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What is a Literature Review? How to Write It (with Examples)

A literature review is a critical analysis and synthesis of existing research on a particular topic. It provides an overview of the current state of knowledge, identifies gaps, and highlights key findings in the literature. 1 The purpose of a literature review is to situate your own research within the context of existing scholarship, demonstrating your understanding of the topic and showing how your work contributes to the ongoing conversation in the field. Learning how to write a literature review is a critical tool for successful research. Your ability to summarize and synthesize prior research pertaining to a certain topic demonstrates your grasp on the topic of study, and assists in the learning process. 

Table of Contents

• What is the purpose of literature review? 
• a. Habitat Loss and Species Extinction: 
• b. Range Shifts and Phenological Changes: 
• c. Ocean Acidification and Coral Reefs: 
• d. Adaptive Strategies and Conservation Efforts: 

How to write a good literature review 

• Choose a Topic and Define the Research Question: 
• Decide on the Scope of Your Review: 
• Select Databases for Searches: 
• Conduct Searches and Keep Track: 
• Review the Literature: 
• Organize and Write Your Literature Review: 
• How to write a literature review faster with Paperpal? 
• Frequently asked questions 

What is a literature review?

A well-conducted literature review demonstrates the researcher’s familiarity with the existing literature, establishes the context for their own research, and contributes to scholarly conversations on the topic. One of the purposes of a literature review is also to help researchers avoid duplicating previous work and ensure that their research is informed by and builds upon the existing body of knowledge.

What is the purpose of literature review?

A literature review serves several important purposes within academic and research contexts. Here are some key objectives and functions of a literature review: 2  

1. Contextualizing the Research Problem: The literature review provides a background and context for the research problem under investigation. It helps to situate the study within the existing body of knowledge. 

2. Identifying Gaps in Knowledge: By identifying gaps, contradictions, or areas requiring further research, the researcher can shape the research question and justify the significance of the study. This is crucial for ensuring that the new research contributes something novel to the field. 

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3. Understanding Theoretical and Conceptual Frameworks: Literature reviews help researchers gain an understanding of the theoretical and conceptual frameworks used in previous studies. This aids in the development of a theoretical framework for the current research. 

4. Providing Methodological Insights: Another purpose of literature reviews is that it allows researchers to learn about the methodologies employed in previous studies. This can help in choosing appropriate research methods for the current study and avoiding pitfalls that others may have encountered. 

5. Establishing Credibility: A well-conducted literature review demonstrates the researcher’s familiarity with existing scholarship, establishing their credibility and expertise in the field. It also helps in building a solid foundation for the new research. 

6. Informing Hypotheses or Research Questions: The literature review guides the formulation of hypotheses or research questions by highlighting relevant findings and areas of uncertainty in existing literature. 

Literature review example

Let’s delve deeper with a literature review example: Let’s say your literature review is about the impact of climate change on biodiversity. You might format your literature review into sections such as the effects of climate change on habitat loss and species extinction, phenological changes, and marine biodiversity. Each section would then summarize and analyze relevant studies in those areas, highlighting key findings and identifying gaps in the research. The review would conclude by emphasizing the need for further research on specific aspects of the relationship between climate change and biodiversity. The following literature review template provides a glimpse into the recommended literature review structure and content, demonstrating how research findings are organized around specific themes within a broader topic. 

Literature Review on Climate Change Impacts on Biodiversity:

Climate change is a global phenomenon with far-reaching consequences, including significant impacts on biodiversity. This literature review synthesizes key findings from various studies: 

a. Habitat Loss and Species Extinction:

Climate change-induced alterations in temperature and precipitation patterns contribute to habitat loss, affecting numerous species (Thomas et al., 2004). The review discusses how these changes increase the risk of extinction, particularly for species with specific habitat requirements. 

b. Range Shifts and Phenological Changes:

Observations of range shifts and changes in the timing of biological events (phenology) are documented in response to changing climatic conditions (Parmesan & Yohe, 2003). These shifts affect ecosystems and may lead to mismatches between species and their resources. 

c. Ocean Acidification and Coral Reefs:

The review explores the impact of climate change on marine biodiversity, emphasizing ocean acidification’s threat to coral reefs (Hoegh-Guldberg et al., 2007). Changes in pH levels negatively affect coral calcification, disrupting the delicate balance of marine ecosystems. 

d. Adaptive Strategies and Conservation Efforts:

Recognizing the urgency of the situation, the literature review discusses various adaptive strategies adopted by species and conservation efforts aimed at mitigating the impacts of climate change on biodiversity (Hannah et al., 2007). It emphasizes the importance of interdisciplinary approaches for effective conservation planning. 

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Writing a literature review involves summarizing and synthesizing existing research on a particular topic. A good literature review format should include the following elements. 

Introduction: The introduction sets the stage for your literature review, providing context and introducing the main focus of your review. 

• Opening Statement: Begin with a general statement about the broader topic and its significance in the field. 
• Scope and Purpose: Clearly define the scope of your literature review. Explain the specific research question or objective you aim to address. 
• Organizational Framework: Briefly outline the structure of your literature review, indicating how you will categorize and discuss the existing research. 
• Significance of the Study: Highlight why your literature review is important and how it contributes to the understanding of the chosen topic. 
• Thesis Statement: Conclude the introduction with a concise thesis statement that outlines the main argument or perspective you will develop in the body of the literature review. 

Body: The body of the literature review is where you provide a comprehensive analysis of existing literature, grouping studies based on themes, methodologies, or other relevant criteria. 

• Organize by Theme or Concept: Group studies that share common themes, concepts, or methodologies. Discuss each theme or concept in detail, summarizing key findings and identifying gaps or areas of disagreement. 
• Critical Analysis: Evaluate the strengths and weaknesses of each study. Discuss the methodologies used, the quality of evidence, and the overall contribution of each work to the understanding of the topic. 
• Synthesis of Findings: Synthesize the information from different studies to highlight trends, patterns, or areas of consensus in the literature. 
• Identification of Gaps: Discuss any gaps or limitations in the existing research and explain how your review contributes to filling these gaps. 
• Transition between Sections: Provide smooth transitions between different themes or concepts to maintain the flow of your literature review. 

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Conclusion: The conclusion of your literature review should summarize the main findings, highlight the contributions of the review, and suggest avenues for future research. 

• Summary of Key Findings: Recap the main findings from the literature and restate how they contribute to your research question or objective. 
• Contributions to the Field: Discuss the overall contribution of your literature review to the existing knowledge in the field. 
• Implications and Applications: Explore the practical implications of the findings and suggest how they might impact future research or practice. 
• Recommendations for Future Research: Identify areas that require further investigation and propose potential directions for future research in the field. 
• Final Thoughts: Conclude with a final reflection on the importance of your literature review and its relevance to the broader academic community. 

Conducting a literature review

Conducting a literature review is an essential step in research that involves reviewing and analyzing existing literature on a specific topic. It’s important to know how to do a literature review effectively, so here are the steps to follow: 1  

Choose a Topic and Define the Research Question:

• Select a topic that is relevant to your field of study. 
• Clearly define your research question or objective. Determine what specific aspect of the topic do you want to explore? 

Decide on the Scope of Your Review:

• Determine the timeframe for your literature review. Are you focusing on recent developments, or do you want a historical overview? 
• Consider the geographical scope. Is your review global, or are you focusing on a specific region? 
• Define the inclusion and exclusion criteria. What types of sources will you include? Are there specific types of studies or publications you will exclude? 

Select Databases for Searches:

• Identify relevant databases for your field. Examples include PubMed, IEEE Xplore, Scopus, Web of Science, and Google Scholar. 
• Consider searching in library catalogs, institutional repositories, and specialized databases related to your topic. 

Conduct Searches and Keep Track:

• Develop a systematic search strategy using keywords, Boolean operators (AND, OR, NOT), and other search techniques. 
• Record and document your search strategy for transparency and replicability. 
• Keep track of the articles, including publication details, abstracts, and links. Use citation management tools like EndNote, Zotero, or Mendeley to organize your references. 

Review the Literature:

• Evaluate the relevance and quality of each source. Consider the methodology, sample size, and results of studies. 
• Organize the literature by themes or key concepts. Identify patterns, trends, and gaps in the existing research. 
• Summarize key findings and arguments from each source. Compare and contrast different perspectives. 
• Identify areas where there is a consensus in the literature and where there are conflicting opinions. 
• Provide critical analysis and synthesis of the literature. What are the strengths and weaknesses of existing research? 

Organize and Write Your Literature Review:

• Literature review outline should be based on themes, chronological order, or methodological approaches. 
• Write a clear and coherent narrative that synthesizes the information gathered. 
• Use proper citations for each source and ensure consistency in your citation style (APA, MLA, Chicago, etc.). 
• Conclude your literature review by summarizing key findings, identifying gaps, and suggesting areas for future research. 

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How to write a literature review faster with Paperpal?

Paperpal, an AI writing assistant, integrates powerful academic search capabilities within its writing platform. With the Research feature, you get 100% factual insights, with citations backed by 250M+ verified research articles, directly within your writing interface with the option to save relevant references in your Citation Library. By eliminating the need to switch tabs to find answers to all your research questions, Paperpal saves time and helps you stay focused on your writing.   

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• Ask a question: Get started with a new document on paperpal.com. Click on the “Research” feature and type your question in plain English. Paperpal will scour over 250 million research articles, including conference papers and preprints, to provide you with accurate insights and citations. 
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• Cite with Confidence: Paperpal makes it easy to incorporate relevant citations and references into your writing, ensuring your arguments are well-supported by credible sources. This translates to a polished, well-researched literature review. 

The literature review sample and detailed advice on writing and conducting a review will help you produce a well-structured report. But remember that a good literature review is an ongoing process, and it may be necessary to revisit and update it as your research progresses. By combining effortless research with an easy citation process, Paperpal Research streamlines the literature review process and empowers you to write faster and with more confidence. Try Paperpal Research now and see for yourself.  

Frequently asked questions

A literature review is a critical and comprehensive analysis of existing literature (published and unpublished works) on a specific topic or research question and provides a synthesis of the current state of knowledge in a particular field. A well-conducted literature review is crucial for researchers to build upon existing knowledge, avoid duplication of efforts, and contribute to the advancement of their field. It also helps researchers situate their work within a broader context and facilitates the development of a sound theoretical and conceptual framework for their studies.

Literature review is a crucial component of research writing, providing a solid background for a research paper’s investigation. The aim is to keep professionals up to date by providing an understanding of ongoing developments within a specific field, including research methods, and experimental techniques used in that field, and present that knowledge in the form of a written report. Also, the depth and breadth of the literature review emphasizes the credibility of the scholar in his or her field.  

Before writing a literature review, it’s essential to undertake several preparatory steps to ensure that your review is well-researched, organized, and focused. This includes choosing a topic of general interest to you and doing exploratory research on that topic, writing an annotated bibliography, and noting major points, especially those that relate to the position you have taken on the topic. 

Literature reviews and academic research papers are essential components of scholarly work but serve different purposes within the academic realm. 3 A literature review aims to provide a foundation for understanding the current state of research on a particular topic, identify gaps or controversies, and lay the groundwork for future research. Therefore, it draws heavily from existing academic sources, including books, journal articles, and other scholarly publications. In contrast, an academic research paper aims to present new knowledge, contribute to the academic discourse, and advance the understanding of a specific research question. Therefore, it involves a mix of existing literature (in the introduction and literature review sections) and original data or findings obtained through research methods. 

Literature reviews are essential components of academic and research papers, and various strategies can be employed to conduct them effectively. If you want to know how to write a literature review for a research paper, here are four common approaches that are often used by researchers.  Chronological Review: This strategy involves organizing the literature based on the chronological order of publication. It helps to trace the development of a topic over time, showing how ideas, theories, and research have evolved.  Thematic Review: Thematic reviews focus on identifying and analyzing themes or topics that cut across different studies. Instead of organizing the literature chronologically, it is grouped by key themes or concepts, allowing for a comprehensive exploration of various aspects of the topic.  Methodological Review: This strategy involves organizing the literature based on the research methods employed in different studies. It helps to highlight the strengths and weaknesses of various methodologies and allows the reader to evaluate the reliability and validity of the research findings.  Theoretical Review: A theoretical review examines the literature based on the theoretical frameworks used in different studies. This approach helps to identify the key theories that have been applied to the topic and assess their contributions to the understanding of the subject.  It’s important to note that these strategies are not mutually exclusive, and a literature review may combine elements of more than one approach. The choice of strategy depends on the research question, the nature of the literature available, and the goals of the review. Additionally, other strategies, such as integrative reviews or systematic reviews, may be employed depending on the specific requirements of the research.

The literature review format can vary depending on the specific publication guidelines. However, there are some common elements and structures that are often followed. Here is a general guideline for the format of a literature review:  Introduction:   Provide an overview of the topic.  Define the scope and purpose of the literature review.  State the research question or objective.  Body:   Organize the literature by themes, concepts, or chronology.  Critically analyze and evaluate each source.  Discuss the strengths and weaknesses of the studies.  Highlight any methodological limitations or biases.  Identify patterns, connections, or contradictions in the existing research.  Conclusion:   Summarize the key points discussed in the literature review.  Highlight the research gap.  Address the research question or objective stated in the introduction.  Highlight the contributions of the review and suggest directions for future research.

Both annotated bibliographies and literature reviews involve the examination of scholarly sources. While annotated bibliographies focus on individual sources with brief annotations, literature reviews provide a more in-depth, integrated, and comprehensive analysis of existing literature on a specific topic. The key differences are as follows: 

References 

• Denney, A. S., & Tewksbury, R. (2013). How to write a literature review.  Journal of criminal justice education ,  24 (2), 218-234. 
• Pan, M. L. (2016).  Preparing literature reviews: Qualitative and quantitative approaches . Taylor & Francis. 
• Cantero, C. (2019). How to write a literature review.  San José State University Writing Center . 

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The Guide to Thematic Analysis

• What is Thematic Analysis?
• Advantages of Thematic Analysis
• Disadvantages of Thematic Analysis
• Thematic Analysis Examples
• How to Do Thematic Analysis
• Thematic Coding
• Collaborative Thematic Analysis
• Thematic Analysis Software
• Thematic Analysis in Mixed Methods Approach
• Abductive Thematic Analysis
• Deductive Thematic Analysis
• Inductive Thematic Analysis
• Reflexive Thematic Analysis
• Thematic Analysis in Observations
• Thematic Analysis in Surveys
• Thematic Analysis for Interviews
• Thematic Analysis for Focus Groups
• Thematic Analysis for Case Studies
• Thematic Analysis of Secondary Data
• Introduction

What is a thematic literature review?

Advantages of a thematic literature review, structuring and writing a thematic literature review.

• Thematic Analysis vs. Phenomenology
• Thematic vs. Content Analysis
• Thematic Analysis vs. Grounded Theory
• Thematic Analysis vs. Narrative Analysis
• Thematic Analysis vs. Discourse Analysis
• Thematic Analysis vs. Framework Analysis
• Thematic Analysis in Social Work
• Thematic Analysis in Psychology
• Thematic Analysis in Educational Research
• Thematic Analysis in UX Research
• How to Present Thematic Analysis Results
• Increasing Rigor in Thematic Analysis
• Peer Review in Thematic Analysis

Thematic Analysis Literature Review

A thematic literature review serves as a critical tool for synthesizing research findings within a specific subject area. By categorizing existing literature into themes, this method offers a structured approach to identify and analyze patterns and trends across studies. The primary goal is to provide a clear and concise overview that aids scholars and practitioners in understanding the key discussions and developments within a field. Unlike traditional literature reviews , which may adopt a chronological approach or focus on individual studies, a thematic literature review emphasizes the aggregation of findings through key themes and thematic connections. This introduction sets the stage for a detailed examination of what constitutes a thematic literature review, its benefits, and guidance on effectively structuring and writing one.

A thematic literature review methodically organizes and examines a body of literature by identifying, analyzing, and reporting themes found within texts such as journal articles, conference proceedings, dissertations, and other forms of academic writing. While a particular journal article may offer some specific insight, a synthesis of knowledge through a literature review can provide a comprehensive overview of theories across relevant sources in a particular field.

Unlike other review types that might organize literature chronologically or by methodology , a thematic review focuses on recurring themes or patterns across a collection of works. This approach enables researchers to draw together previous research to synthesize findings from different research contexts and methodologies, highlighting the overarching trends and insights within a field.

At its core, a thematic approach to a literature review research project involves several key steps. Initially, it requires the comprehensive collection of relevant literature that aligns with the review's research question or objectives. Following this, the process entails a meticulous analysis of the texts to identify common themes that emerge across the studies. These themes are not pre-defined but are discovered through a careful reading and synthesis of the literature.

The thematic analysis process is iterative, often involving the refinement of themes as the review progresses. It allows for the integration of a broad range of literature, facilitating a multidimensional understanding of the research topic. By organizing literature thematically, the review illuminates how various studies contribute to each theme, providing insights into the depth and breadth of research in the area.

A thematic literature review thus serves as a foundational element in research, offering a nuanced and comprehensive perspective on a topic. It not only aids in identifying gaps in the existing literature but also guides future research directions by underscoring areas that warrant further investigation. Ultimately, a thematic literature review empowers researchers to construct a coherent narrative that weaves together disparate studies into a unified analysis.

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Conducting a literature review thematically provides a comprehensive and nuanced synthesis of research findings, distinguishing it from other types of literature reviews. Its structured approach not only facilitates a deeper understanding of the subject area but also enhances the clarity and relevance of the review. Here are three significant advantages of employing a thematic analysis in literature reviews.

Enhanced understanding of the research field

Thematic literature reviews allow for a detailed exploration of the research landscape, presenting themes that capture the essence of the subject area. By identifying and analyzing these themes, reviewers can construct a narrative that reflects the complexity and multifaceted nature of the field.

This process aids in uncovering underlying patterns and relationships, offering a more profound and insightful examination of the literature. As a result, readers gain an enriched understanding of the key concepts, debates, and evolutionary trajectories within the research area.

Identification of research gaps and trends

One of the pivotal benefits of a thematic literature review is its ability to highlight gaps in the existing body of research. By systematically organizing the literature into themes, reviewers can pinpoint areas that are under-explored or warrant further investigation.

Additionally, this method can reveal emerging trends and shifts in research focus, guiding scholars toward promising areas for future study. The thematic structure thus serves as a roadmap, directing researchers toward uncharted territories and new research questions .

Facilitates comparative analysis and integration of findings

A thematic literature review excels in synthesizing findings from diverse studies, enabling a coherent and integrated overview. By concentrating on themes rather than individual studies, the review can draw comparisons and contrasts across different research contexts and methodologies . This comparative analysis enriches the review, offering a panoramic view of the field that acknowledges both consensus and divergence among researchers.

Moreover, the thematic framework supports the integration of findings, presenting a unified and comprehensive portrayal of the research area. Such integration is invaluable for scholars seeking to navigate the extensive body of literature and extract pertinent insights relevant to their own research questions or objectives.

The process of structuring and writing a thematic literature review is pivotal in presenting research in a clear, coherent, and impactful manner. This review type necessitates a methodical approach to not only unearth and categorize key themes but also to articulate them in a manner that is both accessible and informative to the reader. The following sections outline essential stages in the thematic analysis process for literature reviews , offering a structured pathway from initial planning to the final presentation of findings.

Identifying and categorizing themes

The initial phase in a thematic literature review is the identification of themes within the collected body of literature. This involves a detailed examination of texts to discern patterns, concepts, and ideas that recur across the research landscape. Effective identification hinges on a thorough and nuanced reading of the literature, where the reviewer actively engages with the content to extract and note significant thematic elements. Once identified, these themes must be meticulously categorized, often requiring the reviewer to discern between overarching themes and more nuanced sub-themes, ensuring a logical and hierarchical organization of the review content.

Analyzing and synthesizing themes

After categorizing the themes, the next step involves a deeper analysis and synthesis of the identified themes. This stage is critical for understanding the relationships between themes and for interpreting the broader implications of the thematic findings. Analysis may reveal how themes evolve over time, differ across methodologies or contexts, or converge to highlight predominant trends in the research area. Synthesis involves integrating insights from various studies to construct a comprehensive narrative that encapsulates the thematic essence of the literature, offering new interpretations or revealing gaps in existing research.

Presenting and discussing findings

The final stage of the thematic literature review is the discussion of the thematic findings in a research paper or presentation. This entails not only a descriptive account of identified themes but also a critical examination of their significance within the research field. Each theme should be discussed in detail, elucidating its relevance, the extent of research support, and its implications for future studies. The review should culminate in a coherent and compelling narrative that not only summarizes the key thematic findings but also situates them within the broader research context, offering valuable insights and directions for future inquiry.

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Conducting a Literature Review

• Getting Started
• Developing a Question
• Searching the Literature
• Identifying Peer-Reviewed Resources
• Managing Results

Analyzing the Literature

• Writing the Review

Need Help? Ask Your librarian!

Evidence synthesis and critical appraisal are two distinct but interrelated processes in the field of evidence-based practice and research. Here's a breakdown of the differences between them:

Critical Appraisal:

• Definition : Critical appraisal involves systematically evaluating the quality, relevance, and validity of research studies or evidence sources. It aims to assess the strengths and weaknesses of individual studies to determine their trustworthiness and applicability to a particular research question or clinical scenario.
• Focus : Critical appraisal focuses on examining the methodology, design, data analysis, and results of research studies. It involves assessing factors such as study design, sample size, bias, confounding variables, statistical methods, and generalizability.
• Purpose : The purpose of critical appraisal is to identify high-quality evidence that can inform decision-making in healthcare practice, policy, or research. It helps researchers and practitioners assess the credibility and reliability of evidence sources and make informed judgments about their use in practice.

Evidence Synthesis:

• Definition : Evidence synthesis involves systematically collecting, analyzing, and integrating evidence from multiple sources to generate new knowledge, insights, or conclusions about a particular topic or research question. It aims to aggregate and synthesize findings from individual studies to produce a comprehensive summary of the available evidence.
• Focus : Evidence synthesis encompasses a variety of methods, including systematic reviews, meta-analyses, scoping reviews, and narrative reviews. It focuses on synthesizing data, findings, and conclusions from multiple studies to provide a comprehensive overview of the evidence base on a particular topic.
• Purpose : The purpose of evidence synthesis is to provide stakeholders with a robust and comprehensive summary of the existing evidence on a particular topic or research question. It helps identify patterns, trends, inconsistencies, and gaps in the literature, informing decision-making, guiding policy development, and identifying future research priorities.

In summary, critical appraisal involves assessing the quality and validity of individual research studies, while evidence synthesis involves aggregating and synthesizing findings from multiple studies to generate new knowledge or insights about a particular topic. While they are distinct processes, they are often conducted sequentially, with critical appraisal informing the selection and inclusion of studies in evidence synthesis. Together, critical appraisal and evidence synthesis play essential roles in evidence-based practice and research, 

Synthesizing the Articles

Literature reviews synthesize large amounts of information and present it in a coherent, organized fashion. In a literature review you will be combining material from several texts to create a new text – your literature review.

You will use common points among the sources you have gathered to help you synthesize the material. This will help ensure that your literature review is organized by subtopic, not by source. This means various authors' names can appear and reappear throughout the literature review, and each paragraph will mention several different authors.

When you shift from writing summaries of the content of a source to synthesizing content from sources, there is a number things you must keep in mind:

• Look for specific connections and or links between your sources and how those relate to your thesis or question.
• When writing and organizing your literature review be aware that your readers need to understand how and why the information from the different sources overlap.
• Organize your literature review by the themes you find within your sources or themes you have identified. 

You can use a synthesis chart to help keep your sources and main ideas organized. Here are some examples:

• Virginia Commonwealth University Literature Matrix
• Johns Hopkins University Literature Review Matrix
• Writing A Literature Review and Using a Synthesis Matrix Tutorial from NC State University

California State University, Northridge. (2017). Literature Review How-To: Synthesizing Sources. Retrieved from https://libguides.csun.edu/literature-review/synthesis.

Things to Think About

Before you begin to analyze and synthesize the articles you have selected, read quickly through each article to get a sense of what they are about. One way to do this is to read the abstract and the conclusion for each article.

It is also helpful at this stage to begin sorting your articles by type of source; this will help you with the next step in the process. Many papers (but not all) fall into one of two categories:

• Primary source: a report by the original researchers of a study.
• Secondary source: a description or summary of research by somebody other than the original author(s), like a review article.

These are a selection of questions to consider while reading each article selected for your literature review. 

Primary Sources:

• Author and Year
• Purpose of Study
• Type of Study
• Data Collection Method
• Major Findings
• Recommendations
• Key thoughts/comments (eg. strengths and weaknesses)

Secondary Sources (ie. reviews)

• Author and year
• Review questions/purpose
• Key definitions
• Review boundaries
• Appraisal criteria
• Synthesis of studies
• Summary/conclusions

Cronin, P., Ryan, F., & Coughlan, M. (2008). Undertaking a literature review: A step-by-step approach. British Journal of Nursing, 17 (1), 38-43. Retrieved from: https://bit.ly/2wLeCge .

When Am I Done?

You are done with your literature review synthesis when :

• You are not finding any new ideas,
• When you encounter the same authors repeatedly, and/or
• When you feel that you have a strong understanding of the topic
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Lau F, Kuziemsky C, editors. Handbook of eHealth Evaluation: An Evidence-based Approach [Internet]. Victoria (BC): University of Victoria; 2017 Feb 27.

Handbook of eHealth Evaluation: An Evidence-based Approach [Internet].

Chapter 9 methods for literature reviews.

Guy Paré and Spyros Kitsiou .

9.1. Introduction

Literature reviews play a critical role in scholarship because science remains, first and foremost, a cumulative endeavour ( vom Brocke et al., 2009 ). As in any academic discipline, rigorous knowledge syntheses are becoming indispensable in keeping up with an exponentially growing eHealth literature, assisting practitioners, academics, and graduate students in finding, evaluating, and synthesizing the contents of many empirical and conceptual papers. Among other methods, literature reviews are essential for: (a) identifying what has been written on a subject or topic; (b) determining the extent to which a specific research area reveals any interpretable trends or patterns; (c) aggregating empirical findings related to a narrow research question to support evidence-based practice; (d) generating new frameworks and theories; and (e) identifying topics or questions requiring more investigation ( Paré, Trudel, Jaana, & Kitsiou, 2015 ).

Literature reviews can take two major forms. The most prevalent one is the “literature review” or “background” section within a journal paper or a chapter in a graduate thesis. This section synthesizes the extant literature and usually identifies the gaps in knowledge that the empirical study addresses ( Sylvester, Tate, & Johnstone, 2013 ). It may also provide a theoretical foundation for the proposed study, substantiate the presence of the research problem, justify the research as one that contributes something new to the cumulated knowledge, or validate the methods and approaches for the proposed study ( Hart, 1998 ; Levy & Ellis, 2006 ).

The second form of literature review, which is the focus of this chapter, constitutes an original and valuable work of research in and of itself ( Paré et al., 2015 ). Rather than providing a base for a researcher’s own work, it creates a solid starting point for all members of the community interested in a particular area or topic ( Mulrow, 1987 ). The so-called “review article” is a journal-length paper which has an overarching purpose to synthesize the literature in a field, without collecting or analyzing any primary data ( Green, Johnson, & Adams, 2006 ).

When appropriately conducted, review articles represent powerful information sources for practitioners looking for state-of-the art evidence to guide their decision-making and work practices ( Paré et al., 2015 ). Further, high-quality reviews become frequently cited pieces of work which researchers seek out as a first clear outline of the literature when undertaking empirical studies ( Cooper, 1988 ; Rowe, 2014 ). Scholars who track and gauge the impact of articles have found that review papers are cited and downloaded more often than any other type of published article ( Cronin, Ryan, & Coughlan, 2008 ; Montori, Wilczynski, Morgan, Haynes, & Hedges, 2003 ; Patsopoulos, Analatos, & Ioannidis, 2005 ). The reason for their popularity may be the fact that reading the review enables one to have an overview, if not a detailed knowledge of the area in question, as well as references to the most useful primary sources ( Cronin et al., 2008 ). Although they are not easy to conduct, the commitment to complete a review article provides a tremendous service to one’s academic community ( Paré et al., 2015 ; Petticrew & Roberts, 2006 ). Most, if not all, peer-reviewed journals in the fields of medical informatics publish review articles of some type.

The main objectives of this chapter are fourfold: (a) to provide an overview of the major steps and activities involved in conducting a stand-alone literature review; (b) to describe and contrast the different types of review articles that can contribute to the eHealth knowledge base; (c) to illustrate each review type with one or two examples from the eHealth literature; and (d) to provide a series of recommendations for prospective authors of review articles in this domain.

9.2. Overview of the Literature Review Process and Steps

As explained in Templier and Paré (2015) , there are six generic steps involved in conducting a review article:

• formulating the research question(s) and objective(s),
• searching the extant literature,
• screening for inclusion,
• assessing the quality of primary studies,
• extracting data, and
• analyzing data.

Although these steps are presented here in sequential order, one must keep in mind that the review process can be iterative and that many activities can be initiated during the planning stage and later refined during subsequent phases ( Finfgeld-Connett & Johnson, 2013 ; Kitchenham & Charters, 2007 ).

Formulating the research question(s) and objective(s): As a first step, members of the review team must appropriately justify the need for the review itself ( Petticrew & Roberts, 2006 ), identify the review’s main objective(s) ( Okoli & Schabram, 2010 ), and define the concepts or variables at the heart of their synthesis ( Cooper & Hedges, 2009 ; Webster & Watson, 2002 ). Importantly, they also need to articulate the research question(s) they propose to investigate ( Kitchenham & Charters, 2007 ). In this regard, we concur with Jesson, Matheson, and Lacey (2011) that clearly articulated research questions are key ingredients that guide the entire review methodology; they underscore the type of information that is needed, inform the search for and selection of relevant literature, and guide or orient the subsequent analysis. Searching the extant literature: The next step consists of searching the literature and making decisions about the suitability of material to be considered in the review ( Cooper, 1988 ). There exist three main coverage strategies. First, exhaustive coverage means an effort is made to be as comprehensive as possible in order to ensure that all relevant studies, published and unpublished, are included in the review and, thus, conclusions are based on this all-inclusive knowledge base. The second type of coverage consists of presenting materials that are representative of most other works in a given field or area. Often authors who adopt this strategy will search for relevant articles in a small number of top-tier journals in a field ( Paré et al., 2015 ). In the third strategy, the review team concentrates on prior works that have been central or pivotal to a particular topic. This may include empirical studies or conceptual papers that initiated a line of investigation, changed how problems or questions were framed, introduced new methods or concepts, or engendered important debate ( Cooper, 1988 ). Screening for inclusion: The following step consists of evaluating the applicability of the material identified in the preceding step ( Levy & Ellis, 2006 ; vom Brocke et al., 2009 ). Once a group of potential studies has been identified, members of the review team must screen them to determine their relevance ( Petticrew & Roberts, 2006 ). A set of predetermined rules provides a basis for including or excluding certain studies. This exercise requires a significant investment on the part of researchers, who must ensure enhanced objectivity and avoid biases or mistakes. As discussed later in this chapter, for certain types of reviews there must be at least two independent reviewers involved in the screening process and a procedure to resolve disagreements must also be in place ( Liberati et al., 2009 ; Shea et al., 2009 ). Assessing the quality of primary studies: In addition to screening material for inclusion, members of the review team may need to assess the scientific quality of the selected studies, that is, appraise the rigour of the research design and methods. Such formal assessment, which is usually conducted independently by at least two coders, helps members of the review team refine which studies to include in the final sample, determine whether or not the differences in quality may affect their conclusions, or guide how they analyze the data and interpret the findings ( Petticrew & Roberts, 2006 ). Ascribing quality scores to each primary study or considering through domain-based evaluations which study components have or have not been designed and executed appropriately makes it possible to reflect on the extent to which the selected study addresses possible biases and maximizes validity ( Shea et al., 2009 ). Extracting data: The following step involves gathering or extracting applicable information from each primary study included in the sample and deciding what is relevant to the problem of interest ( Cooper & Hedges, 2009 ). Indeed, the type of data that should be recorded mainly depends on the initial research questions ( Okoli & Schabram, 2010 ). However, important information may also be gathered about how, when, where and by whom the primary study was conducted, the research design and methods, or qualitative/quantitative results ( Cooper & Hedges, 2009 ). Analyzing and synthesizing data : As a final step, members of the review team must collate, summarize, aggregate, organize, and compare the evidence extracted from the included studies. The extracted data must be presented in a meaningful way that suggests a new contribution to the extant literature ( Jesson et al., 2011 ). Webster and Watson (2002) warn researchers that literature reviews should be much more than lists of papers and should provide a coherent lens to make sense of extant knowledge on a given topic. There exist several methods and techniques for synthesizing quantitative (e.g., frequency analysis, meta-analysis) and qualitative (e.g., grounded theory, narrative analysis, meta-ethnography) evidence ( Dixon-Woods, Agarwal, Jones, Young, & Sutton, 2005 ; Thomas & Harden, 2008 ).

9.3. Types of Review Articles and Brief Illustrations

EHealth researchers have at their disposal a number of approaches and methods for making sense out of existing literature, all with the purpose of casting current research findings into historical contexts or explaining contradictions that might exist among a set of primary research studies conducted on a particular topic. Our classification scheme is largely inspired from Paré and colleagues’ (2015) typology. Below we present and illustrate those review types that we feel are central to the growth and development of the eHealth domain.

9.3.1. Narrative Reviews

The narrative review is the “traditional” way of reviewing the extant literature and is skewed towards a qualitative interpretation of prior knowledge ( Sylvester et al., 2013 ). Put simply, a narrative review attempts to summarize or synthesize what has been written on a particular topic but does not seek generalization or cumulative knowledge from what is reviewed ( Davies, 2000 ; Green et al., 2006 ). Instead, the review team often undertakes the task of accumulating and synthesizing the literature to demonstrate the value of a particular point of view ( Baumeister & Leary, 1997 ). As such, reviewers may selectively ignore or limit the attention paid to certain studies in order to make a point. In this rather unsystematic approach, the selection of information from primary articles is subjective, lacks explicit criteria for inclusion and can lead to biased interpretations or inferences ( Green et al., 2006 ). There are several narrative reviews in the particular eHealth domain, as in all fields, which follow such an unstructured approach ( Silva et al., 2015 ; Paul et al., 2015 ).

Despite these criticisms, this type of review can be very useful in gathering together a volume of literature in a specific subject area and synthesizing it. As mentioned above, its primary purpose is to provide the reader with a comprehensive background for understanding current knowledge and highlighting the significance of new research ( Cronin et al., 2008 ). Faculty like to use narrative reviews in the classroom because they are often more up to date than textbooks, provide a single source for students to reference, and expose students to peer-reviewed literature ( Green et al., 2006 ). For researchers, narrative reviews can inspire research ideas by identifying gaps or inconsistencies in a body of knowledge, thus helping researchers to determine research questions or formulate hypotheses. Importantly, narrative reviews can also be used as educational articles to bring practitioners up to date with certain topics of issues ( Green et al., 2006 ).

Recently, there have been several efforts to introduce more rigour in narrative reviews that will elucidate common pitfalls and bring changes into their publication standards. Information systems researchers, among others, have contributed to advancing knowledge on how to structure a “traditional” review. For instance, Levy and Ellis (2006) proposed a generic framework for conducting such reviews. Their model follows the systematic data processing approach comprised of three steps, namely: (a) literature search and screening; (b) data extraction and analysis; and (c) writing the literature review. They provide detailed and very helpful instructions on how to conduct each step of the review process. As another methodological contribution, vom Brocke et al. (2009) offered a series of guidelines for conducting literature reviews, with a particular focus on how to search and extract the relevant body of knowledge. Last, Bandara, Miskon, and Fielt (2011) proposed a structured, predefined and tool-supported method to identify primary studies within a feasible scope, extract relevant content from identified articles, synthesize and analyze the findings, and effectively write and present the results of the literature review. We highly recommend that prospective authors of narrative reviews consult these useful sources before embarking on their work.

Darlow and Wen (2015) provide a good example of a highly structured narrative review in the eHealth field. These authors synthesized published articles that describe the development process of mobile health ( m-health ) interventions for patients’ cancer care self-management. As in most narrative reviews, the scope of the research questions being investigated is broad: (a) how development of these systems are carried out; (b) which methods are used to investigate these systems; and (c) what conclusions can be drawn as a result of the development of these systems. To provide clear answers to these questions, a literature search was conducted on six electronic databases and Google Scholar . The search was performed using several terms and free text words, combining them in an appropriate manner. Four inclusion and three exclusion criteria were utilized during the screening process. Both authors independently reviewed each of the identified articles to determine eligibility and extract study information. A flow diagram shows the number of studies identified, screened, and included or excluded at each stage of study selection. In terms of contributions, this review provides a series of practical recommendations for m-health intervention development.

9.3.2. Descriptive or Mapping Reviews

The primary goal of a descriptive review is to determine the extent to which a body of knowledge in a particular research topic reveals any interpretable pattern or trend with respect to pre-existing propositions, theories, methodologies or findings ( King & He, 2005 ; Paré et al., 2015 ). In contrast with narrative reviews, descriptive reviews follow a systematic and transparent procedure, including searching, screening and classifying studies ( Petersen, Vakkalanka, & Kuzniarz, 2015 ). Indeed, structured search methods are used to form a representative sample of a larger group of published works ( Paré et al., 2015 ). Further, authors of descriptive reviews extract from each study certain characteristics of interest, such as publication year, research methods, data collection techniques, and direction or strength of research outcomes (e.g., positive, negative, or non-significant) in the form of frequency analysis to produce quantitative results ( Sylvester et al., 2013 ). In essence, each study included in a descriptive review is treated as the unit of analysis and the published literature as a whole provides a database from which the authors attempt to identify any interpretable trends or draw overall conclusions about the merits of existing conceptualizations, propositions, methods or findings ( Paré et al., 2015 ). In doing so, a descriptive review may claim that its findings represent the state of the art in a particular domain ( King & He, 2005 ).

In the fields of health sciences and medical informatics, reviews that focus on examining the range, nature and evolution of a topic area are described by Anderson, Allen, Peckham, and Goodwin (2008) as mapping reviews . Like descriptive reviews, the research questions are generic and usually relate to publication patterns and trends. There is no preconceived plan to systematically review all of the literature although this can be done. Instead, researchers often present studies that are representative of most works published in a particular area and they consider a specific time frame to be mapped.

An example of this approach in the eHealth domain is offered by DeShazo, Lavallie, and Wolf (2009). The purpose of this descriptive or mapping review was to characterize publication trends in the medical informatics literature over a 20-year period (1987 to 2006). To achieve this ambitious objective, the authors performed a bibliometric analysis of medical informatics citations indexed in medline using publication trends, journal frequencies, impact factors, Medical Subject Headings (MeSH) term frequencies, and characteristics of citations. Findings revealed that there were over 77,000 medical informatics articles published during the covered period in numerous journals and that the average annual growth rate was 12%. The MeSH term analysis also suggested a strong interdisciplinary trend. Finally, average impact scores increased over time with two notable growth periods. Overall, patterns in research outputs that seem to characterize the historic trends and current components of the field of medical informatics suggest it may be a maturing discipline (DeShazo et al., 2009).

9.3.3. Scoping Reviews

Scoping reviews attempt to provide an initial indication of the potential size and nature of the extant literature on an emergent topic (Arksey & O’Malley, 2005; Daudt, van Mossel, & Scott, 2013 ; Levac, Colquhoun, & O’Brien, 2010). A scoping review may be conducted to examine the extent, range and nature of research activities in a particular area, determine the value of undertaking a full systematic review (discussed next), or identify research gaps in the extant literature ( Paré et al., 2015 ). In line with their main objective, scoping reviews usually conclude with the presentation of a detailed research agenda for future works along with potential implications for both practice and research.

Unlike narrative and descriptive reviews, the whole point of scoping the field is to be as comprehensive as possible, including grey literature (Arksey & O’Malley, 2005). Inclusion and exclusion criteria must be established to help researchers eliminate studies that are not aligned with the research questions. It is also recommended that at least two independent coders review abstracts yielded from the search strategy and then the full articles for study selection ( Daudt et al., 2013 ). The synthesized evidence from content or thematic analysis is relatively easy to present in tabular form (Arksey & O’Malley, 2005; Thomas & Harden, 2008 ).

One of the most highly cited scoping reviews in the eHealth domain was published by Archer, Fevrier-Thomas, Lokker, McKibbon, and Straus (2011) . These authors reviewed the existing literature on personal health record ( phr ) systems including design, functionality, implementation, applications, outcomes, and benefits. Seven databases were searched from 1985 to March 2010. Several search terms relating to phr s were used during this process. Two authors independently screened titles and abstracts to determine inclusion status. A second screen of full-text articles, again by two independent members of the research team, ensured that the studies described phr s. All in all, 130 articles met the criteria and their data were extracted manually into a database. The authors concluded that although there is a large amount of survey, observational, cohort/panel, and anecdotal evidence of phr benefits and satisfaction for patients, more research is needed to evaluate the results of phr implementations. Their in-depth analysis of the literature signalled that there is little solid evidence from randomized controlled trials or other studies through the use of phr s. Hence, they suggested that more research is needed that addresses the current lack of understanding of optimal functionality and usability of these systems, and how they can play a beneficial role in supporting patient self-management ( Archer et al., 2011 ).

9.3.4. Forms of Aggregative Reviews

Healthcare providers, practitioners, and policy-makers are nowadays overwhelmed with large volumes of information, including research-based evidence from numerous clinical trials and evaluation studies, assessing the effectiveness of health information technologies and interventions ( Ammenwerth & de Keizer, 2004 ; Deshazo et al., 2009 ). It is unrealistic to expect that all these disparate actors will have the time, skills, and necessary resources to identify the available evidence in the area of their expertise and consider it when making decisions. Systematic reviews that involve the rigorous application of scientific strategies aimed at limiting subjectivity and bias (i.e., systematic and random errors) can respond to this challenge.

Systematic reviews attempt to aggregate, appraise, and synthesize in a single source all empirical evidence that meet a set of previously specified eligibility criteria in order to answer a clearly formulated and often narrow research question on a particular topic of interest to support evidence-based practice ( Liberati et al., 2009 ). They adhere closely to explicit scientific principles ( Liberati et al., 2009 ) and rigorous methodological guidelines (Higgins & Green, 2008) aimed at reducing random and systematic errors that can lead to deviations from the truth in results or inferences. The use of explicit methods allows systematic reviews to aggregate a large body of research evidence, assess whether effects or relationships are in the same direction and of the same general magnitude, explain possible inconsistencies between study results, and determine the strength of the overall evidence for every outcome of interest based on the quality of included studies and the general consistency among them ( Cook, Mulrow, & Haynes, 1997 ). The main procedures of a systematic review involve:

• Formulating a review question and developing a search strategy based on explicit inclusion criteria for the identification of eligible studies (usually described in the context of a detailed review protocol).
• Searching for eligible studies using multiple databases and information sources, including grey literature sources, without any language restrictions.
• Selecting studies, extracting data, and assessing risk of bias in a duplicate manner using two independent reviewers to avoid random or systematic errors in the process.
• Analyzing data using quantitative or qualitative methods.
• Presenting results in summary of findings tables.
• Interpreting results and drawing conclusions.

Many systematic reviews, but not all, use statistical methods to combine the results of independent studies into a single quantitative estimate or summary effect size. Known as meta-analyses , these reviews use specific data extraction and statistical techniques (e.g., network, frequentist, or Bayesian meta-analyses) to calculate from each study by outcome of interest an effect size along with a confidence interval that reflects the degree of uncertainty behind the point estimate of effect ( Borenstein, Hedges, Higgins, & Rothstein, 2009 ; Deeks, Higgins, & Altman, 2008 ). Subsequently, they use fixed or random-effects analysis models to combine the results of the included studies, assess statistical heterogeneity, and calculate a weighted average of the effect estimates from the different studies, taking into account their sample sizes. The summary effect size is a value that reflects the average magnitude of the intervention effect for a particular outcome of interest or, more generally, the strength of a relationship between two variables across all studies included in the systematic review. By statistically combining data from multiple studies, meta-analyses can create more precise and reliable estimates of intervention effects than those derived from individual studies alone, when these are examined independently as discrete sources of information.

The review by Gurol-Urganci, de Jongh, Vodopivec-Jamsek, Atun, and Car (2013) on the effects of mobile phone messaging reminders for attendance at healthcare appointments is an illustrative example of a high-quality systematic review with meta-analysis. Missed appointments are a major cause of inefficiency in healthcare delivery with substantial monetary costs to health systems. These authors sought to assess whether mobile phone-based appointment reminders delivered through Short Message Service ( sms ) or Multimedia Messaging Service ( mms ) are effective in improving rates of patient attendance and reducing overall costs. To this end, they conducted a comprehensive search on multiple databases using highly sensitive search strategies without language or publication-type restrictions to identify all rct s that are eligible for inclusion. In order to minimize the risk of omitting eligible studies not captured by the original search, they supplemented all electronic searches with manual screening of trial registers and references contained in the included studies. Study selection, data extraction, and risk of bias assessments were performed inde­­pen­dently by two coders using standardized methods to ensure consistency and to eliminate potential errors. Findings from eight rct s involving 6,615 participants were pooled into meta-analyses to calculate the magnitude of effects that mobile text message reminders have on the rate of attendance at healthcare appointments compared to no reminders and phone call reminders.

Meta-analyses are regarded as powerful tools for deriving meaningful conclusions. However, there are situations in which it is neither reasonable nor appropriate to pool studies together using meta-analytic methods simply because there is extensive clinical heterogeneity between the included studies or variation in measurement tools, comparisons, or outcomes of interest. In these cases, systematic reviews can use qualitative synthesis methods such as vote counting, content analysis, classification schemes and tabulations, as an alternative approach to narratively synthesize the results of the independent studies included in the review. This form of review is known as qualitative systematic review.

A rigorous example of one such review in the eHealth domain is presented by Mickan, Atherton, Roberts, Heneghan, and Tilson (2014) on the use of handheld computers by healthcare professionals and their impact on access to information and clinical decision-making. In line with the methodological guide­lines for systematic reviews, these authors: (a) developed and registered with prospero ( www.crd.york.ac.uk/ prospero / ) an a priori review protocol; (b) conducted comprehensive searches for eligible studies using multiple databases and other supplementary strategies (e.g., forward searches); and (c) subsequently carried out study selection, data extraction, and risk of bias assessments in a duplicate manner to eliminate potential errors in the review process. Heterogeneity between the included studies in terms of reported outcomes and measures precluded the use of meta-analytic methods. To this end, the authors resorted to using narrative analysis and synthesis to describe the effectiveness of handheld computers on accessing information for clinical knowledge, adherence to safety and clinical quality guidelines, and diagnostic decision-making.

In recent years, the number of systematic reviews in the field of health informatics has increased considerably. Systematic reviews with discordant findings can cause great confusion and make it difficult for decision-makers to interpret the review-level evidence ( Moher, 2013 ). Therefore, there is a growing need for appraisal and synthesis of prior systematic reviews to ensure that decision-making is constantly informed by the best available accumulated evidence. Umbrella reviews , also known as overviews of systematic reviews, are tertiary types of evidence synthesis that aim to accomplish this; that is, they aim to compare and contrast findings from multiple systematic reviews and meta-analyses ( Becker & Oxman, 2008 ). Umbrella reviews generally adhere to the same principles and rigorous methodological guidelines used in systematic reviews. However, the unit of analysis in umbrella reviews is the systematic review rather than the primary study ( Becker & Oxman, 2008 ). Unlike systematic reviews that have a narrow focus of inquiry, umbrella reviews focus on broader research topics for which there are several potential interventions ( Smith, Devane, Begley, & Clarke, 2011 ). A recent umbrella review on the effects of home telemonitoring interventions for patients with heart failure critically appraised, compared, and synthesized evidence from 15 systematic reviews to investigate which types of home telemonitoring technologies and forms of interventions are more effective in reducing mortality and hospital admissions ( Kitsiou, Paré, & Jaana, 2015 ).

9.3.5. Realist Reviews

Realist reviews are theory-driven interpretative reviews developed to inform, enhance, or supplement conventional systematic reviews by making sense of heterogeneous evidence about complex interventions applied in diverse contexts in a way that informs policy decision-making ( Greenhalgh, Wong, Westhorp, & Pawson, 2011 ). They originated from criticisms of positivist systematic reviews which centre on their “simplistic” underlying assumptions ( Oates, 2011 ). As explained above, systematic reviews seek to identify causation. Such logic is appropriate for fields like medicine and education where findings of randomized controlled trials can be aggregated to see whether a new treatment or intervention does improve outcomes. However, many argue that it is not possible to establish such direct causal links between interventions and outcomes in fields such as social policy, management, and information systems where for any intervention there is unlikely to be a regular or consistent outcome ( Oates, 2011 ; Pawson, 2006 ; Rousseau, Manning, & Denyer, 2008 ).

To circumvent these limitations, Pawson, Greenhalgh, Harvey, and Walshe (2005) have proposed a new approach for synthesizing knowledge that seeks to unpack the mechanism of how “complex interventions” work in particular contexts. The basic research question — what works? — which is usually associated with systematic reviews changes to: what is it about this intervention that works, for whom, in what circumstances, in what respects and why? Realist reviews have no particular preference for either quantitative or qualitative evidence. As a theory-building approach, a realist review usually starts by articulating likely underlying mechanisms and then scrutinizes available evidence to find out whether and where these mechanisms are applicable ( Shepperd et al., 2009 ). Primary studies found in the extant literature are viewed as case studies which can test and modify the initial theories ( Rousseau et al., 2008 ).

The main objective pursued in the realist review conducted by Otte-Trojel, de Bont, Rundall, and van de Klundert (2014) was to examine how patient portals contribute to health service delivery and patient outcomes. The specific goals were to investigate how outcomes are produced and, most importantly, how variations in outcomes can be explained. The research team started with an exploratory review of background documents and research studies to identify ways in which patient portals may contribute to health service delivery and patient outcomes. The authors identified six main ways which represent “educated guesses” to be tested against the data in the evaluation studies. These studies were identified through a formal and systematic search in four databases between 2003 and 2013. Two members of the research team selected the articles using a pre-established list of inclusion and exclusion criteria and following a two-step procedure. The authors then extracted data from the selected articles and created several tables, one for each outcome category. They organized information to bring forward those mechanisms where patient portals contribute to outcomes and the variation in outcomes across different contexts.

9.3.6. Critical Reviews

Lastly, critical reviews aim to provide a critical evaluation and interpretive analysis of existing literature on a particular topic of interest to reveal strengths, weaknesses, contradictions, controversies, inconsistencies, and/or other important issues with respect to theories, hypotheses, research methods or results ( Baumeister & Leary, 1997 ; Kirkevold, 1997 ). Unlike other review types, critical reviews attempt to take a reflective account of the research that has been done in a particular area of interest, and assess its credibility by using appraisal instruments or critical interpretive methods. In this way, critical reviews attempt to constructively inform other scholars about the weaknesses of prior research and strengthen knowledge development by giving focus and direction to studies for further improvement ( Kirkevold, 1997 ).

Kitsiou, Paré, and Jaana (2013) provide an example of a critical review that assessed the methodological quality of prior systematic reviews of home telemonitoring studies for chronic patients. The authors conducted a comprehensive search on multiple databases to identify eligible reviews and subsequently used a validated instrument to conduct an in-depth quality appraisal. Results indicate that the majority of systematic reviews in this particular area suffer from important methodological flaws and biases that impair their internal validity and limit their usefulness for clinical and decision-making purposes. To this end, they provide a number of recommendations to strengthen knowledge development towards improving the design and execution of future reviews on home telemonitoring.

9.4. Summary

Table 9.1 outlines the main types of literature reviews that were described in the previous sub-sections and summarizes the main characteristics that distinguish one review type from another. It also includes key references to methodological guidelines and useful sources that can be used by eHealth scholars and researchers for planning and developing reviews.

Typology of Literature Reviews (adapted from Paré et al., 2015).

As shown in Table 9.1 , each review type addresses different kinds of research questions or objectives, which subsequently define and dictate the methods and approaches that need to be used to achieve the overarching goal(s) of the review. For example, in the case of narrative reviews, there is greater flexibility in searching and synthesizing articles ( Green et al., 2006 ). Researchers are often relatively free to use a diversity of approaches to search, identify, and select relevant scientific articles, describe their operational characteristics, present how the individual studies fit together, and formulate conclusions. On the other hand, systematic reviews are characterized by their high level of systematicity, rigour, and use of explicit methods, based on an “a priori” review plan that aims to minimize bias in the analysis and synthesis process (Higgins & Green, 2008). Some reviews are exploratory in nature (e.g., scoping/mapping reviews), whereas others may be conducted to discover patterns (e.g., descriptive reviews) or involve a synthesis approach that may include the critical analysis of prior research ( Paré et al., 2015 ). Hence, in order to select the most appropriate type of review, it is critical to know before embarking on a review project, why the research synthesis is conducted and what type of methods are best aligned with the pursued goals.

9.5. Concluding Remarks

In light of the increased use of evidence-based practice and research generating stronger evidence ( Grady et al., 2011 ; Lyden et al., 2013 ), review articles have become essential tools for summarizing, synthesizing, integrating or critically appraising prior knowledge in the eHealth field. As mentioned earlier, when rigorously conducted review articles represent powerful information sources for eHealth scholars and practitioners looking for state-of-the-art evidence. The typology of literature reviews we used herein will allow eHealth researchers, graduate students and practitioners to gain a better understanding of the similarities and differences between review types.

We must stress that this classification scheme does not privilege any specific type of review as being of higher quality than another ( Paré et al., 2015 ). As explained above, each type of review has its own strengths and limitations. Having said that, we realize that the methodological rigour of any review — be it qualitative, quantitative or mixed — is a critical aspect that should be considered seriously by prospective authors. In the present context, the notion of rigour refers to the reliability and validity of the review process described in section 9.2. For one thing, reliability is related to the reproducibility of the review process and steps, which is facilitated by a comprehensive documentation of the literature search process, extraction, coding and analysis performed in the review. Whether the search is comprehensive or not, whether it involves a methodical approach for data extraction and synthesis or not, it is important that the review documents in an explicit and transparent manner the steps and approach that were used in the process of its development. Next, validity characterizes the degree to which the review process was conducted appropriately. It goes beyond documentation and reflects decisions related to the selection of the sources, the search terms used, the period of time covered, the articles selected in the search, and the application of backward and forward searches ( vom Brocke et al., 2009 ). In short, the rigour of any review article is reflected by the explicitness of its methods (i.e., transparency) and the soundness of the approach used. We refer those interested in the concepts of rigour and quality to the work of Templier and Paré (2015) which offers a detailed set of methodological guidelines for conducting and evaluating various types of review articles.

To conclude, our main objective in this chapter was to demystify the various types of literature reviews that are central to the continuous development of the eHealth field. It is our hope that our descriptive account will serve as a valuable source for those conducting, evaluating or using reviews in this important and growing domain.

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• Cite this Page Paré G, Kitsiou S. Chapter 9 Methods for Literature Reviews. In: Lau F, Kuziemsky C, editors. Handbook of eHealth Evaluation: An Evidence-based Approach [Internet]. Victoria (BC): University of Victoria; 2017 Feb 27.
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• Published: 27 September 2018

A review of recent publication trends from top publishing countries

• Paul Fontelo   ORCID: orcid.org/0000-0003-3186-3215 1 &
• Fang Liu 1  

Systematic Reviews volume  7 , Article number:  147 ( 2018 ) Cite this article

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Evidence-based medicine relies on current best evidence from the medical literature, the patient’s history, and the clinician’s own experience to provide the best care for patients. Systematic reviews and meta-analysis are considered the highest levels of evidence for informing clinical decisions. Recently, reports have shown an increase in the number but a decrease in quality of meta-analysis publications. We reviewed publication trends and determined the countries with the most journal articles and types of publications in PubMed from 1995 to 2015.

We examined journal entries in PubMed from 1995 to 2015 from top publishing countries for total number of publications and citations in core clinical journals and in specific publication types (systematic reviews, meta-analysis, randomized controlled trials).

Yearly, only 30 countries generated 94.6% of all publications and 98.1% of core clinical journals worldwide. All publication types increased but with a significant increase in meta-analysis publications from China. Collaborative and co-authored papers among the 30 countries also showed an increasing trend.

The USA leads in all publication citations and specific publication types, except for meta-analysis where China publishes more. Collaborative publishing among international collaborators is also increasing.

Peer Review reports

Recent best evidence from the literature and health care providers experience form the foundation of evidence-based medicine (EBM) [ 1 ]. In the hierarchy of evidence, randomized controlled trials, systematic reviews, and meta-analysis studies are at the highest levels in the evidence pyramid [ 2 ]. Meta-analysis and review articles are often the most highly cited publications [ 3 ]. Recently, the exponential increase in the number of meta-analysis studies has raised the issue of quality and reliability of meta-analysis publications [ 4 , 5 , 6 , 7 ]. The implications could be consequential because of the high value assigned to meta-analysis and systematic review studies in informing clinical decisions.

The publication type category in the MeSH translation table represents the article’s type of material (ex: case report, clinical trial, editorial, guideline, meta-analysis, etc.) [ 8 ]. The publication type in PubMed represents an article’s “study design” and not the “type of material.”

This paper is an attempt to review recent trends of some publication types in PubMed. It is not an assessment of the quality of journal articles themselves but rather a quantitative look at recent publication trends from top research countries worldwide.

PubMed searches were performed in December 2016 using the following limits: all publications sorted from top publishing countries from 1995 to 2015 and the following search strategies and publication types: meta-analysis, systematic reviews, clinical trials, and randomized controlled trials. A list of countries was created ( n  = 235) based on IPv4 Internet address allocations ( https://en.wikipedia.org/wiki/List_of_countries_by_IPv4_address_allocation ). The top publishing countries was generated from searches of all publications in PubMed for the year 2015. An example of a country search query for Germany is in Appendix 1 . The number of publications in 2015 for each country was sorted, and the top 25 countries with the most publications were selected. Although the limit was initially set to the top 25 countries based on the total number of publications, five other countries that were not on the original list were found to be in the top 25 when specific publication types were analyzed. This brought the total highest publishing countries to 30 countries and regions. All journal articles from the 30 countries published between 1995 and 2015 in journals listed in National Library of Medicine (NLM)’s Abridged Index Medicus (AIM) or “Core Clinical” Journal Titles subset were also searched for publication types labeled as meta-analysis, systematic review, clinical trial, and randomized controlled trial. Examples of search filters for AIM journals are shown in Appendices 2 , 3 , and 4 . The AIM or “Core Clinical” is a subset of MEDLINE [ 8 ] which currently includes about 119 journals. Publications from the 30 countries were reviewed in AIM subset [ 9 , 10 ]. Collaborative or co-authored publications were determined by searching for citations with combined affiliations between each of the top 5 countries and the 30 other countries on the list. In this paper, the term “citation” refers to the entry record of a publication in PubMed, not in its use in the reference section of a manuscript.

An expansion process for a country’s name filter was performed to include the common expression in the affiliation field because of recent changes in PubMed ( https://www.nlm.nih.gov/pubs/techbull/so13/brief/so13_author_affiliations.html ). For example, both “UK” and “United Kingdom” and “Russia” and “Russian Federation” were included in the affiliation filter to search for publications from the UK and Russia, respectively. Changes in indexing of affiliation information were instituted by the NLM in late December 2013 that required a modification of the search algorithm ( https://www.nlm.nih.gov/pubs/techbull/so13/brief/so13_author_affiliations.html ). For the USA, the search algorithm was modified by adding all the names of the 50 states in the USA to compensate for this change in practice. Filter algorithms were continuously revised when “unexpected” results were encountered, such as, when entries from New Mexico state were included in results from Mexico, the country ( Appendix 5 ).

A summary of search procedures for generating the data is as follows: Step 1: Find the countries with the most publications. Filters used in this step were affiliation filter and publication date filter. Step 2: Search for selected publication types from top 30 countries. These searches consisted of three filters: affiliation filter, publication date filter, and publication type filter. Step 3: Search for publications from top countries with selected publication types in core journals. Four search filters were used for this step: affiliation filter, publication date filter, publication type filter, and core journals filter. Step 4: Finally, find collaborative publications from the top publishing countries. Results were analyzed using Microsoft Excel. The search algorithms used in this study are shown in Appendices 1 , 2 , 3 , 4 , and 5 .

All data were from PubMed entries from January 1995 to December 2016. In Fig.  1 , the total number of citations for the top 10 publishing countries from 1995 to 2015 are shown. The other 20 countries are not displayed because the lines were indistinguishable from each other. Research publications from the United States (USA) showed a steady rise and a doubling of publications in the 20-year review period. Starting around 2009, journal articles from China showed an increasing trend that parallels with the USA. Publications from other top publishing countries also showed an increasing trend but at a more gradual pace.

The top 10 publishing countries and total number of entries in PubMed from 1995 to 2015

Table  1 shows data for all publications and the different publication types (systematic review, meta-analysis, clinical trials, and randomized clinical trial) from the top 30 publishing countries for 2015. The USA led in all publications, systematic reviews, clinical trials, and randomized clinical trials, but China published the most number of meta-analysis publications with the USA in second place.

Although we originally planned to determine the top 25 highest publishing countries only, we found that there were five other countries and regions that were represented in the top 25 when data for specific publication types were analyzed. This displaced some countries in the original list of top 25 countries in “All publication types.” We subsequently decided to increase the total highest publishing countries and regions to 30 (Table  1 ). For systematic reviews, five other countries who were in the top 25 were Ireland, 18th; Greece, 21st; New Zealand, 22th; Norway, 23nd; and Hong Kong, 24th. Four countries who were not on the original 25 list but were in the top 25 for meta-analysis publications were Greece, 18th; Hong Kong, 22nd; Norway, 23rd; and Ireland, 24th. Norway was 21st in clinical trial publications and in randomized clinical trials, while New Zealand was in 25th place for randomized clinical trials.

For all publication types in 2015, the USA had more than twice as many publications as China (323,047 vs 144,850), which was second highest (Table  1 ). The United Kingdom (UK) was third highest at 88,271 or 27.3% of the US total. In 2015, the top 10 countries were (from highest to lowest) US, China, UK, Germany, Japan, Italy, France, Canada, Australia, and Spain.

The Abridged Index Medicus (AIM) or “Core Clinical,” a subset of MEDLINE, [ 9 ] which currently lists about 119 journals, contains some of the most highly read and highly cited clinical journals [ 10 ]. We reviewed the publications from the 30 countries in AIM subset and found that from 1995 to 2015 (Table  2 ), the average yearly output from the 30 top producing countries was 93.9% for all publication types and 98.1% for core journals (total number of countries = 235). The average varied only slightly from year-to-year in the 20-year review period.

A review of meta-analysis and systematic review publications from the top 10 publishing countries are shown in Fig.  2 . The results are similar to that seen in Table  1 , where the USA published the most articles in all publications. For China, the rapid growth in meta-analysis publications started in 2009, and eventually surpassing the USA in 2011. Although at the end of 2015 the USA still had more meta-analysis publications than China overall (16,581 vs 15,345), it was already 93% that of the USA and growing at a steeper slope. Compared to the USA, the total percentage of China’s output for total publications, systematic reviews, clinical trials, and randomized controlled trials were much lower—22%, 26%, 14%, and 15%, respectively.

Meta-analysis and systematic reviews all PubMed-indexed publications from 1995 to 2015. Numbers next to the country name indicate 20-year totals

Since “Systematic Review” is not a publication type filter in PubMed, but rather, a subset filter, the search algorithm was modified by including the title and “text word” combination to find articles of that type. The modified filter for systematic reviews was “(systematic review [tw] OR systematic review [tiab] OR meta synthesis [ti] OR cochrane database syst rev [ta] OR systematic literature review [ti] OR pooling project [tw] OR umbrella review [tw])” . Figure  2 shows that the USA leads in systematic reviews that is maintained throughout the 20-year period.

Co-authored publications with the US collaborators account for the highest percentage among the top 30 countries (Table  3 ). In 2015, the USA published 89,060 papers in collaboration with other countries, which is 27.6% of its total publication output (323,047). Collaborators from China were co-authors in 19.8% (highest) of US total publications, followed by 16.0% from the UK, and 12.9% from Canada. In 2015, China published 34,089 co-authored publications (23.5% of total publications), with 51.7% co-authored with US scientists, 14.4% from Hong Kong, and 9.3% from Taiwan. From 1995 to 2015, there was a mix of decreases and increases in cross country co-authorship; however, the absolute numbers of collaborative publications between the top 5 countries and 30 other countries on the list increased from 2093 in 1995 to 357,746 in 2015. For the other top 4 countries (Table  3 ), the most co-authored papers were also with the USA. The overall number of co-authored publications for the 30 top research countries, from 1995 to 2015, was 780,521.

Prior to October 2013, PubMed only indexed the first author’s affiliation. We wanted to determine how the change in policy of listing the affiliation of all authors made a difference, by comparing collaborative publication data for 10 years (2006 to 2015). Figure  3 illustrates the rapid increase in collaborative publications after 2013 as a result of this policy change. Although it can be attributed to the policy change, the increasing trend during the consecutive years may be real, stemming from increased collaborations between institutions internationally. Figure  3 also shows that even before 2013, there were already papers with multiple affiliations in PubMed entries, about 8% for China and 4% for the UK.

Percentage of collaborative publications from the five top publishing countries based on each country’s total publications, 2006–2015

Recent reports of the rapid increase in meta-analysis publications from China prompted this study [ 4 , 5 , 6 , 7 ]. Our review seemed to confirm this trend. Although the majority of total journal articles were still published by researchers in the USA, data from 1995 to 2015 showed that China was almost equal in number to that of the USA in meta-analysis publications. China’s meta-analysis publications are at a steeper slope than any other country since it started in 2009 (Fig.  2 ) and has overtaken all countries in the top 10 category. In this review, we also found an increase in collaborative publishing among the top publishing countries.

Some reports cite evidence-based medicine as the stimulus for the rapid rise in the number of meta-analysis publications in China [ 4 ] and to the pressures of academia [ 6 ]. Ioannidis attributes the recent increase to contracting companies “operating in the domain of evidence synthesis” [ 5 ]. The tools for doing a meta-analysis and systematic reviews are widely accessible. However, this study did not show an increase in systematic reviews.

International collaboration improves the quality of research for all partners although it has some challenges as well [ 11 ]. The growth of collaborative research with China and other countries has been reported [ 11 ]. Publications in international journals from all countries have increased over the years as evidenced by total publications (Table  3 and Fig.  3 ). An even more positive development is the increased international collaborations between the top publishing countries (Fig.  3 ). In 2015 (Table  3 ), co-published papers between China and the USA accounted for 51.7% of China’s co-authored publications. Collaborations with other countries and regions were high as well (Hong Kong 14.4%, Taiwan 9.3%, Australia 7.3%, Japan 7.4%, Canada 6.5%, Germany 6%). In 2015, 27.6% of total US’ publications (34129) were collaborative publications. The most co-authored journal papers were with China, 19.8%; the UK, 16%; Canada, 12.2%; and Germany, 12%. The lack of data for all author affiliations before 2013 makes the trend of earlier international collaborative publications unclear. But from the first authors’ affiliations before 2013 (Fig.  3 ), we can infer that scientists working collaboratively have increased over the years.

Although we attempted to include all publications from the 235 countries with citations in PubMed, we may have missed some publications because some co-authors’ affiliations may not have been indexed in PubMed before 2013. Other reasons may include NLM indexing affiliations of authors only if provided by publishers in their XML submissions; association of authors with multiple institutions and not listing all affiliations; and discontinued editing of author affiliation field in MEDLINE/PubMed citations. In the past, NLM policy was to indicate the affiliation for the first author only and edited the field by adding “USA” ( https://www.nlm.nih.gov/pubs/techbull/so13/brief/so13_author_affiliations.html ). For example, many publications from the USA only list the states or even only the academic institution or the organization where they originated. After 2013, PubMed discontinued adding “USA” in the affiliation field. In our search algorithm, we added all the states in the USA to compensate for this. Some publications from China, Russia, or the Russian Federation that may have listed only their academic affiliations or cities would have missed their country affiliation. Unlike the authors in the USA, we cannot compensate by adding the names of all the states for China and Russia. However, a random search of over 200 articles from Russia and China all showed their countries in the affiliation field. It is unlikely, but this is still a possible limitation of the study.

Wilczynski and Haynes [ 12 ], analyzing the consistency and accuracy of several search strategies, found that using only single terms yielded low sensitivities—76.5% for “Review.pt” and 19% for “Meta analysis.pt.” In our search algorithms, we tried to include filters ( Appendices 2 , 3 , and 4 ), similar to those used by Shojania and Bero [ 13 ] that yielded sensitivities between 93 and 97% and would identify publications that are systematic reviews and meta-analysis. However, there is no assurance that we have found all of these articles. This may be a limitation.

We found in this 20-year review of publications that only 30 countries (out of 235 total reviewed) are responsible for an average of 93.9% of all publications in PubMed. What might explain the few numbers of countries responsible for a majority of the world’s literature? It is likely a consequence of country priorities, lower levels of funding, and the high cost of doing research, although labor costs may be lower [ 14 ]. Biomedical research is often not a top priority in developing countries. However, although the research output of developing counties may be relatively low, many important medical and public health interventions were developed in developing countries, such as life-saving interventions like oral rehydration therapy for diarrhea and vitamin A to reduce infant mortality [ 15 ]. Moreover, collaborative research may be indexed as publications from funding agencies or collaborators in developed countries [ 11 ]. Other countries may also have fewer research and academic institutions. Developing countries can make important contributions to the medical literature, especially in the area of infectious diseases, and increasingly, non-communicable chronic diseases. Top research countries and research funding agencies may need to collaborate more with other countries. Some of this may be occurring through the internationalization of clinical trials that are now done worldwide and increased student and fellowship training [ 11 ].

We had also considered whether the rapid increase of publications might be explained by so-called predatory journals—low-quality journals with little or no peer review, which promise rapid publication but exist solely for profit [ 16 ]. However, we do not believe that these journals are responsible because this evaluation is based only in publications indexed in PubMed. Some data indicate that a few of these types of journals are indexed in PubMed. Moreover, Shen and Bjork also reported that “the problem of predatory open access seems highly contained to just a few countries, where the academic evaluation practices strongly favor international publication, but without further quality checks” [ 17 ].

This study showed the continuing increase in research publications globally. The USA still leads the world in all publications and specific publication types except in meta-analysis where recently China now publishes more. Increasing collaborations and authorships among countries with the USA, China, and other top publishing countries is also increasing.

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This research was supported by the Intramural Research Program of the National Institutes of Health, National Library of Medicine, and Lister Hill National Center for Biomedical Communications.

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The Adoption and Effect of Artificial Intelligence on Human Resources Management, Part B

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Purpose: This study aims to review the existing literature on human resource management (HRM) as a major theme and sub-theme of human resource (HR) analytics. This chapter has the objective of analysing the trends in HR analytics.

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Findings: It was found that research published in the early period concentrated on HRM’s theoretical and conceptual frameworks. In the middle phase, HR analytics gained momentum while the recent publications have reiterated on adopting various tools and technologies for optimum utilisation of resources and sustainable organisational development.

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Awasthi, S. , Bathla, D. and Singh, S. (2023), "A Literature Review on HR Analytics: Trends and Future Challenges", Tyagi, P. , Chilamkurti, N. , Grima, S. , Sood, K. and Balusamy, B. (Ed.) The Adoption and Effect of Artificial Intelligence on Human Resources Management, Part B ( Emerald Studies in Finance, Insurance, and Risk Management ), Emerald Publishing Limited, Leeds, pp. 235-250. https://doi.org/10.1108/978-1-80455-662-720230014

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Moving Trend Analysis Methodology for Hydro-meteorology Time Series Dynamic Assessment

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In the last 30 years, there are many publications in the literature due to global warming and climate change impacts exhibiting non-stationary behaviors in hydro-meteorology time series records especially in the forms of increasing or decreasing trends. The conventional trend analyzes cover the entire recording time with a single straight-line trend and slope. These methods do not provide information about up and down partial moving trends evolution at shorter durations along the entire record length. This paper proposes a dynamic methodology for identifying such evolutionary finite duration moving trend method (MTM) identifications and interpretations. The purpose of choosing MTM was to investigate the dynamic partial trend evolution over the recording period so that dry (decreasing trend) and wet (increasing trend) segments could be objectively identified and these trends could assist in water resources management in the study area. The moving trend analysis is like the classical moving average methodology with one important digression that instead of arithmetic averages and their horizontal line representations, a series of finite duration successive increasing and decreasing trends are identified over a given hydro-meteorology time series record. In general, partial moving trends of 10-year, 20-year, 30-year and 40-year occur above or below the overall trend and thus provide practical insight into the dynamic trend pattern with important implications. The moving trend methodology is applied to annual records of Danube River discharges, New Jersey state wise temperatures and precipitation time series from the City of Istanbul.

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1 Introduction

Global warming due to greenhouse gas (GHG) released into the troposphere causes climate change, which can reflect itself as partial and overall increasing or decreasing trends in any hydro-meteorological time series. It has already been proven by Milly et al. ( 2008 ) that all hydro-meteorological records fall into non-stationary realm with the inclusion of trends. Hydro-meteorological records have systematic components such as trends and variability (Burn and Hag Elnur 2002 ). There are basic methodological contributions that provide probabilistic or statistical trending tests (Mann 1945 ; Kendal 1970 ; Spearman 1904 ; Sen 1968 ; IPCC 2007 ; Şen 2012 ; Alashan 2018 ; Güçlü 2018 ; Ashraf et al. 2021 ). The applications of these methods have increased in an unprecedented way and therefore there are many studies in different disciplines that try to determine the overall (holistic) trend. Hamed ( 2008 ) has proposed different trend detection methodologies in hydro-meteorology records. A review of current trend methodologies is presented by Sonali and Kumar ( 2013 ) and applied these methodologies to temperature records. One of the major problems in the Mann and Kendall (MK) trend identification methodology is the assumption that time series must be serially independent, which cannot be met with hydro-meteorological data and hence pre-whitening (Yue and Wang 2002 ) or over-whitening (Şen 2017 procedures are offered to alleviate this requirement. In different water related disciplines many researchers applied the MK methodology holistically (overall) on a given time series records (Hirsch et al. 1982 ; van Belle and Hughes 1984 ; Hirsch and Slack 1984 ; Cailas et al. 1986 ; Hipel et al. 1988 ; Demaree and Nicolis 1990 ; Yu et al. 1993 ; Gan 1998 ; Taylor and Loftis 1989 ; Lins and Slack 1999 ; Douglas et al. 2000 ; Hamilton et al. 2001 ; Kalra et al. 2008 ; O’Brien et al. 2021 ; Mateus and Pitoto 2022 ).

The averaging of a partially fixed number of sub-time series is the basis of the moving average procedure, which can be weighted or unweighted. The average amount moves over time, repeatedly deleting old data points, leaving the average levels in that order. The unweighted alternative is a simple moving average procedure, where all observations are given the same weight. The weighted moving average, on the other hand, assigns different weights in the mean calculations. The basic idea in weights is that the newest data has more weights for prediction than the old ones, so exponentially increasing weights can be added towards the newest records. Such assignments may dependent on expert opinions, for example Yeh et al. ( 2003 ) proposed exponential weighted moving average control charts to detect small changes in process variability. Lee and Apley ( 2011 ) proposed another graph for the design of the residual-based weighted moving average for autoregressive moving average (ARMA) models (Box and Jenkins 1976 ).

The unweighted moving average method has advantages such as easy understanding and computation, small data requirement from the past, and removal of outliers after certain periods. On the other hand, disadvantages include that the estimate depends on the average length, requires all data from the past and gives the same weight or importance to all data used in the calculations.

The moving trend method (MTM) in this paper is based on the application of the innovative trend analysis (ITA) procedure proposed by Şen ( 2012 ) and used by several authors for hydro-meteorological datasets. Recently, ITA methodology is used along with traditional trend identification methodologies by many authors (Achite et al. 2021 ; Esit et al. 2021 ; Ullah et al. 2022 ; Hirca et al. 2022 ; Fanta et al. 2022 ; Pastagia and Mehta 2022 ; Xie et al. 2022 ; Abbas et al. 2023 ; Birpınar et al. 2023 ).

The main purpose of this paper is to explore the possibility of determining moving trend in a series of sub-times (10-year, 20-year, 30-year and 40-year) within hydro-meteorological time series. This methodology is called the moving trend method (MTM). Alongside the overall (holistic) trend across all records, a set of sub-time trends are presented to recognize the dynamic development behavior of trends. In this way, one can appreciate how trends have developed throughout the practically entire recording with scientific commentary. Sub-times are considered as repetition periods (recurrence intervals) and accordingly probabilities are associated with a set of partial trend slopes. MTM application is made for annual hydro-meteorological records from Danube River discharges, New Jersey state-wise temperatures and Istanbul City precipitation values.

Following a brief literature review in the Section 1 , this article consists subsequent 5 sections covering theoretical and practical aspects of MTM analysis methodology. The importance of the traditional statistical moving average procedure is explained in Section 2 . In connection with this, Section 3 explains the theoretical characteristics of the proposed MTM approach. Section 4 includes three different hydrometeorology recording applications with figures, tables, implications, and inferences. Section 5 presents the pros and cons of the proposed MTM methodology. Finally, Section 6 provides conclusive information about the limitations of the MTM approach and its useful aspects for further research.

2 Moving Average Significance

A series of arithmetic averages with a fixed number of data in a time series is called the moving average procedure, which moves through the series adjacent to the consecutive average. Prior to formal pattern identification in any hydro-meteorology time series, visual inspection reveals several short-term embedded features such as partial trends. Generally, within short periods, a time series has a few statistical and probabilistic components, including possible cascade of spikes (jumps), trend, periodicity, short- and long-term serial dependencies, and random variations. Numerous articles focus on holistic trend determination methodology such as the Mann-Kendal trend test (Mann 1955 ; Sen 1968 ; Kendall 1973 ), over a long-term systematic variation that is a linear function and shows the general trend.

The moving average method provides a series of consecutive averages over a period of m for which the number of data is smaller than whole data length, n. The moving average over m period represents the time series change as a horizontal line. There are several problems with the moving average procedure, such as determining the extension of the moving average to eliminate the original fluctuations in the time series. The resulting moving average time series cannot be used for future trend prediction, which is the main target for objective trend determination. Another problem is with horizontal lines, which can be replaced by straight lines that linearly increase or decrease linearly as partial and local trends; this is the main purpose of this paper recommendation as moving trend methodology (MTM).

3 Moving Trend Method (MTM)

It is well-known that global warming refers to the increasing temperature trend prevailing throughout the Earth; the effects of climate in any hydro-meteorology record series are not global, but local and regional in the forms of either increasing or decreasing trends. Like spatial globalism and regionalism, temporally any given hydro-meteorological time series can have trends over the entire recording period or over desired sub-periods in a series. As mentioned earlier in the Section 1 , MTM is based on innovative trend analysis modified for sub-period trend identification along the following points.

Decide on the duration of a series of periods to determine the trend series record. It is adapted in this paper for 10-year, 20-year, 30-year and 40-year. The last two periods are in line with the World Meteorological Organization’s recommendation for climate change trend identification studies (WHO 2017 ). Meanwhile, the holistic trend for the entire record is also considered for comparison purposes,

Starting from the first record, the trend component of each period is determined according to the innovative trend analysis approach. For this purpose, the trend slope, S T , for each period is calculated according to the following expression.

where m is the duration of period, \({\overline{\text{X}}}_{\text{S}\text{H}}\) ( \({\overline{\text{X}}}_{\text{F}\text{H}}\) ) is the second (first) half of the original time series data during the period,

To plot the linear trend over the corresponding period, the crossing point is taken as the period mid-time, t mp , (abscissa), and the arithmetic mean value of the as \({\overline{\text{X}}}_{\text{P}}\) (ordinate) Thus, moving trend sequences are obtained within the hydro-meteorological data.

4 Application

The Danube River is the second longest river in Europe after the Volga in Russia, with a length of approximately 2,850 km (1,770 mi) and is a river in many parts of Europe, including Austria, Slovakia, Hungary, Croatia, Serbia, Romania, Bulgaria, Moldova and Ukraine. It has a record starting from 1840. Another very long temperature record exists from the USA state of New Jersey, starting from 1895. Rainfall records on the European side of the city of Istanbul in Turkey start from 1936. The application of the MTM is performed for different long-term annual hydro-meteorology variables, including records for Danube River discharges (1840–2010), New Jersey state-wise temperature (1895–2010) and Istanbul precipitation (1939–2020) with their statistical parameters in Table 1 .

For the Danube River annual discharge records, there are 4 graphs in Fig. 1 for the 10-year, 20-year, 30-year and 40-year sequences of moving trend components. The same graphs also show the overall holistic trend component of the records for comparison. The moving trend component of each period fluctuates around the holistic trend, which is an overall approach and does not give detailed information as the serial trend evolution across the whole records in shorter periods than the number of records. The following points are important in the interpretation of comparative trend study.

In all Graphs, Holistic Trend has a Slightly Increasing Slope of 79 m 3 /year,

In Fig. 1 a, there are two extremely wet periods in the past between 1842 and 1852 and 1872–1882, respectively in the 10-year consecutive periods. Since then all 10-year moving trends are in decreasing form and in continuous reduction and the most decreasing 20-year trend appeared between 1982 and 2002. This irrespective or increasing or decreasing tendencies. There are several increasing trends around the overall (holistic) trend an especially in the most recent 10-year (1992–2002) it is also very close to general tendency,

As for the 20-year moving trends, there was only one increasing trend in the past between 1842 and 1862 (see Fig. 1 b). Since then all consecutive 20-year moving trends are in decreasing form and their collective appearance is also in decrease until the end of record where the most decreasing moving trend slope is during 1982–2002 period,

Figure 1 c includes moving trends for 30-year periods, which is the World Meteorological Organization’s proposed standard duration for climate change studies (WHO 2017 ). The only increasing 30-year moving trend is between 1972 and 2002 period, all other moving trends have decreasing tendency around the holistic trend,

Danube River annual discharge trends for a 10-year, b 20-year, c 30-year, d 40-year

The common conclusion from all graphs is that the most dynamic water formations occurred around 1900. Each of these graphs has distinct moving average trends bouncing from increasing (wet) to the decreasing (dry). It is not possible to obtain interconnected moving trend series.

Each graph in Fig. 1 reveals the relative position of different duration MTM components relative to the holistic trend. It is obvious that there are increasing and decreasing finite-period trends above and below, which provide detailed dynamic changes to make the future finite-trend forecast of water resources planning, operation and management. The following points are important for this type of works.

In Fig. 1 a, the 10-year periods represent 10 increasing moving trends, of which 3 are above the overall trend, 5 are below. The number of decreasing trends is 5 and only 2 of them are above the overall trend. This information implies that increasing trends are more effective than decreasing alternatives throughout the entire recording period. Especially after 1980, increasing trends are observed. In the light of these explanations, it can be predicted that the 10-year moving averages of the annual discharges of the Danube River are bound to increase.

Comparing the 10-year moving trends with the 20-year trends in Fig. 1 b shows that the latter trends are closer to the general holistic trend, and most of the trends in this period tend to decrease with increasing tendency throughout the entire recording period,

The 30-year moving trends in Fig. 1 c are closer to the overall holistic trend than the 20-year duration trends. Although there have been two decreasing trends in the past 60 years, there is an increasing trend in the last 30 years,

In Fig. 1 d, the 40-year moving trends are almost like the 30-year trends, there are two trends that have increasing appearance in the last 80 years.

Figure 2 shows all moving trends from different periods collectively to make comparison of the most severe situations dynamically throughout the record length. Among all these periods 30-year moving trends attract attention because of the WHO ( 2017 ) report recommendation. The most variation domain of moving trends is attached with 10-year period. Although short period but has the biggest increasing and decreasing trend variation domain from 4400 m 3 /sec to 6400 m 3 /sec.

Danube River discharge records moving trend collection

As for the New Jersey annual temperature record MTM, the overall trend and moving trends are shown in Fig. 3 . There is a holistic trend that increases with a slope of 0.0175 o F/year. It is worth paying attention to the following points.

In Figs. 3 a and 10-year consecutive moving trends show continuously increasing and decreasing tendencies that take place around the holistic trend. The general tendency of moving trends follows overall temperature increase with ups and downs,

Figure 3 b shows the 20-year consecutive moving trends that follow the overall (holistic) increasing tendency. Especially, between 1970 and 2010 20-year trends are in the form of decreasing trends, but their positions show temperature increases,

Three 30-year periods moving trends are shown in Fig. 3 c, which have standard lengths of records for climate change impact interpretations as recommended by World Meteorological Organization. Increasing and decreasing moving trends are in good accord with the holistic trend. The middle point of each moving trend shown increase in the position of increasing and decreasing trends,

There are two 40-year moving trends in Fig. 3 d. Just opposite the holistic trend, 1930–1970 trend has ignorable slope, whereas the recent moving trend during 1970–2010 period has decreasing trend but its middle point position is higher than the previous one. This point indicates that whether increasing or decreasing 40-year trends they have increasing middle point location by time,

New Jersey annual temperature trends, a 10-year, b 20-year, c 30-year, d 40-year

In Fig. 4 all period moving average trends are shown collectively, which shows that whatever is the moving trend period there is in all increasing trend position irrespective of increasing or decreasing tendency. Although there appear decreasing moving trends in the most recent periods compared to the same set moving trend position is in increase.

New Jersey State wise temperature records moving trend collection

Annual precipitation records of Istanbul City from 1940 to 2012 are shown in Fig. 5 with moving trend components over each periods. The overall trend tends to increase with slope 0.0507 cm/year, which means a very small increase in precipitation record moving means.

For 10-year moving trends below the overall trend indicates possible water shortages that have occurred at various time durations in the past and it is clear from Fig. 5 a that decadal shortages are about 86% (see Fig. 5 a). The only decade with increasing precipitation seems from 1962 to 1972,

20-year moving trends during 1972–1992 and 1992–2002 periods are the same with the holistic trend that shows quite stationary rainfall regime on the average in the last 40 years of the record,

As for the 30-year period during 1982–2002 there appears a slight decrease around the holistic trend. The middle point position of this moving trend lies on the holistic trend line. This means that during the first (second) half of this period moving trend decrease is above (below) the holistic trend (see Fig. 5 c),

Figure 5 d is for 40-year period decreasing moving trend component, which has almost the same slope as the holistic trend again with half slightly over and the next half below the holistic trend.

Istanbul annual precipitation trends, a 10-year, b 20-year, c 30-year, d 40-year

Moving trends of different periods are shown collectively in Fig. 6 , where only 10-year period moving trends expose quite sharp increasing and decreasing trends. Especially, the last 30-year trend indicates a decreasing trend of which the middle point lies on the holistic trend with early (late) half is above (below) the holistic trend.

Istanbul/Florya precipitation records moving trend collection

A set of slope values for moving trends are given in Table 2 for each data set including different periods 10-year, 20-year, 30-year and 40-year, respectively. A wide variety of moving trend slope variations can be noticed for each period. The mean and the standard deviations of each period are also given in the same table.

Of course, the average values are based on positive (increasing) and negative (decreasing) trend values and thus generally show the general trend towards overall positive or negative moving trend values. A common point as for the 30-year period is concerned that all the hydro-meteorology records have decreasing trend slopes. For example, Istanbul moving trend average values are negative for all periods, indicating that it is possible to expect precipitation reduction in future time periods.

5 Discussion

There are different trend identification methodologies in the open literature and some of them require restrictive assumptions that are not very satisfactory for natural hydro-meteorological recording time series, for which the assumption of serial independence is most important. Some are interested in non-parametric procedures in which the natural order of hydro-meteorology time series is replaced, for example, by orders as ranks (Spearman 1904 ). Most of these trending tests require long time series as their results are in biased for short samples. In this article, innovative trend analysis (ITA) methodology is applied as a different approach to overall trend determination, because moving trend components are valid even for time series samples that are significantly shorter than the World Meteorology Organization recommendation of 30 years (WHO 2017 ). Overwhelmingly, theoretical trend identification or practical procedures predominantly consider the entire sample length of a given time series. Many are biased because they do not meet key constraining assumptions such as serial independence, normal (Gaussian) probability distribution function (PDF) or long sample lengths.

Comparing the results of MTM procedure for different sub-periods of a hydro-meteorology time series provides the dynamic behavior of finite length trend development over the recording period. Generally, moving trends fluctuate around the overall trend line. Comparing up and down moving trend numbers to understand the frequency of short-term percentages result in higher (lower) values than the overall trend. Instead of taking future action according to the overall full recording time trend, making dynamic comments considering the sequence of MTM trends, and accordingly, better trending probability in the future.

The innovative aspect of this paper is the dynamic description of the desired partial-time trend analysis instead of holistic classical trend trends that do not show cycles of increasing and decreasing trend evolution over the entire length of the record. Once possible finite-term trend slopes have been identified, it is possible to make same-term future trend slope forecasts for improved water resources management planning and operation.

The MTM methodology provides information about trend slopes, so that during which moving trend duration the maximum and minimum increasing and decreasing slopes occur and, if necessary, average slopes for these two types of trends can be determined.

6 Conclusions

As a result of the greenhouse gas (GHG) emissions into the troposphere, global warming has led to climate change at different increasing or decreasing rates in different parts of the world. In climate change impact studies, trend analysis procedures are important to decide whether there is an increasing or decreasing overall trend for a hydro-meteorological variable at a location, unlike general circulation (climate) models (GCMs). This paper provides moving trend analysis for several sub-periods in a given time series records and their comparison with classical holistic trend procedures in the literature. For this purpose, a dynamic trend evaluation study is carried out by investigating subsequent special moving trend for 10-year, 20-year, 30-year and 40-year periods. The application of the proposed moving trend methodology is given for annual records of Danube River discharges, New Jersey state-wise temperatures and Istanbul City precipitation. Moving trending also provides percentages of decreasing (increasing) trend activity over the entire time series. It is recommended that the application of moving trend analysis sheds light on more dynamic structural behavior of hydro-meteorological records. The only limitation for holistic trend analysis is at least 30 years of data, which is recommended by the World Meteorological Organization and is also valid for the moving trend analysis methodology. There has not been yet any other research using MTM analysis, but in future water resources management studies such part-time trends tend to provide important information about dry and wet trend tendencies and their likely duration.

Data Availability

Data can be provided upon request from the corresponding author.

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Effect of cytoplasmic fragmentation on embryo development, quality, and pregnancy outcome: a systematic review of the literature

• Ariella Yazdani 1 , 3 ,
• Iman Halvaei 2 ,
• Catherine Boniface 1 &
• Navid Esfandiari   ORCID: orcid.org/0000-0003-0979-5236 1 , 4  

Reproductive Biology and Endocrinology volume  22 , Article number:  55 ( 2024 ) Cite this article

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The role of cytoplasmic fragmentation in human embryo development and reproductive potential is widely recognized, albeit without standard definition nor agreed upon implication. While fragmentation is best understood to be a natural process across species, the origin of fragmentation remains incompletely understood and likely multifactorial. Several factors including embryo culture condition, gamete quality, aneuploidy, and abnormal cytokinesis seem to have important role in the etiology of cytoplasmic fragmentation. Fragmentation reduces the volume of cytoplasm and depletes embryo of essential organelles and regulatory proteins, compromising the developmental potential of the embryo. While it has been shown that degree of fragmentation and embryo implantation potential are inversely proportional, the degree, pattern, and distribution of fragmentation as it relates to pregnancy outcome is debated in the literature. This review highlights some of the challenges in analysis of fragmentation, while revealing trends in our evolving knowledge of how fragmentation may relate to functional development of the human embryos, implantation, and pregnancy outcome.

Introduction

Human preimplantation embryo scoring systems have been widely used to predict blastocyst development and implantation rate after in-vitro fertilization (IVF). The grading of embryos on day-2 and -3 after fertilization is largely subjective and interpretation varies across IVF laboratories, as it is commonly based on morphological appearance. Characteristics in early embryo grading schema include the amount of cytoplasmic fragmentation (CF) during early cleavage, speed of cellular division, number, size, and symmetry of cells (blastomeres). As defined by the Istanbul consensus workshop on embryo assessment, a fragment is “an extracellular membrane-bound cytoplasmic structure that is < 45 µm diameter in a day-2 embryo and < 40 µm diameter in a day-3 embryo” [ 1 ]. There are several different systems to evaluate embryo morphology including Hill’s scoring system [ 2 ] Cummins' grading system [ 3 ] ASEBIR grading system [ 1 ], the UK/ACE grading scheme [ 4 ]; each system has its own classification for degree of fragmentation as well as embryo grade. This heterogeneity further complicates analysis of fragmentation in relation to outcomes.

CF has been shown to occur early in embryonic division and is a common phenomenon seen in embryos cultured in vitro. CF has traditionally been used as a metric of embryo implantation potential [ 3 , 5 , 6 , 7 ]. The amount and pattern of fragments are analyzed in early development, incorporated into the embryo grade depending on grading system, and used to help select the most developmentally competent embryo to be transferred during an IVF cycle. This classification system is important as a proportion of embryos within a single cohort will not successfully develop to the blastocyst stage in vitro. Although there are various contributing factors to an embryo’s developmental capacity and viability, it is largely agreed upon that fragmentation plays an important role. It seems that the etiology of embryo fragmentation is not fully understood but it may be related to several factors like gamete quality, culture condition, and genetic abnormalities in the embryo [ 8 ]. It is difficult to directly compare and quantify relative degrees of fragmentation across studies. However, it has been repeatedly shown that the extent of fragmentation and implantation potential are inversely proportional [ 5 , 7 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ]. While a low degree of fragmentation does not seem to significantly impact embryo viability, severe fragmentation does [ 7 , 22 , 23 ]. Alongside the cell to cytoplasmic ratio, the pattern and distribution of fragmentation influence the developmental quality of the embryo [ 7 , 24 ]. There are two main patterns of embryo cytoplasmic fragments: scattered and concentrated. The former is characterized by fragment contact within several blastomeres and is related to aneuploidy [ 25 ]. Time-lapse studies have shown that fragmentation is thought to be a dynamic process, where some fragments can be expelled or reintroduced into the cells as the embryo continues to divide [ 25 , 26 ]. Fragments can also easily move or rotate around the associated blastomere and change their position in the embryo [ 27 ].

Current grading systems used to evaluate cleavage-stage embryos are largely based on day-2 or -3 morphology. This can be problematic, as developmental growth of an embryo is variable and the grade of a developing embryo at one point in time is not guaranteed to persist. For example, studies have suggested that embryo selection on day-2 or -3 based on morphological grade can be unreliable and lead to negative pregnancy outcomes [ 28 , 29 , 30 ]. Accordingly, new parameters for predicting implantation success have been proposed including extended embryo culture to the blastocyst stage to day-5, -6 or -7 [ 31 ]. Delaying embryo transfer to the blastocyst stage is advantageous as it can limit the number of unsuccessful embryo transfers and biochemical pregnancies or clinical pregnancy losses in IVF. While there are multiple reports on the impact of cleavage-stage embryo quality on blastocyst formation and blastocyst quality [ 32 , 33 ], few have specifically looked at the degree of fragmentation as a predictive variable.

In this systematic review, we comprehensively reviewed the available literature on the origin and characteristics of CF, factors affecting CF, and the effect of CF and fragment removal on embryo development and pregnancy rate.

Materials and methods

A search was conducted on October 10, 2023, using PubMed and Google Scholar databases in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines [ 34 ]. In PubMed, the search terms “embryo*[tw] OR cleavage stage [tw] OR "Embryonic Structures"[Mesh] OR "Embryonic Development"[Mesh] OR "Embryo, Mammalian"[Mesh] OR "Cleavage Stage, Ovum"[Mesh]” AND “cytoplasm*[tw] AND fragment*[tw] AND “(Blastocyst*[tw] OR "Blastocyst"[Mesh]) AND (form* OR develop* OR quality*)” were used. A title search in Google Scholar using search terms as above and “embryo cytoplasm fragmentation”, “blastocyst quality”, “blastocyst development” was performed. Only full-text publications in English were included. Full-text articles which did not have any mention of cytoplasmic or embryo fragmentation were excluded, however articles which mentioned both DNA fragmentation and CF were included. Since most of the studies discussing CF also discussed other morphologic features of the embryo, studies that mention embryo morphology, grade or quality were also included. Articles that looked at non-human embryo fragmentation, case reports, case series, book chapters and review papers were excluded. Titles and abstracts were screened, and study quality and bias were assessed. The primary outcomes of interest were embryo quality, blastocyst formation, and pregnancy outcome.

Figure 1 provides details of study screening and inclusion. There were 206 studies screened between the two search engines PubMed ( n =106) and Google Scholar ( n =100). There were 18 duplicates giving a total of 188 articles. Due to the small number of studies from the search criteria, no filter of time was placed. After removal of non-full text articles, articles that used non-human embryos, and articles not relevant to the topic, 20 articles were eligible for inclusion. Forty relevant references from the articles were also extracted, reviewed, and included in this review. These additional articles were reviewed with the same inclusion and exclusion criteria as mentioned above. A total of 60 articles were included in the qualitative synthesis of this review.

Article Identification and Screening

Origin and etiology of CF

The etiology of CF is not completely understood. There are several proposed theories as to why embryos display variable degrees of fragmentation. Fragmentation has been shown to be a natural, unpredictable process both in vitro and in vivo and is documented in various species [ 35 , 36 ]. This suggests that embryo fragmentation is neither species-specific nor solely a byproduct of in vitro culture. Assisted reproductive technology (ART) and IVF techniques, such as time-lapse microscopy (TLM) and transmission electron microscopic (TEM) analyses, have recently allowed for further understanding of embryo developmental potential and fragmentation (Figs.  2 and 3 ). Seven of the included studies in this review propose potential hypotheses as to the origin of CF (Table 1 ). Three of the articles evaluated gamete quality as related to fragmentation in a developing embryo [ 37 , 38 , 39 ].

Human cleavage stage embryos a) Day-2 embryo at 4-cell stage with no fragmentation, b) fragmented Day-2 embryo, c) Day-3 embryo at 8-cell stage with no fragmentation, d) fragmented Day-3 embryo, e) Day-5 cavitating Morula with no fragmentation, f) fragmented Day-5 cavitating Morula

Ultrastructure and organelle microtopography of an embryo fragment by transmission electron microscopy. Ly: primary lysosome, M: mitochondrion, rM: remnant of regressing mitochondrion, MV: mitochondria-vesicle complex, V: vesicle; scale bar: 1 µM

An early study showed that sperm DNA oxidation has been associated with embryo development and quality, and therefore linked to CF [ 37 ]. Nucleolar asynchrony in the zygote from sperm DNA fragmentation has previously been shown to predict future low-quality blastocyst development. A positive correlation has also been found between the percentage of sperm OxiDNA-stained cells with embryo fragmentation on day-2 and -3 of development. Sperm DNA oxidation may therefore be associated with fragmented, nonviable, poor-quality embryos [ 37 ] . A recent study also showed the negative correlation between sperm DNA fragmentation and blastomere DNA fragmentation and blastulation rate [ 40 ]. Further studies are needed to confirm the impact of sperm DNA oxidation on embryo fragmentation.

An observational study documented the degree of fragmentation of human embryos as they progressed through mitotic cell cycles [ 38 ]. In this study, the authors analyzed nearly 2,000 oocytes and 372 embryos, and found that increased embryo fragmentation (>50%) was associated with a specific pattern of development: delayed first division (oocyte spindle detected at 36.2 hours after hCG injection vs. 35.5 hours in low fragmentation), a significantly earlier start of the second mitosis (8.9 hours vs. 10.8 hours after the first mitosis), and a significant delay of the third mitosis after the second mitosis (2.2. hours vs. 0.6 hours). The authors did not comment on whether fragmentation could be a result of the cell dividing before proper chromosome alignment, or if existing aneuploidy resulted in erroneous cleavage patterns [ 38 ].

Polar body (PB) fragmentation has also been investigated in relation to cytoplasmic fragmentation. Ebner et al., in a prospective study analyzed the relationship between a fragmented first PB and embryo quality in patients undergoing ICSI. Two groups of oocytes were analyzed according to PB fragmentation: intact first PBs and those with fragmented PBs. Forty-two hours after ICSI, embryo morphology (i.e., number of blastomeres and degree of fragmentation) was recorded. Overall, a significantly higher percentage of cytoplasmic fragmentation was seen in day-2 embryos that originated from oocytes with fragmented first PBs than those with intact PBs ( P < 0.05). This study further supports the concept that oocyte quality contributes to overall embryo fragmentation and provides evidence that preselection of oocytes may contribute to the prognosis of embryo quality and blastocyst development [ 39 ]. The role of PB fragmentation on embryo quality was confirmed in other studies [ 41 , 42 ], however, a recent study has not recommended considering PB status as a tool for embryo selection [ 43 ].

Beyond analysis of gamete quality, other studies have shown a biochemical relationship between embryo competence and fragmentation. One study showed that disturbances in E-cadherin, a cell adhesion protein that plays a critical role in morphogenesis, occur in embryos with cleavage abnormalities and extensive cytoplasmic fragmentation, suggesting a possible mechanism to the loss of embryonic viability [ 44 ]. Further, by using mitochondrial fluorescence techniques, Van Blerkom et al., found that mitochondrial distribution at the pronuclear stage may be an epigenetic factor related to the organization of the embryo and further embryonic development [ 45 ]. Blastomeres that were deficient in mitochondria and thus ATP at the first or second cell division remained undivided and often died during subsequent culture. Although this study examined morphologically normal (unfragmented) cleavage-stage embryos, it may support the idea that perinuclear mitochondrial distribution and microtubular organization influence developmental capacity of early cleavage-stage embryos [ 45 ]. Higher numbers of mitochondria reported in fragmented compared to the normal blastomeres show the rapid depletion of ATP in the fragmented embryos [ 21 ]. There have also been reports of increased gene transcription of mitochondrial factors like OXPHOS complexes, ATP synthase, and mtDNA content in highly fragmented embryos compared to controls [ 46 ]. Mitochondrial activity is lower and more centralized in fragmented embryos compared to good quality embryos on day-3 [ 47 ]. Mitochondria are the main source of ATP for embryo mitosis, and their proper function is essential for embryo development. More research is needed to elucidate the morphology and role of mitochondria in embryo development, especially in relation to fragmentation.

A subsequent study by Van Blerkom et al., analyzed the temporal and spatial aspects of fragmentation through TLM and TEM analyses from the pronuclear to the 10-12-cell stage. Through TLM, the authors visualized the non-discrete, dynamic nature of fragments and noted that many were “bleb-elaborations” of the plasma membrane and cytoplasm. They characterized two patterns of fragmentation: definitive and pseudo-fragmentation. Definitive fragmentation was described as fragments detached from a blastomere, and pseudo-fragmentation was assigned when the fragments were no longer detectable during subsequent development. Often one developing embryo would show both fragmentation patterns at different stages of development, suggesting that these patterns may have different etiologies and effects on embryo development competence [ 47 ]. Hardarson et al., similarly used TLM to document that fragments are dynamic and can be internalized throughout cleavage during culture periods. The contents of the fragments were noted to be internalized and released into the cytoplasm of the blastomere and seen on multiple time-lapse photographs as a cytoplasmic turbulence. This is the first reported evidence that cellular fragments can “disappear” during the culture period in human IVF [ 26 ]. It seems that in mild to moderate CF, the timing of embryo evaluation and grading can affect the reported percent of fragmentation.

Lastly, we have included a preliminary study performed by Sermondade et al., that suggests a specific subgroup of patients who have had repeated IVF failures (presumably due to a recurring high rate of fragmented embryos) may benefit from early intrauterine embryo transfer at the zygote stage (2PN) [ 48 ]. Data showed a delivery rate per oocyte retrieval of 18.9%, which was significantly higher than the delivery rate of 7.5% in the matched control group. The results were encouraging and suggestive of a safe, non-invasive rescue strategy for patients who experience recurrent highly fragmented embryos and failed IVF attempts. The data further suggests that fertilized oocytes of this subgroup may have deficiencies in certain maternal factors (i.e., stress-response factors) that do not allow normal embryo development in culture environments [ 48 ]. Another study was also confirmed application of zygote transfer in patients with history of low-quality embryos [ 49 ]. However, further studies are required to verify the impact of this technique for patients with history of fragmented embryos.

Apoptosis is another proposed etiology of fragmentation. Apoptosis may occur in blastomeres with defective cytoplasm or abnormal chromosomes, leading to embryo fragmentation [ 50 ]. There are several studies reporting apoptosis in both fragments and neighboring blastomeres in a fragmented embryo [ 24 , 50 ]. Chi et al., showed that fragments are associated with both apoptosis and necrosis [ 21 ]. One of the factors that appears to induce apoptosis in blastomeres is suboptimal culture conditions such as hypoxia [ 51 ]. In addition, there are controversial reports on the role of reactive oxygen species (ROS) in embryo fragmentation [ 52 , 53 ]. It has been shown that ROS are present at high levels in the culture media of fragmented embryos [ 52 , 54 ]. Chen et al., recently showed that embryo culture in 5% oxygen, from days 1 to 3, is associated with higher embryo quality and live birth rate compared to 20% oxygen [ 55 ]. The effects of culture condition modifications, such as hypoxia and ROS, on embryo fragmentation need to be clarified to understand the importance of culture condition in this process.

Membrane compartmentalization of DNA, abnormal cytokinesis, and extra vesicular formation are other proposed theories for embryo fragmentation [ 8 ]. Defects or damages in mitochondria are associated with low ATP and high ROS production leading to a compromised cell division and cytokinesis [ 27 ]. In addition, there is a correlation between embryo fragmentation and ploidy status. Chavez et al., showed that CF was seen in a high proportion of aneuploid embryos, and that meiotic and mitotic errors may cause fragmentation in different cell development stages. Meiotic errors were associated with fragmentation at one-cell stage while mitotic errors were associated with fragmentation at interphase or after first cytokinesis [ 56 ]. Chromosomally abnormal embryos often have severe fragmentation, which may be another cause of CF [ 55 , 57 ].

Overall, the precise cause of CF has yet to be clearly defined. The above investigations have elucidated potential sources and associations of what is likely a complex and multifactorial process and represent our current understanding of CF origin.

What is contained in CF?

Four of the included studies used various technological advances to study the contents of CF in human embryos (Table 2 ). Two studies used TEM methods to evaluate fragment ultrastructure (Fig.  3 ) [ 21 , 58 ]. Fragments were extracted from embryos with 10-50% fragmentation and the ultrastructure evaluated by TEM. Micrographs showed that the fragments had a distinct membrane containing cytoplasmic organelles including mitochondria, mitochondria-vesicle complexes, Golgi apparatus, primary lysosomes, and vacuoles. Mitochondria were the most abundant structure.

In an additional evaluation of CF contents, Johansson et al., analyzed DNA content of fragments to define a cutoff diameter for an anucleate fragment or blastomere. Findings showed that 98% of fragments <45 µm on day-2 and 97% of those <40 µm on day-3 contained no DNA and, if not reabsorbed into a blastomere, showed a loss of cytoplasm. Presence of essential blastomere organelles such as mitochondria, mRNA, and proteins within cytoplasmic fragments were related to embryo development arrest [ 59 ]. Lastly, Chi et al., also used TEM to examine ultrastructure of the human fragmented embryos and found that blastomeres with anucleate fragments contained fewer mitochondria in their cytoplasm compared to normal blastomeres [ 21 ].

Cell death and CF

Eight of the included studies analyzed the relationship between cell death and embryo fragmentation (Table 3 ). Five studies analyzed the status of chromatin in arrested fragmented embryos through a combined technique for simultaneous nuclear and terminal transferase-mediated DNA end labelling (TUNEL) [ 24 , 60 , 61 , 62 , 63 ]. Two studies used a comet assay to analyze DNA fragmentation [ 21 , 63 ]. Four of the eight studies used Annexin V staining [ 21 , 61 , 62 , 63 ] with three including the presence of propidium iodide (PI) to compare apoptosis to necrosis [ 21 , 61 , 63 ].

Jurisicova et al., used a combined nuclear and fragmented DNA labeling approach which allowed distinction between chromatin status and DNA fragmentation, which serve as markers of apoptosis versus necrosis respectively [ 60 ]. After fertilization, embryos were stained with 4,6-diamidino-2-phenylindole (DAPI). In cases of compromised cell membrane integrity, DAPI stain was observed in the cytoplasm as a sign of necrosis. Concomitant use of TUNEL labeling reflected the integrity of the DNA and allowed distinction between necrotic and apoptotic cells. Through combined techniques of DAPI/TUNEL, TEM, scanning electron microscopy (SEM) and stereomicroscopic observations, 153 of 203 (75.4%) fragmented early cleavage-stage embryos displayed signs of apoptosis (i.e., chromatin condensation, cellular shrinkage, DNA fragmentation, presence of cell corpses) with or without normal nuclei [ 60 ].

Similarly, Levy et al., analyzed early arrested or fragmented preimplantation embryos and the pattern of DNA fragmentation using TUNEL assay and the presence of phosphatidylserine through Fluorescein isothiocyanate (FITC)-labelled Annexin V, a phosphatidylserine binding protein. The authors observed TUNEL staining in one or more nuclei of 15 out of 50 (30%) arrested embryos from the 2-cell stage to uncompacted morulae, all of which had high degrees of CF. Furthermore, embryos with regular-sized blastomeres without fragmentation were all TUNEL negative [ 50 ].

A separate prospective study by Antczak et al., explored the possible association between fragmentation and apoptosis using PI and Annexin V staining of plasma membrane phosphatidylserine and TUNEL analysis of blastomere DNA [ 24 ]. In contradistinction to prior studies, these authors found no direct correlation between fragmentation and apoptosis. Virtually all blastomeres that were PI negative, intact or fragmented, showed no TUNEL or annexin V fluorescence, suggesting no signs of apoptosis [ 24 ].

Liu et al., used a similar methodology of TUNEL labeling and Annexin V staining to detect markers of apoptosis in fragmented human embryos derived from IVF [ 61 ]. Overall, highly fragmented embryos had apoptotic features including bright fluorescence (positive TUNEL labeling signifying DNA fragmentation) on the cell corpses and in intact blastomeres [ 61 ]. By staining cells with both annexin V and PI, this study was able to demonstrate that apoptosis occurs frequently in fragmented human embryos and the coexistence of apoptotic, necrotic and viable sibling blastomeres can occur. Sibling blastomeres within an embryo often showed apoptotic features that led to secondary necrosis while others did not initiate apoptosis. The authors did not find a significant difference in the expression frequency of apoptotic genes between viable and nonviable or arrested embryos [ 61 ].

Chi et al., stained human embryos ( n =10) with annexin V and PI and found that human fragmented embryos exhibited characteristics of both necrosis and apoptosis [ 20 ]. Rather than TUNEL assay, these authors used a modified sperm comet assay to investigate DNA fragmentation of human fragmented embryos. They found that 6/7 human fragmented embryos (85.1%) stained positively for PI with the intensity of staining increasing with the degree of fragmentation. Of note, DNA fragmentation was observed in fragmented human embryos but not in the normal embryo [ 21 ].

Metcalfe et al., analyzed the expression of 11 BCL-2 family genes in normally developing embryos and in severely fragmented embryos [ 64 ]. They found that the expression of BCL-2 family genes was highest in the pronuclear stage and eight-cell stages, and lowest at the two-cell, four-cell, and blastocyst stages in developmentally intact embryos. Furthermore, the expression did not change in fragmented embryos, suggesting that embryo fragmentation does not likely compromise mRNA integrity and gene detection [ 64 ]. However, like Liu et al., [ 61 ] these authors did detect far fewer pro-apoptotic BCL-2 genes in fragmented embryos at the eight-cell stage. The authors noted that these findings do not distinguish between iatrogenic apoptosis from suboptimal in-vitro culture conditions [ 64 ]. A separate study by Jurisicova et al. similarly analyzed gene expression at the 2-, 4- and 8-cell stage of fragmented embryos. Embryos that had 30-50% fragmentation showed a significant increase in Hrk mRNA levels, a BCL-2 protein encoding gene ( P = 0.016). Further, these authors found an increase in Caspase-3 mRNA in fragmented embryos, as well as induction of Caspase-3-like enzyme activity in nucleated fragments, although this finding was not statistically significant [ 65 ].

Van Blerkom et al., also used TUNEL assay in conjunction with the comet assay as a method of identifying the specific pattern of cell death (necrosis, lysis or apoptosis) and the extent of DNA damage in developing embryos [ 47 ]. They analyzed the integrity of the plasma membrane through annexin V staining with PI. They examined both transient and persistent fragment clusters at day-3 and 3.5 embryos for evidence of programed cell death using time-lapse video and TEM. In contrast to previous studies, they found no indication of nuclear DNA damage or loss of membrane integrity. These results, led the authors to hypothesize that the fragmentation observed was not characteristic of programed cell death, but rather resembled features of oncosis. The culture in this study was not severely oxygen-deprived and thus the authors concluded that this oncosis-like process was potentially a result of disproportionate mitochondrial segregation during the first cleavage division. Without sufficient mitochondria, the early blastomeres did not maintain adequate ATP for normal cell function which may have precipitated an ATP-driven oncosis-like process [ 47 ].

Lastly, a study by Bencomo et al., found correlations between the degree of apoptosis in human granulosa-lutein (GL) cells, the outcome of IVF-ET cycle, the percentage of embryo fragmentation, and patient’s age [ 66 ]. Human GL cells were collected from follicular fluid, cultured for 48 hours, and marked with caspACE FITC-VAD-FMK, a fluorescent marker for activated caspases. Results showed that GL cells of older women (>38 years old) were significantly more susceptible to apoptosis at 43.2 ± 18.0% compared to the younger group (<38 years old) with a mean percentage of apoptotic cells 33 ± 17.2%. Women who had a positive pregnancy had a lower level of apoptosis in GL cultures than those who did not get pregnant (30.2 ± 14% vs. 40.4 ± 19.5%). There was a positive correlation between embryo fragmentation and GL cell apoptosis ( r = 0.214). Overall, the level of apoptosis of cultured GL cells was correlated with IVF outcome [ 66 ].

These studies demonstrate the diversity among techniques to evaluate cell death in the developing embryo. TUNEL labeling, sperm comet assay, annexin V staining or some combination of these techniques have been described. Furthermore, there are discrepancies between the stage at which apoptosis might occur, with majority of studies cited here suggesting that cell death occurs in early stages of development before blastocyst formation. While some studies suggest that fragmented embryos display signs of apoptosis, these findings are still disputed and the distinction between apoptosis and necrosis is not clearly defined in the literature.

Patient age and CF

There are inconsistencies within the literature regarding the relationship between maternal age and CF. A total of six studies in this review focused on this relationship (Table 4 ). Three of the studies found a positive correlation between patient age and degree of embryo fragmentation [ 67 , 68 , 69 ]. The other three studies found no age-related correlation between embryo fragmentation or quality [ 7 , 70 , 71 ].

A retrospective study by Ziebe et al., compared the relationship between age of women undergoing IVF and the proportion of anucleate fragmentation in cleavage-stage embryos. Using a logistic regression analysis, the authors compared the percentage of transfers using fragmented embryos with age; the odds of fragmentation increased by 3% per year (OR 1.033 [95% CI 0.996, 1.071]). There was a linear relationship between age and embryo fragmentation rate, with an increase in fragmentation of 0.76% per year (95% CI -0.09%, 1.61%) [ 68 ].

Keltz et al., assessed various predictors of embryo fragmentation in IVF and found that increased maternal age and lower number of oocytes and embryos were associated with increased embryo fragmentation. There was a significant difference between cycles with fragmented embryos ( n =74) at a mean age of 36.9 ± 4.24 years as compared to cycles with no fragmented embryos ( n =234) at a mean age of 35.4 ± 4.74 years. Overall, this retrospective analysis of fresh IVF cycles found that embryo fragmentation is indeed associated with older age and ultimately poor cycle outcome [ 67 ].

Contrary to these findings, an early study by Alikani et al., showed no relationship between maternal age and CF [ 7 ]. In a retrospective analysis of degree and pattern of embryo fragmentation on days 2 and 3, they defined five patterns of fragmentation. Both the degree and pattern of fragmentation impacted pregnancy and implantation rate, but the authors found no correlation between appearance of any CF pattern and maternal age. The average maternal age in their population was 35.7 ± 4.25 years [ 7 ]. Another study by Stensen et al., analyzed the effect of chronological age on oocyte quality (assessed by maturity) and embryo quality (assessed by cleavage-stage, blastomere size and embryo fragmentation). Women were divided into five age groups: ≤25, 26–30, 31–35, 36–40 and ≥41 years. The embryo morphological score was based on fragmentation and blastomere size with score of 0-4 where score of 4 being equally sized blastomeres and no fragmentation and score of 0 being cleavage arrest or morphologically abnormal embryo. The mean oocyte score and embryo morphology score were not found to be significantly different across the age groups [ 70 ]. Wu et al., also showed that age does not influence embryo fragmentation. Patient ages ranged from 20 to 44 years with a mean age of 30.6 ± 4.6 years and were divided into age groups of ≤29, 30–34, 35–37, 38–40, and ≥41 years of age. Analysis of embryos with similar degrees of fragmentation was used to assess whether maternal age was associated with embryo fragmentation and blastocyst development. There was no correlation between age and embryo fragmentation as a continuous variable ( r = 0.02; P = 0.25) nor was there a correlation when age was divided into the groups ( P = 0.2). They also found that neither age ( r = -0.08; P =0.16) nor degree of fragmentation ( r = -0.01; P = 0.81) had a significant impact on blastocyst development [ 71 ].

Recently, a retrospective time-lapse study evaluated the implantation rate of 379 fragmented embryos. The results showed that there was an association between advanced maternal age and fragmentation. Fragmentation rate was higher in patients ˃35 compared to patients ≤35 years old. It seems that the lower quality of oocytes in older patients results in increasing fragmentation [ 69 ]. Overall, the included studies have differing conclusions on the effect of maternal age and CF; varying definitions and analysis of CF remain a limitation.

IVF vs ICSI procedures and CF

Five of the included studies compared embryo quality between conventional IVF and intracytoplasmic sperm injection (ICSI) procedures (Table 5 ). Two of these studies found that ICSI was associated with impaired embryo morphology compared to IVF [ 72 , 73 ], while the other three showed no difference in embryo quality between the two fertilization modalities [ 74 , 75 , 76 ]. There were no studies within our search that identified embryos created by ICSI having greater morphology grade, or less embryo fragmentation, than IVF.

Frattarelli et al., directly examined the effect of ICSI on embryo fragmentation and implantation rate compared to IVF. There was a significant difference in mean embryo grade between IVF and ICSI. IVF patients had significantly more grade I, or non-fragmented, embryos compared to the ICSI group ( P < 0.01). However, there was no significant difference in mean number of embryos per embryo grade II – IV [ 72 ].

Similarly, Hsu et al., compared embryo quality, morphology, and cleavage after ICSI with standard IVF patients. They defined the grading system from 1 – 5, ranging from no fragments (grade 1) to severe or complete fragmentation (grade 5). They found that for the overall population, when comparing ICSI and IVF patients after matching for age and number of embryos transferred, the number of embryos with good morphology was significantly greater in the IVF group compared to ICSI ( P < 0.006). The average morphology scores, similar to the results of Frattarelli et al., were significantly different between the ICSI group and the IVF group. They also found IVF patients’ embryos to have significantly better cleavage rate than those from ICSI patients ( P < 0.001) [ 73 ].

Garello et al., evaluated if fertilization via ICSI influences pronuclear orientation, PB placement, and embryo quality when compared to IVF. Embryos were assessed using morphology, and grouped as good (grades 1-2), average (grades 3-4), or poor (grades 5-6). Embryos were also assessed for cleavage regularity and proportion of fragmentation (0, <20%, 20–50%, >50%). There was no statistically significant difference in mean morphology (good, average, poor) between the groups, although they did note an apparent increase in grade 4 versus grade 3 embryos after ICSI procedure. The two groups had similar proportions of fragmentation [ 74 ].

Two other studies took a unique approach in comparing embryo quality in ICSI and IVF patients by using randomized sibling oocytes [ 75 , 76 ]. Yoeli et al., studied oocytes retrieved from patients with a less than 40% fertilization rate in a previous standard IVF cycle and divided these oocytes into a conventional insemination group and an ICSI group. Each group had over 1400 oocytes. Overall, there was no significant difference between the IVF and ICSI groups in terms of cleavage rate or rate of high-quality embryos (both Grade A embryos with ≤10% fragmentation and embryos with ≤20% fragmentation) [ 75 ]. Ruiz et al., also analyzed sibling oocytes in patients who had failed intrauterine insemination attempts. The authors similarly found no significant difference in fertilization rates and degree of fragmentation between ICSI and standard IVF groups [ 76 ]. Most studies included in the search criteria showed that ART techniques such as ICSI do not significantly impact fragmentation rate in developing embryos, suggesting that ICSI is not a significant contributor to poorer outcomes by way of embryo fragmentation. Of note, the timing of cumulus cell denudation after conventional IVF is a matter of debate; none of the included studies in this review performed short-time insemination. In a meta-analysis reviewing denudation times, the number of good quality embryos produced after retaining cumulus cells was similar to those produced after early removal of these cells, suggesting that brief insemination has no impact on CF [ 77 ]. Liu et al. also showed that short insemination time is not associated with different outcomes in terms of embryo development [ 78 ].

Effect of CF on embryo development

It is commonly believed that CF has detrimental effects on embryo development. Thirteen of the included studies found a negative effect of CF on embryo development (Table 6 ). Various approaches have been used to propose a hypothesis as to how increased fragmentation impedes embryo development.

Van Blerkom et al., showed through time-lapse video and TEM that fragments physically impede cell-cell interactions, interfering with compaction, cavitation, and blastocyst formation [ 63 ]. In an ultrastructural observational study by Sathananthan et al., 15 embryos were cultured with human ampullary cell lines and TEM used to evaluate embryo development. They noted degeneration of blastomeres, including incomplete incorporation of chromatin into nuclei and formation of micronuclei, which was possibly a consequence of being adjacent to blastomere fragments [ 79 ]. A much larger prospective study by Antczak and Van Blerkom analyzed 2293 fertilized eggs from 257 IVF cycles to examine the effect of fragmentation on the distribution of eight regulatory proteins. Fragmentation reduced the volume of cytoplasm and depleted embryos of essential organelles or regulatory proteins, compromising the embryo developmental potential. They also found that specific fragmentation patterns during various stages of embryo development, i.e., 2- and 4-cell stages, were associated with embryo viability and therefore could have clinical application in the selection of embryos for transfer [ 24 ]. As previously mentioned, fragmentation may affect compacted/morula and blastocyst quality [ 80 ]. Cell exclusion at this stage is due to failure or abnormal expression of proteins involved in compaction [ 44 , 81 ]. Blastomeres may also irregularly divide, resulting in fragmentation and exclusion from compaction [ 82 ], and excluded cells have a high rate of aneuploidy [ 83 ]. Blastocyst quality from fully compacted embryos has been reported to be higher than blastocysts with partial compaction [ 84 ].

The hypothesis that fragmentation reflects inherent embryogenetic abnormalities, such as aneuploidy, increased mosaicism, or polyploidy, is supported by multiple studies in this review [ 55 , 57 , 85 ]. Morphologically poor-quality embryos, defined by amount of fragmentation, were often found to have concomitant chromosomal abnormalities [ 57 , 85 ]. Culture environment has also been implicated in presence and degree of fragmentation. For example, Morgan et al., using video-cinematography found that embryos cultured on a monolayer of feeder cells had fewer fragments than did embryos cultured alone [ 86 ]. In addition to aneuploidy and external environment, degree of fragmentation also appears to be related to embryo quality. Both Alikani et al., and Hardy et al., have shown that a small degree of fragmentation (<15%) on day-2 embryos did not affect blastocyst formation but increased (> 15%) fragmentation was associated with significantly reduced blastocyst development [ 23 , 87 ]. Similarly, a prospective study of over 4000 embryos by Guerif et al., showed that the rate of blastocyst formation increased significantly with decreased fragmentation (<20%) on day-2 embryos [ 32 ].

A separate study by Ivec et al., graded day-4 and -5 morulae based on the degree of fragmentation (<5%, 5%–20%, or >20%) and compared their blastocyst development rate. They found a negative correlation between degree of fragmentation and clinically usable blastocysts, optimal blastocysts, and those with a hatching zona pellucida. Through logistic regression analysis, they found that with each increase in percentage of fragmentation in morulae, there was a 4% decrease in the odds of hatching (OR: 0.96, 95% CI: 0.95–0.98;  P < 0.001) and optimal blastocyst formation (OR: 0.96, 95% CI: 0.94–0.97;  P < 0.001) [ 88 ]. It is important to point out that the degree of embryo fragmentation, no matter at what stage of development, is measured subjectively without standardized methods. One study from Hnida et al., included here recognized this limitation and used a computer-controlled system for multilevel embryo morphology analysis [ 89 ]. The degree of fragmentation was evaluated based on digital image sequences and correlated to the blastomere size. Fragments were defined to be anucleate with an average diameter of <40 µm. Not surprisingly, the mean blastomere volume decreased significantly with increasing degree of fragmentation ( P < 0.001). In addition, average blastomere size was significantly affected by the degree of fragmentation and multinuclearity which may function as a biomarker for embryo quality [ 89 ]. Furthermore, Sjöblom et al., analyzed the relationship of morphological characteristics to the developmental potential of embryos [ 90 ]. These authors, similar to Hnida et al., found that a large cytoplasmic deficit, i.e., blastomeres not filling the space under the zona, was detrimental to blastocyst development (P < 0.044). However, this is the only study in which the extent of CF observed was not significantly associated with blastocyst development [ 90 ]. Another study using time-lapse imaging showed an association between cytoplasmic fragments at the two-cell stage and perivitelline threads. Perivitelline threads can be observed as the cytoplasmic membrane withdraws from the zona pellucida during embryo cleavage. Ultimately, the presence of these threads, despite the level of fragmentation, did not affect embryo development [ 91 ]. As demonstrated by the studies described here, the degree of CF has a largely negative effect on embryo development.

Effect of CF on embryo implantation and pregnancy

In addition to evaluating the effect of CF on preimplantation embryo development, it is important to assess the effect of CF on implantation and pregnancy outcomes. Five of the included studies have shown a negative effect of CF on implantation or pregnancy outcome (Table 7 ). Assuming that increased fragmentation is detrimental to embryo development, implantation, and pregnancy outcome, it is important to understand the embryo scoring system that determines the best embryo for transfer. Giorgetti et al., used single embryo transfers to devise an embryo scoring pattern to best predict successful implantation. Not surprisingly, higher pregnancy rates were observed with embryos that displayed no fragmentation. The authors found that both pregnancy rate and live birth rate were significantly correlated with a 4-point score based on cleavage rate, fragmentation, irregularities displayed, and presence of a 4-cell embryo on day-2 [ 12 ].

Racowsky et al., assessed if multiple evaluations of an embryo improve selection quality and thus implantation and pregnancy success. They noted that an increased level of fragmentation on both day-2 and -3 was associated with a significant reduction in the number of fetuses that developed to 12 weeks. They also noted that severe fragmentation (>50%) impaired overall embryo viability and may be related to low pregnancy rates and high risk of congenital malformations. The authors ultimately concluded that single day morphological evaluation on day-2 or day-3 has the same predictive value to a multi-day scoring system [ 22 ].

Another retrospective analysis of 460 fresh embryo transfers by Ebner et al., sought to determine the impact of embryo fragmentation on not just pregnancy, but also obstetric and perinatal outcomes. There was a significant relationship between fragmentation and implantation and clinical pregnancy rate, but not with multiple pregnancy rate or ongoing pregnancy rate [ 10 ]. Alikani et al., also studied embryo fragmentation and its implications for implantation and pregnancy rate and included fragmentation pattern into their discussion. They too found a significant decrease in implantation and pregnancy rate as the degree of fragmentation increased. They identified an effect on pregnancy rate when the degree of fragmentation was greater than 35%. The authors went on to discuss that not all fragmentations are detrimental to the embryo development and that the pattern of fragmentation matters. They found that fragmentation pattern type IV, defined as having large fragments distributed randomly and associated with uneven cells, had significantly lower implantation and clinical pregnancy rates when compared to types I-III. They concluded that detaching blastomere cytoplasm as large fragments is most detrimental to embryo development and implantation rate. In contrast, small, scattered fragments (type III) did not seem to appreciably affect the cell number or pose a serious threat to further development [ 7 ].

Lastly, Paternot et al., used sequential imaging techniques and a computer-assisted scoring system to study blastocyst development and the effect of fragmentation on clinical pregnancy. The authors reviewed the volume reduction over time as a measure of embryo fragmentation. They analyzed volumes on day-1 to -3 and found a significant association between total embryo volume and pregnancy rate on both day-2 ( P = 0.003) and day-3 ( P = 0.0003), with the total volume measured on day-3 being the best predictor of pregnancy outcome [ 92 ]. In contrast, Lahav-Baratz recently showed that there was no association between fragmentation rate and abortion or live birth rate. It was concluded that fragmented embryos still have implantation potential and could be considered for transfer when applicable [ 69 ].

Effect of CF removal on embryo development

The effect of fragment removal on IVF outcomes has been controversial. Six of the studies included in this review discussed the impact of removing fragments on embryo development (Table 8 ) [ 7 , 67 , 93 , 94 , 95 , 96 ]. The literature is mixed, with some studies showing improvement in embryo development quality after fragmentation removal [ 7 , 93 ], and others showing no difference at all [ 70 , 94 , 95 ].

Alikani et al., were one of the first investigators to define various patterns of fragmentation and perform microsurgical fragment removal to improve implantation potential [ 7 ]. The authors found that the pattern and degree of fragmentation, and not merely the presence of fragmentation, was significant. When assisted hatching and microsurgical fragment removal was performed, there was an overall 4% increase in implantation rate. They concluded that the removal of the fragments possibly restored the spatial relationship of the cells and limited the interference of cell-cell contact. Further, their preliminary data showed that blastocysts formed after fragment removal were better organized than their unmanipulated counterparts [ 7 ].

Eftekhari-Yazdi et al., similarly studied the effect of fragment removal on blastocyst formation and quality of embryos [ 93 ]. They compared day-2 embryos without removal of fragments to those that fragments were microsurgically removed. There were significantly higher quality embryos in defragmented group compared to the control. Furthermore, fragment removal improved the blastocyst quality compared to the control group. There was also a reduction of apoptotic and necrotic cells in experimental group when compared with the control group [ 93 ].

Two separate studies by Keltz et al., assessed implantation, clinical pregnancy, and birth outcomes after defragmentation [ 67 ], as well as embryo development and fragmentation rate after day-3 embryo defragmentation [ 94 ]. The authors first compared cycle outcomes between low-grade embryos that underwent micromanipulation for fragment removal (>10% fragmentation) and high-grade embryos that did not undergo defragmentation but were hatched on day 3. When compared, the defragmented group showed no difference in rates of implantation, clinical pregnancy, live birth, spontaneous abortion, or fetal defects as compared to the cycles that included all top-grade embryos. Factors associated with poor IVF prognosis and formation of embryo fragments included advanced age, decreased number of oocytes and embryos, and embryo grade [ 67 ].

A separate prospective randomized study by Keltz et al., looked more specifically at day-5 fragmentation, compaction, morulation and blastulation rates after low grade day-3 embryo defragmentation [ 94 ]. Paired embryos from the same patient, not intended to be transferred, were randomly placed in either the experimental group, assisted hatching and embryo defragmentation, or control group (assisted hatching alone). Paired embryos had no difference in mean cell number, percent fragmentation, and grade before randomization. Results showed that on day-5, embryos in the defragmentation group had significantly diminished fragmentation when compared with controls; however, there was no difference in compaction rate, morula formation rate or blastocyst formation rate. Embryo grade generally improved in the treatment group, but this was not statistically significant. Overall, in both groups, improved embryo development was significantly associated with lower levels of fragmentation in the day-3 embryos, supporting the idea that defragmented embryos maintain their reduced fragmented state throughout preimplantation development. Of note, this study had 35 embryos in each group and was limited to lower grade embryos not intended for transfer [ 94 ].

Another, larger prospective randomized study by Halvaei et al., compared the effect of microsurgical removal of fragments on ART outcomes. The authors divided 150 embryos with 10-50% fragmentation into three groups, case ( n =50), sham ( n =50), and control ( n =50). They found no significant difference in rates of clinical pregnancy, miscarriage, live birth, multiple pregnancies, or congenital anomalies between these groups, ultimately showing that cosmetic microsurgery on preimplantation embryos to remove CFs had no beneficial effect [ 95 ].

Lastly, a pilot study by Yumoto et al., aimed to decrease CF in developing embryos by removing the zona pellucida of abnormally fertilized (3PN) donated oocytes [ 96 ]. Although they did not attempt to remove fragments themselves, this study is included as ZP-free oocytes are sometimes encountered in or because of ART procedures, i.e., ICSI. The results suggest that the rate of fragmentation is decreased after mechanical ZP removal. The authors concluded that ZP is not always necessary for normal embryo development since the ZP-free embryos developed normally, maintained their cell adhesions, and had a decreased rate of fragmentation [ 96 ]. It seems that defragmentation of an aneuploid or severely fragmented embryo, only improves the embryo morphology grade but the quality and fate of embryo is not changed [ 97 ].

CF and chromosomal abnormalities in embryo

Although the relationship between DNA fragmentation and chromosomal abnormalities has been more commonly explored in the literature, CF may also be related to intrinsic chromosomal abnormalities in developing embryos. Fourteen studies included in this review explored this relationship (Table 9 ) [ 55 , 56 , 85 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 ].

CF was rarely seen in embryos with normal chromosomal content. Findikli et al., studied DNA fragmentation and aneuploidy in poor quality embryos by TUNEL and fluorescent in situ hybridization (FISH) techniques. Within seven chromosomally abnormal embryos, each had variable degrees of CF [ 98 ]. This study suggests that DNA fragmentation, being a sign of chromosomal abnormalities, may exist together with CF.

An earlier study by Munne et al., examined 524 embryos using FISH analysis for three to five chromosomes. While controlling for age, they divided the embryos into three groups: arrested, slow and/or fragmented, or morphologically and developmentally normal. They found that polyploidy was the most common chromosomal abnormality in the arrested embryo group and decreased with increasing embryonic competence, with 44.5% polyploidy in arrested compared to 2.1% in morphologically normal embryos. Maternal age was not associated with polyploidy rates, but aneuploidy significantly increased with maternal age in morphologically normal human embryos [ 57 ]. Another early study by Almeida and Bolton also examined the relationship between chromosomal abnormalities and embryonic developmental potential. They found that cleavage-stage embryos with poor morphology, defined as irregular shaped blastomeres with severe fragmentation, showed a higher incidence of chromosomal abnormalities than those with good morphology [ 100 ]. Magli et al., found a more direct relationship between chromosomal abnormalities and embryo fragmentation in a larger retrospective study of nearly 1600 embryos. There was a strong association between percentage of fragmentation and chromosomal abnormalities (monosomies and trisomies), where 90% of chromosomal abnormalities were found in embryos with greater than 40% fragmentation [ 101 ].

Another retrospective study comparing maternal age to embryo morphology and chromosomal abnormalities was conducted by Moayeri et al., By examining nine chromosomes in day-3 embryos, they found that morphology predicted chromosomal status in the advanced maternal age group (≥38 years old), but not in younger patients. Fragmentation alone predicted euploidy in both the advanced maternal age and younger groups. This suggests that cellular fragmentation may be a predictor of chromosomal competence and thus embryo developmental potential [ 102 ].

In contrast, Baltaci et al., examined 1,000 embryos and concluded that embryo morphology was not predictive of euploidy and that a considerable number of chromosomally abnormal embryos with good development potential may be selected for embryo transfer. They used FISH for five chromosomes and found that a large proportion of both normal and aneuploid embryos were evaluated as top quality (grade I). For example, 66% of chromosomally abnormal embryos were of good quality (grade I and II). They found no significant difference among aneuploid embryos when distributed by age. However, a higher embryo quality found in normal compared to aneuploid embryos [ 103 ].

In addition, Pellestor et al., compared the relationship between morphology and chromosomal abnormalities in two separate studies. The first study found that aneuploidy was the most frequently observed abnormality after cytogenetic analysis of preimplantation embryos [ 55 ]. They defined the quality of embryos as good (grade I and II) and poor (grades III and IV). There was an increased chromosomal abnormality in poor quality embryos (84.3%) when compared to embryos with good quality (33.9%). Both aneuploidy and fragmentation were shown to be predominant in poor quality embryos, whereas mosaicism and polyploidy were the most frequent abnormalities in good quality embryos [ 55 ]. Pellestor et al., also performed cytogenetic analysis on 411 poor-quality embryos (grade IV) [ 85 ]. Ninety percent of the successfully analyzed cases showed abnormal chromosome complements, with aneuploidy being the most frequently observed. These results further support that a large majority of poor grade embryos are chromosomally abnormal and ultimately offer low chance of reproductive success for either embryo transfer or cryopreservation [ 85 ].

A separate study by Chavez et al., combined time-lapse imaging with karyotypic status of blastomeres in the 4-cell embryo to test whether blastomere behavior may reflect chromosomal abnormalities, using array comparative genomic hybridization (aCGH), during early cleavage [ 56 ]. In time-lapse observations, a large proportion of aneuploid and triploid, but not euploid embryos, exhibited cellular fragmentation. They showed that the probability of aneuploidy increased with higher fragmentation and only 65% of the fragmented embryo would be expected to form blastocyst. Furthermore, all the aneuploid embryos with additional unbalanced sub-chromosomal errors exhibited CF. The authors concluded that although fragmentation alone at a single point in time does not predict embryo developmental potential, time-lapse imaging with dynamic fragmentation screening may help detect embryonic aneuploidy [ 56 ].

Two more recent studies also used aCGH to evaluate the association between embryo ploidy and fragmentation. Vera-Rodriguez et al., in a retrospective study, compared the rate of embryo aneuploidy between two groups of high (≥25%) and low (˂25%) fragmentation. They found that the rate of aneuploidy in high and low fragmentation was 62.5 and 46.3%, respectively. However, the difference was not statistically significant concluding that using degree of fragmentation alone is not suggested to predict the embryo ploidy status [ 107 ]. Minasi et al., in a case series evaluated 1730 blastocyst ploidy with aCGH. They showed that there is no significant difference between day-3 embryo morphology and embryo ploidy. However, the quality of blastocyst (inner cell mass grade, trophectoderm grade, degree of expansion) was associated with embryo ploidy [ 106 ].

In a recent meta-analysis, it was shown there is trend between degree of fragmentation and rate of aneuploidy [ 109 ]. A major source of controversy in both early and recent studies on aneuploidy and fragmentation is the variation in the methods and criteria used to evaluate these factors. One of the aspects that differ across studies include the technique for detecting aneuploidy; FISH vs aCGH. Recent studies have used aCGH to detect aneuploidy and found no clear relationship in this regard. Also, the quality of the matching between groups, the design of the study (retrospective vs prospective), the timing of the fragmentation assessment, the use of time-lapse imaging to monitor the fate of fragments are the other reasons for this discrepancy. There is still the lack of a clear cut-off point for the percentage of fragmentation to predict aneuploidy. Further powerful studies using new methods like next gene sequencing and tile-lapse systems are recommended to shed light on the relationship between fragmentation and aneuploidy.

The literature highlights that poor quality embryos have a higher incidence of chromosomal abnormalities. Notably, CF is rarely observed in embryos with normal chromosomal content. Technological advancements, such as TLM, offer promising avenues to enhance our understanding and detection of embryonic aneuploidy. Overall, these studies underscore the complexity of the relationship between fragmentation and chromosomal abnormalities, emphasizing the need for continued research to refine embryo selection strategies and improve reproductive outcomes.

Discussion and conclusion

The role of fragmentation in human embryo development and reproductive potential is widely recognized, albeit without standard definition nor agreed upon implication. While it has been shown that degree of fragmentation and embryo implantation potential are inversely proportional [ 5 , 7 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ], the degree, pattern, and distribution of fragmentation as it relates to pregnancy outcome is debated in the literature. Our qualitative synthesis of 60 articles related to the study of embryo fragmentation and reproductive outcomes highlighted some of the challenges in analysis of fragmentation, while revealing trends in our evolving knowledge of how fragmentation may relate to functional development of the human embryo.

While fragmentation is best understood to be a natural process across species, the origin of fragmentation remains incompletely understood and likely multifactorial. Degree of fragmentation has been plausibly correlated to sperm DNA oxidation [ 37 ], errors in division [ 37 ], mitochondrial distribution [ 45 ], and overall embryo quality [ 39 ]. However, some causes of fragmentation are based on outdated studies and require validation in future research with higher quality and more advanced techniques. While cause of fragmentation remains a focus of investigation, advances in technology have allowed for more detailed analysis of its effect on embryo development and reproductive outcome. At the cellular level, increased fragmentation has been shown to be associated with higher rates of apoptosis, necrosis, and programmed cell death of cleavage-stage embryos [ 60 , 61 , 62 ]. Given the recognized significance of fragmentation on embryo development, it follows that many studies have been focused on IVF and ART impacts on fragmentation, as well as determining quantitative reproductive outcomes. In terms of other influences on degree of fragmentation, patient age was not universally found to be significantly associated with fragmentation [ 7 , 70 , 71 ] although age is certainly known to influence embryo quality. Most studies included in the search criteria showed that ART such as ICSI do not significantly impact fragmentation rate in developing embryos [ 74 , 75 , 76 ]. Those studies that found significant differences in embryo grading either between conventional fertilization and ICSI either did not find a difference in implantation or pregnancy rate or did not study it, suggesting that ICSI is not a significant contributor to poorer ART outcomes by way of embryo fragmentation.

In synthesizing the available data on ART and pregnancy outcomes with varying degrees of embryo fragmentation, most included studies did find a negative impact of increasing fragmentation on reproductive success while severe fragmentation does appear to be associated with poorer implantation rate and clinical pregnancy rate. This association may be related to the observation that increased fragmentation at the cleavage-stage embryo is related to chromosomal abnormalities incompatible with ongoing development or pregnancy.

The reviewed studies have several limitations. There are different grading systems in use that may impact detecting and reporting the degree of CF. Different criteria and terminology used in different studies may in turn make the comparison of outcome measures difficult. Another factor is the distribution pattern of CF. There are two types of scattered and concentrated fragments with different prognoses that is not considered in grading systems. Therefore, due to the lack of a standard cleavage-stage embryo grading system, comparing different studies should be done with caution. In addition, evaluation of embryo fragmentation is mostly based on individual observation which is subjective and has inter- and intra-observer subjectivity leading to high variable results even if performed by an experienced embryologist [ 110 ]. TLM is considered as a non-invasive tool and evaluates the embryo quality continuously and without the need to remove the embryo from the incubator [ 111 ]. The use of this technology allows for the analysis of embryo morphokinetics and has advanced knowledge of the developing embryo. Recently, artificial intelligence (AI) including machine learning and neural network has gained popularity in various fields of medicine including IVF and embryology. Accuracy of AI in prediction of fragmentation has been studied with encouraging results [ 112 ]. Further advances in technology will promote the use of AI as a tool in defining the effect of fragmentation on human embryo development and reproductive potential.

Although the precise origin and the importance of external or iatrogenic factors on fragmentation of cleavage-stage embryos varies in the literature, there is more consensus regarding severe fragmentation worsening reproductive outcomes. Given this important pattern, and the availability of increasingly sophisticated embryologic technology, further research is warranted to characterize more completely preventative or rescue techniques to improve reproductive outcomes.

Availability of data and materials

No datasets were generated or analysed during the current study.

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Yazdani, A., Halvaei, I., Boniface, C. et al. Effect of cytoplasmic fragmentation on embryo development, quality, and pregnancy outcome: a systematic review of the literature. Reprod Biol Endocrinol 22 , 55 (2024). https://doi.org/10.1186/s12958-024-01217-7

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SYSTEMATIC REVIEW article

The role of counseling for non-traditional students in formal higher education: a scoping review provisionally accepted.

• 1 Department of Pedagogy and Primary Education, National and Kapodistrian University of Athens, Greece

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Since the mid-20th century, the number of adult students enrolled in formal higher education (HE) programs has significantly increased. The profile of non-traditional students differs significantly from that of traditional students in terms of their characteristics, learning methods, obstacles and challenges, motivations for learning, and conditions for effective learning. Unlike traditional students, adult students often balance family, work, and educational responsibilities, necessitating a more nuanced approach to support and guidance. However, most HE institutions primarily serve the needs of traditional student populations, which results in limited support available to adult students. This scoping review aimed to explore and map the existing literature on the role of adult (or non-traditional) students counseling in the context of formal HE. We focused on literature related to academic advising for non-traditional students in formal HE, restricting our search to both empirical and non-empirical articles published in peer-reviewed journals between 2010 and 2022. Employing Arksey and O'Malley's scoping review method and the PRISMA-ScR Checklist, we searched four databases (EBSCOhost, Crossref, Semantic Scholar, and ERIC), supplemented by a manual search. Of the 1,330 articles identified and screened, 25 studies met the eligibility criteria. Our review included 17 empirical and eight non-empirical studies, with the majority conducted in the USA (21 of 25). Thematic analysis revealed five key research areas (or themes): academic advising practices, perceptions of advising, technology, and advising, advising models, and academic success. The most common research theme, advising practices for adult (undergraduate and doctoral) students, constituted 52% of the studies (n=13). Drawing from our analysis, we discuss current trends and future development in advising non-traditional students within formal HE settings. The added value of academic advising for adult students is explored, and any potential gaps in research literature knowledge are identified.

Keywords: Academic advising, Counseling, non-traditional students, adult students, higher education

Received: 25 Dec 2023; Accepted: 16 May 2024.

Copyright: © 2024 Stamou, Tsoli and Babalis. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Ms. Panagiota Stamou, National and Kapodistrian University of Athens, Department of Pedagogy and Primary Education, Athens, Greece

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