basic importance of literature review

• UConn Library
• Literature Review: The What, Why and How-to Guide
• Introduction

Literature Review: The What, Why and How-to Guide — Introduction

• Getting Started
• How to Pick a Topic
• Strategies to Find Sources
• Evaluating Sources & Lit. Reviews
• Tips for Writing Literature Reviews
• Writing Literature Review: Useful Sites
• Citation Resources
• Other Academic Writings

What are Literature Reviews?

So, what is a literature review? "A literature review is an account of what has been published on a topic by accredited scholars and researchers. In writing the literature review, your purpose is to convey to your reader what knowledge and ideas have been established on a topic, and what their strengths and weaknesses are. As a piece of writing, the literature review must be defined by a guiding concept (e.g., your research objective, the problem or issue you are discussing, or your argumentative thesis). It is not just a descriptive list of the material available, or a set of summaries." Taylor, D.  The literature review: A few tips on conducting it . University of Toronto Health Sciences Writing Centre.

Goals of Literature Reviews

What are the goals of creating a Literature Review?  A literature could be written to accomplish different aims:

• To develop a theory or evaluate an existing theory
• To summarize the historical or existing state of a research topic
• Identify a problem in a field of research 

Baumeister, R. F., & Leary, M. R. (1997). Writing narrative literature reviews .  Review of General Psychology , 1 (3), 311-320.

What kinds of sources require a Literature Review?

• A research paper assigned in a course
• A thesis or dissertation
• A grant proposal
• An article intended for publication in a journal

All these instances require you to collect what has been written about your research topic so that you can demonstrate how your own research sheds new light on the topic.

Types of Literature Reviews

What kinds of literature reviews are written?

Narrative review: The purpose of this type of review is to describe the current state of the research on a specific topic/research and to offer a critical analysis of the literature reviewed. Studies are grouped by research/theoretical categories, and themes and trends, strengths and weakness, and gaps are identified. The review ends with a conclusion section which summarizes the findings regarding the state of the research of the specific study, the gaps identify and if applicable, explains how the author's research will address gaps identify in the review and expand the knowledge on the topic reviewed.

• Example : Predictors and Outcomes of U.S. Quality Maternity Leave: A Review and Conceptual Framework:  10.1177/08948453211037398  

Systematic review : "The authors of a systematic review use a specific procedure to search the research literature, select the studies to include in their review, and critically evaluate the studies they find." (p. 139). Nelson, L. K. (2013). Research in Communication Sciences and Disorders . Plural Publishing.

• Example : The effect of leave policies on increasing fertility: a systematic review:  10.1057/s41599-022-01270-w

Meta-analysis : "Meta-analysis is a method of reviewing research findings in a quantitative fashion by transforming the data from individual studies into what is called an effect size and then pooling and analyzing this information. The basic goal in meta-analysis is to explain why different outcomes have occurred in different studies." (p. 197). Roberts, M. C., & Ilardi, S. S. (2003). Handbook of Research Methods in Clinical Psychology . Blackwell Publishing.

• Example : Employment Instability and Fertility in Europe: A Meta-Analysis:  10.1215/00703370-9164737

Meta-synthesis : "Qualitative meta-synthesis is a type of qualitative study that uses as data the findings from other qualitative studies linked by the same or related topic." (p.312). Zimmer, L. (2006). Qualitative meta-synthesis: A question of dialoguing with texts .  Journal of Advanced Nursing , 53 (3), 311-318.

• Example : Women’s perspectives on career successes and barriers: A qualitative meta-synthesis:  10.1177/05390184221113735

Literature Reviews in the Health Sciences

• UConn Health subject guide on systematic reviews Explanation of the different review types used in health sciences literature as well as tools to help you find the right review type
• << Previous: Getting Started
• Next: How to Pick a Topic >>
• Last Updated: Sep 21, 2022 2:16 PM
• URL: https://guides.lib.uconn.edu/literaturereview

News alert: UC Berkeley has announced its next university librarian

Secondary menu

• Log in to your Library account
• Hours and Maps
• Connect from Off Campus
• UC Berkeley Home

Search form

Conducting a literature review: why do a literature review, why do a literature review.

• How To Find "The Literature"
• Found it -- Now What?

Besides the obvious reason for students -- because it is assigned! -- a literature review helps you explore the research that has come before you, to see how your research question has (or has not) already been addressed.

You identify:

• core research in the field
• experts in the subject area
• methodology you may want to use (or avoid)
• gaps in knowledge -- or where your research would fit in

It Also Helps You:

• Publish and share your findings
• Justify requests for grants and other funding
• Identify best practices to inform practice
• Set wider context for a program evaluation
• Compile information to support community organizing

Great brief overview, from NCSU

Want To Know More?

• Next: How To Find "The Literature" >>
• Last Updated: Apr 25, 2024 1:10 PM
• URL: https://guides.lib.berkeley.edu/litreview

A Guide to Literature Reviews

Importance of a good literature review.

• Conducting the Literature Review
• Structure and Writing Style
• Types of Literature Reviews
• Citation Management Software This link opens in a new window
• Acknowledgements

A literature review is not only a summary of key sources, but  has an organizational pattern which combines both summary and synthesis, often within specific conceptual categories . A summary is a recap of the important information of the source, but a synthesis is a re-organization, or a reshuffling, of that information in a way that informs how you are planning to investigate a research problem. The analytical features of a literature review might:

• Give a new interpretation of old material or combine new with old interpretations,
• Trace the intellectual progression of the field, including major debates,
• Depending on the situation, evaluate the sources and advise the reader on the most pertinent or relevant research, or
• Usually in the conclusion of a literature review, identify where gaps exist in how a problem has been researched to date.

The purpose of a literature review is to:

• Place each work in the context of its contribution to understanding the research problem being studied.
• Describe the relationship of each work to the others under consideration.
• Identify new ways to interpret prior research.
• Reveal any gaps that exist in the literature.
• Resolve conflicts amongst seemingly contradictory previous studies.
• Identify areas of prior scholarship to prevent duplication of effort.
• Point the way in fulfilling a need for additional research.
• Locate your own research within the context of existing literature [very important].
• << Previous: Definition
• Next: Conducting the Literature Review >>
• Last Updated: May 10, 2024 11:34 AM
• URL: https://libguides.mcmaster.ca/litreview

Literature Reviews

• Getting started

What is a literature review?

Why conduct a literature review, stages of a literature review, lit reviews: an overview (video), check out these books.

• Types of reviews
• 1. Define your research question
• 2. Plan your search
• 3. Search the literature
• 4. Organize your results
• 5. Synthesize your findings
• 6. Write the review
• Artificial intelligence (AI) tools
• Thompson Writing Studio This link opens in a new window
• Need to write a systematic review? This link opens in a new window

Contact a Librarian

Ask a Librarian

Definition: A literature review is a systematic examination and synthesis of existing scholarly research on a specific topic or subject.

Purpose: It serves to provide a comprehensive overview of the current state of knowledge within a particular field.

Analysis: Involves critically evaluating and summarizing key findings, methodologies, and debates found in academic literature.

Identifying Gaps: Aims to pinpoint areas where there is a lack of research or unresolved questions, highlighting opportunities for further investigation.

Contextualization: Enables researchers to understand how their work fits into the broader academic conversation and contributes to the existing body of knowledge.

tl;dr  A literature review critically examines and synthesizes existing scholarly research and publications on a specific topic to provide a comprehensive understanding of the current state of knowledge in the field.

What is a literature review NOT?

❌ An annotated bibliography

❌ Original research

❌ A summary

❌ Something to be conducted at the end of your research

❌ An opinion piece

❌ A chronological compilation of studies

The reason for conducting a literature review is to:

Literature Reviews: An Overview for Graduate Students

While this 9-minute video from NCSU is geared toward graduate students, it is useful for anyone conducting a literature review.

Writing the literature review: A practical guide

Available 3rd floor of Perkins

Writing literature reviews: A guide for students of the social and behavioral sciences

Available online!

So, you have to write a literature review: A guided workbook for engineers

Telling a research story: Writing a literature review

The literature review: Six steps to success

Systematic approaches to a successful literature review

Request from Duke Medical Center Library

Doing a systematic review: A student's guide

• Next: Types of reviews >>
• Last Updated: May 17, 2024 8:42 AM
• URL: https://guides.library.duke.edu/litreviews

Services for...

• Faculty & Instructors
• Graduate Students
• Undergraduate Students
• International Students
• Patrons with Disabilities

• Harmful Language Statement
• Re-use & Attribution / Privacy
• Support the Libraries

Libraries | Research Guides

Literature reviews, what is a literature review, learning more about how to do a literature review.

• Planning the Review
• The Research Question
• Choosing Where to Search
• Organizing the Review
• Writing the Review

A literature review is a review and synthesis of existing research on a topic or research question. A literature review is meant to analyze the scholarly literature, make connections across writings and identify strengths, weaknesses, trends, and missing conversations. A literature review should address different aspects of a topic as it relates to your research question. A literature review goes beyond a description or summary of the literature you have read. 

• Sage Research Methods Core Collection This link opens in a new window SAGE Research Methods supports research at all levels by providing material to guide users through every step of the research process. SAGE Research Methods is the ultimate methods library with more than 1000 books, reference works, journal articles, and instructional videos by world-leading academics from across the social sciences, including the largest collection of qualitative methods books available online from any scholarly publisher. – Publisher

• Next: Planning the Review >>
• Last Updated: May 2, 2024 10:39 AM
• URL: https://libguides.northwestern.edu/literaturereviews

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

• View all journals
• Explore content
• About the journal
• Publish with us
• Sign up for alerts
• CAREER FEATURE
• 04 December 2020
• Correction 09 December 2020

How to write a superb literature review

Andy Tay is a freelance writer based in Singapore.

You can also search for this author in PubMed   Google Scholar

Literature reviews are important resources for scientists. They provide historical context for a field while offering opinions on its future trajectory. Creating them can provide inspiration for one’s own research, as well as some practice in writing. But few scientists are trained in how to write a review — or in what constitutes an excellent one. Even picking the appropriate software to use can be an involved decision (see ‘Tools and techniques’). So Nature asked editors and working scientists with well-cited reviews for their tips.

Access options

Access Nature and 54 other Nature Portfolio journals

Get Nature+, our best-value online-access subscription

24,99 € / 30 days

cancel any time

Subscribe to this journal

Receive 51 print issues and online access

185,98 € per year

only 3,65 € per issue

Rent or buy this article

Prices vary by article type

Prices may be subject to local taxes which are calculated during checkout

doi: https://doi.org/10.1038/d41586-020-03422-x

Interviews have been edited for length and clarity.

Updates & Corrections

Correction 09 December 2020 : An earlier version of the tables in this article included some incorrect details about the programs Zotero, Endnote and Manubot. These have now been corrected.

Hsing, I.-M., Xu, Y. & Zhao, W. Electroanalysis 19 , 755–768 (2007).

Article   Google Scholar  

Ledesma, H. A. et al. Nature Nanotechnol. 14 , 645–657 (2019).

Article   PubMed   Google Scholar  

Brahlek, M., Koirala, N., Bansal, N. & Oh, S. Solid State Commun. 215–216 , 54–62 (2015).

Choi, Y. & Lee, S. Y. Nature Rev. Chem . https://doi.org/10.1038/s41570-020-00221-w (2020).

Download references

Related Articles

• Research management

I’m worried I’ve been contacted by a predatory publisher — how do I find out?

Career Feature 15 MAY 24

How I fled bombed Aleppo to continue my career in science

Career Feature 08 MAY 24

Illuminating ‘the ugly side of science’: fresh incentives for reporting negative results

US halts funding to controversial virus-hunting group: what researchers think

News 16 MAY 24

Japan can embrace open science — but flexible approaches are key

Correspondence 07 MAY 24

US funders to tighten oversight of controversial ‘gain of function’ research

News 07 MAY 24

Mount Etna’s spectacular smoke rings and more — April’s best science images

News 03 MAY 24

Postdoc in CRISPR Meta-Analytics and AI for Therapeutic Target Discovery and Priotisation (OT Grant)

APPLICATION CLOSING DATE: 14/06/2024 Human Technopole (HT) is a new interdisciplinary life science research institute created and supported by the...

Human Technopole

Research Associate - Metabolism

Houston, Texas (US)

Baylor College of Medicine (BCM)

Postdoc Fellowships

Train with world-renowned cancer researchers at NIH? Consider joining the Center for Cancer Research (CCR) at the National Cancer Institute

Bethesda, Maryland

NIH National Cancer Institute (NCI)

Faculty Recruitment, Westlake University School of Medicine

Faculty positions are open at four distinct ranks: Assistant Professor, Associate Professor, Full Professor, and Chair Professor.

Hangzhou, Zhejiang, China

Westlake University

PhD/master's Candidate

PhD/master's Candidate    Graduate School of Frontier Science Initiative, Kanazawa University is seeking candidates for PhD and master's students i...

Kanazawa University

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Quick links

• Explore articles by subject
• Guide to authors
• Editorial policies

Purdue Online Writing Lab Purdue OWL® College of Liberal Arts

Writing a Literature Review

Welcome to the Purdue OWL

This page is brought to you by the OWL at Purdue University. When printing this page, you must include the entire legal notice.

Copyright ©1995-2018 by The Writing Lab & The OWL at Purdue and Purdue University. All rights reserved. This material may not be published, reproduced, broadcast, rewritten, or redistributed without permission. Use of this site constitutes acceptance of our terms and conditions of fair use.

A literature review is a document or section of a document that collects key sources on a topic and discusses those sources in conversation with each other (also called synthesis ). The lit review is an important genre in many disciplines, not just literature (i.e., the study of works of literature such as novels and plays). When we say “literature review” or refer to “the literature,” we are talking about the research ( scholarship ) in a given field. You will often see the terms “the research,” “the scholarship,” and “the literature” used mostly interchangeably.

Where, when, and why would I write a lit review?

There are a number of different situations where you might write a literature review, each with slightly different expectations; different disciplines, too, have field-specific expectations for what a literature review is and does. For instance, in the humanities, authors might include more overt argumentation and interpretation of source material in their literature reviews, whereas in the sciences, authors are more likely to report study designs and results in their literature reviews; these differences reflect these disciplines’ purposes and conventions in scholarship. You should always look at examples from your own discipline and talk to professors or mentors in your field to be sure you understand your discipline’s conventions, for literature reviews as well as for any other genre.

A literature review can be a part of a research paper or scholarly article, usually falling after the introduction and before the research methods sections. In these cases, the lit review just needs to cover scholarship that is important to the issue you are writing about; sometimes it will also cover key sources that informed your research methodology.

Lit reviews can also be standalone pieces, either as assignments in a class or as publications. In a class, a lit review may be assigned to help students familiarize themselves with a topic and with scholarship in their field, get an idea of the other researchers working on the topic they’re interested in, find gaps in existing research in order to propose new projects, and/or develop a theoretical framework and methodology for later research. As a publication, a lit review usually is meant to help make other scholars’ lives easier by collecting and summarizing, synthesizing, and analyzing existing research on a topic. This can be especially helpful for students or scholars getting into a new research area, or for directing an entire community of scholars toward questions that have not yet been answered.

What are the parts of a lit review?

Most lit reviews use a basic introduction-body-conclusion structure; if your lit review is part of a larger paper, the introduction and conclusion pieces may be just a few sentences while you focus most of your attention on the body. If your lit review is a standalone piece, the introduction and conclusion take up more space and give you a place to discuss your goals, research methods, and conclusions separately from where you discuss the literature itself.

Introduction:

• An introductory paragraph that explains what your working topic and thesis is
• A forecast of key topics or texts that will appear in the review
• Potentially, a description of how you found sources and how you analyzed them for inclusion and discussion in the review (more often found in published, standalone literature reviews than in lit review sections in an article or research paper)
• Summarize and synthesize: Give an overview of the main points of each source and combine them into a coherent whole
• Analyze and interpret: Don’t just paraphrase other researchers – add your own interpretations where possible, discussing the significance of findings in relation to the literature as a whole
• Critically Evaluate: Mention the strengths and weaknesses of your sources
• Write in well-structured paragraphs: Use transition words and topic sentence to draw connections, comparisons, and contrasts.

Conclusion:

• Summarize the key findings you have taken from the literature and emphasize their significance
• Connect it back to your primary research question

How should I organize my lit review?

Lit reviews can take many different organizational patterns depending on what you are trying to accomplish with the review. Here are some examples:

• Chronological : The simplest approach is to trace the development of the topic over time, which helps familiarize the audience with the topic (for instance if you are introducing something that is not commonly known in your field). If you choose this strategy, be careful to avoid simply listing and summarizing sources in order. Try to analyze the patterns, turning points, and key debates that have shaped the direction of the field. Give your interpretation of how and why certain developments occurred (as mentioned previously, this may not be appropriate in your discipline — check with a teacher or mentor if you’re unsure).
• Thematic : If you have found some recurring central themes that you will continue working with throughout your piece, you can organize your literature review into subsections that address different aspects of the topic. For example, if you are reviewing literature about women and religion, key themes can include the role of women in churches and the religious attitude towards women.
• Qualitative versus quantitative research
• Empirical versus theoretical scholarship
• Divide the research by sociological, historical, or cultural sources
• Theoretical : In many humanities articles, the literature review is the foundation for the theoretical framework. You can use it to discuss various theories, models, and definitions of key concepts. You can argue for the relevance of a specific theoretical approach or combine various theorical concepts to create a framework for your research.

What are some strategies or tips I can use while writing my lit review?

Any lit review is only as good as the research it discusses; make sure your sources are well-chosen and your research is thorough. Don’t be afraid to do more research if you discover a new thread as you’re writing. More info on the research process is available in our "Conducting Research" resources .

As you’re doing your research, create an annotated bibliography ( see our page on the this type of document ). Much of the information used in an annotated bibliography can be used also in a literature review, so you’ll be not only partially drafting your lit review as you research, but also developing your sense of the larger conversation going on among scholars, professionals, and any other stakeholders in your topic.

Usually you will need to synthesize research rather than just summarizing it. This means drawing connections between sources to create a picture of the scholarly conversation on a topic over time. Many student writers struggle to synthesize because they feel they don’t have anything to add to the scholars they are citing; here are some strategies to help you:

• It often helps to remember that the point of these kinds of syntheses is to show your readers how you understand your research, to help them read the rest of your paper.
• Writing teachers often say synthesis is like hosting a dinner party: imagine all your sources are together in a room, discussing your topic. What are they saying to each other?
• Look at the in-text citations in each paragraph. Are you citing just one source for each paragraph? This usually indicates summary only. When you have multiple sources cited in a paragraph, you are more likely to be synthesizing them (not always, but often
• Read more about synthesis here.

The most interesting literature reviews are often written as arguments (again, as mentioned at the beginning of the page, this is discipline-specific and doesn’t work for all situations). Often, the literature review is where you can establish your research as filling a particular gap or as relevant in a particular way. You have some chance to do this in your introduction in an article, but the literature review section gives a more extended opportunity to establish the conversation in the way you would like your readers to see it. You can choose the intellectual lineage you would like to be part of and whose definitions matter most to your thinking (mostly humanities-specific, but this goes for sciences as well). In addressing these points, you argue for your place in the conversation, which tends to make the lit review more compelling than a simple reporting of other sources.

Harvey Cushing/John Hay Whitney Medical Library

• Collections
• Research Help

YSN Doctoral Programs: Steps in Conducting a Literature Review

• Biomedical Databases
• Global (Public Health) Databases
• Soc. Sci., History, and Law Databases
• Grey Literature
• Trials Registers
• Data and Statistics
• Public Policy
• Google Tips
• Recommended Books
• Steps in Conducting a Literature Review

What is a literature review?

A literature review is an integrated analysis -- not just a summary-- of scholarly writings and other relevant evidence related directly to your research question.  That is, it represents a synthesis of the evidence that provides background information on your topic and shows a association between the evidence and your research question.

A literature review may be a stand alone work or the introduction to a larger research paper, depending on the assignment.  Rely heavily on the guidelines your instructor has given you.

Why is it important?

A literature review is important because it:

• Explains the background of research on a topic.
• Demonstrates why a topic is significant to a subject area.
• Discovers relationships between research studies/ideas.
• Identifies major themes, concepts, and researchers on a topic.
• Identifies critical gaps and points of disagreement.
• Discusses further research questions that logically come out of the previous studies.

APA7 Style resources

APA Style Blog - for those harder to find answers

1. Choose a topic. Define your research question.

Your literature review should be guided by your central research question.  The literature represents background and research developments related to a specific research question, interpreted and analyzed by you in a synthesized way.

• Make sure your research question is not too broad or too narrow.  Is it manageable?
• Begin writing down terms that are related to your question. These will be useful for searches later.
• If you have the opportunity, discuss your topic with your professor and your class mates.

2. Decide on the scope of your review

How many studies do you need to look at? How comprehensive should it be? How many years should it cover? 

• This may depend on your assignment.  How many sources does the assignment require?

3. Select the databases you will use to conduct your searches.

Make a list of the databases you will search. 

Where to find databases:

• use the tabs on this guide
• Find other databases in the Nursing Information Resources web page
• More on the Medical Library web page
• ... and more on the Yale University Library web page

4. Conduct your searches to find the evidence. Keep track of your searches.

• Use the key words in your question, as well as synonyms for those words, as terms in your search. Use the database tutorials for help.
• Save the searches in the databases. This saves time when you want to redo, or modify, the searches. It is also helpful to use as a guide is the searches are not finding any useful results.
• Review the abstracts of research studies carefully. This will save you time.
• Use the bibliographies and references of research studies you find to locate others.
• Check with your professor, or a subject expert in the field, if you are missing any key works in the field.
• Ask your librarian for help at any time.
• Use a citation manager, such as EndNote as the repository for your citations. See the EndNote tutorials for help.

Review the literature

Some questions to help you analyze the research:

• What was the research question of the study you are reviewing? What were the authors trying to discover?
• Was the research funded by a source that could influence the findings?
• What were the research methodologies? Analyze its literature review, the samples and variables used, the results, and the conclusions.
• Does the research seem to be complete? Could it have been conducted more soundly? What further questions does it raise?
• If there are conflicting studies, why do you think that is?
• How are the authors viewed in the field? Has this study been cited? If so, how has it been analyzed?

Tips: 

• Review the abstracts carefully.  
• Keep careful notes so that you may track your thought processes during the research process.
• Create a matrix of the studies for easy analysis, and synthesis, across all of the studies.
• << Previous: Recommended Books
• Last Updated: Jan 4, 2024 10:52 AM
• URL: https://guides.library.yale.edu/YSNDoctoral

Reference management. Clean and simple.

Literature review

How to write a literature review in 6 steps

How do you write a good literature review? This step-by-step guide on how to write an excellent literature review covers all aspects of planning and writing literature reviews for academic papers and theses.

How to write a systematic literature review [9 steps]

How do you write a systematic literature review? What types of systematic literature reviews exist and where do you use them? Learn everything you need to know about a systematic literature review in this guide

What is a literature review? [with examples]

Not sure what a literature review is? This guide covers the definition, purpose, and format of a literature review.

Get science-backed answers as you write with Paperpal's Research feature

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. 

Find academic papers related to your research topic faster. Try Research on Paperpal  

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. 

Strengthen your literature review with factual insights. Try Research on Paperpal for free!    

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. 

Write and Cite as you go with Paperpal Research. Start now for free.   

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. 

Whether you’re exploring a new research field or finding new angles to develop an existing topic, sifting through hundreds of papers can take more time than you have to spare. But what if you could find science-backed insights with verified citations in seconds? That’s the power of Paperpal’s new Research feature!  

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.   

Here’s how to use the Research feature:  

• 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. 
• Review and Save: Paperpal summarizes the information, while citing sources and listing relevant reads. You can quickly scan the results to identify relevant references and save these directly to your built-in citations library for later access. 
• 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 . 

Paperpal is an AI writing assistant that help academics write better, faster with real-time suggestions for in-depth language and grammar correction. Trained on millions of research manuscripts enhanced by professional academic editors, Paperpal delivers human precision at machine speed.  

Try it for free or upgrade to  Paperpal Prime , which unlocks unlimited access to premium features like academic translation, paraphrasing, contextual synonyms, consistency checks and more. It’s like always having a professional academic editor by your side! Go beyond limitations and experience the future of academic writing.  Get Paperpal Prime now at just US$19 a month!

Related Reads:

• Empirical Research: A Comprehensive Guide for Academics 
• How to Write a Scientific Paper in 10 Steps 
• How Long Should a Chapter Be?
• How to Use Paperpal to Generate Emails & Cover Letters?

6 Tips for Post-Doc Researchers to Take Their Career to the Next Level

Self-plagiarism in research: what it is and how to avoid it, you may also like, how to write a high-quality conference paper, how paperpal’s research feature helps you develop and..., how paperpal is enhancing academic productivity and accelerating..., how to write a successful book chapter for..., academic editing: how to self-edit academic text with..., 4 ways paperpal encourages responsible writing with ai, what are scholarly sources and where can you..., how to write a hypothesis types and examples , measuring academic success: definition & strategies for excellence, what is academic writing: tips for students.

Want to create or adapt books like this? Learn more about how Pressbooks supports open publishing practices.

Chapter 1: Introduction

Learning objectives.

At the conclusion of this chapter, you will be able to:

• Identify the purpose of the literature review in  the research process
• Distinguish between different types of literature reviews

1.1 What is a Literature Review?

Pick up nearly any book on research methods and you will find a description of a literature review.  At a basic level, the term implies a survey of factual or nonfiction books, articles, and other documents published on a particular subject.  Definitions may be similar across the disciplines, with new types and definitions continuing to emerge.  Generally speaking, a literature review is a:

• “comprehensive background of the literature within the interested topic area…” ( O’Gorman & MacIntosh, 2015, p. 31 ).
• “critical component of the research process that provides an in-depth analysis of recently published research findings in specifically identified areas of interest.” ( House, 2018, p. 109 ).
• “written document that presents a logically argued case founded on a comprehensive understanding of the current state of knowledge about a topic of study” ( Machi & McEvoy,  2012, p. 4 ).

As a foundation for knowledge advancement in every discipline, it is an important element of any research project.  At the graduate or doctoral level, the literature review is an essential feature of thesis and dissertation, as well as grant proposal writing.  That is to say, “A substantive, thorough, sophisticated literature review is a precondition for doing substantive, thorough, sophisticated research…A researcher cannot perform significant research without first understanding the literature in the field.” ( Boote & Beile, 2005, p. 3 ).  It is by this means, that a researcher demonstrates familiarity with a body of knowledge and thereby establishes credibility with a reader.  An advanced-level literature review shows how prior research is linked to a new project, summarizing and synthesizing what is known while identifying gaps in the knowledge base, facilitating theory development, closing areas where enough research already exists, and uncovering areas where more research is needed. ( Webster & Watson, 2002, p. xiii )

A graduate-level literature review is a compilation of the most significant previously published research on your topic. Unlike an annotated bibliography or a research paper you may have written as an undergraduate, your literature review will outline, evaluate and synthesize relevant research and relate those sources to your own thesis or research question. It is much more than a summary of all the related literature.

It is a type of writing that demonstrate the importance of your research by defining the main ideas and the relationship between them. A good literature review lays the foundation for the importance of your stated problem and research question.

Literature reviews:

• define a concept
• map the research terrain or scope
• systemize relationships between concepts
• identify gaps in the literature ( Rocco & Plathotnik, 2009, p. 128 )

The purpose of a literature review is to demonstrate that your research question  is meaningful. Additionally, you may review the literature of different disciplines to find deeper meaning and understanding of your topic. It is especially important to consider other disciplines when you do not find much on your topic in one discipline. You will need to search the cognate literature before claiming there is “little previous research” on your topic.

Well developed literature reviews involve numerous steps and activities. The literature review is an iterative process because you will do at least two of them: a preliminary search to learn what has been published in your area and whether there is sufficient support in the literature for moving ahead with your subject. After this first exploration, you will conduct a deeper dive into the literature to learn everything you can about the topic and its related issues.

Literature Review Tutorial

1.2 Literature Review Basics

An effective literature review must:

• Methodologically analyze and synthesize quality literature on a topic
• Provide a firm foundation to a topic or research area
• Provide a firm foundation for the selection of a research methodology
• Demonstrate that the proposed research contributes something new to the overall body of knowledge of advances the research field’s knowledge base. ( Levy & Ellis, 2006 ).

All literature reviews, whether they are qualitative, quantitative or both, will at some point:

• Introduce the topic and define its key terms
• Establish the importance of the topic
• Provide an overview of the amount of available literature and its types (for example: theoretical, statistical, speculative)
• Identify gaps in the literature
• Point out consistent finding across studies
• Arrive at a synthesis that organizes what is known about a topic
• Discusses possible implications and directions for future research

1.3 Types of Literature Reviews

There are many different types of literature reviews, however there are some shared characteristics or features.  Remember a comprehensive literature review is, at its most fundamental level, an original work based on an extensive critical examination and synthesis of the relevant literature on a topic. As a study of the research on a particular topic, it is arranged by key themes or findings, which may lead up to or link to the  research question.  In some cases, the research question will drive the type of literature review that is undertaken.

The following section includes brief descriptions of the terms used to describe different literature review types with examples of each.   The included citations are open access, Creative Commons licensed or copyright-restricted.

1.3.1 Types of Review

1.3.1.1 conceptual.

Guided by an understanding of basic issues rather than a research methodology. You are looking for key factors, concepts or variables and the presumed relationship between them. The goal of the conceptual literature review is to categorize and describe concepts relevant to your study or topic and outline a relationship between them. You will include relevant theory and empirical research.

Examples of a Conceptual Review:

• Education : The formality of learning science in everyday life: A conceptual literature review. ( Dohn, 2010 ).
• Education : Are we asking the right questions? A conceptual review of the educational development literature in higher education. ( Amundsen & Wilson, 2012 ).

1.3.1.2 Empirical

An empirical literature review collects, creates, arranges, and analyzes numeric data reflecting the frequency of themes, topics, authors and/or methods found in existing literature. Empirical literature reviews present their summaries in quantifiable terms using descriptive and inferential statistics.

Examples of an Empirical Review:

• Nursing : False-positive findings in Cochrane meta-analyses with and without application of trial sequential analysis: An empirical review. ( Imberger, Thorlund, Gluud, & Wettersley, 2016 ).
• Education : Impediments of e-learning adoption in higher learning institutions of Tanzania: An empirical review ( Mwakyusa & Mwalyagile, 2016 ).

1.3.1.3 Exploratory

Unlike a synoptic literature review, the purpose here is to provide a broad approach to the topic area. The aim is breadth rather than depth and to get a general feel for the size of the topic area. A graduate student might do an exploratory review of the literature before beginning a synoptic, or more comprehensive one.

Examples of an Exploratory Review:

• Education : University research management: An exploratory literature review. ( Schuetzenmeister, 2010 ).
• Education : An exploratory review of design principles in constructivist gaming learning environments. ( Rosario & Widmeyer, 2009 ).

1.3.1.4 Focused

A type of literature review limited to a single aspect of previous research, such as methodology. A focused literature review generally will describe the implications of choosing a particular element of past research, such as methodology in terms of data collection, analysis and interpretation.

Examples of a Focused Review:

• Nursing : Clinical inertia in the management of type 2 diabetes mellitus: A focused literature review. ( Khunti, Davies, & Khunti, 2015 ).
• Education : Language awareness: Genre awareness-a focused review of the literature. ( Stainton, 1992 ).

1.3.1.5 Integrative

Critiques past research and draws overall conclusions from the body of literature at a specified point in time. Reviews, critiques, and synthesizes representative literature on a topic in an integrated way. Most integrative reviews are intended to address mature topics or  emerging topics. May require the author to adopt a guiding theory, a set of competing models, or a point of view about a topic.  For more description of integrative reviews, see Whittemore & Knafl (2005).

Examples of an Integrative Review:

• Nursing : Interprofessional teamwork and collaboration between community health workers and healthcare teams: An integrative review. ( Franklin,  Bernhardt, Lopez, Long-Middleton, & Davis, 2015 ).
• Education : Exploring the gap between teacher certification and permanent employment in Ontario: An integrative literature review. ( Brock & Ryan, 2016 ).

1.3.1.6 Meta-analysis

A subset of a  systematic review, that takes findings from several studies on the same subject and analyzes them using standardized statistical procedures to pool together data. Integrates findings from a large body of quantitative findings to enhance understanding, draw conclusions, and detect patterns and relationships. Gather data from many different, independent studies that look at the same research question and assess similar outcome measures. Data is combined and re-analyzed, providing a greater statistical power than any single study alone. It’s important to note that not every systematic review includes a meta-analysis but a meta-analysis can’t exist without a systematic review of the literature.

Examples of a Meta-Analysis:

• Education : Efficacy of the cooperative learning method on mathematics achievement and attitude: A meta-analysis research. ( Capar & Tarim, 2015 ).
• Nursing : A meta-analysis of the effects of non-traditional teaching methods on the critical thinking abilities of nursing students. ( Lee, Lee, Gong, Bae, & Choi, 2016 ).
• Education : Gender differences in student attitudes toward science: A meta-analysis of the literature from 1970 to 1991. ( Weinburgh, 1995 ).

1.3.1.7 Narrative/Traditional

An overview of research on a particular topic that critiques and summarizes a body of literature. Typically broad in focus. Relevant past research is selected and synthesized into a coherent discussion. Methodologies, findings and limits of the existing body of knowledge are discussed in narrative form. Sometimes also referred to as a traditional literature review. Requires a sufficiently focused research question. The process may be subject to bias that supports the researcher’s own work.

Examples of a Narrative/Traditional Review:

• Nursing : Family carers providing support to a person dying in the home setting: A narrative literature review. ( Morris, King, Turner, & Payne, 2015 ).
• Education : Adventure education and Outward Bound: Out-of-class experiences that make a lasting difference. ( Hattie, Marsh, Neill, & Richards, 1997 ).
• Education : Good quality discussion is necessary but not sufficient in asynchronous tuition: A brief narrative review of the literature. ( Fear & Erikson-Brown, 2014 ).
• Nursing : Outcomes of physician job satisfaction: A narrative review, implications, and directions for future research. ( Williams & Skinner, 2003 ).

1.3.1.8 Realist

Aspecific type of literature review that is theory-driven and interpretative and is intended to explain the outcomes of a complex intervention program(s).

Examples of a Realist Review:

• Nursing : Lean thinking in healthcare: A realist review of the literature. ( Mazzacato, Savage, Brommels, 2010 ).
• Education : Unravelling quality culture in higher education: A realist review. ( Bendermacher, Egbrink, Wolfhagen, & Dolmans, 2017 ).

1.3.1.9 Scoping

Tend to be non-systematic and focus on breadth of coverage conducted on a topic rather than depth. Utilize a wide range of materials; may not evaluate the quality of the studies as much as count the number. One means of understanding existing literature. Aims to identify nature and extent of research; preliminary assessment of size and scope of available research on topic. May include research in progress.

Examples of a Scoping Review:

• Nursing : Organizational interventions improving access to community-based primary health care for vulnerable populations: A scoping review. ( Khanassov, Pluye, Descoteaux, Haggerty,  Russell, Gunn, & Levesque, 2016 ).
• Education : Interdisciplinary doctoral research supervision: A scoping review. ( Vanstone, Hibbert, Kinsella, McKenzie, Pitman, & Lingard, 2013 ).
• Nursing : A scoping review of the literature on the abolition of user fees in health care services in Africa. ( Ridde, & Morestin, 2011 ).

1.3.1.10 Synoptic

Unlike an exploratory review, the purpose is to provide a concise but accurate overview of all material that appears to be relevant to a chosen topic. Both content and methodological material is included. The review should aim to be both descriptive and evaluative. Summarizes previous studies while also showing how the body of literature could be extended and improved in terms of content and method by identifying gaps.

Examples of a Synoptic Review:

• Education : Theoretical framework for educational assessment: A synoptic review. ( Ghaicha, 2016 ).
• Education : School effects research: A synoptic review of past efforts and some suggestions for the future. ( Cuttance, 1981 ).

1.3.1.11 Systematic Review

A rigorous review that follows a strict methodology designed with a presupposed selection of literature reviewed.  Undertaken to clarify the state of existing research, the evidence, and possible implications that can be drawn from that.  Using comprehensive and exhaustive searching of the published and unpublished literature, searching various databases, reports, and grey literature.  Transparent and reproducible in reporting details of time frame, search and methods to minimize bias.  Must include a team of at least 2-3 and includes the critical appraisal of the literature.  For more description of systematic reviews, including links to protocols, checklists, workflow processes, and structure see “ A Young Researcher’s Guide to a Systematic Review “.

Examples of a Systematic Review:

• Education : The potentials of using cloud computing in schools: A systematic literature review ( Hartmann, Braae, Pedersen, & Khalid, 2017 )
• Nursing : Is butter back? A systematic review and meta-analysis of butter consumption and risk of cardiovascular disease, diabetes, and total mortality. ( Pimpin, Wu, Haskelberg, Del Gobbo, & Mozaffarian, 2016 ).
• Education : The use of research to improve professional practice: a systematic review of the literature. ( Hemsley-Brown & Sharp, 2003 ).
• Nursing : Using computers to self-manage type 2 diabetes. ( Pal, Eastwood, Michie, Farmer, Barnard, Peacock, Wood, Inniss, & Murray, 2013 ).

1.3.1.12 Umbrella/Overview of Reviews

Compiles evidence from multiple systematic reviews into one document. Focuses on broad condition or problem for which there are competing interventions and highlights reviews that address those interventions and their effects. Often used in recommendations for practice.

Examples of an Umbrella/Overview Review:

• Education : Reflective practice in healthcare education: An umbrella review. ( Fragknos, 2016 ).
• Nursing : Systematic reviews of psychosocial interventions for autism: an umbrella review. ( Seida, Ospina, Karkhaneh, Hartling, Smith, & Clark, 2009 ).

For a brief discussion see “ Not all literature reviews are the same ” (Thomson, 2013).

1.4 Why do a Literature Review?

The purpose of the literature review is the same regardless of the topic or research method. It tests your own research question against what is already known about the subject.

1.4.1 First – It’s part of the whole. Omission of a literature review chapter or section in a graduate-level project represents a serious void or absence of critical element in the research process.

The outcome of your review is expected to demonstrate that you:

• can systematically explore the research in your topic area
• can read and critically analyze the literature in your discipline and then use it appropriately to advance your own work
• have sufficient knowledge in the topic to undertake further investigation

1.4.2 Second – It’s good for you!

• You improve your skills as a researcher
• You become familiar with the discourse of your discipline and learn how to be a scholar in your field
• You learn through writing your ideas and finding your voice in your subject area
• You define, redefine and clarify your research question for yourself in the process

1.4.3 Third – It’s good for your reader. Your reader expects you to have done the hard work of gathering, evaluating and synthesizes the literature.  When you do a literature review you:

• Set the context for the topic and present its significance
• Identify what’s important to know about your topic – including individual material, prior research, publications, organizations and authors.
• Demonstrate relationships among prior research
• Establish limitations of existing knowledge
• Analyze trends in the topic’s treatment and gaps in the literature

1.4.4 Why do a literature review?

• To locate gaps in the literature of your discipline
• To avoid reinventing the wheel
• To carry on where others have already been
• To identify other people working in the same field
• To increase your breadth of knowledge in your subject area
• To find the seminal works in your field
• To provide intellectual context for your own work
• To acknowledge opposing viewpoints
• To put your work in perspective
• To demonstrate you can discover and retrieve previous work in the area

1.5 Common Literature Review Errors

Graduate-level literature reviews are more than a summary of the publications you find on a topic.  As you have seen in this brief introduction, literature reviews are a very specific type of research, analysis, and writing.  We will explore these topics more in the next chapters.  Some things to keep in mind as you begin your own research and writing are ways to avoid the most common errors seen in the first attempt at a literature review.  For a quick review of some of the pitfalls and challenges a new researcher faces when he/she begins work, see “ Get Ready: Academic Writing, General Pitfalls and (oh yes) Getting Started! ”.

As you begin your own graduate-level literature review, try to avoid these common mistakes:

• Accepts another researcher’s finding as valid without evaluating methodology and data
• Contrary findings and alternative interpretations are not considered or mentioned
• Findings are not clearly related to one’s own study, or findings are too general
• Insufficient time allowed to define best search strategies and writing
• Isolated statistical results are simply reported rather than synthesizing the results
• Problems with selecting and using most relevant keywords, subject headings and descriptors
• Relies too heavily on secondary sources
• Search methods are not recorded or reported for transparency
• Summarizes rather than synthesizes articles

In conclusion, the purpose of a literature review is three-fold:

• to survey the current state of knowledge or evidence in the area of inquiry,
• to identify key authors, articles, theories, and findings in that area, and
• to identify gaps in knowledge in that research area.

A literature review is commonly done today using computerized keyword searches in online databases, often working with a trained librarian or information expert. Keywords can be combined using the Boolean operators, “and”, “or” and sometimes “not”  to narrow down or expand the search results. Once a list of articles is generated from the keyword and subject heading search, the researcher must then manually browse through each title and abstract, to determine the suitability of that article before a full-text article is obtained for the research question.

Literature reviews should be reasonably complete, and not restricted to a few journals, a few years, or a specific methodology or research design. Reviewed articles may be summarized in the form of tables, and can be further structured using organizing frameworks such as a concept matrix.

A well-conducted literature review should indicate whether the initial research questions have already been addressed in the literature, whether there are newer or more interesting research questions available, and whether the original research questions should be modified or changed in light of findings of the literature review.

The review can also provide some intuitions or potential answers to the questions of interest and/or help identify theories that have previously been used to address similar questions and may provide evidence to inform policy or decision-making. ( Bhattacherjee, 2012 ).

Read Abstract 1.  Refer to Types of Literature Reviews.  What type of literature review do you think this study is and why?  See the Answer Key for the correct response.

Nursing : To describe evidence of international literature on the safe care of the hospitalised child after the World Alliance for Patient Safety and list contributions of the general theoretical framework of patient safety for paediatric nursing.

An integrative literature review between 2004 and 2015 using the databases PubMed, Cumulative Index of Nursing and Allied Health Literature (CINAHL), Scopus, Web of Science and Wiley Online Library, and the descriptors Safety or Patient safety, Hospitalised child, Paediatric nursing, and Nursing care.

Thirty-two articles were analysed, most of which were from North American, with a descriptive approach. The quality of the recorded information in the medical records, the use of checklists, and the training of health workers contribute to safe care in paediatric nursing and improve the medication process and partnerships with parents.

General information available on patient safety should be incorporated in paediatric nursing care. ( Wegner, Silva, Peres, Bandeira, Frantz, Botene, & Predebon, 2017 ).

Read Abstract 2.  Refer to Types of Literature Reviews.  What type of lit review do you think this study is and why?  See the Answer Key for the correct response.

Education : The focus of this paper centers around timing associated with early childhood education programs and interventions using meta-analytic methods. At any given assessment age, a child’s current age equals starting age, plus duration of program, plus years since program ended. Variability in assessment ages across the studies should enable everyone to identify the separate effects of all three time-related components. The project is a meta-analysis of evaluation studies of early childhood education programs conducted in the United States and its territories between 1960 and 2007. The population of interest is children enrolled in early childhood education programs between the ages of 0 and 5 and their control-group counterparts. Since the data come from a meta-analysis, the population for this study is drawn from many different studies with diverse samples. Given the preliminary nature of their analysis, the authors cannot offer conclusions at this point. ( Duncan, Leak, Li, Magnuson, Schindler, & Yoshikawa, 2011 ).

Test Yourself

See Answer Key for the correct responses.

The purpose of a graduate-level literature review is to summarize in as many words as possible everything that is known about my topic.

A literature review is significant because in the process of doing one, the researcher learns to read and critically assess the literature of a discipline and then uses it appropriately to advance his/her own research.

Read the following abstract and choose the correct type of literature review it represents.

Nursing: E-cigarette use has become increasingly popular, especially among the young. Its long-term influence upon health is unknown. Aim of this review has been to present the current state of knowledge about the impact of e-cigarette use on health, with an emphasis on Central and Eastern Europe. During the preparation of this narrative review, the literature on e-cigarettes available within the network PubMed was retrieved and examined. In the final review, 64 research papers were included. We specifically assessed the construction and operation of the e-cigarette as well as the chemical composition of the e-liquid; the impact that vapor arising from the use of e-cigarette explored in experimental models in vitro; and short-term effects of use of e-cigarettes on users’ health. Among the substances inhaled by the e-smoker, there are several harmful products, such as: formaldehyde, acetaldehyde, acroleine, propanal, nicotine, acetone, o-methyl-benzaldehyde, carcinogenic nitrosamines. Results from experimental animal studies indicate the negative impact of e-cigarette exposure on test models, such as ascytotoxicity, oxidative stress, inflammation, airway hyper reactivity, airway remodeling, mucin production, apoptosis, and emphysematous changes. The short-term impact of e-cigarettes on human health has been studied mostly in experimental setting. Available evidence shows that the use of e-cigarettes may result in acute lung function responses (e.g., increase in impedance, peripheral airway flow resistance) and induce oxidative stress. Based on the current available evidence, e-cigarette use is associated with harmful biologic responses, although it may be less harmful than traditional cigarettes. (J ankowski, Brożek, Lawson, Skoczyński, & Zejda, 2017 ).

• Meta-analysis
• Exploratory

Education: In this review, Mary Vorsino writes that she is interested in keeping the potential influences of women pragmatists of Dewey’s day in mind while presenting modern feminist re readings of Dewey. She wishes to construct a narrowly-focused and succinct literature review of thinkers who have donned a feminist lens to analyze Dewey’s approaches to education, learning, and democracy and to employ Dewey’s works in theorizing on gender and education and on gender in society. This article first explores Dewey as both an ally and a problematic figure in feminist literature and then investigates the broader sphere of feminist pragmatism and two central themes within it: (1) valuing diversity, and diverse experiences; and (2) problematizing fixed truths. ( Vorsino, 2015 ).

Image Attributions

Literature Reviews for Education and Nursing Graduate Students Copyright © by Linda Frederiksen is licensed under a Creative Commons Attribution 4.0 International License , except where otherwise noted.

Share This Book

• University of Texas Libraries

Literature Reviews

Steps in the literature review process.

• What is a literature review?
• Define your research question
• Determine inclusion and exclusion criteria
• Choose databases and search
• Review Results
• Synthesize Results
• Analyze Results
• Librarian Support
• You may need to some exploratory searching of the literature to get a sense of scope, to determine whether you need to narrow or broaden your focus
• Identify databases that provide the most relevant sources, and identify relevant terms (controlled vocabularies) to add to your search strategy
• Finalize your research question
• Think about relevant dates, geographies (and languages), methods, and conflicting points of view
• Conduct searches in the published literature via the identified databases
• Check to see if this topic has been covered in other discipline's databases
• Examine the citations of on-point articles for keywords, authors, and previous research (via references) and cited reference searching.
• Save your search results in a citation management tool (such as Zotero, Mendeley or EndNote)
• De-duplicate your search results
• Make sure that you've found the seminal pieces -- they have been cited many times, and their work is considered foundational 
• Check with your professor or a librarian to make sure your search has been comprehensive
• Evaluate the strengths and weaknesses of individual sources and evaluate for bias, methodologies, and thoroughness
• Group your results in to an organizational structure that will support why your research needs to be done, or that provides the answer to your research question  
• Develop your conclusions
• Are there gaps in the literature?
• Where has significant research taken place, and who has done it?
• Is there consensus or debate on this topic?
• Which methodological approaches work best?
• For example: Background, Current Practices, Critics and Proponents, Where/How this study will fit in 
• Organize your citations and focus on your research question and pertinent studies
• Compile your bibliography

Note: The first four steps are the best points at which to contact a librarian. Your librarian can help you determine the best databases to use for your topic, assess scope, and formulate a search strategy.

Videos Tutorials about Literature Reviews

This 4.5 minute video from Academic Education Materials has a Creative Commons License and a British narrator.

Recommended Reading

• Last Updated: Oct 26, 2022 2:49 PM
• URL: https://guides.lib.utexas.edu/literaturereviews

Why is it important to do a literature review in research?

The importance of scientific communication in the healthcare industry

The Importance and Role of Biostatistics in Clinical Research

 “A substantive, thorough, sophisticated literature review is a precondition for doing substantive, thorough, sophisticated research”. Boote and Baile 2005

Authors of manuscripts treat writing a literature review as a routine work or a mere formality. But a seasoned one knows the purpose and importance of a well-written literature review.  Since it is one of the basic needs for researches at any level, they have to be done vigilantly. Only then the reader will know that the basics of research have not been neglected.

The aim of any literature review is to summarize and synthesize the arguments and ideas of existing knowledge in a particular field without adding any new contributions.   Being built on existing knowledge they help the researcher to even turn the wheels of the topic of research.  It is possible only with profound knowledge of what is wrong in the existing findings in detail to overpower them.  For other researches, the literature review gives the direction to be headed for its success. 

The common perception of literature review and reality:

As per the common belief, literature reviews are only a summary of the sources related to the research. And many authors of scientific manuscripts believe that they are only surveys of what are the researches are done on the chosen topic.  But on the contrary, it uses published information from pertinent and relevant sources like

• Scholarly books
• Scientific papers
• Latest studies in the field
• Established school of thoughts
• Relevant articles from renowned scientific journals

and many more for a field of study or theory or a particular problem to do the following:

• Summarize into a brief account of all information
• Synthesize the information by restructuring and reorganizing
• Critical evaluation of a concept or a school of thought or ideas
• Familiarize the authors to the extent of knowledge in the particular field
• Encapsulate
• Compare & contrast

By doing the above on the relevant information, it provides the reader of the scientific manuscript with the following for a better understanding of it:

• It establishes the authors’  in-depth understanding and knowledge of their field subject
• It gives the background of the research
• Portrays the scientific manuscript plan of examining the research result
• Illuminates on how the knowledge has changed within the field
• Highlights what has already been done in a particular field
• Information of the generally accepted facts, emerging and current state of the topic of research
• Identifies the research gap that is still unexplored or under-researched fields
• Demonstrates how the research fits within a larger field of study
• Provides an overview of the sources explored during the research of a particular topic

Importance of literature review in research:

The importance of literature review in scientific manuscripts can be condensed into an analytical feature to enable the multifold reach of its significance.  It adds value to the legitimacy of the research in many ways:

• Provides the interpretation of existing literature in light of updated developments in the field to help in establishing the consistency in knowledge and relevancy of existing materials
• It helps in calculating the impact of the latest information in the field by mapping their progress of knowledge.
• It brings out the dialects of contradictions between various thoughts within the field to establish facts
• The research gaps scrutinized initially are further explored to establish the latest facts of theories to add value to the field
• Indicates the current research place in the schema of a particular field
• Provides information for relevancy and coherency to check the research
• Apart from elucidating the continuance of knowledge, it also points out areas that require further investigation and thus aid as a starting point of any future research
• Justifies the research and sets up the research question
• Sets up a theoretical framework comprising the concepts and theories of the research upon which its success can be judged
• Helps to adopt a more appropriate methodology for the research by examining the strengths and weaknesses of existing research in the same field
• Increases the significance of the results by comparing it with the existing literature
• Provides a point of reference by writing the findings in the scientific manuscript
• Helps to get the due credit from the audience for having done the fact-finding and fact-checking mission in the scientific manuscripts
• The more the reference of relevant sources of it could increase more of its trustworthiness with the readers
• Helps to prevent plagiarism by tailoring and uniquely tweaking the scientific manuscript not to repeat other’s original idea
• By preventing plagiarism , it saves the scientific manuscript from rejection and thus also saves a lot of time and money
• Helps to evaluate, condense and synthesize gist in the author’s own words to sharpen the research focus
• Helps to compare and contrast to  show the originality and uniqueness of the research than that of the existing other researches
• Rationalizes the need for conducting the particular research in a specified field
• Helps to collect data accurately for allowing any new methodology of research than the existing ones
• Enables the readers of the manuscript to answer the following questions of its readers for its better chances for publication
• What do the researchers know?
• What do they not know?
• Is the scientific manuscript reliable and trustworthy?
• What are the knowledge gaps of the researcher?

22. It helps the readers to identify the following for further reading of the scientific manuscript:

• What has been already established, discredited and accepted in the particular field of research
• Areas of controversy and conflicts among different schools of thought
• Unsolved problems and issues in the connected field of research
• The emerging trends and approaches
• How the research extends, builds upon and leaves behind from the previous research

A profound literature review with many relevant sources of reference will enhance the chances of the scientific manuscript publication in renowned and reputed scientific journals .

References:

http://www.math.montana.edu/jobo/phdprep/phd6.pdf

journal Publishing services  |  Scientific Editing Services  |  Medical Writing Services  |  scientific research writing service  |  Scientific communication services

Related Topics:

Meta Analysis

Scientific Research Paper Writing

Medical Research Paper Writing

Scientific Communication in healthcare

pubrica academy

Related posts.

Statistical analyses of case-control studies

PUB - Selecting material (e.g. excipient, active pharmaceutical ingredient) for drug development

Selecting material (e.g. excipient, active pharmaceutical ingredient, packaging material) for drug development

PUB - Health Economics of Data Modeling

Health economics in clinical trials

Comments are closed.

• Case report
• Open access
• Published: 18 May 2024

Detection of two synchronous histologically different renal cell carcinoma subtypes in the same kidney: a case report and review of the literature

• Mohamed Sakr 1 ,
• Merhan Badran   ORCID: orcid.org/0000-0002-1337-5165 1 ,
• Sarah Ahmed Hassan   ORCID: orcid.org/0000-0001-5032-5223 1 ,
• Mohamed Elsaqa 1 ,
• Mohamed Anwar Elwany 1 ,
• Nevine M. F. El Deeb 1 &
• Mohamed Sharafeldeen 1  

Journal of Medical Case Reports volume  18 , Article number:  250 ( 2024 ) Cite this article

Metrics details

Introduction

Renal cell carcinoma (RCC) is the dominant primary renal malignant neoplasm, encompassing a significant portion of renal tumors. The presence of synchronous yet histologically distinct ipsilateral RCCs, however, is an exceptionally uncommon phenomenon that is rather under-described in the literature regarding etiology, diagnosis, management, and later outcomes during follow-up.

Case presentation

We aim to present the 9th case of a combination chromophobe RCC (ChRCC) and clear cell RCC (ccRCC) in literature, according to our knowledge, for a 69-year-old North African, Caucasian female patient who, after complaining of loin pain and hematuria, was found to have two right renal masses with preoperative computed tomography (CT) and underwent right radical nephrectomy. Pathological examination later revealed the two renal masses to be of different histologic subtypes.

The coexistence of dissimilar RCC subtypes can contribute to diverse prognostic implications. Further research should focus on enhancing the complex, yet highly crucial, preoperative detection and pathological examination to differentiate multiple renal lesions. Planning optimal operative techniques (radical or partial nephrectomy), selecting suitable adjuvant regimens, and reporting long-term follow-up outcomes of patients in whom synchronous yet different RCC subtypes were detected are of utmost importance.

Peer Review reports

The simultaneous coexistence of renal cell carcinoma (RCC) with other renal neoplasms is a rare occurrence. Literature has described many cases of benign tumors occurring synchronously with RCC in the same kidney. Even more uncommon is the presence of multiple different RCC subtypes as separate tumors or sometimes even within a single tumor [ 1 , 2 , 3 , 4 , 5 ] . This simultaneous occurrence of different RCC subtypes poses challenges in preoperative detection, operative techniques, postoperative follow-up, and adjuvant regimens. In this case report, we present a unique instance of synchronous clear cell renal cell carcinoma (ccRCC) and chromophobe renal cell carcinoma (ChRCC), contributing to the existing literature on this subject. We also review similar cases reported previously, discuss and compare methods for preoperative diagnosis of multifocal RCCs and their differentiation, explore operative approaches, and address challenges in the postoperative period and prognosis estimation.

Due to the rarity of this condition, there is a lack of literature reports detailing both its preoperative course, including detection and differentiation, and its postoperative course regarding adjuvant therapy and long-term follow-up. Therefore, we aim to present this case and review similar cases in the literature to underscore the urgent need for further research in this area.

A 69-year-old North African Caucasian female patient presented to the Urology department at Alexandria Medical Center, Egypt, with complaints of right loin pain and hematuria. The patient's medical history was notable for hypertension, which had been managed with lisinopril 10 mg once daily for the past eight years. Prior to this medication, her blood pressure had been controlled through dietary and lifestyle modifications, including salt restriction and exercise. There was no significant surgical history. The patient was G1P1, with one living offspring. She is a homemaker and does not smoke or consume alcohol. Her father had hypertension, but otherwise, her family history was unremarkable.

On admission, her vitals were within normal range, including a blood pressure of 135/90 mmHg, a pulse rate of 88 beats per minute, and a temperature of 36.7°C. Abdominal examination showed only right flank tenderness without a palpable mass. Otherwise, the physical examination was unremarkable, and there were no abnormalities found during the neurological examination.

The lab results showed anemia, indicated by a hemoglobin level of 9.5 g/dL, and a normal serum creatinine level of 0.7 mg/dL [ 6 , 7 ]. Liver function tests were within normal ranges, and urinalysis showed trace protein and numerous red blood cells without casts. Multi-slice computed tomography (MSCT) revealed two right renal masses. The first one was an upper polar mainly anterior, totally endophytic, enhancing soft tissue mass lesion measuring 6.5 cm and invading the middle calyx with a RENAL score [ 8 ] of 11A (Fig.  1 A). The other smaller mass was a lower polar exophytic lesion measuring 1.3cm (Fig.  1 B). An apparent left paraaortic lymph node measuring 10 × 8.3 mm was detected. Multiple calyceal filling defects at the delayed phase suggesting blood clots were also reported. Metastatic workup was free.

Multi-slice computed tomography displaying two right renal masses. A The first mass was an upper polar mainly anterior, totally endophytic, enhancing soft tissue mass lesion measuring 6.5 cm and invading the middle calyx. B The second smaller mass was a lower polar exophytic lesion measuring 1.3 cm

Considering the history of hematuria, diagnostic cystoscopy, and right retrograde contrast study were done intraoperatively to exclude upper tract urothelial tumor (Fig.  2 ), the latter showing no filling defect of the pelvicalyceal system. The patient then underwent laparoscopic right radical nephrectomy with a presumptive clinical diagnosis of multicentric neoplastic renal process, mostly RCC.

Intraoperative right retrograde contrast study showing no filling defect of the pelvicalyceal system. This right retrograde contrast study was performed since the patient originally presented with hematuria. After no pelvicalyceal filling defect was detected, the surgical team proceeded to the right laparoscopic radical nephrectomy

Serial sectioning of the specimen grossly revealed two distinct well-circumscribed masses. The larger mass extended from the upper pole to the midzone of the kidney and measured 4.6 × 4 × 4 cm. Its cut surface was solid hemorrhagic brown with few yellowish areas. The tumor did not invade the renal sinus, renal vein, pelvicalyceal system, or perinephric fat grossly (Fig.  3 A). Microscopic examination of the larger mass revealed a well-circumscribed nonencapsulated neoplastic growth formed of sheets and trabeculae of polygonal cells having abundant eosinophilic cytoplasm and well-defined cell outlines with plant-like cell borders. The cells had round to oval nuclei, showing mild to moderate pleomorphism with occasional prominent nucleoli. Irregular raisinoid nuclei with irregular nuclear membranes and occasional perinuclear halos were also noted (Fig.  3 B–D). No necrosis, sarcomatoid, or rhabdoid features were detected. The tumor was morphologically diagnosed as ChRCC, confirmed by immunohistochemical positivity for CK-7 and CD117 (Fig.  3 E and F).

Pathological gross and microscopic examination of the larger, upper polar right renal mass (chromophobe renal cell carcinoma). A Macroscopic examination revealed a well-circumscribed non-encapsulated mass having a hemorrhagic brown cut section extending from the upper pole to the midzone of the kidney. B Low power examination revealed a well-circumscribed neoplastic growth formed of sheets of oncocytic cells with focal tubular pattern (H & E: × 40). C The tumor cells have well-defined cell borders and eosinophilic cytoplasm. Their nuclei are rounded to oval with occasional prominent nucleoli (arrows), perinuclear halos are also seen (arrowheads) (H &E, × 200). D The neoplastic cells are arranged in trabeculae; they have abundant eosinophilic cytoplasm and round to oval nuclei with occasional raisinoid nuclei (arrows) and perinuclear halos (arrowheads). (H &E, × 400). E The tumor cells are strongly positive for CK-7 (CK-7, × 100), and F The tumor cells are positive for CD117 (CD117, × 200)

The second smaller mass was located at the lower pole of the kidney, it measured 1.3 × 1 × 0.8 cm and was partially exophytic. Its cut section was light brown with minute cystic spaces. Again, no invasion of the renal sinus, renal vein, pelvicalyceal system, or perinephric fat was detected grossly (Fig.  4 A). Histopathological examination revealed a different histologic subtype of renal cell carcinoma forming a well-circumscribed neoplastic growth and having a fibrous pseudo-capsule. It was formed of clear cells arranged in solid sheets as well as nests / alveolar pattern separated by delicate vascular spaces. Focally, a tubular pattern was also seen. The cells had clear cytoplasm and mildly pleomorphic nuclei with conspicuous nucleoli at high power examination. No necrosis, rhabdoid, or sarcomatoid features were noted (Fig.  4 B-D). This tumor was morphologically diagnosed as ccRCC, with a nuclear grade of 2 (according to the WHO/ISUP grading system) and was confirmed by negative immunohistochemical staining of the neoplastic cells for both CK-7 and CD117 (Fig.  4 E and F). Both tumors did not invade the renal sinus, renal vein, renal pelvis, or perinephric fat microscopically. One unit of packed red blood cells was administered intraoperatively.

Pathological gross and microscopic examination of the smaller, lower polar right renal mass (clear cell renal cell carcinoma). A Macroscopic examination revealed a partially exophytic mass at the lower pole of the kidney (arrows). The mass is light brown and shows minute cystic spaces. B The tumor is formed of clear cells arranged as nests and tubules (lower part of the image) separated from the non-neoplastic renal parenchyma (upper part of the image) by a fibrous pseudo-capsule (asterisks) (H &E: × 40). C Nests of tumor cells separated by thin stroma (H &E: × 200). D The neoplastic cells have clear cytoplasm, and mildly pleomorphic nuclei, with occasional conspicuous nucleoli (nuclear grade 2) (arrows). Note the evident intervening richly vascular septae between tumor cells (H & E, × 400). E The tumor cells are negative for CK-7 (Right) with positive internal control detected in the normal renal tubules (left) (CK-7, × 100), and the tumor cells are negative for CD117 (CD117, × 200) ( F )

After surgery, the patient received 500 mL of isotonic saline every 12 h for one day and intravenous ceftriaxone 1 gm every 12 h for five days, along with paracetamol as needed for pain management. Her postoperative recovery was favorable, with a repeat hemoglobin level of 10.4 g/dL and serum creatinine level of 0.8 mg/dL. No specific adjuvant therapy was prescribed, and she was discharged one week later with prescriptions for levofloxacin 750 mg once daily for two weeks and ibuprofen tablets for pain relief as needed.

She was scheduled for 3 monthly follow-up visits. During the 3-month and 6-month follow-up appointments, laboratory and imaging tests, including complete blood count, renal function tests, and computed tomographic (CT) studies of the chest, abdomen, and pelvis were all unremarkable.

The coexistence of two histologically distinct renal cell carcinomas (RCC) within the same kidney is an exceedingly rare phenomenon. Most documented instances of synchronously coexisting neoplasms with RCC in the literature have involved benign neoplasms [ 1 , 2 , 3 , 4 , 5 ]. However, our case presents a unique occurrence involving a combination of chromophobe RCC (ChRCC) and clear cell RCC (ccRCC) simultaneously occurring in the same kidney. To the best of our knowledge, this is the ninth reported case of such a combination in the literature. Furthermore, unlike many cases reported in the literature where intraoperative detection was the case, the multifocal RCC in our patient was successfully identified through preoperative imaging.

RCC constitutes 85% of all renal neoplasms. It arises from the renal tubular epithelium and is frequently asymptomatic upon diagnosis [ 5 , 9 ]. RCCs are categorized into clear-cell, papillary, chromophobe, collecting duct, and unclassified carcinomas [ 10 ]. Clear cell (ccRCC) is the most common subtype, accounting for 75% of RCC cases, followed by papillary (pRCC) at 10% and chromophobe (ChRCC) at 5% [ 2 , 11 ]. Accurately distinguishing between these RCC subtypes is vital and essential to guarantee the most appropriate treatment plan and prognosis for the patient [ 5 ].

The coexistence of RCC in the same kidney with other neoplasms, whether benign or malignant, is rare, and the presence of different RCC histologic subtypes together is even more exceptionally uncommon [ 1 , 2 , 3 , 4 , 5 ]. The most frequently reported combinations include RCC with oncocytoma, angiomyolipoma (rarely without tuberous sclerosis), or even an adrenal adenoma [ 12 ]. The synchronous presence of multiple dissimilar histologic subtypes of RCC is even rarer and can present as two spatially separate, histologically distinct RCCs or a single discrete tumor composed of two types of RCC tumor components.

Many theories were proposed to explain the phenomenon of multiple yet different RCCs coexisting: the theory of cancer stem cells (CSCs) provides a potential explanation for the emergence of two or three dissimilar renal tumors [ 2 , 4 , 9 ]. Other hypotheses are the evolution of one subtype into another [ 2 ], as oncocytomas transforming into pRCC [ 13 ] , or the infiltration of an aggressive tumor into another tumor, as collecting duct carcinoma (CDC) infiltrating pRCC [ 4 ].

We constituted a thorough literature review of reports of cases with synchronous dissimilar RCC histologic subtypes in Table  1 . We believe that our case adds to the literature on the topic. Our patient is considered the 9th case presenting with the combination of ccRCC and ChRCC in the literature. We also discussed the authors’ approach to preoperative detection and differentiation, selection of operative technique, and postoperative follow-up problems in terms of difficulties in estimating prognosis and unclear follow-up outcomes in the literature.

Regarding differentiation using histological features under light microscopy, ccRCC is characterized by a solid to alveolar growth pattern with abundant vascular networks and occasional tubule formation, with cytoplasm of tumor cells varying from clear to eosinophilic granular. These findings were in accordance with those found in our ccRCC. ChRCC is identified by polygonal cells forming sheets and trabeculae with eosinophilic granular cytoplasm, with occasional irregular raisinoid nuclei, irregular nuclear membranes, and perinuclear halos, again consistent with our findings in the ChRCC. Furthermore, electron microscopy revealed the presence of numerous characteristic small cytoplasmic vesicles in the chromophobe areas [ 9 ].

In our case, the larger tumor was ChRCC and showed positive immunohistochemical staining for CK7 and CD117, while the smaller tumor was ccRCC and displayed negative immunohistochemical staining for both CK-7 and CD117. These results are in accordance with the reported immunohistochemical profile of both tumors in literature [ 14 , 15 ].

Preoperative knowledge of the coexistence of multiple RCC subtypes in the same kidney is important not only for planning the surgical approach, especially if nephron-sparing surgery is opted for, but also for postoperative determination of prognosis, since not all RCC subtypes are of similar aggressive tendencies, and applicability of possible neoadjuvant regimens.

Imaging, thus, is a cornerstone tool in our armamentarium to determine this coexistence. In a report by Capaccio et al ., ultrasound (US) was able to recognize the presence of multiple renal tumors in 1 of 5 cases versus CT in 4 of 5 cases [ 16 ]; the lower number of cases in which multiplicity of renal lesions is detected by the US may be explained by the lower sensitivity of US in detecting small renal nodules than that of CT [ 17 ] . Although CT has proven useful in detecting multifocal lesions, its ability to do so is limited. As a result, it is still relatively common to discover unsuspected multifocal disease during surgery. Capaccio et al . also concluded that different enhancement patterns on CT may enable the preoperative detection of tumors with different histology within the same kidney [ 16 ]; however, distinguishing different renal tumors on CT presents challenges, as the image is influenced not only by the main histologic type but also by factors such as the degree of differentiation, size, and presence of necrosis. Our MSCT successfully identified a multifocal neoplastic renal process, revealing two lesions: a 6.5 cm predominantly anterior endophytic upper polar lesion and a 1.3 cm exophytic lower polar lesion.

Treatment strategies for renal tumors vary based on the patient's overall condition, as well as tumor characteristics, including size, position, relationship, number, and aggressiveness [ 16 ]. In terms of aggressiveness, clear-cell renal cancers have the highest malignant potential and a 5-year survival rate of 50–60%, while papillary and chromophobe renal cell carcinomas are associated with lower metastatic potential and an overall 5-year survival of 80–90% [ 18 , 19 ].

While most literature favors radical nephrectomy for treating synchronous dissimilar coexisting RCCs, recent studies have shown that patients with sporadic single or multiple ipsilateral renal tumors may opt for nephron-sparing surgery, which yields comparable oncological results with low morbidity and recurrence rates [ 20 ]. Our patient underwent radical nephrectomy, with negative margins for both tumors and no invasion of the renal pedicle or Gerota's fascia.

Due to the relatively short follow-up periods (typically 3–6 months) in case reports of patients with multifocal synchronous RCC found in the literature, estimating prognosis can be challenging, with insufficient information about long-term outcomes [ 5 ]. The presence of multifocal pathology may increase the risk of recurrence for the patient [ 1 ]. Additionally, the various subtypes of renal tumors can influence disease-free survival after radical nephrectomy, making it difficult to assign patients to specific adjuvant therapy protocols when two separate and distinct carcinomas are present in a nephrectomy specimen [ 5 ]. Our patient showed no involvement of the renal arterial and venous pedicle, suprarenal glands, Gerota's fascia, or distant organs on preoperative imaging. In addition, her follow-up plan, consisting of a CT chest, abdomen, and pelvis and laboratory estimation of hemoglobin and serum creatinine levels every three months, was unremarkable. However, estimating the prognosis is still challenging due to the limited information on follow-up in the literature. In addition, our case was not assigned adjuvant chemotherapy or radiotherapy, reflecting the difficulty in selecting specific adjuvant regimens when multiple dissimilar RCCs coexist also reported in the literature [ 5 ].

Given the scarcity of reports, challenges in preoperative detection and differentiation, the possible intraoperative discovery of multifocality, and the dilemma in selecting appropriate adjuvant regimens for cases with multiple dissimilar RCCs, further research on this topic is urgently needed. This research should focus on enhancing preoperative detection and differentiation of multiple renal lesions, planning optimal operative techniques (radical or partial nephrectomy), selecting suitable adjuvant regimens, and reporting long-term follow-up outcomes. Since the management, prognosis, and long-term survival of different histological subtypes of RCC may be different, accurate recognition of the possible coexistence of these tumors is extremely critical and mandates multidisciplinary involvement, including meticulous preoperative imaging by radiologists and proper, thorough grossing of nephrectomy specimens by pathologists.

Availability of data and materials

Data included in the manuscript.

Abbreviations

Renal cell carcinoma

Clear cell renal cell carcinoma

Chromophobe renal cell carcinoma

Multi-slice computed tomography

Papillary renal cell carcinoma

Cancer stem cells

Collocting duct carcinoma

Delto J, Hussein SE, Fukuma B, Abello A, Alexis J, Mastrogiovanni L, et al . Multifocal synchronous chromophobe, papillary, and clear cell renal cell carcinoma in a single kidney. J Urol Surg. 2018;5:200–2.

Article   Google Scholar  

Tyritzis SI, Alexandrou PT, Migdalis V, Koritsiadis G, Anastasiou I. Synchronous chromophobe and papillary renal cell carcinoma. First report and review of the pathogenesis theories. Pathol Int. 2009;59:193–6.

Article   PubMed   Google Scholar  

Harlow BL, Klaassen Z, Holzman SA, Reinstatler L, Franken AA, Kavuri S, et al . Multiple discordant histology after nephrectomy: descriptive analysis and outcomes. Clin Genitourin Cancer. 2016;14:e171–5.

Arık D, Açıkalın M, Can C. Papillary renal cell carcinoma and collecting duct carcinoma combination. A case report and review of synchronous renal cell carcinoma subtypes in the same kidney. Arch Med Sci AMS. 2015;11:686–90.

Kang S, Ko Y, Kang S, Kim J, Kim C, Park H, et al . Two different renal cell carcinomas and multiple angiomyolipomas in a patient with tuberous sclerosis. Korean J Urol. 2010;51:729.

Article   PubMed   PubMed Central   Google Scholar  

Ceriotti F, Boyd JC, Klein G, Henny J, Queralto J, Kairisto V, et al . Reference intervals for serum creatinine concentrations: assessment of available data for global application. Clin Chem. 2008;54(3):559–66.

Article   CAS   PubMed   Google Scholar  

Turner J, Parsi M, Badireddy M. Anemia. StatPearls. Treasure Island (FL) ineligible companies. StatPearls Publishing. Copyright © 2023, StatPearls Publishing LLC.; 2023.

Parsons RB, Canter D, Kutikov A, Uzzo RG. RENAL nephrometry scoring system: the radiologist’s perspective. Am J Roentgenol. 2012;199(3):W355–9.

Roehrl MHA, Selig MK, Nielsen GP, Dal Cin P, Oliva E. A renal cell carcinoma with components of both chromophobe and papillary carcinoma. Virchows Arch. 2007;450:93–101.

Na K, Kim HS, Park YK, Chang SG, Kim YW. Multifocal renal cell carcinoma of different histological subtypes in autosomal dominant polycystic kidney disease. Korean J Pathol. 2012;46:382.

Li G, Cottier M, Sabido O, Gentil-Perret A, Lambert C, Genin C, et al . Different DNA Loidy patterns for the differentiation of common subtypes of renal tumors. Cell Oncol. 2005;27:51–6.

PubMed   PubMed Central   Google Scholar  

Yin G, Zheng S, Zhou C, Li Y. Concurrent angiomyolipoma and chromophobe renal cell carcinoma in the same kidney: a case report. Asian J Surg. 2023;46(5):2268–9.

Al-Saleem T, Balsara B, Liu Z, Feder M, Testa J, Wu H, et al . Renal oncocytoma with loss of chromosomes Y and 1 evolving to papillary carcinoma in connection with gain of chromosome 7. Coincidence or progression? Cancer Genet Cytogenet. 2005;163:81–5.

Zhao W, Tian B, Wu C, Peng Y, Wang H, Gu W-L, et al . DOG1, cyclin D1, CK7, CD117 and vimentin are useful immunohistochemical markers in distinguishing chromophobe renal cell carcinoma from clear cell renal cell carcinoma and renal oncocytoma. Pathol Res Pract. 2015;211(4):303–7.

Kim M, Joo JW, Lee SJ, Cho YA, Park CK, Cho NH. Comprehensive immunoprofiles of renal cell carcinoma subtypes. Cancers. 2020;12(3):602.

Article   CAS   PubMed   PubMed Central   Google Scholar  

Capaccio E, Varca V, Simonato A, Toncini C, Carmignani G, Derchi LE. Synchronous parenchymal renal tumors of different histology in the same kidney. Acta Radiol. 2009;50(10):1187–92.

Jamis-Dow C, Choyke P, Jennings SB, Linehan W, Thakore KN, Walther M. Small (< or = 3-cm) renal masses: detection with CT versus US and pathologic correlation. Radiology. 1996;198(3):785–8.

Cheville J, Lohse C, Zincke H, Weaver A, Blute M. Comparisons of outcome and prognostic features among histologic subtypes of renal cell carcinoma. Am J Surg Pathol. 2003;27:612–24.

Renshaw A, Henske E, Loughlin K, Shapiro C, Weinberg D. Aggressive variants of chromophobe renal cell carcinoma. Cancer. 1996;78:1756–61.

Krambeck AE, Iwaszko MR, Leibovich BC, Cheville JC, Frank I, Blute ML. Long-term outcome of multiple ipsilateral renal tumours found at the time of planned nephron-sparing surgery. BJUI. 2008;101:1375–9.

Kuroda N, Shiotsu T, Kawada C, Shuin T, Hes O, Michal M, et al . Clear cell papillary renal cell carcinoma and clear cell renal cell carcinoma arising in acquired cystic disease of the kidney: an immunohistochemical and genetic study. Ann Diagn Pathol. 2011;15:282–5.

Lee T, Kim W, Lee S, Kang K, Jeong Y, Kang M, et al . Double synchronous primary renal cell carcinoma with different histotypes. Clin Nephrol. 2010;74:164–5.

Jun S-Y, Cho K-J, Kim C-S, Ayala AG, Ro JY. Triple synchronous neoplasms in one kidney: report of a case and review of the literature. Ann Diagn Pathol. 2003;7:374–80.

Auguet T, Molina JC, Lorenzo A, Vila J, Sirvent JJ, Richart C. Synchronus renal cell carcinoma and Bellini duct carcinoma: a case report on a rare coincidence. World J Urol. 2000;18:449–51.

Daniel L, Zattara-Cannoni H, Lechevallier E, Pellissier J. Association of a renal papillary carcinoma with a low grade tumour of the collecting ducts. J Clin Pathol. 2001;54(8):637–9.

Gong Y, Sun X, Haines GK III, Pins MR. Renal cell carcinoma, chromophobe type, with collecting duct carcinoma and sarcomatoid components. Arch Pathol Lab Med. 2003;127(1):e38–40.

Lindgren V, Paner GP, Flanigan RC, Clark JI, Campbell SC, Picken MM. Renal tumor with overlapping distal nephron morphology and karyotype. Arch Pathol Lab Med. 2004;128(11):1274–8.

Cho N, Kim S, Ha M, Kim HJ. Simultaneous heterogenotypic renal cell carcinoma: immunohistochemical and karyoptic analysis by comparative genomic hybridization. Urol Int. 2004;72(4):344–8.

Matei D-V, Rocco B, Varela R, Verweij F, Scardino E, Renne G, et al . Synchronous collecting duct carcinoma and papillary renal cell carcinoma: a case report and review of the literature. Anticancer Res. 2005;25(1B):579–86.

PubMed   Google Scholar  

Kawano N, Inayama Y, Nakaigawa N, Yao M, Ogawa T, Aoki I, et al . Composite distal nephron-derived renal cell carcinoma with chromophobe and collecting duct carcinomatous elements. Pathol Int. 2005;55:360–5.

Tsai T-H, Tang S-H, Chuang F-P, Wu S-T, Sun G-H, Yu D-S, et al . Ipsilateral synchronous neoplasms of kidney presenting as acute pyelonephritis and bladder metastasis. Urology. 2009;73(5):1163.e9-e11.

Quiroga-Garza G, Piña-Oviedo S, Cuevas-Ocampo K, Goldfarb R, Schwartz MR, Ayala AG, et al . Synchronous clear cell renal cell carcinoma and tubulocystic carcinoma: genetic evidence of independent ontogenesis and implications of chromosomal imbalances in tumor progression. Diagn Pathol. 2012;7(1):1–7.

Esposito M, Varca V, Simonato A, Toncini C, Carmignani G, Derchi L. Coexistence of different histotypes of renal carcinoma: our experience and literature review. Rivista Urol. 2009;76:130–2.

CAS   Google Scholar  

Download references

Acknowledgements

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author information

Authors and affiliations.

Faculty of Medicine, Alexandria University, Champollion Street, Alexandria, Egypt

Mohamed Sakr, Merhan Badran, Sarah Ahmed Hassan, Mohamed Elsaqa, Mohamed Anwar Elwany, Nevine M. F. El Deeb & Mohamed Sharafeldeen

You can also search for this author in PubMed   Google Scholar

Contributions

MS and MB shared in the conception and design of the work, data acquisition and analysis, drafting and revising the manuscript, and literature review. NMFE and SAH performed the pathological investigation of the kidney. ME and MS shared in the conception, design of the work, data acquisition, and supervision. MAE interpreted data and revised the manuscript. All authors approved the final version of the manuscript.

Corresponding author

Correspondence to Merhan Badran .

Ethics declarations

Ethics approval and consent to participate.

The ethical research board committee of Alexandria Main University Hospital waived the ethical approval for reporting this case. Written informed consent was provided by our patient for medical care, research, and publishing. The patient is not identified. This case was carried out in accordance with the Helsinki Declaration contents.

Consent for publication

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Competing interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Additional information

Publisher's note.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ . The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/ ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Cite this article.

Sakr, M., Badran, M., Hassan, S.A. et al. Detection of two synchronous histologically different renal cell carcinoma subtypes in the same kidney: a case report and review of the literature. J Med Case Reports 18 , 250 (2024). https://doi.org/10.1186/s13256-024-04527-x

Download citation

Received : 25 December 2023

Accepted : 27 March 2024

Published : 18 May 2024

DOI : https://doi.org/10.1186/s13256-024-04527-x

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

• Clear cell renal cell carcinoma (ccRCC)
• Chromophobe renal cell carcinoma (ChRCC)
• Synchronous renal cell carcinoma
• Different histology

Journal of Medical Case Reports

ISSN: 1752-1947

• Submission enquiries: Access here and click Contact Us
• General enquiries: [email protected]

An official website of the United States government

The .gov means it's official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you're on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

• Publications
• Account settings
• Browse Titles

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

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.

• Ammenwerth E., de Keizer N. An inventory of evaluation studies of information technology in health care. Trends in evaluation research, 1982-2002. International Journal of Medical Informatics. 2004; 44 (1):44–56. [ PubMed : 15778794 ]
• Anderson S., Allen P., Peckham S., Goodwin N. Asking the right questions: scoping studies in the commissioning of research on the organisation and delivery of health services. Health Research Policy and Systems. 2008; 6 (7):1–12. [ PMC free article : PMC2500008 ] [ PubMed : 18613961 ] [ CrossRef ]
• Archer N., Fevrier-Thomas U., Lokker C., McKibbon K. A., Straus S.E. Personal health records: a scoping review. Journal of American Medical Informatics Association. 2011; 18 (4):515–522. [ PMC free article : PMC3128401 ] [ PubMed : 21672914 ]
• Arksey H., O’Malley L. Scoping studies: towards a methodological framework. International Journal of Social Research Methodology. 2005; 8 (1):19–32.
• A systematic, tool-supported method for conducting literature reviews in information systems. Paper presented at the Proceedings of the 19th European Conference on Information Systems ( ecis 2011); June 9 to 11; Helsinki, Finland. 2011.
• Baumeister R. F., Leary M.R. Writing narrative literature reviews. Review of General Psychology. 1997; 1 (3):311–320.
• Becker L. A., Oxman A.D. In: Cochrane handbook for systematic reviews of interventions. Higgins J. P. T., Green S., editors. Hoboken, nj : John Wiley & Sons, Ltd; 2008. Overviews of reviews; pp. 607–631.
• Borenstein M., Hedges L., Higgins J., Rothstein H. Introduction to meta-analysis. Hoboken, nj : John Wiley & Sons Inc; 2009.
• Cook D. J., Mulrow C. D., Haynes B. Systematic reviews: Synthesis of best evidence for clinical decisions. Annals of Internal Medicine. 1997; 126 (5):376–380. [ PubMed : 9054282 ]
• Cooper H., Hedges L.V. In: The handbook of research synthesis and meta-analysis. 2nd ed. Cooper H., Hedges L. V., Valentine J. C., editors. New York: Russell Sage Foundation; 2009. Research synthesis as a scientific process; pp. 3–17.
• Cooper H. M. Organizing knowledge syntheses: A taxonomy of literature reviews. Knowledge in Society. 1988; 1 (1):104–126.
• Cronin P., Ryan F., Coughlan M. Undertaking a literature review: a step-by-step approach. British Journal of Nursing. 2008; 17 (1):38–43. [ PubMed : 18399395 ]
• Darlow S., Wen K.Y. Development testing of mobile health interventions for cancer patient self-management: A review. Health Informatics Journal. 2015 (online before print). [ PubMed : 25916831 ] [ CrossRef ]
• Daudt H. M., van Mossel C., Scott S.J. Enhancing the scoping study methodology: a large, inter-professional team’s experience with Arksey and O’Malley’s framework. bmc Medical Research Methodology. 2013; 13 :48. [ PMC free article : PMC3614526 ] [ PubMed : 23522333 ] [ CrossRef ]
• Davies P. The relevance of systematic reviews to educational policy and practice. Oxford Review of Education. 2000; 26 (3-4):365–378.
• Deeks J. J., Higgins J. P. T., Altman D.G. In: Cochrane handbook for systematic reviews of interventions. Higgins J. P. T., Green S., editors. Hoboken, nj : John Wiley & Sons, Ltd; 2008. Analysing data and undertaking meta-analyses; pp. 243–296.
• Deshazo J. P., Lavallie D. L., Wolf F.M. Publication trends in the medical informatics literature: 20 years of “Medical Informatics” in mesh . bmc Medical Informatics and Decision Making. 2009; 9 :7. [ PMC free article : PMC2652453 ] [ PubMed : 19159472 ] [ CrossRef ]
• Dixon-Woods M., Agarwal S., Jones D., Young B., Sutton A. Synthesising qualitative and quantitative evidence: a review of possible methods. Journal of Health Services Research and Policy. 2005; 10 (1):45–53. [ PubMed : 15667704 ]
• Finfgeld-Connett D., Johnson E.D. Literature search strategies for conducting knowledge-building and theory-generating qualitative systematic reviews. Journal of Advanced Nursing. 2013; 69 (1):194–204. [ PMC free article : PMC3424349 ] [ PubMed : 22591030 ]
• Grady B., Myers K. M., Nelson E. L., Belz N., Bennett L., Carnahan L. … Guidelines Working Group. Evidence-based practice for telemental health. Telemedicine Journal and E Health. 2011; 17 (2):131–148. [ PubMed : 21385026 ]
• Green B. N., Johnson C. D., Adams A. Writing narrative literature reviews for peer-reviewed journals: secrets of the trade. Journal of Chiropractic Medicine. 2006; 5 (3):101–117. [ PMC free article : PMC2647067 ] [ PubMed : 19674681 ]
• Greenhalgh T., Wong G., Westhorp G., Pawson R. Protocol–realist and meta-narrative evidence synthesis: evolving standards ( rameses ). bmc Medical Research Methodology. 2011; 11 :115. [ PMC free article : PMC3173389 ] [ PubMed : 21843376 ]
• Gurol-Urganci I., de Jongh T., Vodopivec-Jamsek V., Atun R., Car J. Mobile phone messaging reminders for attendance at healthcare appointments. Cochrane Database System Review. 2013; 12 cd 007458. [ PMC free article : PMC6485985 ] [ PubMed : 24310741 ] [ CrossRef ]
• Hart C. Doing a literature review: Releasing the social science research imagination. London: SAGE Publications; 1998.
• Higgins J. P. T., Green S., editors. Cochrane handbook for systematic reviews of interventions: Cochrane book series. Hoboken, nj : Wiley-Blackwell; 2008.
• Jesson J., Matheson L., Lacey F.M. Doing your literature review: traditional and systematic techniques. Los Angeles & London: SAGE Publications; 2011.
• King W. R., He J. Understanding the role and methods of meta-analysis in IS research. Communications of the Association for Information Systems. 2005; 16 :1.
• Kirkevold M. Integrative nursing research — an important strategy to further the development of nursing science and nursing practice. Journal of Advanced Nursing. 1997; 25 (5):977–984. [ PubMed : 9147203 ]
• Kitchenham B., Charters S. ebse Technical Report Version 2.3. Keele & Durham. uk : Keele University & University of Durham; 2007. Guidelines for performing systematic literature reviews in software engineering.
• Kitsiou S., Paré G., Jaana M. Systematic reviews and meta-analyses of home telemonitoring interventions for patients with chronic diseases: a critical assessment of their methodological quality. Journal of Medical Internet Research. 2013; 15 (7):e150. [ PMC free article : PMC3785977 ] [ PubMed : 23880072 ]
• Kitsiou S., Paré G., Jaana M. Effects of home telemonitoring interventions on patients with chronic heart failure: an overview of systematic reviews. Journal of Medical Internet Research. 2015; 17 (3):e63. [ PMC free article : PMC4376138 ] [ PubMed : 25768664 ]
• Levac D., Colquhoun H., O’Brien K. K. Scoping studies: advancing the methodology. Implementation Science. 2010; 5 (1):69. [ PMC free article : PMC2954944 ] [ PubMed : 20854677 ]
• Levy Y., Ellis T.J. A systems approach to conduct an effective literature review in support of information systems research. Informing Science. 2006; 9 :181–211.
• Liberati A., Altman D. G., Tetzlaff J., Mulrow C., Gøtzsche P. C., Ioannidis J. P. A. et al. Moher D. The prisma statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: Explanation and elaboration. Annals of Internal Medicine. 2009; 151 (4):W-65. [ PubMed : 19622512 ]
• Lyden J. R., Zickmund S. L., Bhargava T. D., Bryce C. L., Conroy M. B., Fischer G. S. et al. McTigue K. M. Implementing health information technology in a patient-centered manner: Patient experiences with an online evidence-based lifestyle intervention. Journal for Healthcare Quality. 2013; 35 (5):47–57. [ PubMed : 24004039 ]
• Mickan S., Atherton H., Roberts N. W., Heneghan C., Tilson J.K. Use of handheld computers in clinical practice: a systematic review. bmc Medical Informatics and Decision Making. 2014; 14 :56. [ PMC free article : PMC4099138 ] [ PubMed : 24998515 ]
• Moher D. The problem of duplicate systematic reviews. British Medical Journal. 2013; 347 (5040) [ PubMed : 23945367 ] [ CrossRef ]
• Montori V. M., Wilczynski N. L., Morgan D., Haynes R. B., Hedges T. Systematic reviews: a cross-sectional study of location and citation counts. bmc Medicine. 2003; 1 :2. [ PMC free article : PMC281591 ] [ PubMed : 14633274 ]
• Mulrow C. D. The medical review article: state of the science. Annals of Internal Medicine. 1987; 106 (3):485–488. [ PubMed : 3813259 ] [ CrossRef ]
• Evidence-based information systems: A decade later. Proceedings of the European Conference on Information Systems ; 2011. Retrieved from http://aisel ​.aisnet.org/cgi/viewcontent ​.cgi?article ​=1221&context ​=ecis2011 .
• Okoli C., Schabram K. A guide to conducting a systematic literature review of information systems research. ssrn Electronic Journal. 2010
• Otte-Trojel T., de Bont A., Rundall T. G., van de Klundert J. How outcomes are achieved through patient portals: a realist review. Journal of American Medical Informatics Association. 2014; 21 (4):751–757. [ PMC free article : PMC4078283 ] [ PubMed : 24503882 ]
• Paré G., Trudel M.-C., Jaana M., Kitsiou S. Synthesizing information systems knowledge: A typology of literature reviews. Information & Management. 2015; 52 (2):183–199.
• Patsopoulos N. A., Analatos A. A., Ioannidis J.P. A. Relative citation impact of various study designs in the health sciences. Journal of the American Medical Association. 2005; 293 (19):2362–2366. [ PubMed : 15900006 ]
• Paul M. M., Greene C. M., Newton-Dame R., Thorpe L. E., Perlman S. E., McVeigh K. H., Gourevitch M.N. The state of population health surveillance using electronic health records: A narrative review. Population Health Management. 2015; 18 (3):209–216. [ PubMed : 25608033 ]
• Pawson R. Evidence-based policy: a realist perspective. London: SAGE Publications; 2006.
• Pawson R., Greenhalgh T., Harvey G., Walshe K. Realist review—a new method of systematic review designed for complex policy interventions. Journal of Health Services Research & Policy. 2005; 10 (Suppl 1):21–34. [ PubMed : 16053581 ]
• Petersen K., Vakkalanka S., Kuzniarz L. Guidelines for conducting systematic mapping studies in software engineering: An update. Information and Software Technology. 2015; 64 :1–18.
• Petticrew M., Roberts H. Systematic reviews in the social sciences: A practical guide. Malden, ma : Blackwell Publishing Co; 2006.
• Rousseau D. M., Manning J., Denyer D. Evidence in management and organizational science: Assembling the field’s full weight of scientific knowledge through syntheses. The Academy of Management Annals. 2008; 2 (1):475–515.
• Rowe F. What literature review is not: diversity, boundaries and recommendations. European Journal of Information Systems. 2014; 23 (3):241–255.
• Shea B. J., Hamel C., Wells G. A., Bouter L. M., Kristjansson E., Grimshaw J. et al. Boers M. amstar is a reliable and valid measurement tool to assess the methodological quality of systematic reviews. Journal of Clinical Epidemiology. 2009; 62 (10):1013–1020. [ PubMed : 19230606 ]
• Shepperd S., Lewin S., Straus S., Clarke M., Eccles M. P., Fitzpatrick R. et al. Sheikh A. Can we systematically review studies that evaluate complex interventions? PLoS Medicine. 2009; 6 (8):e1000086. [ PMC free article : PMC2717209 ] [ PubMed : 19668360 ]
• Silva B. M., Rodrigues J. J., de la Torre Díez I., López-Coronado M., Saleem K. Mobile-health: A review of current state in 2015. Journal of Biomedical Informatics. 2015; 56 :265–272. [ PubMed : 26071682 ]
• Smith V., Devane D., Begley C., Clarke M. Methodology in conducting a systematic review of systematic reviews of healthcare interventions. bmc Medical Research Methodology. 2011; 11 (1):15. [ PMC free article : PMC3039637 ] [ PubMed : 21291558 ]
• Sylvester A., Tate M., Johnstone D. Beyond synthesis: re-presenting heterogeneous research literature. Behaviour & Information Technology. 2013; 32 (12):1199–1215.
• Templier M., Paré G. A framework for guiding and evaluating literature reviews. Communications of the Association for Information Systems. 2015; 37 (6):112–137.
• Thomas J., Harden A. Methods for the thematic synthesis of qualitative research in systematic reviews. bmc Medical Research Methodology. 2008; 8 (1):45. [ PMC free article : PMC2478656 ] [ PubMed : 18616818 ]
• Reconstructing the giant: on the importance of rigour in documenting the literature search process. Paper presented at the Proceedings of the 17th European Conference on Information Systems ( ecis 2009); Verona, Italy. 2009.
• Webster J., Watson R.T. Analyzing the past to prepare for the future: Writing a literature review. Management Information Systems Quarterly. 2002; 26 (2):11.
• Whitlock E. P., Lin J. S., Chou R., Shekelle P., Robinson K.A. Using existing systematic reviews in complex systematic reviews. Annals of Internal Medicine. 2008; 148 (10):776–782. [ PubMed : 18490690 ]

This publication is licensed under a Creative Commons License, Attribution-Noncommercial 4.0 International License (CC BY-NC 4.0): see https://creativecommons.org/licenses/by-nc/4.0/

• 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.
• PDF version of this title (4.5M)
• Disable Glossary Links

In this Page

• Introduction
• Overview of the Literature Review Process and Steps
• Types of Review Articles and Brief Illustrations
• Concluding Remarks

Related information

• PMC PubMed Central citations
• PubMed Links to PubMed

Recent Activity

• Chapter 9 Methods for Literature Reviews - Handbook of eHealth Evaluation: An Ev... Chapter 9 Methods for Literature Reviews - Handbook of eHealth Evaluation: An Evidence-based Approach

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Connect with NLM

National Library of Medicine 8600 Rockville Pike Bethesda, MD 20894

Web Policies FOIA HHS Vulnerability Disclosure

Help Accessibility Careers

To read this content please select one of the options below:

Please note you do not have access to teaching notes, unlocking the potential of industry 4.0 in brics nations: a systematic literature review and meta-analysis.

International Journal of Quality & Reliability Management

ISSN : 0265-671X

Article publication date: 17 May 2024

This study is intended to introduce and summarise Industry 4.0 practices in BRICS nations (the abbreviation “BRICS” is made up of the first letters of the member countries: Brazil, Russia, India, China and South Africa) and determine each nation’s current contribution to Industry 4.0 practice implementation based on past literature. As the BRICS countries continue to play an essential role in the global economy, it is significant to understand Industry 4.0, focussing on these emerging economies.

Design/methodology/approach

To assess the present research work on Industry 4.0 practices and research studies in BRICS nations, a systematic literature review (SLR) is performed using the articles available on the SCOPUS database. This study is a descriptive analysis based on the frequency and year of publications, the most influential universities, most influential journals and most influential articles. Similarly, this study consists of category analysis based on multi-criteria decision-making (MCDM) methods, research design used, research method utilised, different data analysis techniques and different Industry 4.0 technologies were used to solve different applications in the BRICS nations.

According to the analysis of past literature, the primary identified practices are centred on operations productivity, waste management, energy reduction and sustainable processes. It also found that despite the abundance of research on Industry 4.0, the major academic journal publications are restricted to a small number of industries and issues in which the manufacturing and automotive industries are front runners. The categorisation of selected papers based on the year of publication demonstrates that the number of publications has been rising. It is also found that China and India, out of the BRICS countries, have contributed significantly to Industry 4.0-related publications by contributing 61 percent of the total articles identified. Similarly, this study identified that qualitative research design is the most adopted framework for research, and empirical triangulation is the least adopted framework in this field. The categorisation of selected articles facilitates the identification of numerous gaps, such as that 67.14% of the literature research is qualitative.

Practical implications

Understanding Industry 4.0 in the BRICS nations helps to identify opportunities for international collaboration and future cooperation possibilities. This study helps to promote collaboration between BRICS countries and other nations, organisations or businesses interested in capitalising on these growing economies' assets and capabilities related to Industry 4.0 technologies. This study helps to provide essential insights into the economic, technological and societal impacts, allowing for effective decision-making and strategic planning for a sustainable and competitive future. So, this contribution links the entire world in terms of the better utilisation of resources, the reduction of downtime, improving product quality, personalised products and the development of human resource capabilities through the application of cutting-edge technologies for nearly half of the world’s population.

Originality/value

In this study, BRICS nations are selected due to their significant impact on the world regarding social, economic and environmental contributions. In the current review, 423 articles published up to August 2022 were selected from the SCOPUS database. The comparison analysis of each BRICS nation in the form of applications of Industry 4.0, the primary area of focus, leading industry working, industry involvement with universities and the area that needs attention are discussed. To the best of our knowledge, this is the most recent SLR and meta-analysis study about Industry 4.0 in BRICS nations, which analysed the past available literature in nine different descriptive and category-wise classifications, considering a total of 423 articles. Based on this SLR, this study makes some important recommendations and future directions that will help achieve social, economic and environmental sustainability in BRICS nations.

• Industry 4.0
• BRICS nations
• Emerging economies
• Competitive advantages
• Literature review
• Meta-analysis

Yadav, A. , Yadav, G. and Desai, T.N. (2024), "Unlocking the potential of Industry 4.0 in BRICS nations: a systematic literature review and meta-analysis", International Journal of Quality & Reliability Management , Vol. ahead-of-print No. ahead-of-print. https://doi.org/10.1108/IJQRM-06-2023-0180

Emerald Publishing Limited

Copyright © 2024, Emerald Publishing Limited

Related articles

We’re listening — tell us what you think, something didn’t work….

Report bugs here

All feedback is valuable

Please share your general feedback

Join us on our journey

Platform update page.

Visit emeraldpublishing.com/platformupdate to discover the latest news and updates

Questions & More Information

Answers to the most commonly asked questions here

• Open access
• Published: 14 May 2024

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

30 Accesses

Metrics details

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.

Balaban B, Brison D, Calderon G, Catt J, Conaghan J, Cowan L, et al. The Istanbul consensus workshop on embryo assessment: proceedings of an expert meeting. Hum Reprod. 2011;26:1270–83.

Article   Google Scholar  

Hill GA, Freeman M, Bastias MC, Jane Rogers B, Herbert CM, Osteen KG, et al. The influence of oocyte maturity and embryo quality on pregnancy rate in a program for in vitro fertilization-embryo transfer. Fertil Steril. 1989;52:801–6.

Article   CAS   PubMed   Google Scholar  

Cummins JM, Breen TM, Harrison KL, Shaw JM, Wilson LM, Hennessey JF. A formula for scoring human embryo growth rates in in vitro fertilization: Its value in predicting pregnancy and in comparison with visual estimates of embryo quality. J In Vitro Fertil Embryo Transfer. 1986;3:284–95.

Article   CAS   Google Scholar  

Cutting R, Morroll D, Roberts SA, Pickering S, Rutherford A, on behalf of the BFS and ACE. Elective Single Embryo Transfer: Guidelines for Practice British Fertility Society and Association of Clinical Embryologists. Hum Fertil. 2008;11:131–46.

Edwards RG, Fishel SB, Cohen J, Fehilly CB, Purdy JM, Slater JM, et al. Factors influencing the success of in vitro fertilization for alleviating human infertility. J In Vitro Fert Embryo Transf. 1984;1:3–23.

Puissant F, Van Rysselberge M, Barlow P, Deweze J, Leroy F. Embryo scoring as a prognostic tool in IVF treatment. Hum Reprod. 1987;2:705–8.

Alikani M, Cohen J, Tomkin G, Garrisi GJ, Mack C, Scott RT. Human embryo fragmentation in vitro and its implications for pregnancy and implantation. Fertil Steril. 1999;71:836–42.

Cecchele A, Cermisoni GC, Giacomini E, Pinna M, Vigano P. Cellular and Molecular Nature of Fragmentation of Human Embryos. Int J Mol Sci. 2022;23:1349.

Article   CAS   PubMed   PubMed Central   Google Scholar  

Claman P, Armant DR, Seibel MM, Wang TA, Oskowitz SP, Taymor ML. The impact of embryo quality and quantity on implantation and the establishment of viable pregnancies. J In Vitro Fert Embryo Transf. 1987;4:218–22.

Ebner T, Yaman C, Moser M, Sommergruber M, Pölz W, Tews G. Embryo fragmentation in vitro and its impact on treatment and pregnancy outcome. Fertil Steril. 2001;76:281–5.

Erenus M, Zouves C, Rajamahendran P, Leung S, Fluker M, Gomel V. The effect of embryo quality on subsequent pregnancy rates after in vitro fertilization. Fertil Steril. 1991;56:707–10.

Giorgetti C, Terriou P, Auquier P, Hans E, Spach JL, Salzmann J, et al. Embryo score to predict implantation after in-vitro fertilization: based on 957 single embryo transfers. Hum Reprod. 1995;10:2427–31.

Holte J, Berglund L, Milton K, Garello C, Gennarelli G, Revelli A, et al. Construction of an evidence-based integrated morphology cleavage embryo score for implantation potential of embryos scored and transferred on day 2 after oocyte retrieval. Hum Reprod. 2007;22:548–57.

Roseboom TJ, Vermeiden JP, Schoute E, Lens JW, Schats R. The probability of pregnancy after embryo transfer is affected by the age of the patient, cause of infertility, number of embryos transferred and the average morphology score, as revealed by multiple logistic regression analysis. Hum Reprod. 1995;10:3035–41.

Shulman A, Ben-Nun I, Ghetler Y, Kaneti H, Shilon M, Beyth Y. Relationship between embryo morphology and implantation rate after in vitro fertilization treatment in conception cycles. Fertil Steril. 1993;60:123–6.

Staessen C, Janssenswillen C, Van den Abbeel E, Devroey P, Van Steirteghem AC. Avoidance of triplet pregnancies by elective transfer of two good quality embryos. Hum Reprod. 1993;8:1650–3.

Visser DS, Fourie FR. The applicability of the cumulative embryo score system for embryo selection and quality control in an in-vitro fertilization/embryo transfer programme. Hum Reprod. 1993;8:1719–22.

Volpes A, Sammartano F, Coffaro F, Mistretta V, Scaglione P, Allegra A. Number of good quality embryos on day 3 is predictive for both pregnancy and implantation rates in in vitro fertilization/intracytoplasmic sperm injection cycles. Fertil Steril. 2004;82:1330–6.

Article   PubMed   Google Scholar  

Ziebe S, Petersen K, Lindenberg S, Andersen AG, Gabrielsen A, Andersen AN. Embryo morphology or cleavage stage: how to select the best embryos for transfer after in-vitro fertilization. Hum Reprod. 1997;12:1545–9.

Fujimoto VY, Browne RW, Bloom MS, Sakkas D, Alikani M. Pathogenesis, developmental consequences, and clinical correlations of human embryo fragmentation. Fertil Steril. 2011;95:1197–204.

Chi H-J, Koo J-J, Choi S-Y, Jeong H-J, Roh S-I. Fragmentation of embryos is associated with both necrosis and apoptosis. Fertil Steril. 2011;96:187–92.

Racowsky C, Ohno-Machado L, Kim J, Biggers JD. Is there an advantage in scoring early embryos on more than one day? Hum Reprod. 2009;24:2104–13.

Article   PubMed   PubMed Central   Google Scholar  

Hardy K, Stark J, Winston RML. Maintenance of the inner cell mass in human blastocysts from fragmented embryos. Biol Reprod. 2003;68:1165–9.

Antczak M, Van Blerkom J. Temporal and spatial aspects of fragmentation in early human embryos: possible effects on developmental competence and association with the differential elimination of regulatory proteins from polarized domains. Hum Reprod. 1999;14:429–47.

Mio Y, Maeda K. Time-lapse cinematography of dynamic changes occurring during in vitro development of human embryos. Am J Obstet Gynecol. 2008;199(660):e1-5.

Google Scholar  

Hardarson T, Löfman C, Coull G, Sjögren A, Hamberger L, Edwards RG. Internalization of cellular fragments in a human embryo: time-lapse recordings. Reprod Biomed Online. 2002;5:36–8.

Van Blerkom J. The Enigma of Fragmentation in Early Human Embryos: Possible Causes and Clinical Relevance. Essential IVF. Boston: Springer US; 2004. 377–421.

Rijnders PM, Jansen CA. The predictive value of day 3 embryo morphology regarding blastocyst formation, pregnancy and implantation rate after day 5 transfer following in-vitro fertilization or intracytoplasmic sperm injection. Hum Reprod. 1998;13:2869–73.

Graham J, Han T, Porter R, Levy M, Stillman R, Tucker MJ. Day 3 morphology is a poor predictor of blastocyst quality in extended culture. Fertil Steril. 2000;74:495–7.

Milki AA, Hinckley MD, Gebhardt J, Dasig D, Westphal LM, Behr B. Accuracy of day 3 criteria for selecting the best embryos. Fertil Steril. 2002;77:1191–5.

Gardner DK, Vella P, Lane M, Wagley L, Schlenker T, Schoolcraft WB. Culture and transfer of human blastocysts increases implantation rates and reduces the need for multiple embryo transfers. Fertil Steril. 1998;69:84–8.

Guerif F, Le Gouge A, Giraudeau B, Poindron J, Bidault R, Gasnier O, et al. Limited value of morphological assessment at days 1 and 2 to predict blastocyst development potential: a prospective study based on 4042 embryos. Hum Reprod. 2007;22:1973–81.

Rienzi L, Ubaldi F, Iacobelli M, Romano S, Minasi MG, Ferrero S, et al. Significance of morphological attributes of the early embryo. Reprod Biomed Online. 2005;10:669–81.

Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71.

Killeen ID, Moore NW. The morphological appearance and development of sheep ova fertilized by surgical insemination. J Reprod Fertil. 1971;24:63–70.

Enders AC, Hendrickx AG, Binkerd PE. Abnormal development of blastocysts and blastomeres in the rhesus monkey. Biol Reprod. 1982;26:353–66.

Meseguer M, Martínez-Conejero JA, O’Connor JE, Pellicer A, Remohí J, Garrido N. The significance of sperm DNA oxidation in embryo development and reproductive outcome in an oocyte donation program: a new model to study a male infertility prognostic factor. Fertil Steril. 2008;89:1191–9.

Stensen MH, Tanbo TG, Storeng R, Åbyholm T, Fedorcsak P. Fragmentation of human cleavage-stage embryos is related to the progression through meiotic and mitotic cell cycles. Fertil Steril. 2015;103:374-81.e4.

Ebner T. First polar body morphology and blastocyst formation rate in ICSI patients. Human Reproduction. 2002;17:2415–8.

Sedó CA, Bilinski M, Lorenzi D, Uriondo H, Noblía F, Longobucco V, et al. Effect of sperm DNA fragmentation on embryo development: clinical and biological aspects. JBRA Assist Reprod. 2017;21:343–50.

PubMed Central   Google Scholar  

Rose BI, Laky D. Polar body fragmentation in IVM oocytes is associated with impaired fertilization and embryo development. J Assist Reprod Genet. 2013;30:679–82.

Zhou W, Fu L, Sha W, Chu D, Li Y. Relationship of polar bodies morphology to embryo quality and pregnancy outcome. Zygote. 2016;24:401–7.

Yang Y, Tan W, Chen C, Jin L, Huang B. Correlation of the position and status of the polar body from the fertilized oocyte to the euploid status of blastocysts. Front Genet. 2022;13:1006870. https://doi.org/10.3389/fgene.2022.1006870 .

Alikani M. Epithelial cadherin distribution in abnormal human pre-implantation embryos. Hum Reprod. 2005;20:3369–75.

Van Blerkom J, Davis P, Alexander S. Differential mitochondrial distribution in human pronuclear embryos leads to disproportionate inheritance between blastomeres: relationship to microtubular organization ATP content and competence. Hum Reprod. 2000;15:2621–33.

Otasevic V, Surlan L, Vucetic M, Tulic I, Buzadzic B, Stancic A, et al. Expression patterns of mitochondrial OXPHOS components, mitofusin 1 and dynamin-related protein 1 are associated with human embryo fragmentation. Reprod Fertil Dev. 2016;28:319–27.

Wilding M, Dale B, Marino M, di Matteo L, Alviggi C, Pisaturo ML, et al. Mitochondrial aggregation patterns and activity in human oocytes and preimplantation embryos. Hum Reprod. 2001;16:909–17.

Sermondade N, Delarouzière V, Ravel C, Berthaut I, Verstraete L, Mathieu E, et al. Characterization of a recurrent poor-quality embryo morphology phenotype and zygote transfer as a rescue strategy. Reprod Biomed Online. 2012;24:403–9.

Gat I, Levron J, Yerushalmi G, Dor J, Brengauz M, Orvieto R. Should zygote intrafallopian transfer be offered to all patients with unexplained repeated in-vitro fertilization cycle failures? J Ovarian Res. 2014;7:7.

Yang HW, Hwang KJ, Kwon HC, Kim HS, Choi KW, Oh KS. Detection of reactive oxygen species (ROS) and apoptosis in human fragmented embryos. Hum Reprod. 1998;13:998–1002.

Chen EY, Fujinaga M, Giaccia AJ. Hypoxic microenvironment within an embryo induces apoptosis and is essential for proper morphological development. Teratology. 1999;60:215–25.

Lee T-H, Lee M-S, Liu C-H, Tsao H-M, Huang C-C, Yang Y-S. The association between microenvironmental reactive oxygen species and embryo development in assisted reproduction technology cycles. Reprod Sci. 2012;19:725–32.

Lan K-C, Lin Y-C, Chang Y-C, Lin H-J, Tsai Y-R, Kang H-Y. Limited relationships between reactive oxygen species levels in culture media and zygote and embryo development. J Assist Reprod Genet. 2019;36:325–34.

Bedaiwy MA, Falcone T, Mohamed MS, Aleem AAN, Sharma RK, Worley SE, et al. Differential growth of human embryos in vitro: Role of reactive oxygen species. Fertil Steril. 2004;82:593–600.

Pellestor F, Girardet A, Andréo B, Arnal F, Humeau C. Relationship between morphology and chromosomal constitution in human preimplantation embryo. Mol Reprod Dev. 1994;39:141–6.

Chavez SL, Loewke KE, Han J, Moussavi F, Colls P, Munne S, et al. Dynamic blastomere behaviour reflects human embryo ploidy by the four-cell stage. Nat Commun. 2012;3:1251.

Munné S, Alikani M, Tomkin G, Grifo J, Cohen J. Embryo morphology, developmental rates, and maternal age are correlated with chromosome abnormalities. Fertil Steril. 1995;64(2):382–91. Corrected and republished in: Fertil Steril. 2019 Oct;112(4 Suppl1):e71–e80.

Halvaei I, Khalili MA, Nottola SA. A novel method for transmission electron microscopy study of cytoplasmic fragments from preimplantation human embryos. Microsc Res Tech. 2016;79:459–62.

Johansson M, Hardarson T, Lundin K. There is a cutoff limit in diameter between a blastomere and a small anucleate fragment. J Assist Reprod Genet. 2003;20:309–13.

Jurisicova A, Varmuza S, Casper RF. Programmed cell death and human embryo fragmentation. Mol Hum Reprod. 1996;2:93–8.

Liu HC, He ZY, Mele CA, Veeck LL, Davis O, Rosenwaks Z. Expression of apoptosis-related genes in human oocytes and embryos. J Assist Reprod Genet. 2000;17:521–33.

Levy R, Benchaib M, Cordonier H, Souchier C, Guerin JF. Annexin V labelling and terminal transferasemediated DNA end labelling (TUNEL) assay in human arrested embryos. Mol Hum Reprod. 1998;4(8):775–83. https://doi.org/10.1093/molehr/4.8.775 .

Van Blerkom J, Davis P, Alexander S. A microscopic and biochemical study of fragmentation phenotypes in stage-appropriate human embryos. Hum Reprod. 2001;16(4):719–29. https://doi.org/10.1093/humrep/16.4.719 .

Metcalfe AD, Hunter HR, Bloor DJ, Lieberman BA, Picton HM, Leese HJ, Kimber SJ, Brison DR. Expression of 11 members of the BCL-2 family of apoptosis regulatory molecules during human preimplantation embryo development and fragmentation. Mol Reprod Dev. 2004;68(1):35–50. https://doi.org/10.1002/mrd.20055 .

Jurisicova A, Antenos M, Varmuza S, Tilly J, Casper R. Expression of apoptosis-related genes during human preimplantation embryo development: potential roles for the Harakiri gene product and Caspase-3 in blastomere fragmentation. Mol Hum Reprod. 2003;9:133–41.

Bencomo E, Pérez R, Arteaga M-F, Acosta E, Peña O, Lopez L, et al. Apoptosis of cultured granulosa-lutein cells is reduced by insulin-like growth factor I and may correlate with embryo fragmentation and pregnancy rate. Fertil Steril. 2006;85:474–80.

Keltz MD, Skorupski JC, Bradley K, Stein D. Predictors of embryo fragmentation and outcome after fragment removal in in vitro fertilization. Fertil Steril. 2006;86:321–4.

Ziebe S, Loft A, Petersen JH, Andersen AG, Lindenberg S, Petersen K, et al. Embryo quality and developmental potential is compromised by age. Acta Obstet Gynecol Scand. 2001;80:169–74.

Lahav-Baratz S, Blais I, Koifman M, Dirnfeld M, Oron G. Evaluation of fragmented embryos implantation potential using time-lapse technology. J Obstet Gynaecol Res. 2023;49:1560–70.

Stensen MH, Tanbo T, Storeng R, Byholm T, Fèdorcsak P. Routine morphological scoring systems in assisted reproduction treatment fail to reflect age-related impairment of oocyte and embryo quality. Reprod Biomed Online. 2010;21:118–25.

Wu DH, Reynolds K, Maxwell R, Lindheim SR, Aubuchon M, Thomas MA. Age does not influence the effect of embryo fragmentation on successful blastocyst development. Fertil Steril. 2011;95:2778–80.

Frattarelli JL, Leondires MP, Miller BT, Segars JH. Intracytoplasmic sperm injection increases embryo fragmentation without affecting clinical outcome. J Assist Reprod Genet. 2000;17:207–12.

Hsu MI, Mayer J, Aronshon M, Lanzendorf S, Muasher S, Kolm P, et al. Embryo implantation in in vitro fertilization and intracytoplasmic sperm injection: impact of cleavage status, morphology grade, and number of embryos transferred. Fertil Steril. 1999;72:679–85.

Garello C, Baker H, Rai J, Montgomery S, Wilson P, Kennedy CR, et al. Pronuclear orientation, polar body placement, and embryo quality after intracytoplasmic sperm injection and in-vitro fertilization: further evidence for polarity in human oocytes? Hum Reprod. 1999;14:2588–95.

Yoeli R, Orvieto R, Ashkenazi J, Shelef M, Ben-Rafael Z, Bar-Hava I. Comparison of embryo quality between intracytoplasmic sperm injection and in vitro fertilization in sibling oocytes. J Assist Reprod Genet. 2008;25:23–8.

Ruiz A, Remohí J, Minguez Y, Guanes PP, Simón C, Pellicer A. The role of in vitro fertilization and intracytoplasmic sperm injection in couples with unexplained infertility after failed intrauterine insemination. Fertil Steril. 1997;68:171–3.

Zhang XD, Liu JX, Liu WW, Gao Y, Han W, Xiong S, et al. Time of insemination culture and outcomes of in vitro fertilization: a systematic review and meta-analysis. Hum Reprod Update. 2013;19:685–95.

Liu J, Zhang X, Yang Y, Zhao J, Hao D, Zhang J, et al. Long-time vs. short-time insemination of sibling eggs. Exp Ther Med. 2016;12:3756–60.

Sathananthan H, Bongso A, Ng SC, Ho J, Mok H, Ratnam S. Ultrastructure of preimplantation human embryos co-cultured with human ampullary cells. Hum Reprod. 1990;5:309–18.

Coticchio G, Barrie A, Lagalla C, Borini A, Fishel S, Griffin D, et al. Plasticity of the human preimplantation embryo: developmental dogmas, variations on themes and self-correction. Hum Reprod Update. 2021;27:848–65.

Watson AJ. The cell biology of blastocyst development. Mol Reprod Dev. 1992;33:492–504.

Hur C, Nanavaty V, Yao M, Desai N. The presence of partial compaction patterns is associated with lower rates of blastocyst formation, sub-optimal morphokinetic parameters and poorer morphologic grade. Reprod Biol Endocrinol. 2023;21:12.

Lagalla C, Tarozzi N, Sciajno R, Wells D, Di Santo M, Nadalini M, et al. Embryos with morphokinetic abnormalities may develop into euploid blastocysts. Reprod Biomed Online. 2017;34:137–46.

Ebner T, Moser M, Shebl O, Sommergruber M, Gaiswinkler U, Tews G. Morphological analysis at compacting stage is a valuable prognostic tool for ICSI patients. Reprod Biomed Online. 2009;18:61–6.

Pellestor F, Dufour MC, Arnal F, Humeau C. Direct assessment of the rate of chromosomal abnormalities in grade IV human embryos produced by in-vitro fertilization procedure. Hum Reprod. 1994;9(2):293–302. https://doi.org/10.1093/oxfordjournals.humrep.a138497 .

Morgan K, Wiemer K, Steuerwald N, Hoffman D, Maxson W, Godke R. Use of videocinematography to assess morphological qualities of conventionally cultured and cocultured embryos. Hum Reprod. 1995;10:2371–6.

Alikani M, Calderon G, Tomkin G, Garrisi J, Kokot M, Cohen J. Cleavage anomalies in early human embryos and survival after prolonged culture in-vitro. Hum Reprod. 2000;15:2634–43.

Ivec M, Kovacic B, Vlaisavljevic V. Prediction of human blastocyst development from morulas with delayed and/or incomplete compaction. Fertil Steril. 2011;96:1473-1478.e2.

Hnida C, Engenheiro E, Ziebe S. Computer-controlled, multilevel, morphometric analysis of blastomere size as biomarker of fragmentation and multinuclearity in human embryos. Hum Reprod. 2004;19:288–93.

Sjöblom P, Menezes J, Cummins L, Mathiyalagan B, Costello MF. Prediction of embryo developmental potential and pregnancy based on early stage morphological characteristics. Fertil Steril. 2006;86:848–61.

Kellam L, Pastorelli LM, Bastida AM, Senkbeil A, Montgomery S, Fishel S, et al. Perivitelline threads in cleavage-stage human embryos: observations using time-lapse imaging. Reprod Biomed Online. 2017;35:646–56.

Paternot G, Debrock S, De Neubourg D, D’Hooghe TM, Spiessens C. Semi-automated morphometric analysis of human embryos can reveal correlations between total embryo volume and clinical pregnancy. Hum Reprod. 2013;28:627–33.

Eftekhari-Yazdi P, Valojerdi MR, Ashtiani SK, Eslaminejad MB, Karimian L. Effect of fragment removal on blastocyst formation and quality of human embryos. Reprod Biomed Online. 2006;13:823–32.

Keltz M, Fritz R, Gonzales E, Ozensoy S, Skorupski J, Stein D. Defragmentation of low grade day 3 embryos resulted in sustained reduction in fragmentation, but did not improve compaction or blastulation rates. Fertil Steril. 2010;94:2406–8.

Halvaei I, Khalili MA, Esfandiari N, Safari S, Talebi AR, Miglietta S, et al. Ultrastructure of cytoplasmic fragments in human cleavage stage embryos. J Assist Reprod Genet. 2016;33:1677–84.

Yumoto K, Shimura T, Mio Y. Removing the zona pellucida can decrease cytoplasmic fragmentations in human embryos: a pilot study using 3PN embryos and time-lapse cinematography. J Assist Reprod Genet. 2020;37:1349–54.

Sordia-Hernandez LH, Morales-Martinez FA, Frazer-Moreira LM, Villarreal-Pineda L, Sordia-Piñeyro MO, Valdez-Martinez OH. Clinical Pregnancy After Elimination of Embryo Fragments Before Fresh Cleavage-stage Embryo Transfer. J Family Reprod Health. 2020;14(3):198–204. https://doi.org/10.18502/jfrh.v14i3.4674 .

Findikli N, Kahraman S, Kumtepe Y, Donmez E, Benkhalifa M, Biricik A, et al. Assessment of DNA fragmentation and aneuploidy on poor quality human embryos. Reprod Biomed Online. 2004;8:196–206.

Munné S, Alikani M, Tomkin G, Grifo J, Cohen J. Embryo morphology, developmental rates, and maternal age are correlated with chromosome abnormalities. Fertil Steril. 1995;64:382–91.

Almeida PA, Bolton VN. The relationship between chromosomal abnormality in the human preimplantation embryo and development in vitro. Reprod Fertil Dev. 1996;8:235–41.

Magli MC, Gianaroli L, Ferraretti AP. Chromosomal abnormalities in embryos. Mol Cell Endocrinol. 2001;183(Suppl 1):S29-34.

Moayeri SE, Allen RB, Brewster WR, Kim MH, Porto M, Werlin LB. Day-3 embryo morphology predicts euploidy among older subjects. Fertil Steril. 2008;89:118–23.

Baltaci V, Satiroglu H, Kabukçu C, Ünsal E, Aydinuraz B, Üner Ö, et al. Relationship between embryo quality and aneuploidies. Reprod Biomed Online. 2006;12:77–82.

Ziebe S, Lundin K, Loft A, Bergh C, Nyboe Anderson A, Selleskog U. FISH analysis for chromosomes 13, 16, 18, 21, 22, X and Y in all blastomeres of IVF pre-embryos from 144 randomly selected donated human oocytes and impact on pre-embryo morphology. Hum Reprod. 2003;18:2575–81.

Delimitreva SM, Zhivkova RS, Vatev ITS, Toncheva DI. Chromosomal disorders and nuclear and cell destruction in cleaving human embryos. Int J Dev Biol. 2005;49:409–16.

Minasi MG, Colasante A, Riccio T, Ruberti A, Casciani V, Scarselli F, Spinella F, Fiorentino F, Varricchio MT, Greco E. Correlation between aneuploidy, standard morphology evaluation and morphokinetic development in 1730 biopsied blastocysts: a consecutive case series study. Hum Reprod. 2016;31(10):2245–54. https://doi.org/10.1093/humrep/dew183 . Epub 2016 Sep 2.

Vera-Rodriguez M, Chavez SL, Rubio C, Reijo Pera RA, Simon C. Prediction model for aneuploidy in early human embryo development revealed by single-cell analysis. Nat Commun. 2015;6:7601. https://doi.org/10.1038/ncomms8601 .

Magli MC, Gianaroli L, Ferraretti AP, Lappi M, Ruberti A, Farfalli V. Embryo morphology and development are dependent on the chromosomal complement. Fertil Steril. 2007;87(3):534–41. https://doi.org/10.1016/j.fertnstert.2006.07.1512 . Epub 2006 Nov 21.

Bamford T, Barrie A, Montgomery S, Dhillon-Smith R, Campbell A, Easter C, et al. Morphological and morphokinetic associations with aneuploidy: a systematic review and meta-analysis. Hum Reprod Update. 2022;28:656–86.

Baxter Bendus AE, Mayer JF, Shipley SK, Catherino WH. Interobserver and intraobserver variation in day 3 embryo grading. Fertil Steril. 2006;86:1608–15.

Lundin K, Park H. Time-lapse technology for embryo culture and selection. Ups J Med Sci. 2020;125:77–84.

Leahy BD, Jang WD, Yang HY, Struyven R, Wei D, Sun Z, et al. Automated Measurements of Key Morphological Features of Human Embryos for IVF. Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics). 2020.

Download references

We did not receive any funding to prepare this manuscript. We are grateful for receiving an editorial waiver for this manuscript.

Author information

Authors and affiliations.

Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Vermont Medical Center, The Robert Larner College of Medicine at the University of Vermont, Burlington, VT, 05405, USA

Ariella Yazdani, Catherine Boniface & Navid Esfandiari

Department of Anatomical Sciences, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran

Iman Halvaei

Present address: Obstetrics and Gynecology Institute, Cleveland Clinic Foundation, Cleveland, OH, 44195, USA

Ariella Yazdani

Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology and Reproductive Sciences, University of Vermont, 111 Colchester Avenue, Burlington, Vermont, 05401, USA

Navid Esfandiari

You can also search for this author in PubMed   Google Scholar

Contributions

All authors have made substantial contributions to this manuscript. NE designed the work, critically reviewed and edited the manuscript. AY, IH and CB made substantial contribution in writing the manuscript. All authors have approved the paper for submission.

Corresponding author

Correspondence to Navid Esfandiari .

Ethics declarations

Ethics approval and consent to participate.

This is a review paper and does not involve human participants, human data or human tissue.

Consent for publication

This manuscript does not contain any individual person’s data in any form (including any individual details, images or videos).

Competing interests

The authors declare no competing interests.

Additional information

Publisher's note.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ . The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/ ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Cite this article.

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

Download citation

Received : 20 November 2023

Accepted : 01 April 2024

Published : 14 May 2024

DOI : https://doi.org/10.1186/s12958-024-01217-7

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

• Fragmentation
• Embryo development
• Implantation
• In vitro fertilization
• Pregnancy outcome

Reproductive Biology and Endocrinology

ISSN: 1477-7827

• General enquiries: [email protected]