracy when applications for ethical review of these studies are both submitted and reviewed [ 72 , 81 ] and for incorporating more adaptations and accommodations into the recruitment process such as ensuring information is cognitively accessible [ 37 ].

Recent research has identified a number of barriers and facilitators to involving adults lacking consent in trials [ 19 , 34 ] leading to the creation of guidance, for example, for recruiting adults with impaired mental capacity at the end of life in research [ 19 ]. Recent initiatives to address the inclusion of underserved groups in research more broadly, such as the NIHR INCLUDE project [ 1 ], have led to the development of the INCLUDE Impaired Capacity to Consent Framework which is a tool to help researchers to design and conduct trials that are more inclusive of people with impaired capacity to consent [ 82 ].

Other studies have focused on the role of personal consultees and legal representatives. This includes a study that found that making ethically complex decisions about research on behalf of someone else can be challenging for many family members, with some experiencing a decisional and emotional burden as a result [ 83 ]. Current work includes the development of the first decision aid for families making decisions about research on behalf of someone who lacks the capacity to consent [ 84 ] which is currently being evaluated as a ‘Study Within a Trial’ (or ‘SWAT’) (CONSULT) [ 85 ] and the development of resources to help researchers [ 47 ].

Despite the ongoing work, there is a need for a more sustained effort to ensure that these groups have an equitable opportunity to participate in trials. More research is needed into how researchers can design more inclusive trials, and the involvement of health and social care professionals as nominated consultees, and the use of professional legal representatives when necessary. Unlike questions about why other underserved groups have been excluded from research, the legal position regarding people who lack capacity is that their inclusion requires justification [ 29 ]. Clearer guidance is required on how this justification is understood and interpreted.

A number of recommendations for further research at a policy and legislation level have been previously made, including proposals by the Nuffield Council on Bioethics [ 86 ] that consideration be given to extend the role of the welfare attorney in England and Wales to include decisions about research, both within the Mental Capacity Act [ 71 ] and the Clinical Trials Regulations [ 70 ]. There is also uncertainty about the role of Lasting Power of Attorney in decisions about research participation [ 78 ], with families wanting greater support and guidance when making decisions [ 83 ].

Adult and paediatric emergency and urgent care trials

Trials involving adults in emergency situations may encounter additional complexities. The challenges of obtaining consent from patients who are suddenly unable to communicate or convey their own wishes are encountered in trial contexts ranging from intrapartum [ 87 ] and acute coronary syndrome [ 88 ] to acute stroke where it has been described as the rate-limiting step in treatment RCTs [ 89 ]. Emergency and urgent care trials are conducted in a range of settings including prehospital [ 90 ] and critical care [ 91 ].

Historically, children have not received evidence-based healthcare in emergency and critical care settings due to their exclusion from trials arising from similar practical and ethical issues to those encountered in adult trials in these time-critical settings [ 92 ]. In order to increase the chances of saving a child’s life, treatments need to be given without delay, so there is no time to seek informed consent from parents or legal representatives. Even if there is a brief window of opportunity for recruitment discussions, parents may not be present or may be highly distressed and lack the capacity to make an informed decision about the use of their child’s information and potential ongoing involvement [ 93 ].

Emergency research is when treatment needs to be given urgently [ 94 ] and recruitment cannot be delayed until the patient either regains capacity or a consultee or legal representative can be found [ 95 ]. In such circumstances, research without prior consent (RWPC, also referred to as ‘deferred consent’) is permissible in many jurisdictions including the USA, Canada, parts of Australasia, and the UK through both the Mental Capacity Act [ 71 ] and the 2006 Amendment to the 2004 EU Clinical Trials Regulations [ 96 ]. However, there are variations in the provisions for RWPC in emergency research, both between and within countries [ 97 ]. Within the UK, for example, the law in Scotland does not provide any ‘exemptions’ or alternatives for the involvement of adults not able to consent for themselves in clinical trials in emergency situations [ 94 ]. This meant that trials such as RECOVERY-RS [ 98 ], which compared respiratory strategies for patients with COVID-19 respiratory failure, could not recruit Scottish patients. Similarly, the UK-REBOA trial in life-threatening torso haemorrhage was unable to recruit in Scotland despite being coordinated from there [ 99 ].

In recognition of the need to conduct these vital trials with children, various legal frameworks for paediatric trials have also been amended nationally and internationally, enabling research to be conducted without prior consent. In 2008, UK legislation was amended to allow research without prior consent in such circumstances [ 100 ], yet there was a lack of knowledge about how and when research teams should broach these research discussions with parents in a way that avoided further burdening families. There was also a need for guidance to inform what should happen when a child dies after trial enrolment without parents’ prior knowledge or consent. Despite the 2008 legislation that enabled much-needed research on emergency treatments for children, there was hesitancy amongst clinical and research communities about conducting trials involving critically ill children [ 101 ].

The use of RWPC in both adult and child populations is ethically complex, with diverse views about the acceptability of enrolling acutely ill patients without consent [ 102 ]. There are particular challenges around gaining ethical approval for the use of RWPC in borderline or ‘middle ground’ cases where a patient may be conscious or coherent, yet their condition or the lack of time limits the possibility of informed consent [ 103 ]. These, and other challenges [ 34 ], can lead to consent-based recruitment bias which means that patients enrolled in RCTs may not necessarily be representative of critically ill patients in clinical practice [ 20 , 104 ]. This has the potential to cause harm by obscuring any treatment effect [ 105 ].

A recent study in the UK (Perspectives Study) explored consent and recruitment in adult critical care research [ 106 ] and identified strategies to enhance consent and recruitment processes. This led to the development of good practice guidance and other resources including an accessible animation for members of the public [ 107 ]. An animation aimed at adults enrolled in emergency care research which describes RWPC was developed by another research team (CoMMiTED Study) [ 108 ]. Systematic reviews have explored stakeholders’ views about the acceptability of RWPC [ 109 ], including ethnic minority populations’ views [ 110 ]. Such studies have found that RWPC is generally acceptable to patients, families, and practitioners but highlighted the importance of contextual factors.

The CATheter infections in Children Trial (CATCH) was the first UK trial to include research without prior consent when comparing the effectiveness of different types of central venous catheters to prevent bloodstream infections in children. An embedded study (called CONNECT [ 111 ]) explored parent and practitioner views and experiences of recruitment and consent and found that parents were momentarily shocked or surprised when they were informed that their child had already been entered into CATCH without their consent [ 101 ]. However, initial concerns were often quickly addressed by practitioner explanations about why it had not been possible to seek consent before enrolment and how the trial interventions were already used in clinical care. To prevent burden and assist decision-making, parents stated it was important for the research staff to assess the appropriate timing of research discussions after a child’s enrolment in a trial. They suggested that the researcher should consult with the bedside nurse about appropriate timing and only approach parents after the initial emergency situation has passed, when a child’s condition has stabilised [ 101 ]. The CONNECT study used these findings alongside wider research, involving practitioners, families [ 112 ], and children [ 113 ] with experience in emergency care, to develop guidance for future paediatric and neonatal trials [ 114 ]. Since its publication in 2015, CONNECT guidance has informed the successful conduct of five studies. This includes the first clinical trial of a drug for long-lasting seizures (EcLiPSE trial), which successfully recruited to time and target with a 93% consent rate and led to changes in clinical guidelines for children in status epilepticus [ 115 ].

Research into consent in emergency settings is high on the trials methodological research agenda and was identified as a research priority by Clinical Trials Units in a UK survey [ 116 ]. Areas for future research involving adults identified by the Perspectives Study included the need for evidence-based guidance on the procedures for professionals acting as a consultee or legal representative and identifying strategies to communicate with relatives of critically ill patients about research, including where a participant enrolled without prior consent subsequently dies [ 106 ]. The NIHR RfPB-funded study ‘ENHANCE’ will begin in 2023 and aims to address this gap in knowledge through the involvement of bereaved families and other key stakeholders.

Ongoing work in paediatric populations aims to assess and refine CONNECT guidance in low- and middle-income countries. Further work is needed to explore views on research without prior consent in underserved populations, such as parents who do not speak English and who are often excluded from qualitative studies and guidance development.

The need for more guidance for RECs who are reviewing emergency and urgent care trials and support for consent processes for patients and members of the public who join research teams and advise on studies, has also been highlighted [ 106 , 109 , 117 ].

Conclusions

The need for alternative consent processes that address the inadvertent exclusion of certain populations has been detailed in this article. Drives for trial efficiency, lack of funding, or time for adaptation often result in the exclusion of certain populations. However, inequities in health outcomes will continue to be exacerbated by health research until trials become more inclusive of underserved populations. Alongside methodological innovation, further research is required to establish good practice, develop evidence-based guidance, and support skill acquisition in the global research workforce. Our key recommendations for future research are summarised in Table 1 . Importantly, this should be done in collaboration with people with lived experience and those who care for them.

The populations detailed above are not the only areas where consent is complex or alternative pathways are required. Some trials have complex consent processes, not because of their recruited population, but due to an innovative treatment or trial design, such as cluster RCTs and Trials within Cohorts (TwiCs) [ 118 ]. As we progress with the innovation of trial design, we must progress methodological innovation in consent at the same pace or risk leaving certain populations behind. Many of the methodological lessons learnt and proposed adjustments, such as the routine provision of accessible information, could also benefit other underserved groups including those with lower literacy levels and English language proficiency, as well as the wider population of potential research participants.

The TMRP Complex and Alternate Consent Pathways group is driving forward this research agenda in the UK and is open to new members to share methodological learning. We have updated the NIHR Clinical Trials Toolkit [ 119 ] to reflect the most up-to-date research in this area. However, as this commentary has shown, current guidance remains limited in its utility and requires greater clarity and practical applicability for researchers, participants, family members, and ethical review committees. We are keen to use the momentum of the group to identify others with an interest in this area in order to collaboratively develop the research agenda and address the consent-based ethical and methodological challenges in trials. Many of these issues are not restricted to the UK but are encountered internationally, which raises additional challenges when conducting multi-national trials [ 58 , 97 , 120 ]. We encourage researchers from other regions and jurisdictions to share their experiences and ongoing research programmes and to contribute to developing an international research agenda to address these global challenges.

Availability of data and materials

Not applicable as no dataset was generated.

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Acknowledgements

We would like to thank the wider contributors to the Complex and Alternate Consent Pathways group and the MRC-NIHR Trials Methodology Research Partnership who have participated in the discussions at various stages of this work. JW would like to acknowledge the support of the QuinteT research group, University of Bristol.

No funding was received for this work. VS is supported by a National Institute of Health Research Advanced Fellowship (CONSULT) funded by the Welsh government through Health and Care Research Wales (NIHR-FS(A)-2021). AMR is supported by a Wellcome Trust Fellowship (Capacity, Consent and Autonomy https://capacityconsent.leeds.ac.uk/ ) (219754/Z/19/Z). AV is supported by a National Institute for Health Research Advanced Fellowship (NIHR302240). KG is supported by funding from the Chief Scientist Office of the Scottish Government’s Health and Social Care Directorate (CZU/3/3). This work was supported by the MRC-NIHR Trials Methodology Research Partnership (MR/S014357/1). RH is supported in part by the Wellcome Trust (209841/Z/17/Z and 223290/Z/21/Z), EPSRC (EP/T020792/1), and the NIHR Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol. RH also serves on various local, regional, and national ethics committees and related groups. None of the organisations played a role in the drafting of this article, and the opinions stated are those of the authors.

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Amy M. Russell and Victoria Shepherd are joint first authors.

Authors and Affiliations

Leeds Institute of Health Sciences, University of Leeds, Leeds, UK

Amy M. Russell

Centre for Trials Research, Cardiff University, 4th floor Neuadd Meirionnydd, Heath Park, Cardiff, CF14 4YS, UK

Victoria Shepherd

Department of Public Health, Policy and Systems, Institute of Population Health, University of Liverpool, Liverpool, UK

Kerry Woolfall & Bridget Young

Health Services Research Unit, University of Aberdeen, Aberdeen, UK

Katie Gillies

Department of Psychology and Language Sciences, University College London, London, UK

Anna Volkmer

Department of Health Professions, Manchester Metropolitan University, Manchester, UK

Centre for Ethics in Medicine, Population Health Science, Bristol Medical School, University of Bristol, Bristol, UK

Richard Huxtable

Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK

Alexander Perkins

Medical Research Council Clinical Trials Unit at University College London (MRC CTU at UCL), Institute of Clinical Trials and Methodology, University College London, London, UK

Nurulamin M. Noor

Centre for Evaluation and Methods, Wolfson Institute of Population Health, Queen Mary University London, London, UK

Beverley Nickolls

Population Health Science, Bristol Medical School, University of Bristol, Bristol, UK

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The original idea for this Complex and Alternate Consent Pathways group (C&ACP) arose from the discussions in the Trial Methodology Research Partnership (TMRP) Qualitative Research group and the Inclusivity subgroup of the Trial Conduct Working Group and was led by JW. All authors are members of the C&ACP group and contributed to the iterative discussion of the content and structure of the manuscript. AR and VS wrote the first draft of the paper, and all authors contributed to the revision of it. The authors read and approved the final manuscript.

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Correspondence to Victoria Shepherd .

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Russell, A.M., Shepherd, V., Woolfall, K. et al. Complex and alternate consent pathways in clinical trials: methodological and ethical challenges encountered by underserved groups and a call to action. Trials 24 , 151 (2023). https://doi.org/10.1186/s13063-023-07159-6

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• Interventions to suppress puberty in adolescents experiencing gender dysphoria or incongruence: a systematic review
• Article Text
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• http://orcid.org/0000-0001-5898-0900 Jo Taylor ,
• Alex Mitchell ,
• Ruth Hall ,
• Claire Heathcote ,
• Trilby Langton ,
• Lorna Fraser ,
• http://orcid.org/0000-0002-0415-3536 Catherine Elizabeth Hewitt
• Department of Health Sciences , University of York , York , UK
• Correspondence to Dr Jo Taylor, Health Sciences, University of York, York, North Yorkshire, UK; dohs-gender-research{at}york.ac.uk

Background Treatment to suppress or lessen effects of puberty are outlined in clinical guidelines for adolescents experiencing gender dysphoria/incongruence. Robust evidence concerning risks and benefits is lacking and there is a need to aggregate evidence as new studies are published.

Aim To identify and synthesise studies assessing the outcomes of puberty suppression in adolescents experiencing gender dysphoria/incongruence.

Methods A systematic review and narrative synthesis. Database searches (Medline, Embase, CINAHL, PsycINFO, Web of Science) were performed in April 2022, with results assessed independently by two reviewers. An adapted version of the Newcastle-Ottawa Scale for cohort studies was used to appraise study quality. Only moderate-quality and high-quality studies were synthesised. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines were used.

Results 11 cohort, 8 cross-sectional and 31 pre-post studies were included (n=50). One cross-sectional study was high quality, 25 studies were moderate quality (including 5 cohort studies) and 24 were low quality. Synthesis of moderate-quality and high-quality studies showed consistent evidence demonstrating efficacy for suppressing puberty. Height increased in multiple studies, although not in line with expected growth. Multiple studies reported reductions in bone density during treatment. Limited and/or inconsistent evidence was found in relation to gender dysphoria, psychological and psychosocial health, body satisfaction, cardiometabolic risk, cognitive development and fertility.

Conclusions There is a lack of high-quality research assessing puberty suppression in adolescents experiencing gender dysphoria/incongruence. No conclusions can be drawn about the impact on gender dysphoria, mental and psychosocial health or cognitive development. Bone health and height may be compromised during treatment. More recent studies published since April 2022 until January 2024 also support the conclusions of this review.

PROSPERO registration number CRD42021289659.

Data availability statement

Data sharing not applicable as no datasets generated and/or analysed for this study.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See:  http://creativecommons.org/licenses/by-nc/4.0/ .

https://doi.org/10.1136/archdischild-2023-326669

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WHAT IS ALREADY KNOWN ON THIS TOPIC

Increasing numbers of children and adolescents experiencing gender dysphoria/incongruence are being referred to specialist gender services.

National and international guidelines have changed over time and outline that medications to suppress puberty can be considered for adolescents experiencing gender dysphoria/incongruence.

Several systematic reviews report a limited evidence base for these treatments, and uncertainty about the benefits, risks and long-term effects.

WHAT THIS STUDY ADDS

No high-quality studies were identified that used an appropriate study design to assess the outcomes of puberty suppression in adolescents experiencing gender dysphoria/incongruence.

There is insufficient and/or inconsistent evidence about the effects of puberty suppression on gender-related outcomes, mental and psychosocial health, cognitive development, cardiometabolic risk, and fertility.

There is consistent moderate-quality evidence, although from mainly pre-post studies, that bone density and height may be compromised during treatment.

HOW THIS STUDY MIGHT AFFECT RESEARCH, POLICY OR PRACTICE

There is a lack of high-quality evidence to support the use of puberty suppression in adolescents experiencing gender dysphoria/incongruence, and large well-designed research is needed.

Introduction

Over the last 10-15 years, increasing numbers of children and adolescents experiencing gender dysphoria/incongruence are being referred to specialist paediatric gender services. 1 2

Gender dysphoria/incongruence in childhood is associated with high rates of co-occurring mental health and psychosocial difficulties, which can affect health and well-being. 3 Clinical guidelines recommend psychosocial care to alleviate gender-related distress and any co-occurring difficulties. For pubertal adolescents, medications to suppress or lessen effects of puberty are also outlined. Gonadotropin-releasing hormone analogues (GnRH-a) are used as first-line treatment, although other drugs with anti-androgenic properties including progestins and spironolactone are used in this population. 4 5 The effects differ depending on whether they are initiated in early puberty or mid-puberty, as well as the type of intervention used, with GnRH-a suppressing puberty when started early or suspending further progression when initiated in mid-puberty, and anti-androgens instead blocking specific downstream effects of sex hormones. 4

Rationales for puberty suppression in the Dutch treatment protocol, which has informed practice internationally, were to alleviate worsening gender dysphoria, allow time for gender exploration, and pause development of secondary sex characteristics to make passing in the desired gender role easier. 6 Practice guidelines propose other indications for puberty suppression, including allowing time and/or capacity for decision-making about masculinising or feminising hormone interventions, and improving quality of life. 4 7 8

Criteria in early treatment protocols for puberty suppression specified adolescents be at least age 12 years, at Tanner stage 2 in puberty, experienced gender dysphoria in childhood which persisted and intensified during puberty and met criteria for diagnosis of gender dysphoria. 6 It was also expected that any psychosocial difficulties that could interfere with treatment were managed. 6 The World Professional Association for Transgender Health standards of care 4 and other practice guidelines 5 8 9 have broadened these criteria, for example, removing minimum age. However, other recent guidelines have taken a more cautious approach and restricted inclusion criteria in response to uncertainties in the evidence base. 7 10

Systematic reviews have consistently found mainly low-quality evidence, limited data on key outcomes or long-term follow-up. 11–16 These reviews report that while puberty suppression may offer some benefit, there are concerns about the impact on bone health, and uncertainty regarding cognitive development, psychosocial outcomes and cardiometabolic health. They conclude there is insufficient evidence to support clinical recommendations.

The proliferation of research in this area and lack of evidence to support practice means there is an ongoing need to aggregate evidence. This systematic review aims to synthesise evidence published to April 2022 that reports outcomes of puberty suppression in adolescents experiencing gender dysphoria/incongruence.

The review forms part of a linked series examining the epidemiology, care pathways, outcomes and experiences for children and adolescents experiencing gender dysphoria/incongruence and is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. 17 The protocol was registered on PROSPERO (CRD42021289659. 18

Search strategy

A single search strategy was used to identify studies comprising two combined concepts: ‘children’, which included all terms for children and adolescents and ‘gender dysphoria’, which included associated terms such as gender-related distress and gender incongruence, and gender identity terms including transgender, gender diverse and non-binary.

MEDLINE ( online supplemental table S1 ), EMBASE and PsycINFO through OVID, CINAHL Complete through EBSCO, and Web of Science (Social Science Citation Index) were searched (13–23 May 2021 and updated on 27 April 2022).

Supplemental material

Reference lists of included studies and relevant systematic reviews were assessed for inclusion. 11–16 19 20

Inclusion criteria

The review included published research that reported outcomes of interventions used to suppress puberty for children and/or adolescents experiencing gender dysphoria/incongruence ( table 1 ).

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Inclusion and exclusion criteria

Selection process

The results of database and other searches were uploaded to Covidence 21 and screened independently by two reviewers. Full texts of potentially relevant articles were retrieved and reviewed against inclusion criteria by two reviewers independently. Disagreements were resolved through discussion and inclusion of a third reviewer.

Data extraction

Data on study characteristics, methods and reported outcomes were extracted into prepiloted data extraction templates by one reviewer and second-checked by another.

Study quality

Critical appraisal was undertaken by two reviewers independently, with consensus reached through discussion and involvement of a third reviewer where necessary.

Quality was assessed using a modified version ( online supplemental file 1 ) of the Newcastle-Ottawa Scale for cohort studies, a validated scale of eight items covering three domains: selection, comparability and outcome. 22 Scale modification included not scoring certain question(s) for cross-sectional and single-group designs, or particular outcomes; specification of key confounders to assess comparability of cohorts; guidance regarding sufficiency of follow-up and use of numerical scores for items and overall (maximum score 9 for cohorts, 8 for pre-post and cross-sectional studies with comparator). Total scores were calculated as percentages to account for different total scores (≤50% low quality, >50%–75% moderate quality, >75% high quality).

Narrative synthesis methods were used because of heterogeneity in study design, intervention, comparator, outcome and measurement. Due to high risk of bias in low-quality studies, these were excluded from the synthesis.

When synthesising results by outcome domains, care was taken to differentiate between different study designs, comparators and interventions. Where possible, potential differences in effects by birth-registered sex, treatment duration or treatment in early puberty versus late puberty were examined.

The database search yielded 28 147 records, 3181 of which were identified as potentially relevant for the linked systematic reviews and full texts reviewed. From these, 50 studies met inclusion criteria for this review ( figure 1 ).

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Study flow diagram.

Study characteristics

Studies were published from 2006 to 2022 with the majority published in 2020–2022 (n=29). Studies were conducted in the Netherlands (n=17), 23–39 the US (n=15), 40–54 the UK (n=6), 55–60 Canada (n=4), 61–64 three in Belgium 65–67 and Israel 68–70 and one in Brazil 71 and Germany 72 ( online supplemental table S2 ).

The 50 studies included 11 cohorts comparing adolescents experiencing gender dysphoria/incongruence receiving puberty suppression with a comparator, 35 39–42 45 49 50 52 56 72 8 cross-sectional with a comparator 23 33 37 47 51 53 60 71 and 31 pre-post single group studies. 24–32 34 36 38 43 44 46 48 54 55 57–59 61–70 More than half of studies (n=29) used retrospective chart review.

All but 4 studies selected adolescents experiencing gender dysphoria/incongruence from specialist gender or endocrinology services: 43 from single services (in Belgium, Israel, the Netherlands and the UK these were large regional or national services) and 3 from multiple US services. 48–50 The other four included three US studies (national survey recruiting via community settings, 53 clinical and community settings, 51 US Military Healthcare Data Repository 54 ) and a study from Brazil recruiting via Facebook. 71

Overall, studies included 10 673 participants: 9404 were adolescents experiencing gender dysphoria/incongruence (4702 received puberty suppression, 4702 did not) and 1269 other comparators. Comparator groups included adolescents or adults experiencing gender dysphoria/incongruence who had not received puberty suppression, 35 39 40 42 51–53 60 71 72 untreated adolescents not experiencing gender dysphoria/incongruence, 36 47 50 both of these comparators 23 33 37 56 or adolescents receiving treatment for a different medical reason. 41 45 49

Most studies (n=39) assessed GnRH-a. In one, some participants received GnRH-a and some (birth-registered males) spironolactone. 62 In another, GnRH-a or progestins/anti-androgens were used but numbers taking each were not reported. 40 Among the other 11 studies, 5 assessed effects of progestins (cyproterone acetate, 66 67 lynestrenol, 65 66 medroxyprogesterone 44 and levonorgestrel-releasing intrauterine system 41 ) as alternatives to GnRH-a, 41 44 65–67 1 assessed bicalutamide 46 and 5 did not specify. 43 52–54 71

Of the 50 studies, 29 reported outcomes for feminising or masculinising hormones as well as for puberty suppression, either by including a mixed sample of those receiving the two different interventions or by assessing those who progressed to hormones following puberty suppression.

The most frequently measured outcomes were puberty suppression (n=30) and physical health outcomes (n=27) ( figure 2 , online supplemental table S3 ). Gender-related outcomes and body image were measured in five and four studies, respectively. Psychological health was measured in 13 studies, psychosocial in 9 studies and cognitive/neurodevelopmental outcomes in 3 studies. Side effects were reported in six, bone health in nine, and one study measured fertility.

Outcome categories by study quality and design.

One cross-sectional study was rated high quality, 37 25 moderate quality 23 24 29–32 34–36 39 48–51 54–59 64 65 67–69 and 24 low quality. 25–28 33 38 40–47 52 53 60–63 66 70–72 Of the 11 cohort studies, which were the only studies to include a comparator and assess outcomes over time, only 5 were rated moderate quality ( figure 2 , online supplemental table S4 ). 35 39 49 50 56

In most studies, there were concerns about sample representativeness due to single site recruitment, inclusion of a selected group and/or poor reporting of the eligible population. In studies including a comparator, most did not report or control for key differences between groups and only four used matched controls. 23 33 41 47 Most studies presented results for birth-registered males and females separately or controlled for this. Few studies controlled for age or Tanner stage or co-interventions that could influence outcomes.

Overall, studies used appropriate methods to ascertain exposure and assess outcomes. Adequacy of follow-up was evident in 18 studies, with multiple studies not reporting treatment duration, including participants receiving treatment at baseline, and not aligning follow-up with treatment initiation. Missing data at follow-up/analysis or poor reporting of this affected many studies.

Four studies did not report separate outcome data for adolescents receiving puberty suppression or masculinising/feminising hormones. 39 54 60 71 Two of these were of moderate quality and not included in the synthesis, 39 54 one of which was the only study to assess fertility outcomes. 39 One moderate-quality study assessed amplitude of click-evoked otoacoustic emissions. 23 This was excluded from the synthesis on the basis of not being clinically relevant.

Synthesis of outcomes

Gender dysphoria and body satisfaction.

Two pre-post studies measured gender dysphoria and body satisfaction (with primary and secondary sex or neutral body characteristics) and reported no change before and after receiving treatment 24 55 ( table 2 ).

Gender-related, body image, psychological, psychosocial, and cognitive/neurodevelopmental outcomes

Psychological health

One cross-sectional 37 and two pre-post studies 24 55 measured symptoms of depression (n=1), anxiety (n=1), anger (n=1), internalising and externalising symptoms (n=3), suicide and/or self-harm (n=2) and psychological functioning (n=2).

Three studies assessed internalising and externalising symptoms with one reporting improvements in both (pre-post 24 ), one improvement in internalising but not externalising symptoms when compared with adolescents under assessment by a gender service (cross-sectional 37 ) and one observed no change in either (pre-post). 55

For other psychological outcomes, there was either a single study, or two studies showing inconsistent results, with studies reporting either a small to moderate significant improvement or no change ( table 2 ).

Psychosocial outcomes

One cohort 56 and two pre-post 24 55 studies measured psychosocial functioning, one pre-post study assessed quality of life 55 and one cross-sectional study measured peer-relations ( table 2 ). 37

For psychosocial functioning, both pre-post studies reported no clinically significant change at follow-up. 24 55 The cohort study compared adolescents who were not immediately eligible for puberty suppression and received psychological support only, and adolescents who additionally received GnRH-a after 6 months. 56 Improvements were seen in both groups after 6 months of psychological support. This improvement was maintained over time for those receiving psychological support only. For those receiving GnRH-a, further improvements were observed at 12 and 18 months. At 18 months, psychosocial functioning in this group was considerably higher than in those still waiting for puberty suppression, and similar to adolescents not experiencing gender dysphoria/incongruence. However, there were considerably fewer participants included at final follow-up.

There was no change in quality of life pre-post, 55 and treated adolescents had better peer-relations compared with adolescents under assessment at a gender service but poorer peer-relations than adolescents not experiencing gender dysphoria/incongruence. 37

Cognitive/neurodevelopmental outcomes

One cross-sectional study measured executive functioning and found no difference between adolescents who were treated for <1 year compared with those not treated, but worse executive functioning in those treated for >1 year compared with those not treated. 51 A pre-post study found no differences in features typically associated with autism spectrum condition after treatment ( table 2 ). 59

Physical health outcomes

Bone health.

Five studies found decreases in bone mineral apparent density and z-scores pre-post treatment; however, absolute measures generally remained stable or increased/decreased slightly. 29 32 34 55 58 Results were similar across birth-registered males and females. 29 32 55 58 One study considered timing of treatment, and found similar decreases among those starting GnRH-a in early or late puberty ( table 3 ). 32

Physical health outcomes and side effects

Cardiometabolic health

Twelve pre-post studies measured body mass index (BMI), and in 10 studies there was no evidence of a clinically significant change in BMI and/or BMI SD score. 29 30 32 34 55 57 65 67–69 In one study, BMI increased for birth-registered males but not females. 58 Another study found BMI increased for birth-registered females who started GnRH-a in early puberty or mid-puberty, and birth-registered males in early puberty. 36

Three studies assessed cholesterol markers, one after GnRH-a (no changes), 34 one after cyproterone acetate (decrease in high-density lipoprotein (HDL) and triglycerides) 67 and one after lynestrenol (decrease in HDL, increase in low-density lipoprotein). 65 Three studies assessing GnRH-a reported blood pressure: two found similar systolic and diastolic blood pressure before and after treatment, 34 68 and one found a non-clinically significant increase in diastolic but not systolic blood pressure. 69 Two studies measured markers of diabetes (fasting glucose, HbA1c and/or insulin) and noted no changes. 65 67

Other physiological parameters

Five pre-post studies assessed other parameters from blood tests undertaken at baseline and follow-up, 30 31 34 65 67 three in those treated with GnRH-a, 30 31 34 one lynestrenol 65 and one cyproterone acetate. 67 Measurements included haemoglobin count (n=3), haematocrit percentage (n=3), creatinine (n=4), aspartate aminotransferase (n=3), alanine aminotransferase (n=3), γ-glutamyl transferase (n=1), alkaline phosphatase (n=2), prolactin (n=2), free thyroxin (n=3), thyroid-stimulating hormone (n=3), sex hormone binding globulin (n=3), vitamin D levels (n=1), dehydroepiandrosterone sulfate (n=3) and androstenedione (n=2). For most outcomes, no changes were reported. Where there were changes, these were not consistent in direction across studies.

One pre-post study assessing GnRH-a reported QTc prolongation, 64 and found no change in mean QTc, with no participants outside normal range.

Side effects

A cohort study of GnRH-a reported side effects including mild headaches or hot flushes (~20%) and moderate/severe headaches or hot flushes, mild fatigue, mood swings, weight gain and sleep problems (<10%) ( table 3 ). 55

Two studies assessed other medications and reported headaches and hot flushes as common and an increase in acne in a sample of birth-registered females receiving lynestrenol, 65 and complaints of fatigue in birth-registered males receiving cyproterone acetate. 67

Puberty suppression

Hormone levels.

Hormone levels were reported in nine studies of GnRH-a (two cohort, 49 50 seven pre-post 30 34 36 48 55 68 69 ), two in birth-registered females, 34 69 one in birth-registered males 68 and six including both ( table 4 ). 30 36 48–50 55

Puberty suppression outcomes

Five studies reported decreases in luteinising hormone, follicle-stimulating hormone, oestradiol and testosterone after receiving GnRH-a. 30 34 48 68 69 Another study, which reported luteinising and follicle-stimulating hormones, also found decreases in both pre-post. 55 One study reported that where baseline levels were high due to puberty starting, decreases were reported in testosterone and oestradiol. 36 One cohort study reporting pre-post data found smaller decreases in luteinising hormone, follicle-stimulating hormone, oestradiol and testosterone compared with other studies; however, it included a younger population, some of who were likely prepubertal. 50 The other cohort study included a comparator of adolescents with precocious puberty and found similar decreases in luteinising hormone and oestradiol. 49

One pre-post study of lynestrenol (birth-registered females) found a decrease in luteinising hormones but not follicle-stimulating hormone, oestradiol or testosterone. 65 One study of cyproterone acetate (birth-registered males) found no changes in luteinising hormone, follicle-stimulating hormone or oestradiol, but a decrease in total testosterone. 67

Pubertal progression

Puberty development was reported in four studies (two cohort, two pre-post). 30 35 49 67 One only included birth-registered males, 67 and three included both birth-registered males and females. 30 35 49

A cohort study assessing GnRH-a reported clinical pubertal escape in 2/21 adolescents treated for gender dysphoria/incongruence, in the form of breast enlargement or testicular enlargement together with deepening of voice, compared with no children treated for precocious puberty. 49 A pre-post study reported a decrease in testicular volume in birth-registered males, but unclear results with regard to breast development in birth-registered females (most started treatment at Tanner stage 4–5). 30 A pre-post study of birth-registered males using cyproterone acetate reported decreases in facial shaving and spontaneous erections. 67

A cohort study assessed whether secondary sex characteristics differed depending on receipt or timing of GnRH-a, and whether this affected which surgical interventions/techniques were later used. 35 The study found breast size was smallest in birth-registered females who received GnRH-a in Tanner stage 2/3 and largest in untreated participants. Those treated early in puberty were less likely to require a mastectomy and when surgery was required it was less burdensome. In birth-registered males, penile length was greater in those who received GnRH-a at Tanner stage 4/5 compared with Tanner stage 2/3, and greatest in untreated participants. 35 Those who received GnRH-a early required more invasive vaginoplasty techniques than those who received it later or not at all.

Menstrual suppression

Three studies (one cohort, two pre-post) measured menstrual suppression in birth-registered females, and found full suppression at follow-up, 30 49 55 which was similar to the effect seen in those with precocious puberty in the cohort study. 49

Height/Growth

Eleven studies (1 cohort, 50 10 pre-post 29 30 32 34 36 55 57 58 65 67 ) reported height, nine after GnRH-a, 29 30 32 34 36 50 55 57 58 one lynestrenol 65 and one cyproterone acetate. 67 The cohort study found a similar height velocity between the GnRH-a group and adolescent controls. 50 Six studies reported height Z or SD score 29 30 34 55 57 67 with two studies finding no change, 34 55 two a decrease for birth-registered males but not females, 29 57 one a decrease across birth-registered males and females 30 and one a decrease in birth-registered males with cyproterone acetate. 67 Absolute measures of height generally increased slightly or remained the same. 29 30 32 34 36 58 65 67

Body composition

Two studies reported changes in body composition pre-post, 30 57 reporting a significant decrease in lean mass SD score 57 and percentage 30 in males and females. One also measured body fat percentage and reported significant increases in both groups. 30

Bone geometry

One pre-post study measured the subperiosteal width and endocortical diameter of the hip bone and found that in birth-registered males these increased in those starting GnRH-a in early puberty and mid-puberty, but only in the early puberty group for birth-registered females. 36

This systematic review identified 50 studies reporting outcomes relating to puberty suppression in adolescents experiencing gender dysphoria/incongruence. No high-quality studies using an appropriate design were identified, and only four measured gender dysphoria as an outcome. Only 5 of the 11 cohort studies, which were the only studies to compare groups over time, were rated as moderate quality. 35 40 49 50 56

There was evidence from multiple mainly pre-post studies that puberty suppression exerts its expected physiological effect, as previously demonstrated in children with precocious puberty. 73 In adolescents experiencing gender dysphoria/incongruence, puberty suppression is initiated at different stages of puberty, 74 and two studies found that the effects on secondary sex characteristics may vary depending on whether treatment is initiated in early puberty versus mid-puberty, with potentially different outcomes for birth-registered males and females. 30 35 Multiple studies also found that bone density is compromised during puberty suppression, and gains in height may lag behind that seen in other adolescents. High-quality research is needed to confirm these findings; however, these potential risks should be explained to adolescents considering puberty suppression.

These findings add to other systematic reviews in concluding there is insufficient and/or inconsistent evidence about the effects of puberty suppression on gender dysphoria, body satisfaction, psychological and psychosocial health, cognitive development, cardiometabolic risk and fertility. 11–16 Regarding psychological health, one recent systematic review 14 reported some evidence of benefit while others have not. The results in this review found no consistent evidence of benefit. Inclusion of only moderate-quality to high-quality studies may explain this difference, as 8 of the 12 studies reporting psychological outcomes were rated as low-quality.

The lack of representativeness of samples and comparability of selected control groups were key concerns across studies. Only one study attempted to compare puberty suppression with psychosocial care, which is the only other treatment offered for gender dysphoria/incongruence in childhood, and this included a small sample, limited analyses, and little detail about the intervention. 56 Other studies lacked information about any psychological care provided to participants, and in studies that included a comparator there was limited information about any differences between groups. Large, well-designed studies with appropriate comparators that enable long-term outcomes of puberty suppression to be measured are needed.

Many studies reported effects of both puberty suppressants and hormones used in later adolescence for feminisation/masculinisation. In adolescents, GnRH-a often continues during hormone treatment, 74 or for adolescents who do not receive puberty suppression, GnRH-a or other anti-androgens may be offered at initiation of hormones. 66 This makes long-term follow-up of puberty suppression difficult to assess, including any differences between the types of interventions that are offered and when these are initiated, and the few studies reporting long-term outcomes either did not control for this or reported overall effects for both interventions. Although recent studies suggest nearly all adolescents who receive puberty suppression go on to feminising/masculinising hormones, 74–76 research is still needed to assess whether suppression will have any lasting effects for those who do not. Aggregation of studies reporting proportions of adolescents who progress to hormones and reasons for discontinuation would also offer useful insights.

Interim report

The Cass Review has submitted an interim report to NHS England, which sets out our work to date, what has been learnt so far and the approach going forward. The report does not set out final recommendations at this stage.

At present there is a single specialist service providing gender identity services for children and young people – the Gender Identity Development Service (GIDS) at the Tavistock and Portman NHS Foundation Trust.

In recent years GIDS has experienced a significant increase in referrals which has contributed to long waiting lists and growing concern about how the NHS should most appropriately assess, diagnose and care for this population of children and young people.

Key points – context

• The rapid increase in the number of children requiring support and the complex case-mix means that the current clinical model, with a single national provider, is not sustainable in the longer term. 
•  We need to know more about the population being referred and outcomes. There has not been routine and consistent data collection, which means it is not possible to accurately track the outcomes and pathways that children and young people take through the service.  
•  There is lack of consensus and open discussion about the nature of gender dysphoria and therefore about the appropriate clinical response. 
•  Because the specialist service has evolved rapidly and organically in response to demand, the clinical approach and overall service design has not been subjected to some of the normal quality controls that are typically applied when new or innovative treatments are introduced.   

Key points – moving forward

• Children and young people with gender incongruence or dysphoria must receive the same standards of clinical care, assessment and treatment as every other child or young person accessing health services.  
• The care of this group of children and young people is everyone’s business. Our initial work indicates that clinicians at all levels feel they have the transferable skills and commitment to support these children and young people, but there needs to be agreement and guidance about the appropriate clinical assessment process that should take place at primary, secondary and tertiary level, underpinned by better data and evidence.  
• Addressing the challenges will require service transformation, with support offered at different levels of the health service.
• The Review’s research programme will not just build the evidence base in the UK but will also contribute to the global evidence base, meaning that young people, their families, carers and the clinicians supporting them can make more informed decisions about the right path for them.    

A fundamentally different service model is needed which is more in line with other paediatric provision, to provide timely and appropriate care for children and young people needing support around their gender identity. This must include support for any other clinical presentations that they may have.

It is essential that these children and young people can access the same level of psychological and social support as any other child or young person in distress, from their first encounter with the NHS and at every level within the service.

The Review team will work with NHS England, providers and the broader stakeholder community to further define the service model and workforce implications.

At this stage the Review is not able to provide advice on the use of hormone treatments due to gaps in the evidence base. Recommendations will be developed as our research programme progresses.

• Download the Interim report

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A systematic review of the clinical features of pneumonia in children aged 5-9 years: Implications for guidelines and research

Priya m kevat.

1 Murdoch Children’s Research Institute, Melbourne, Victoria, Australia

2 University of Melbourne, Melbourne, Victoria, Australia

3 Royal Children’s Hospital Melbourne, Melbourne, Victoria, Australia

Melinda Morpeth

Hamish graham, associated data.

Childhood pneumonia presents a large global burden, though most data and guidelines focus on children less than 5 years old. Less information is available about the clinical presentation of pneumonia in children 5-9 years of age. Appropriate diagnostic and treatment algorithms may differ from those applied to younger children. This systematic literature review aimed to identify clinical features of pneumonia in children aged 5-9 years, with a focus on delineation from other age groups and comparison with existing WHO guidance for pneumonia in children less than 5 years old.

We searched MEDLINE, EMBASE and PubMed databases for publications that described clinical features of pneumonia in children 5-9 years old, from any country with no date restriction in English. The quality of included studies was evaluated using a modified Effective Public Health Project Practice (EPHPP) tool. Data relating to research context, study type, clinical features of pneumonia and comparisons with children less than 5 years old were extracted. For each clinical feature of pneumonia, we described mean percentage (95% confidence interval) of participants with this finding in terms of aetiology (all cause vs Mycoplasma pneumoniae ), and method of diagnosis (radiological vs clinical).

We included 15 publications, eight addressing all-cause pneumonia and seven addressing Mycoplasma pneumoniae . Cough and fever were common in children aged 5-9 years with pneumonia. Tachypnoea was documented in around half of patients. Dyspnoea/difficulty breathing and chest indrawing were present in approximately half of all-cause pneumonia cases, with no data on indrawing in the outpatient setting. Chest and abdominal pain were documented in around one third of cases of all-cause pneumonia, based on limited numbers. In addition to markers of pneumonia severity used in children <5 years, pallor has been identified as being associated with poorer outcomes alongside comorbidities and nutritional status.

Conclusions

Quality research exploring clinical features of pneumonia, treatment and outcomes in children aged 5-9 years using consistent inclusion criteria, definitions of features and age ranges are urgently needed to better inform practice and guidelines. Based on limited data fever and cough are common in this age group, but tachypnoea cannot be relied on for diagnosis. While waiting for better evidence, broader attention to features such as chest and abdominal pain, the role of chest radiographs for diagnosis in the absence of symptoms such as tachypnoea, and risk factors which may influence patient disposition (chest indrawing, pallor, nutritional status) warrant consideration by clinicians.

Protocol registration

PROSPERO: CRD42020213837.

Childhood pneumonia is responsible for a large mortality burden globally however most guidelines for low resource settings are focused on pneumonia in children less than 5 years old [ 1 , 2 ]. Focus on young children has been justified by the fact that more than 90% of childhood pneumonia deaths occur in young children less than 5 years of age [ 3 ]. Yet pneumonia is also important for older children. Global Burden of Disease estimates suggest that pneumonia accounts for around 7% of deaths in children aged 5-9 years [ 3 ].

While children aged 5-9 years are generally regarded as at lower risk for pneumonia and pneumonia death, the risk may still be substantial in certain contexts or patient cohorts (for example, children with chronic health conditions or disability). Appropriate diagnostic and treatment algorithms may differ from those applied to younger children and this group has not been addressed in previous guidelines.

The aim of this review was to describe the available evidence for clinical features of pneumonia in children aged 5-9 years in community, primary care, or hospital settings, with a focus on delineation from other age groups and comparison with existing WHO guidance for pneumonia in young children.

The protocol for this study was registered on PROSPERO, the international prospective register of systematic reviews (registration number CRD42020213837). We searched MEDLINE via Ovid, EMBASE via Ovid and PubMed in August 2020 using key search terms including synonyms for pneumonia, ages 5-9 years, and clinical findings or diagnosis (example in Appendix S1 in the Online Supplementary Document ). No date restriction was applied. We did not restrict by location of study but for practical reasons we restricted the search to studies available in English language.

We included studies that contained original data on the clinical features of pneumonia among children aged 5-9 years, published in English language. We excluded case reports, small case series (<10 participants), conference abstracts, or those in which data relating to children aged 5-9 years was not meaningfully disaggregated.

PK completed initial title and abstract screening. Full-text screening was completed by three reviewers (PK, MM, AG), with each article screened by two of these reviewers (PK, MM, AG) and any conflicts resolved by the majority opinion from the third remaining reviewer (PK, MM, AG). Reference lists of included articles were searched to identify additional relevant studies missed from the search.

We extracted data from included studies with a standardised data extraction tool. Information extracted included: year of publication, study details, inclusion and exclusion criteria, pneumonia diagnostic/case definition criteria, aetiological agent(s), participant characteristics (including socioeconomic status), presence of comorbid conditions, respiratory and extra-pulmonary clinical features, chest radiograph findings, treatment received, and outcomes, with comparison to the under 5 years age group wherever possible. Data extraction was completed by two reviewers (PK, MM), with data from each article extracted by one of these reviewers (PK, MM) and the extracted information checked by the second reviewer (PK, MM). Any conflicts were resolved by the majority opinion from a third reviewer (AG).

We separated data from studies describing pneumonia of any aetiology (all-cause pneumonia) and studies describing pneumonia attributed to Mycoplasma pneumoniae , given that several studies addressed Mycoplasma pneumoniae specifically. For each clinical feature, we described the number and percentage of patients who were documented to have the feature in each study. Using aggregated data of all studies which included each clinical feature we calculated the mean percentage and 95% confidence interval according to the cause of pneumonia (all-cause and attributable to Mycoplasma pneumoniae ) and the method of diagnosis (radiological or clinical). If studies stipulated their inclusion criteria as a clinical diagnosis with or without radiological diagnosis, they were included in the studies based on clinical diagnosis for analysis (as we were unable to identify which participants had a radiograph performed). Due to the relatively weak quality of the studies identified and the variable nature of the data from the studies we did not perform any additional statistical analysis, to avoid over-interpretation of the data available.

We used the EPHPP tool to evaluate the risk of bias in included studies [ 4 ]. This tool was modified to assess the study designs included (Table S1 in the Online Supplementary Document ). Application of the EPHPP tool required separate evaluation and consensus between two reviewers (PK, MM).

The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement was followed, with a checklist completed (Table S2 in the Online Supplementary Document ) [ 5 ].

A total of 2641 references were retrieved, and an additional four relevant publications were identified through reference list screening ( Figure 1 ). After duplicates were removed, 1776 references were screened, and 301 proceeded to full-text review. Two articles were excluded as the full text was unavailable, after authors were contacted twice to request them. Fifteen studies were included in qualitative synthesis after inclusion and exclusion criteria were applied.

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram.

Study descriptions

Studies had variable methods to identify patients with pneumonia. Seven of the 15 studies included children with radiologically confirmed pneumonia (two of these requiring clinical features in addition) and eight of the 15 studies were based on clinical diagnosis with or without a radiograph. The heterogeny in diagnostic methods was significant. For example, one study based on radiological diagnosis only included patients with obvious chest indrawing. Furthermore, of those based on clinical diagnosis, three studies included children with or without a radiograph being performed, three required clinician diagnosis alone, and two studies were of Mycoplasma pneumoniae positive patients that described clinical features and/or chest radiograph changes consistent with pneumonia. Eight studies addressed all-cause pneumonia ( Table 1 ) whilst seven discussed pneumonia attributable to Mycoplasma pneumonia e, based on a variety of diagnostic assays ( Table 2 ). Three out of the 15 studies, Macpherson et al [ 12 ], Salih et al [ 13 ] and Forgie et al [ 11 ], were from low or lower-middle income settings. Twelve studies described inpatients only, one study by Harris et al [ 9 ] was of outpatients, and two studies by Korppi et al [ 8 ] and Othman et al [ 19 ] included a combination of inpatients and outpatients.

Clinical features described in children aged 5-9 y diagnosed with pneumonia of any aetiology (all-cause pneumonia)

CAP – community acquired pneumonia, RCT – randomised controlled trial, WCC – white cell count, PFTs – pulmonary function tests, ALRI – acute lower respiratory infection, CXR – chest x-ray, y – year, mo – months

*Values significant with P  < 0.05 when the <2 years group was compared to the ≥2 years group (combined data for 2-4 years and ≥5 years).

†Corrected percentage value due to error in calculated percentage within study.

‡Tachypnoea was defined by age-specific WHO criteria: respiratory rate >50 breaths/min in infants <12 months old, >40 breaths/min in children aged 1-5 years and >30 breaths/min in children aged ≥6 years.

§Conventional therapy = amoxicillin/clavulanate if ≤5 years of age and erythromycin if >5 y of age.

‖Abnormal respiratory rate was defined as >24 breaths/min for patients ≤2 year of age and >20 breaths/min for patients >2 year of age.

¶Fever was defined as ≥100.5°F oral or ≥101°F rectal, or history in the last 24 h.

**Absolute numbers and percentages are extrapolated data.

†† P values not calculated in this study.

‡‡Weight <80% of median value using National Center for Health Statistics reference values (United States Department of Health, Education and Welfare, 1976).

Clinical features described in children aged 5-9 y diagnosed with pneumonia attributable to Mycoplasma pneumoniae

ICD-10 - International Classification of Diseases 10th edition, CXR – chest x-ray, PCR – polymerase chain reaction, CAP – community acquired pneumonia, LRTI – lower respiratory tract infection, ICU – intensive care unit, VATS – video-assisted thorascopic surgery, y – years, d – days

*Pneumonia pattern characterised by WHO Standardization of Interpretation of Chest Radiographs for the diagnosis of community acquired pneumonia in children.

†Study text states that “one-half of the children had lobar pneumonia in both groups”, however study Figure 3 suggests a higher number (between 40 and 60 patients with lobar pneumonia for each of the ≤5 years and >5 years groups).

‡Data for a symptom/sign was included if able to be disaggregated from combined data.

§ P values relate to comparison of <5 years group with 5 to <10 years and 10-14 years groups.

‖Tachypnoea was defined as a respiratory rate >99 th percentile for age.

¶Includes any type of rash, urticaria and Stevens-Johnson Syndrome.

**112/134 total patients had CXRs, fraction of children aged 7-15 years who had CXRs not specified.

††Absolute numbers and percentages not described.

Three of the eight studies that explored all-cause pneumonia included patients with comorbid conditions, three specifically excluded those with comorbidities, and two did not specify information about comorbidities. A significant proportion of participants aged 5-9 years in study by Macpherson et al had comorbid disease including malaria (28.77%), asthma (10.91%), neurological disorders (10.77%), severe malnutrition (9.48%) or HIV (8.32%) [ 12 ]. Meanwhile, 46% of children aged 5-14 years in study by Salih et al were underweight [ 13 ], and a variety of underlying chronic comorbid conditions were described by Udomittipong et al but not disaggregated by age [ 10 ]. Within the group of studies addressing Mycoplasma pneumoniae , four included those with chronic conditions or comorbidities, two excluded children with these and one did not specify information about comorbidities. Chronic pulmonary disease and asthma were most frequently described as pre-existing underlying disease [ 17 , 19 , 20 ].

Most studies were of weak quality when assessed with the EPHPP tool ( Table 1 and Table 2 ). The exceptions were Macpherson et al [ 12 ] and Harris et al [ 9 ], which were assessed as moderate quality. There were seven retrospective observational studies, six studies with prospective recruitment of participants, one randomized controlled trial (RCT) and one descriptive study based on interview and questionnaire data. Describing clinical features of pneumonia was a primary objective in thirteen of the studies; two were not conducted with this as a primary aim but included clinical features of pneumonia in a description of participants. Many studies (8/15) did not specify or utilise a standardised data collection method. Although all studies included participants aged 5-9 years, study populations also included older and younger children. Three studies provided data disaggregated for the 5-9 age range exactly; the remaining twelve studies overlapped with the target population with a sufficiently close age range to be representative. In some studies, there was a paucity of disaggregated data relating to clinical features in children 5-9 years old. There were also differing definitions and terms for some clinical features between studies. Most importantly, the definition of fast breathing varied from >20 breaths per minute [ 9 ], to >40 breaths per minute [ 8 ], to a respiratory rate >99 th percentile for age [ 20 ].

Study outcomes

Aggregated data regarding the proportion of older children with specific respiratory symptoms and extra-pulmonary clinical features is summarised in Table 3 .

Overall data regarding proportion of children with specific clinical features in included studies

*Includes dyspnoea/difficulty breathing/gasping/breathlessness, combined data from 4-6 and ≥7-14 age groups from Gao et al included [ 14 ].

†Includes flaring/nasal flaring.

‡Includes indrawing/recession/chest wall indrawing/chest recession/chest retraction, Forgie et al excluded from analysis as study selected for patients with indrawing [ 11 ].

§Includes all utilised definitions of tachypnoea and abnormal respiratory rate, data pertaining to respiratory rate of ≥40 breaths per minute rather than ≥50 breaths per minute included from Juvén et al [ 7 ].

‖Includes crepitations/rales/crackles/pulmonary crackles at onset, data included if able to be disaggregated from other abnormal breath sounds, combined data from 4-6 and ≥7-14 age groups from Gao et al included [ 14 ].

¶Includes wheeze/wheezes/wheezing/auscultation – wheezing, data included if able to be disaggregated from other abnormal breath sounds, fraction and percentage of children with auscultation finding rather than reported symptom included from Sondergaard et al [ 20 ].

**Includes all utilised definitions of fever, data pertaining to fever >37.5°C rather than fever >39.5°C included from Korppi et al [ 8 ].

††includes any pallor present

‡‡Includes inability to drink/poor appetite/refusal to eat/cannot eat or drink/feeding difficulties.

§§Data included if able to be disaggregated from other gastrointestinal symptoms.

‖‖Data included if able to be disaggregated from pain at other sites.

¶¶Includes chest pain/thoracic pain.

***Includes any type of rash, urticaria and Stevens-Johnson Syndrome.

Cough was the most common clinical feature, documented in around 90% of patients in both all-cause and Mycoplasma cohorts, whether diagnosed clinically or radiologically. Fever was also common in both cohorts but more common in Mycoplasma (91.7%, 95% confidence interval (CI) = 91.2-92.3) compared to all-cause pneumonia (74.8%, 95% CI = 73.6-76.0).

Tachypnoea was identified in around half of patients overall but less frequently in the Mycoplasma cohort (all-cause pneumonia 55.4%, 95% CI = 53.6-57.2 and Mycoplasma pneumoniae 40.1%, 95% CI = 37.9-42.3). The study of outpatients by Harris et al had the highest prevalence of tachypnoea but the lowest threshold for defining tachypnoea (>20 breaths per minute for children older than 2 years) [ 9 ]. The percentage of patients with tachypnoea was lower for patients with a radiological diagnosis (all-cause pneumonia 48.0%, 95% CI = 42.9-53.1 and Mycoplasma pneumoniae 8.5%, 95% CI = 7.7-9.2) compared to a clinical diagnosis (all-cause pneumonia 77.0% comprising 1 study with 937/1216 patients and Mycoplasma pneumoniae 50.1%, 95% CI = 48.5-51.7). Of note, less than 10% of patients with a radiological diagnosis of Mycoplasma pneumoniae had documented tachypnoea.

Dyspnoea/difficulty breathing was documented in 29.1% (95% CI = 28.2-30.8) of all-cause pneumonia patients and 23.1% (95% CI = 22.4-23.8) of Mycoplasma pneumoniae patients. In the all-cause pneumonia cohort, the proportion of patients with dyspnoea was higher in the clinical diagnosis group (43.0%, 95% CI = 42.3-43.7) compared to the radiological (14.9%, 95% CI = 13.7-16.1). Chest indrawing was observed in approximately half of all-cause pneumonia cases, all of which were based on clinical diagnosis. There was only one small study of Mycoplasma pneumoniae patients which documented chest-indrawing in 30.0% (14/46) of patients [ 19 ]. Crackles or crepitations were variably described between studies but documented in around one half of patients overall. Wheeze or rhonchi were described in around one quarter of patients.

Chest and abdominal pain were each included in two studies of all-cause pneumonia (radiological diagnosis) and both were documented in around one third of patients. Abdominal pain was included in one small study of Mycoplasma pneumoniae patients (radiological diagnosis) and was found in 17% (11/66) of patients [ 15 ]. Headache, nausea and vomiting also occurred in around one third of patients in the all-cause pneumonia cohort, though these are non-specific symptoms that may occur in a range of illnesses. Skin manifestations were described in one study addressing Mycoplasma pneumoniae with data disaggregated by age and, in this study, were found in 25% (21/88) children [ 20 ].

With respect to chest radiograph findings in all studies, one study by Gao et al selected for patients with segmental/lobar Mycoplasma pneumoniae and additionally reported on the presence of pleural effusions (4%-5%) [ 14 ]. Aside from this, only a small number of study participants overall in the 5-9 year age range had disaggregated chest radiograph findings reported ( Table 4 ). Lobar changes were documented in around half of patients who had chest radiographs but any further conclusions are limited by the variable inclusion and diagnostic criteria and limited data.

Chest radiograph findings document in studies in children 5-9 y with pneumonia

*Data included if able to be disaggregated from other chest x-ray findings and both numerator and denominator clearly stated.

†Includes lobar consolidation/lobal consolidation/lobar infiltration and segmental/lobar pneumonia, Gao et al excluded from analysis as selected for patients with segmental/lobar pneumonia [ 14 ].

‡Includes interstitial changes/interstitial pattern.

§Includes pleural effusion/empyema, combined data from 4-6 y and ≥7-14 y groups from Gao et al included [ 14 ], data for pleural effusion rather than single case of empyema included from Sondergaard et al [ 20 ].

Outcome data for children aged 5-9 years with pneumonia were available from a single study of inpatients in Kenya, which was also the largest study in the review [ 12 ]. Macpherson et al described risk factors associated with mortality in children aged 5-14 years admitted to hospital with pneumonia [ 12 ]. Outcome information was available for 1825/1832 (99.5%) patients, of whom 145 (7.9%) died. Inpatient case fatality was higher in children aged 10-14 years compared to the 5-9 year age group (14.05% vs 6.43%, P  < 0.001). For children aged 5-10 years, risk factors for death demonstrated in multi-variate analysis included the presence of severe pallor (OR = 9.89, 95% CI = 4.68 to 20.93, P  < 0.001), mild/moderate pallor (OR = 2.85, 95% CI = 1.35-6, P  < 0.006), reduced consciousness (OR = 6.27, 95% CI = 2.8-14.08, P  < 0.001), central cyanosis (OR = 6.35, 95% CI = 1.33-30.25, P  < 0.02), a weight for age Z-score of≤-3 SD (OR = 2.99, 95% CI = 1.61-5.55, P  < 0.001) and comorbid HIV (OR = 2.49, 95% CI = 1.18-5.28, P  < 0.017). A respiratory rate >30 breaths per minute and inability to drink were associated with poor outcome, though did not reach statistical significance. Sex, presence of grunting, crackles, chest wall indrawing and comorbid malaria were not associated with mortality and wheeze was found to be relatively protective (not statistically significant). Additional analysis demonstrated that the combination of clinical characteristics used by WHO to define severe pneumonia in children less than 5 years old was poor in discriminating those at risk of death (sensitivity: 0.56, specificity: 0.68 and AUC: 0.62) in this study.

Regarding pneumonia severity and the need for inpatient treatment in children aged 5-9 years, there is little additional data to draw upon beyond the study by Macpherson et al [ 12 ]. Studies involving outpatients either did not describe chest indrawing or did not disaggregate data by age in combination with admission status [ 8 , 9 , 19 ]. Whilst lethargy was documented frequently, reduced consciousness as a specific sign was only described in the study by Macpherson et al [ 12 ].

Comparison with clinical features of pneumonia in younger children was made in six out of eight all-cause pneumonia studies and all seven Mycoplasma pneumoniae studies ( Table 1 and Table 2 ). In all studies which included chest and abdominal pain and compared frequency between older and younger children, they were found to be more common in older children [ 6 - 8 ]. Crocker et al found that abdominal pain was a reported symptom in all 12 cases in which pleural effusion or empyema were detected in children aged 3-16 years [ 6 ]. Comparison of chest auscultation findings between age groups demonstrated no clear trends, with some studies finding crackles and wheeze to be more common in younger children but other studies reporting greater frequency in older children [ 7 , 9 , 13 ]. Similarly, one study found that normal breath sounds were more common in children older than 5 years and another found that it was less common [ 7 , 11 ]. Inconsistent use of terms for auscultation findings between studies limited comparison. In a study of 127 children with Mycoplasma pneumoniae , Ma et al found that children less than 5 years of age were more likely to have a severe illness course, including intensive care unit admission, supplemental oxygen requirement and need for video-assisted thoracoscopic surgery (VATS) [ 15 ]. Vomiting also occurred more often in younger children with Mycoplasma pneumoniae [ 15 , 19 ]. Segmental or lobar consolidation on chest radiograph was a more common finding in older children for both all-cause pneumonia and Mycoplasma pneumoniae groups [ 13 , 16 , 18 ].

Comparative analysis of clinical features between those with and without comorbidities was not possible as data was not disaggregated for subgroups of participants with comorbidities in the 5-9 year age range in studies that included such participants.

There is a paucity of quality evidence describing clinical features of pneumonia in children aged 5-9 years. This review explored findings from 15 studies, eight addressing pneumonia of all causes and seven addressing pneumonia attributable to Mycoplasma pneumoniae . The lack of evidence highlights the urgent need for research to understand clinical features, treatment approaches and outcomes for children 5-9 years of age with pneumonia, which remains one of the highest causes of death in this age group globally [ 3 ]. However, the evidence that does exist indicates that applying existing WHO definitions of pneumonia for children under 5 years of age, to this older age group, is likely to lower the diagnostic yield.

Current WHO guidelines for children under 5 years old distinguish simple cough from pneumonia based on the presence or absence of tachypnoea. Among studies in this review, tachypnoea lacked standard definitions and this complicates interpretation of findings. However approximately only half of patients in the all-cause pneumonia cohort were documented to have tachypnoea, and this was lower for Mycoplasma pneumoniae patients, notably those diagnosed radiologically. Higher proportions of children with pneumonia in clinically diagnosed groups may represent later diagnosis. Alternatively, it may reflect greater emphasis on accurate measurement and recording of respiratory rate in clinicians using clinical diagnosis. The data on clinical diagnosis regarding tachypnoea in the all-cause pneumonia cohort is based on the Kenyan study, which is a cohort of sick children in a high burden setting. Yet, even amongst these patients around 1 in 4 did not have tachypnoea (respiratory rate >30 breaths per minute) documented on admission [ 12 ]. The measurement of respiratory rate is a skill which is often not performed well or documented correctly; the evidence indicates that it cannot be relied upon to identify pneumonia among older children with cough [ 21 ].

If tachypnoea cannot be relied on to diagnose pneumonia in older children, then addition of other symptoms to aid diagnostic approaches should be considered. Although the study numbers are small, chest pain and abdominal pain were relatively common in children aged5-9 years with all-cause pneumonia, whether due to their ability to report symptoms, or to the likelihood that researchers sought to identify these symptoms in older children. Chest radiographs may also have a greater role in diagnosing children with pneumonia in this age group, particularly in the setting of persistent cough and fever without other signs to confirm pneumonia (or alternative diagnoses). It should be noted, the data on chest radiograph findings in pneumonia in this age group is limited and there is insufficient data supporting the use of radiographs to distinguish pneumonia aetiology (eg, Mycoplasma from all-cause).

Symptoms used to define severe pneumonia in children <5 years of age, such as reduced conscious state, central cyanosis and/or hypoxia (oxygen saturation <90%) and inability to eat or drink [ 1 , 2 ], still have relevance in older children in low and lower-middle income settings in terms of their risk of mortality and therefore the severity of pneumonia. Similarly, nutritional status and underlying chronic conditions (including HIV) are associated with mortality in older children and should be part of any risk stratification approach used by clinicians to determine the need for admission and treatment [ 1 , 2 ]. Pallor, whether mild, moderate or severe, was identified as being associated with a higher risk of mortality in children 5-9 years old and should also be part of a clinician’s consideration of risk and patient disposition [ 12 ]. This is consistent with recent evidence suggesting that pallor is an important marker of serious disease in younger age groups [ 22 - 24 ]. The sign of chest indrawing has been an important and evolving marker of pneumonia severity and therefore need for admission in guidelines for children under 5 years old [ 25 ]. This review identified no data on the management of chest indrawing in children aged 5-9 years in the outpatient setting. Given chest compliance reduces with age [ 25 ], it is reasonable to suspect that chest indrawing may indicate greater severity in older children, as its presence may suggest generation of greater intrathoracic pressures to maintain ventilation. The Kenyan study in this review examined risk of death in older children with pneumonia and found no association between chest indrawing and mortality [ 12 ]. This finding, among others described above, is based on a single study in one context and should be interpreted with caution. Of note no radiological studies of all-cause pneumonia documented the presence or absence of chest indrawing in patients, despite its potential importance in guiding treatment.

Our review identified several studies relating to Mycoplasma pneumoniae in children 5-9 years of age mostly from high income countries, from which data has been reported separately to not unduly influence data on all-cause pneumonia, and to consider differences in clinical features. While Mycoplasma pneumoniae is important in pneumonia in older children, the emphasis on this organism in this review may represent bias on the part of researchers in considering it above other aetiologies. There is a clear need for more data on other potential aetiologies (eg, influenza), but particularly those relevant in the global context, such as HIV and tuberculosis.

Based on the available evidence for Mycoplasma pneumoniae , there are no respiratory clinical features that can distinguish it from pneumonia of other aetiologies in children aged 5-9 years. This is consistent with other studies that demonstrated no clinical or radiological features to identify Mycoplasma pneumoniae and guide therapeutic decisions [ 26 , 27 ]. Considering Mycoplasma pneumoniae as an aetiology and treating this possibility is therefore important, including in HIV positive children among whom it has also been shown to be common [ 28 ]. Skin symptoms may be useful in distinguishing Mycoplasma pneumoniae as a potential aetiological agent in pneumonia in older children, however there may be bias in seeking and reporting on these symptoms in studies focused on Mycoplasma pneumoniae and disaggregated supportive evidence was available from only one study in this review [ 20 ]. Separately, a review by Schalock and Dinulos [ 29 ] specifically addressing Mycoplasma pneumoniae -induced cutaneous disease in paediatric and adult populations and a study by Sauteur et al [ 30 ] in paediatric patients aged 3-18 years described skin manifestations as a feature of Mycoplasma pneumoniae , such as exanthematous skin eruptions, urticaria, erythema nodosum, Mycoplasma pneumoniae -induced rash and mucositis (MIRM) and Stevens-Johnson Syndrome. A key limitation in determining aetiology is that available diagnostic tests for Mycoplasma pneumoniae may not distinguish infection from carriage [ 31 ].

Implications for WHO pneumonia guidelines

The relatively weak quality of studies and limited evidence in this review should be kept in mind when interpreting the findings. Evidence related to risk factors for death, for example, is derived from a single study of moderate quality. Different definitions (eg, for tachypnoea), different nomenclatures (eg, crepitations) and absence of documentation of key signs (eg, chest indrawing) should be noted. Nonetheless, there are some implications to be considered for WHO guidelines while further research is conducted and evidence is generated.

Cough and fever are common clinical features in pneumonia in children aged 5-9 years. However, tachypnoea, used to define pneumonia according to WHO criteria in children <5 years of age, may not be present in older children with pneumonia. Inclusion of chest pain and abdominal pain in diagnostic approaches for older children might expand recognition of pneumonia in this age group, especially if other signs are absent. Furthermore, chest radiographs may have greater importance for diagnosis. Clear definitions of tachypnoea are required for both clinical application and to standardise future research.

Symptoms reflecting severity of pneumonia in children <5 years of age (eg, reduced conscious state, hypoxia and inability to drink) have relevance in older children in low resource settings with respect to risk of mortality, and therefore severity of pneumonia. Separate to these markers of severe disease, other patient factors such as poor nutritional status, comorbid chronic conditions and pallor are associated with poor outcomes. As a result, they should be part of the clinician’s consideration of risk of a poor outcome for children aged 5-9 years with pneumonia, and inform decision making on patient disposition.

There is minimal data on chest indrawing in children aged 5-9 years, particularly its management in outpatient settings, to guide management recommendations. Without further evidence, it may be safest to recommend admission if chest indrawing is present.

Although there are differences in the proportions of patients with clinical features between the all-cause pneumonia and Mycoplasma cohorts, these cannot be used to distinguish pneumonia of different aetiologies in children aged 5-9 years on an individual level. Guidelines should account for causative agents other than pneumococcus and antibiotic recommendations should be altered accordingly. The addition of an antibiotic to cover for Mycoplasma pneumoniae (eg, macrolide) when treating pneumonia in this age group should be strongly considered, particularly in severe cases, in children with malnutrition and/or other co-morbidities, and when deterioration occurs on alternate therapy. Skin symptoms may be useful in distinguishing Mycoplasma pneumoniae as a potential aetiological agent in pneumonia in children aged 5-9 years, though there is limited evidence available and large potential for bias.

Limitations

This review was conducted with a rigorous systematic approach, broad search strategy to capture relevant publications and methods to minimise risk of bias. It was limited by the databases that were searched, restriction of publications to the English language and unavailability of two full-text articles. Overall, the key limitation is the breadth and depth of existing research pertaining to pneumonia in children aged 5-9 years that is available to inform decision making.

Further studies exploring clinical features of pneumonia in children aged 5-9 years are warranted to strengthen evidence and understanding of the presentation of pneumonia in this age group. Studies using consistent definitions of clinical features and age ranges would enable aggregation of data and comparison between studies and settings. A wider range of studies in outpatient and inpatient settings, which identify clinical features associated with pneumonia severity and help to define critical values of concern for key signs, eg, tachypnoea, would better identify children at risk of poor outcomes. Conversely, understanding the prevalence of features such as chest indrawing in outpatient settings would aid in guiding safe management of children in the community.

Studies describing pneumonia aetiology and associated clinical features in children aged 5-9 years are needed to better inform antimicrobial choices, or clinical scenarios in which particular antimicrobial choices should be prioritised.

Studies should also explore the presentation of pneumonia in children aged 5-9 years with comorbid chronic conditions, given that this group is likely to be at higher risk of recurrent and more severe pneumonia.

CONCLUSIONS

There is a lack of evidence describing clinical features of pneumonia in children aged 5-9 years highlighting an urgent need for further research to guide best practice. Despite the quality and quantity of data, there are some findings which should be considered in relation to whether existing WHO definitions of pneumonia in children less than 5 years of age can be applied to older children. Based on limited data fever and cough are common in this age group, but tachypnoea cannot be relied on for diagnosis. While waiting for better evidence, broader attention to features such as chest and abdominal pain, the role of chest radiographs for diagnosis in the absence of symptoms such as tachypnoea, and risk factors which may influence patient disposition (chest indrawing, pallor, nutritional status) warrants consideration by clinicians.

Additional material

Acknowledgments.

Full list of ARI Review group : Trevor Duke, Hamish Graham, Steve Graham, Amy Gray, Amanda Gwee, Claire von Mollendorf, Kim Mulholland, Fiona Russell (leadership group, MCRI/University of Melbourne); Maeve Hume-Nixon, Saniya Kazi, Priya Kevat, Eleanor Neal, Cattram Nguyen, Alicia Quach, Rita Reyburn, Kathleen Ryan, Patrick Walker, Chris Wilkes (lead researchers, MCRI); Poh Chua (research librarian, RCH); Yasir Bin Nisar, Jonathon Simon, Wilson Were (WHO).

Acknowledgements: We would like to acknowledge librarian, Poh Chua, at the Royal Children’s Hospital Melbourne, who assisted with formulating and conducting our literature search.

Disclaimer: The authors alone are responsible for the views expressed in this publication and they do not necessarily represent the views, decisions or policies of the World Health Organization.

Funding: Funding was provided by the World Health Organization (WHO).

Authorship contributions: HG, AG and members of the ARI Review group conceived the study and initiated the study design. PK and AG led the conduct of searches. Data extraction was led by MM and PK with input from AG. Data analysis was conducted by PK, AG, and MM. The manuscript was drafted by PK, with input from AG, MM and HG. All authors contributed to revisions and approved the final manuscript.

Competing interests: The authors completed the ICMJE Unified Competing Interest Form (available upon request from the corresponding author), and declare no conflicts of interest.