objectives of systematic literature review

Easy guide to conducting a systematic review

Affiliations.

• 1 Discipline of Child and Adolescent Health, University of Sydney, Sydney, New South Wales, Australia.
• 2 Department of Nephrology, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.
• 3 Education Department, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.
• PMID: 32364273
• DOI: 10.1111/jpc.14853

A systematic review is a type of study that synthesises research that has been conducted on a particular topic. Systematic reviews are considered to provide the highest level of evidence on the hierarchy of evidence pyramid. Systematic reviews are conducted following rigorous research methodology. To minimise bias, systematic reviews utilise a predefined search strategy to identify and appraise all available published literature on a specific topic. The meticulous nature of the systematic review research methodology differentiates a systematic review from a narrative review (literature review or authoritative review). This paper provides a brief step by step summary of how to conduct a systematic review, which may be of interest for clinicians and researchers.

Keywords: research; research design; systematic review.

© 2020 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).

Publication types

• Systematic Review
• Research Design*

• Methodology
• Open access
• Published: 01 March 2018

An introduction to overviews of reviews: planning a relevant research question and objective for an overview

• Harriet Hunt   ORCID: orcid.org/0000-0003-1254-0568 1 ,
• Alex Pollock 2 ,
• Pauline Campbell 3 ,
• Lise Estcourt 4 &
• Ginny Brunton 5  

Systematic Reviews volume  7 , Article number:  39 ( 2018 ) Cite this article

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Overviews of systematic reviews are a relatively new approach to synthesising evidence, and research methods and associated guidance are developing. Within this paper we aim to help readers understand key issues which are essential to consider when taking the first steps in planning an overview. These issues relate to the development of clear, relevant research questions and objectives prior to the development of an overview protocol.

Initial discussions and key concepts for this paper were formed during a workshop on overview methods at the 2016 UK Cochrane Symposium, at which all members of this author group presented work and contributed to wider discussions. Detailed descriptions of the various key features of overviews and their different objectives were created by the author group based upon current evidence (Higgins J, Green S. Cochrane Handbook Syst Rev Interv. 2011;4:5, Pollock M, et al. Sys Rev. 2016;5:190-205, Pollock A, et al. Cochrane overviews of reviews: exploring the methods and challenges. UK and Ireland: Cochrane Symposium; 2016, Pieper D, et al. Res Syn Meth. 2014;5:187–99, Lunny C, et al. Sys Rev. 2016;5:4-12, Hartling L, et al. Comparing multiple treatments: an introduction to overviews of reviews. In 23rd Cochrane Colloquium; 2015, Hartling L, et al. Plos One. 2012;7:1-8, Ballard M, Montgomery P. Res Syn Meth. 2017;8:92-108) and author experiences conducting overviews.

Within this paper we introduce different types of overviews and suggest common research questions addressed by these overviews. We briefly reflect on the key features and objectives of the example overviews discussed.

Conclusions

Clear decisions relating to the research questions and objectives are a fundamental first step during the initial planning stages for an overview. Key stakeholders should be involved at the earliest opportunity to ensure that the planned overview is relevant and meaningful to the potential end users of the overview. Following best practice in common with other forms of systematic evidence synthesis, an overview protocol should be published, ensuring transparency and reducing opportunities for introduction of bias in the conduct of the overview.

Peer Review reports

It is estimated that around 22 new systematic reviews are published every day [ 1 ]. In order to keep pace with the increasing volume of reviews, new methodological approaches have been developed for synthesising this evidence including overviews (systematic reviews of systematic reviews). Overviews are most frequently employed where multiple systematic reviews already exist on similar or related topics, and aim to systematically bring together, appraise and synthesise the results of related systematic reviews. Overviews have evolved to address a growing need to filter the information overload, improve access to targeted information and inform healthcare decision-making [ 2 , 3 ]. Overviews can be useful tools to support decision-making by clinicians, policy makers and developers of clinical guidelines [ 2 , 4 ]. There are a range of factors to reflect upon prior to deciding whether to conduct an overview, including consideration of the methodological challenges and uncertainties. These challenges are discussed in depth in our accompanying paper on this topic [ 5 ].

Overviews are known by a variety of different names, all potentially reflecting different aspects and aims of the syntheses. Terms used include: overview; umbrella review; meta-review; (systematic) review of (systematic) reviews; synthesis of systematic reviews; and summary of systematic reviews. The common feature of the methods associated with all of these terms is the fundamental process of synthesising evidence which is derived, often exclusively, from systematic reviews. The systematic review forms the primary ‘unit of analysis’ and is the basis upon which an overview is built [ 6 ].

The term ‘overview of systematic reviews’ (often shortened to ‘overview’) has gained widespread acceptance, and is the term used by Cochrane to describe a review of systematic reviews published in the Cochrane Library [ 7 ]. We use the term ‘overview’ within this paper to describe systematic summaries of systematic review evidence, in line with the most commonly used terminology.

Overviews can play a role in signposting the reader to evidence, summarising existing research or highlighting the absence of evidence [ 7 ]. For this reason, overviews can provide an ‘entry point’ for policy makers and other consumers by summarising broad issues and current knowledge around a topic, and directing the reader to more detailed, fine-grained material contained in component systematic reviews and primary research [ 8 , 9 , 10 ].

Likewise, the involvement of stakeholders at an early point in planning and conducting an overview may help in shaping these aims for maximum overview impact [ 2 , 11 , 12 ].

Overviews arguably have a valuable role where evidence relating to a specific topic exists but is conflicting, bringing together reviews in a transparent and systematic way and aiding informed decision making by gathering, appraising and systematically analysing this evidence. While the evidence synthesised within an overview may be used to generate new insights and understanding, it is important to note that overviews are fundamentally a method of bringing together, summarising and enhancing accessibility of existing evidence.

Overviews are a relatively new and emerging method of summarising evidence, and consequently universally-accepted guidance for good practice relating to the conduct of overviews is currently lacking [ 5 , 13 , 14 , 15 , 16 , 17 ]. During a 2016 UK Cochrane Symposium workshop [ 18 ] focused on the methods and challenges associated with overviews, it became apparent that there was a need to clarify, and distinguish between, different types of overviews and the objectives which these overviews addressed. Within this paper, we therefore describe types of overview and the common research questions and objectives they address. Within a second, linked paper [ 5 ], we build on this description of overview types, objectives and research questions, illustrating this through the use of five exemplar overviews, and exploring the impact and implications of different methodological approaches.

In presenting and discussing common research questions addressed by overviews with different objectives, and relating this to real examples in the second paper [ 5 ], we aim to help readers understand important issues to consider during the first steps to planning an overview.

Research questions and objectives addressed by overviews

In common with all research, overviews are carried out to address a clearly-stated research question. When planning an overview, determining the nature of the initial research question, and identifying who is asking the question, will dictate the scope of the overview objective(s). The objectives of an overview may include summarising existing evidence on a range of different topics, including: interventions; diagnostic accuracy of medical tests or procedures; prognosis or risk prediction; health equity [ 19 ]; or more qualitative aspects associated with any of the above, such as patient preference or device acceptability. In addition to summarising the results of multiple systematic reviews on related topics, overviews may also be used to investigate different aspects of questions already tackled by existing systematic reviews, such as variations in population, condition or intervention [ 10 , 12 , 12 ]. One example of this latter approach is provided in an overview which aimed to synthesise current evidence of the relationship between sedentary behaviour and health outcomes [ 20 ], reporting variation in results across populations and condition studied.

The principles which guide development of focussed clinical questions for systematic reviews remain valid for the development of research questions for overviews. Clearly defining the target population and setting, context, intervention, index test or phenomenon of interest, comparator or reference standard and outcome or treatment decisions are all essential parts of any overview protocol. The research question and overall overview objective will dictate the ‘type’ of overview that is required. This may be an overview of specific types of systematic review, or of systematic reviews which contain specific types of primary research study.

These defining elements of research questions and objectives are illustrated in Table  1 , and we consider the objectives of each overview type in more detail below.

Overviews of intervention reviews

Overviews of intervention reviews should be considered when the research question relates to the effectiveness of one or more intervention. Common objectives for overviews of intervention reviews are detailed below.

To summarise evidence from more than one systematic review of different interventions for the same condition or problem

This is the primary purpose of Cochrane Overviews of Interventions, and a number of overviews of interventions have been employed to tackle this objective [ 21 , 22 , 23 ].

For example, one overview has brought together all systematic reviews of interventions to improve arm function in people with stroke [ 22 ], whilst another overview has summarised systematic reviews of conservative interventions for the treatment of incontinence in women [ 21 ]. One example of a mixed methods overview assessed all workplace health promotion interventions using healthcare or wellbeing outcomes from systematic reviews of effectiveness, combining these with syntheses of identified policy documents and research on stakeholders’ perspectives of workplace intervention programmes [ 23 ].

To summarise evidence from more than one systematic review of the same intervention for the same condition or problem where different outcomes are addressed in different systematic reviews

Overviews of interventions can be used to summarise evidence assessing different outcomes for the same condition. Generally, systematic reviews should include all outcomes that are important to people making decisions about and influenced by an intervention. This includes the involvement of stakeholders in order to reflect aspects important to people receiving an intervention [ 24 ], and should be incorporated at the study, review and overview levels. Not all systematic reviews, however, focus on a single condition or outcome. For example, one overview has brought together all systematic reviews of the use of red cell transfusion to prevent or treat common complications in people with sickle cell disease, such as painful crises, stroke and acute chest syndrome [ 25 ]. This overview assessed the prevention of these complications during high-risk situations such as surgery, pregnancy or a sub-population identified as at high risk of a particular complication, such as abnormal transcranial Doppler and risk of stroke in children. Another overview summarised the safety of long-acting beta agonists (regular formoterol or salmeterol) in children with asthma with outcomes including all-cause mortality, non-fatal serious adverse events, asthma-related deaths and asthma-related non-fatal serious events [ 26 ]. This overview was prompted by concerns raised by two large surveillance studies in adults with asthma [ 27 , 28 ] that found an increased risk of asthma-related mortality in those who took regular salmeterol and the weaker evidence base for the effectiveness of long-acting beta agonists in children.

To summarise evidence from more than one systematic review of the same intervention for different conditions, problems or populations

The same or similar interventions are often used for different conditions or different studies and reviews may focus on different populations. This type of evidence may be of interest where more than one patient population is being addressed, as generalisability of the effect may be more extensive. One recent example is of an overview of reviews of cognitive rehabilitation for different cognitive problems in people with stroke [ 29 ].

To summarise evidence about adverse effects of an intervention from more than one systematic review of use of the intervention for one or more conditions

Systematic reviews often report information on adverse effects, but few reviews are conducted with the main aim to report rates of these events. This may well change following the recent publication of the PRISMA harms checklist [ 30 ]. Due to the rarity of many adverse events, randomised controlled trials rarely contain sufficient data to give an accurate indication of prevalence [ 31 , 32 ]. It would therefore be inappropriate to rely on systematic reviews based solely on trial data to profile adverse events of a specific intervention, except in the rare situations where the recording of adverse effects data is the primary aim of the trial [ 33 ]. It may be appropriate to include data not previously included in a systematic review such as when conducting a Health Technology Assessment (HTA) report, developing a clinical practice guideline or developing resources such as BMJ Clinical Evidence . One overview summarising evidence on adverse effects of herbal medicines across all conditions takes this broader approach to systematic review evidence and provides an example of methodological challenges encountered [ 34 ].

Overviews of diagnostic test accuracy reviews

Overviews of diagnostic test accuracy reviews should be considered when the research question relates to the accuracy of one or more diagnostic test. Common objectives for overviews of diagnostic test accuracy reviews are addressed below.

To summarise evidence from more than one systematic review of diagnostic test accuracy assessing the same medical test to address the same condition or problem

The purpose of diagnostic test accuracy overviews is to form a summary of systematic review evidence in order to address a specific research question, where the unit of interest is systematic reviews of diagnostic test accuracy. These systematic reviews are designed to assess existing evidence of the diagnostic accuracy of a test or device using standard measures of accuracy (sensitivity and specificity) rather than measures of effectiveness as with reviews of interventions. Systematic reviews of diagnostic test accuracy commonly encounter greater heterogeneity than intervention reviews, due to variation in study populations, in the testing environment and context, or in procedures used to conduct the tests involved [ 35 ]. Overviews of diagnostic test accuracy which aim to assess the accuracy of a single medical test generally have more potential for identifying sources of heterogeneity than overviews which address a number of additional variables such as multiple tests or devices [ 35 ]. An example in which this approach has been taken is the overview of systematic review evidence of the diagnostic accuracy of endoscopic ultrasonography (EUS) for the preoperative loco-regional staging of primary gastric cancer [ 36 ]. The authors reported that substantial heterogeneity may have influenced the applicability of clinical usefulness for endoscopic ultrasonography for pre-operative loco-staging of primary gastric cancer [ 36 ]. By undertaking an overview, the authors were able to identify the need for greater understanding of the sources of heterogeneity before recommendations could be made about the clinical usefulness of EUS. Overview authors were also able to make more nuanced practice recommendations on test performance, and this ability to pinpoint specific areas for further research as well as issue practice guidance demonstrates a potential benefit of overviews.

To summarise evidence from more than one systematic review of diagnostic test accuracy assessing different medical tests to address the same condition or problem

Overviews assessing the diagnostic test accuracy of different medical tests addressing the same condition are similar in terms of scope and objectives to the overviews described in the previous section, with the key difference that a number of different medical tests are being assessed within included systematic reviews. For example, a recently-conducted overview summarising the diagnostic test accuracy of brief cognitive assessments for identifying dementia in a primary care population [ 37 ] included evidence from a range of systematic reviews of diagnostic test accuracy of a number of different brief cognitive assessments. This enabled conclusions to be drawn about the accuracy of specific tests within the primary care population, and signposted a gap in current evidence for direct comparisons of the diagnostic accuracy of individual tests for identifying dementia in primary care. Again, these broader recommendations were made possible through the wider synthesis of existing evidence than had previously been conducted in this specific setting.

Overviews of reviews of prognosis/prevalence

Overviews of reviews of prognosis/prevalence should be considered when the objective is to summarise evidence about prognosis/prevalence from more than one systematic review. The implementation of overview methodology in this field is relatively recent, but there are a growing number of systematic reviews specifically investigating the predictive value of tests and devices, prognostic information and/or prognostic models. These address questions such as ‘what is the most likely course of this health condition?’ ‘What factors are associated with outcome?’ and ‘are there risk groups likely to have different outcomes?’ [ 38 ]. One example of such an overview evaluated the prognostic evidence alongside evidence on treatment, harms, diagnosis, classification and outcomes used for managing neck pain [ 39 ].

Overviews of reviews of risk factors

These overviews incorporate disease aetiology or risk factors when the risks of interest may not directly relate to prognostic variables or risk prediction models. When planning to conduct an overview of systematic review evidence in order to explore the effect of putative risk factors on a range of variables, factors to consider include whether the primary interest in conducting the overview is to explore associations between markers of a disease and known risk factors, or whether the main focus is the impact of those risk factors on single or multiple outcomes. An example overview addressing the latter purpose is an overview which aimed to evaluate the strength and validity of the evidence for the association between adiposity and risk of developing or dying from cancer [ 40 ]. The authors of this work found strong evidence of an association between obesity and 11 of the 36 studied cancer sites and subtypes. The cancers for which there was strong evidence of an association with obesity were mainly cancers of digestive organs and female hormone-related malignancies. The authors of the overview concluded that whilst other associations could be genuine, substantial uncertainty remains for the other cancers studied.

Overviews of qualitative reviews

Overviews of reviews of qualitative reviews should be considered when the objective is to summarise systematic review evidence relating to qualitative views or experiences. There is clear guidance available on the good conduct of an overview of qualitative syntheses [ 6 ], with commonalities across all types of overviews. Common features include employing an a priori peer-reviewed protocol formed around a clearly pre-specified research question with detailed inclusion and exclusion criteria, search strategies and methods for data extraction and appraisal, followed by clear and replicable methods for synthesis and summary of included data [ 6 ]. An example overview using qualitative data as well as quantitative information is provided by an overview exploring improving quality of care for persons with diabetes looking at a broad range of interventions, including patient education and support, telemedicine, organisational changes and outcomes relating to the process of care [ 10 ]. In combining these approaches, overview authors had potential to synthesise data on patient experiences of quality of care alongside quantitative evaluation of effectiveness, which could result in a richer set of evidence for informing practice and policy.

Whilst many overviews tacitly assess quantitative outcomes reported in systematic reviews [ 6 ], often the nature of overviews results in narrative synthesis which can draw on either quantitative or qualitative data within included systematic reviews. In this sense, many overviews include elements of qualitative data identified within the source systematic reviews.

Results and Discussion

There are many similarities between overviews and systematic reviews, and the principles which guide the planning of a systematic review (including production of a clinically-relevant research question and a pre-specified peer reviewed protocol) are relevant in conducting an overview [ 2 ]. Within this paper, we have described a brief classification to organise common research questions and objectives, using overviews based on frameworks developed within the Cochrane Handbooks for Systematic Reviews of Interventions [ 41 ] and Diagnostic Test Accuracy [ 42 ]. These descriptions cover overviews of intervention reviews, overviews of diagnostic test accuracy reviews, overviews of reviews of prognosis/prevalence, overviews of reviews of risk factors and overviews of reviews of qualitative studies.

Overviews aim to summarise evidence and to signpost readers to relevant sources to support decision making; this paper has highlighted that there are a wide range of potential reasons for selecting to do an overview, and that these varied reasons lead to overviews which may have a number of different methodological features.

Overviews of reviews of different interventions for the same condition, or of the same intervention but looking at different outcomes, will have high clinical relevance where clinical decisions are made between different treatments. Overviews of intervention reviews, bringing together evidence relating to the effectiveness of a specific treatment applied in alternative populations or settings will be of interest to healthcare providers delivering that treatment, or to consumers seeking information about the effective interventions. Overviews of risk factors will have similar clinical interest and potential relevance for policymakers and regulators. Overviews relating to the adverse effects of an intervention in the same or different conditions may allow commonalities to be drawn across a broader range of evidence than in a more focussed systematic review, with the potential to highlight equivalence or patterns not previously identified. Similarly, overviews of systematic reviews of diagnostic test accuracy provide an opportunity to gain greater insights into test accuracy data summarised across different populations, settings or other variables, with potential to reduce the impact of data heterogeneity by drawing on a broader evidence base. Overviews of prognosis are also increasing in number and scope, offering potential to provide useful insights by summarising evidence of the likely course of a condition, factors associated with health outcomes or identifying risk groups associated with different health outcomes [ 38 ] . When applied within systematic frameworks, overviews of qualitative evidence provide scope for creating theoretically-defined conceptions of complex topics [ 43 ].

Often, the scope of systematic reviews can be described as either ‘lumping’ or ‘splitting’ information [ 44 , 45 ]. Lumping refers to finding commonalities across different approaches, whereas splitting creates a more narrowly-refined focus within a broader research field. Systematic reviews of primary research often split data by addressing a focussed and specific research question which may not be very useful for informing broader clinical and policy decision making. Conversely, overviews commonly adopt a ‘lumping’ approach, allowing greater leeway for generality in research findings [ 45 ], and arguably having greater applicability for policy makers. There are clearly challenges in ‘lumping’ large volumes of information, and presenting this in an accessible format, which is relevant and useful to the end user. Another significant challenge in lumping information is how to consistently synthesise such information in the face of inevitable heterogeneity.

The classification we have employed here suggests a range of common objectives and research questions which may be addressed by an overview, where the primary objective is to summarise the existing body of systematic review evidence on a topic. The scope of this summary of evidence is defined by previously stated inclusion and exclusion criteria [ 6 , 13 ]. This summary of evidence should not simply duplicate the reporting of individual systematic review summaries, but instead should aim to synthesise across included systematic review evidence in order to bring new insights to existing evidence. The suitability of reanalysis of existing data within an overview is debated, and it has been argued that, where novel analyses are the aim, conducting a review of trials may be more appropriate than an overview of reviews [ 14 ]. Methodological guidance on the reporting of systematic reviews using individual participant data has been published by the PRISMA-IPD Group [ 46 ] and may prove relevant to reporting within overviews which aim to incorporate novel analyses. It is clearly important for the stated overview research questions and objectives to specify any plans for data analysis, and for this to be planned with reference to the available methodological guidance, and with appropriate justification of the use of any overview of reviews, rather than a review of trials.

At its broadest sense, the common purpose of an overview is to provide an accessible summary of evidence, in order to support decision making by clinicians, policy makers and developers of clinical guidelines [ 2 ]. It is now widely accepted that in order to ensure relevance and impact of health research, key stakeholders (including but not restricted to people with a healthcare condition, their families, friends and caregivers, health professionals and decision makers) should be involved in the process [ 47 , 48 ]. Central to the conduct of an overview are the people involved in its production. From formulating the question to conducting the overview and disseminating findings, the specific purpose of an overview may change depending on who is asking the research question and clearly stakeholders should be actively involved throughout the process. The involvement of key stakeholders, including patients and their families or carers, should occur at the earliest opportunity in order to ensure that the planned overview is relevant and meaningful to the potential end users of the overview.

Overviews are a relatively new methodological approach and consequently a number of aspects of overview methodology remain uncertain. It is the responsibility of a research team to decide on their approach before conducting an overview; central to this is determining what type of overview is to be conducted. Clear decisions relating to the research questions and objectives to be addressed by the overview are a fundamental first step during the initial planning stages for an overview, and should be developed with the involvement of key stakeholders. Following best practice, these aspects should be covered within a published overview protocol as a mechanism for ensuring transparency and reducing opportunities for introduction of bias in the conduct of the overview. Our second paper [ 5 ] outlines a number of key methodological decisions which we consider important to address when planning an overview, and which will be important to incorporate within an overview protocol.

Despite a need for improved guidance for the conduct of overviews [ 2 ], there are a number of resources available which support the conduct of overviews [ 2 , 6 , 7 , 13 ], and updates to the relevant chapter of the Cochrane Handbook are currently in production [ 7 ]. Further guidance on the less common types of overview (such as those addressing reviews of diagnostic tests accuracy and prognosis) and more challenging aspects of overview production, such as methods for narratively synthesising findings, dealing with missing data, poor reporting and dealing with complexity versus granularity [ 10 ], would be a great benefit to those tackling overviews. In the absence of empirical evidence to support the selection and implementation of overview methods, we believe that the use of illustrated examples of real-life overviews will be helpful to authors planning new overviews, and to those seeking to establish evidence relating to optimal overview methods. This is therefore the focus of our second paper on this topic [ 5 ].

Abbreviations

British Medical Journal

Health Technology Assessment

Preferred Reporting Items for Systematic Reviews and Meta-Analyses [systematic review reporting guidelines]

Preferred Reporting Items for Systematic Reviews and Meta-Analyses – Individual Patient Data

International Prospective Register of Systematic Reviews

Randomised Controlled Trials

Page MJ, Shamseer L, Altman DG, Tetzlaff J, Sampson M, Tricco AC, Catalá-López F, Li L, Reid EK, Sarkis-Onofre R, Epidemiology MD. reporting characteristics of systematic reviews of biomedical research: a cross-sectional study. PLoS medicine. 2016;13(5):e1002028.

Article   PubMed   PubMed Central   Google Scholar  

Hartling L, et al. A descriptive analysis of overviews of reviews published between 2000 and 2011. PLoS One. 2012;7(11):e49667.

Article   CAS   PubMed   PubMed Central   Google Scholar  

Smith V, Devane D, Begley CM, Clarke M. Methodology in conducting a systematic review of systematic reviews of healthcare interventions. BMC Medical Res. Methodology. 2011;11(1):15–21.

Google Scholar  

Lunny C, et al. Toward a comprehensive evidence map of overview of systematic review methods: paper 1—purpose, eligibility, search and data extraction. Systematic Reviews. 2017;6(1):231.

Pollock A, et al. Selecting and implementing overview methods: implications from five exemplar overviews. Systematic Reviews. 2017;6(1):145.

Aromataris E, et al. Summarizing systematic reviews: methodological development, conduct and reporting of an umbrella review approach. Int J Evidence-Based Healthcare. 2015;13(3):132–40.

Article   Google Scholar  

Becker, L. and A. Oxman, Chapter 22: Overviews of reviews., in Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 H. JPT and G. S, Editors. 2011, The Cochrane Collaboration.

Pieper D, Antoine SL, Morfeld JC, Mathes T, Eikermann M. Methodological approaches in conducting overviews: current state in HTA agencies. Res Synthesis Methods. 2014;5(3):187–99.

Lunny C, Brennan SE, McDonald S, McKenzie JE. Evidence map of studies evaluating methods for conducting, interpreting and reporting overviews of systematic reviews of interventions: rationale and design. Systematic reviews. 2016;5(1):4.

Worswick J, et al. Improving quality of care for persons with diabetes: an overview of systematic reviews—what does the evidence tell us? Systematic Reviews. 2013;2(1):26.

Caird J, et al. Mediating policy-relevant evidence at speed: are systematic reviews of systematic reviews a useful approach? Evidence Policy. 2015;11(1):81–97.

Whitlock EP, et al. Using existing systematic reviews in complex systematic reviews using existing systematic reviews in complex systematic reviews. Ann Intern Med. 2008;148(10):776–82.

Article   PubMed   Google Scholar  

Pollock M, et al. What guidance is available for researchers conducting overviews of reviews of healthcare interventions? A scoping review and qualitative metasummary. Systematic Reviews. 2016;5(1):190–205.

Hartling L, et al. Comparing multiple treatments: an introduction to overviews of reviews. In 23rd Cochrane Colloquium: Filtering the information overload for better decisions. Vienna: Wiley; 2015.

Ballard M, Montgomery P. Risk of bias in overviews of reviews: a scoping review of methodological guidance and four-item checklist. Res Synthesis Methods. 2017;8

Pieper D, Buechter R, Jerinic P, Eikermann M. Overviews of reviews often have limited rigor: a systematic review. J Clin Epidemiol. 2012;65(12):1267–73.

Thomson D, Foisy M, Oleszczuk M, Wingert A, Chisholm A, Hartling L. Overview of reviews in child health: evidence synthesis and the knowledge base for a specific population. Evidence-Based Child Health: A Cochrane Rev J. 2013;8(1):3–10.

Pollock A, et al. Cochrane overviews of reviews: exploring the methods and challenges. Birmingham: UK and Ireland Cochrane Symposium; 2016.

Hoving JL, et al. Work participation and arthritis: a systematic overview of challenges, adaptations and opportunities for interventions. Rheumatology. 2013;52(7):1254–64.

de Rezende LFM, et al. Sedentary behavior and health outcomes: an overview of systematic reviews. PLoS One. 2014;9(8):e105620.

McClurg D, et al. Conservative interventions for urinary incontinence in women: an overview of Cochrane systematic reviews. Cochrane Database Syst Rev. 2016;9

Pollock A, et al. Interventions for improving upper limb function after stroke. Cochrane Database Syst Rev. 2014;11

Brunton G, et al. Developing evidence-informed, employer-led workplace health. London: EPPI-Centre, Social Science Research Unit, UCL Institute of Education, University College London; 2016.

Harris J, et al. How stakeholder participation can contribute to systematic reviews of complex interventions. J Epidemiol Community Health. 2016;70(2):207–14.

Article   CAS   PubMed   Google Scholar  

Estcourt LJ, et al. Red blood cell transfusion to treat or prevent complications in sickle cell disease: an overview of Cochrane reviews. Cochrane Database of Syst Rev. 2016;2

Cates CJ, Oleszczuk M, Stovold E, Wieland LS. Safety of regular formoterol or salmeterol in children with asthma: an overview of Cochrane reviews. Cochrane Database Syst Rev. 2012;(10):CD010005. https://doi.org/10.1002/14651858.CD010005.pub .

Castle W, et al. Serevent nationwide surveillance study: comparison of salmeterol with salbutamol in asthmatic patients who require regular bronchodilator treatment. BMJ. 1993;306(6884):1034–7.

Nelson HS, et al. The salmeterol multicenter asthma research trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. CHEST J. 2006;129(1):15–26.

Article   CAS   Google Scholar  

Gillespie DC, Bowen A, Chung CS, Cockburn J, Knapp P, Pollock A. Rehabilitation for post-stroke cognitive impairment: an overview of recommendations arising from systematic reviews of current evidence. Clin Rehabil. 2015;29(2):120–8.

Zorzela L, Loke YK, Ioannidis JP, Golder S, Santaguida P, Altman DG, Moher D, Vohra S. PRISMA harms checklist: improving harms reporting in systematic reviews. BMJ. 2016;352:i157.

Frieden TR. Evidence for health decision making—beyond randomized, controlled trials. N Engl J Med. 2017;377(5):465–75.

Berlin JA, Glasser SC, Ellenberg SS. Adverse event detection in drug development: recommendations and obligations beyond phase 3. Am J Public Health. 2008;98(8):1366–71.

Loke YK, et al. Systematic reviews of adverse effects: framework for a structured approach. BMC Med Res Methodol. 2007;7:32.

Posadzki P, Watson LK, Ernst E. Adverse effects of herbal medicines: an overview of systematic reviews. Clin Med (Lond). 2013;13(1):7–12.

Bossuyt P, et al., Chapter 11: Interpreting results and drawing conclusions. In:, in Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy Deeks JJ, Bossuyt PM, and Gatsonis C, Editors. 2013, The Cochrane Collaboration.

Mocellin S, Pasquali S. Diagnostic accuracy of endoscopic ultrasonography (EUS) for the preoperative locoregional staging of primary gastric cancer. Cochrane Database Syst Rev. 2015;2

Hunt, H., E. Kuzma, and H. C, A review of existing systematic reviews summarising the accuracy of brief cognitive assessments for identifying dementia, particularly for use in primary care. Protocol., in PROSPERO 2016: PROSPERO online.

Williams, K. and C. Moons. An Introduction to Systematic Reviews of Prognosis. [Powerpoint presentation] 2012; Available from: https://www.google.co.uk/url?sa=t&rct=j&q=&esrc=s&source=web&cd=1&cad=rja&uact=8&ved=0ahUKEwixm4Pz-6fZAhWQZlAKHbntBR8QFggxMAA&url=http%3A%2F%2Fmethods.cochrane.org%2Fsites%2Fmethods.cochrane.org.prognosis%2Ffiles%2Fpublic%2Fuploads%2FAuckland%2520presentation_p . Accessed 15 Feb 2018.

Santaguida L, et al. A description of the methodology used in an overview of reviews to evaluate evidence on the treatment, harms, diagnosis/ classification, prognosis and outcomes used in the management of neck pain. Open Orthopaedics. 2013;7(Suppl 4 : M2):461–72.

Kyrgiou M, et al. Adiposity and cancer at major anatomical sites: umbrella review of the literature. BMJ. 2017;356

Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from http://handbook.cochrane.org .

Deeks JJ, Bossuyt PM, and Gatsonis C, Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy 2013, The Cochrane Collaboration: Available from: http://methods.cochrane.org/sdt/ . Accessed 15 Feb 2018.

Gentles SJ, et al. Reviewing the research methods literature: principles and strategies illustrated by a systematic overview of sampling in qualitative research. Systematic Reviews. 2016;5(1):172.

Weir MC, et al. Decisions about lumping vs. splitting of the scope of systematic reviews of complex interventions are not well justified: a case study in systematic reviews of health care professional reminders. J Clin Epidemiol. 2012;65(7):756–63.

Baker PR, et al. The benefits and challenges of conducting an overview of systematic reviews in public health: a focus on physical activity. J Public Health. 2014;36(3):517–21.

Stewart LA, et al. Preferred reporting items for a systematic review and meta-analysis of individual participant data: the PRISMA-IPD statement. JAMA. 2015;313(16):1657–65.

INVOLVE Exploring the impact of public involvement on the quality of research: examples. 2013.

Kreis J, et al. Consumer involvement in systematic reviews of comparative effectiveness research. Health Expect. 2013;16(4):323–37.

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Acknowledgements

The views and opinion expressed herein are those of the authors and do not necessarily reflect those of the funding bodies.

Research conducted by Harriet Hunt referred to within this paper [ 38 ] was supported as part of doctoral programme funding by the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care South West Peninsula (PenCLAHRC). The overview conducted by Pollock [ 3 ] was supported by a project grant from the Chief Scientist Office of the Scottish Government. The overview conducted by McClurg [ 5 ] was supported by a project grant by the Physiotherapy Research Foundation.

Alex Pollock is employed by the Nursing, Midwifery and Allied Health Professions (NMAHP) Research Unit, which is supported by the Chief Scientist Office of the Scottish Government. Pauline Campbell is supported by the Chief Nurses Office of the Scottish Government.

The overview conducted by Estcourt [ 7 ] was supported by an NIHR Cochrane Programme Grant for the Safe and Appropriate Use of Blood Components.

The overview conducted by Brunton [ 10 ] was commissioned by the Department of Health as part of an ongoing programme of work on health policy research synthesis.

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Harriet Hunt

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Pauline Campbell

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Lise Estcourt

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HH and AP wrote the original draft, with PC, LE and GB contributing sections and comments on following drafts of the manuscript. HH wrote the final manuscript with contributions from AP, PC, LE and GB. All authors read and approved the final manuscript.

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Hunt, H., Pollock, A., Campbell, P. et al. An introduction to overviews of reviews: planning a relevant research question and objective for an overview. Syst Rev 7 , 39 (2018). https://doi.org/10.1186/s13643-018-0695-8

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• Meta-analysis
• Systematized

Definition:

"A term used to describe a conventional overview of the literature, particularly when contrasted with a systematic review (Booth et al., 2012, p. 265).

Characteristics:

• Provides examination of recent or current literature on a wide range of subjects
• Varying levels of completeness / comprehensiveness, non-standardized methodology
• May or may not include comprehensive searching, quality assessment or critical appraisal

Mitchell, L. E., & Zajchowski, C. A. (2022). The history of air quality in Utah: A narrative review.  Sustainability ,  14 (15), 9653.  doi.org/10.3390/su14159653

Booth, A., Papaioannou, D., & Sutton, A. (2012). Systematic approaches to a successful literature review. London: SAGE Publications Ltd.

"An assessment of what is already known about a policy or practice issue...using systematic review methods to search and critically appraise existing research" (Grant & Booth, 2009, p. 100).

• Assessment of what is already known about an issue
• Similar to a systematic review but within a time-constrained setting
• Typically employs methodological shortcuts, increasing risk of introducing bias, includes basic level of quality assessment
• Best suited for issues needing quick decisions and solutions (i.e., policy recommendations)

Learn more about the method:

Khangura, S., Konnyu, K., Cushman, R., Grimshaw, J., & Moher, D. (2012). Evidence summaries: the evolution of a rapid review approach.  Systematic reviews, 1 (1), 1-9.  https://doi.org/10.1186/2046-4053-1-10

Virginia Commonwealth University Libraries. (2021). Rapid Review Protocol .

Quarmby, S., Santos, G., & Mathias, M. (2019). Air quality strategies and technologies: A rapid review of the international evidence.  Sustainability, 11 (10), 2757.  https://doi.org/10.3390/su11102757

Grant, M.J. & Booth, A. (2009). A typology of reviews: an analysis of the 14 review types and associated methodologies.  Health Information & Libraries Journal , 26(2), 91-108. https://www.doi.org/10.1111/j.1471-1842.2009.00848.x

Developed and refined by the Evidence for Policy and Practice Information and Co-ordinating Centre (EPPI-Centre), this review "map[s] out and categorize[s] existing literature on a particular topic, identifying gaps in research literature from which to commission further reviews and/or primary research" (Grant & Booth, 2009, p. 97).

Although mapping reviews are sometimes called scoping reviews, the key difference is that mapping reviews focus on a review question, rather than a topic

Mapping reviews are "best used where a clear target for a more focused evidence product has not yet been identified" (Booth, 2016, p. 14)

Mapping review searches are often quick and are intended to provide a broad overview

Mapping reviews can take different approaches in what types of literature is focused on in the search

Cooper I. D. (2016). What is a "mapping study?".  Journal of the Medical Library Association: JMLA ,  104 (1), 76–78. https://doi.org/10.3163/1536-5050.104.1.013

Miake-Lye, I. M., Hempel, S., Shanman, R., & Shekelle, P. G. (2016). What is an evidence map? A systematic review of published evidence maps and their definitions, methods, and products.  Systematic reviews, 5 (1), 1-21.  https://doi.org/10.1186/s13643-016-0204-x

Tainio, M., Andersen, Z. J., Nieuwenhuijsen, M. J., Hu, L., De Nazelle, A., An, R., ... & de Sá, T. H. (2021). Air pollution, physical activity and health: A mapping review of the evidence.  Environment international ,  147 , 105954.  https://doi.org/10.1016/j.envint.2020.105954

Booth, A. (2016). EVIDENT Guidance for Reviewing the Evidence: a compendium of methodological literature and websites . ResearchGate. https://doi.org/10.13140/RG.2.1.1562.9842 . 

Grant, M.J. & Booth, A. (2009). A typology of reviews: an analysis of the 14 review types and associated methodologies.  Health Information & Libraries Journal , 26(2), 91-108.  https://www.doi.org/10.1111/j.1471-1842.2009.00848.x

"A type of review that has as its primary objective the identification of the size and quality of research in a topic area in order to inform subsequent review" (Booth et al., 2012, p. 269).

• Main purpose is to map out and categorize existing literature, identify gaps in literature—great for informing policy-making
• Search comprehensiveness determined by time/scope constraints, could take longer than a systematic review
• No formal quality assessment or critical appraisal

Learn more about the methods :

Arksey, H., & O'Malley, L. (2005) Scoping studies: towards a methodological framework.  International Journal of Social Research Methodology ,  8 (1), 19-32.  https://doi.org/10.1080/1364557032000119616

Levac, D., Colquhoun, H., & O’Brien, K. K. (2010). Scoping studies: Advancing the methodology. Implementation Science: IS, 5, 69. https://doi.org/10.1186/1748-5908-5-69

Example : 

Rahman, A., Sarkar, A., Yadav, O. P., Achari, G., & Slobodnik, J. (2021). Potential human health risks due to environmental exposure to nano-and microplastics and knowledge gaps: A scoping review.  Science of the Total Environment, 757 , 143872.  https://doi.org/10.1016/j.scitotenv.2020.143872

A review that "[compiles] evidence from multiple...reviews into one accessible and usable document" (Grant & Booth, 2009, p. 103). While originally intended to be a compilation of Cochrane reviews, it now generally refers to any kind of evidence synthesis.

• Compiles evidence from multiple reviews into one document
• Often defines a broader question than is typical of a traditional systematic review

Choi, G. J., & Kang, H. (2022). The umbrella review: a useful strategy in the rain of evidence.  The Korean Journal of Pain ,  35 (2), 127–128.  https://doi.org/10.3344/kjp.2022.35.2.127

Aromataris, E., Fernandez, R., Godfrey, C. M., Holly, C., Khalil, H., & Tungpunkom, P. (2015). Summarizing systematic reviews: Methodological development, conduct and reporting of an umbrella review approach. International Journal of Evidence-Based Healthcare , 13(3), 132–140. https://doi.org/10.1097/XEB.0000000000000055

Rojas-Rueda, D., Morales-Zamora, E., Alsufyani, W. A., Herbst, C. H., Al Balawi, S. M., Alsukait, R., & Alomran, M. (2021). Environmental risk factors and health: An umbrella review of meta-analyses.  International Journal of Environmental Research and Public Dealth ,  18 (2), 704.  https://doi.org/10.3390/ijerph18020704

A meta-analysis is a "technique that statistically combines the results of quantitative studies to provide a more precise effect of the result" (Grant & Booth, 2009, p. 98).

• Statistical technique for combining results of quantitative studies to provide more precise effect of results
• Aims for exhaustive, comprehensive searching
• Quality assessment may determine inclusion/exclusion criteria
• May be conducted independently or as part of a systematic review

Berman, N. G., & Parker, R. A. (2002). Meta-analysis: Neither quick nor easy. BMC Medical Research Methodology , 2(1), 10. https://doi.org/10.1186/1471-2288-2-10

Hites R. A. (2004). Polybrominated diphenyl ethers in the environment and in people: a meta-analysis of concentrations.  Environmental Science & Technology ,  38 (4), 945–956.  https://doi.org/10.1021/es035082g

A systematic review "seeks to systematically search for, appraise, and [synthesize] research evidence, often adhering to the guidelines on the conduct of a review" provided by discipline-specific organizations, such as the Cochrane Collaboration (Grant & Booth, 2009, p. 102).

• Aims to compile and synthesize all known knowledge on a given topic
• Adheres to strict guidelines, protocols, and frameworks
• Time-intensive and often takes months to a year or more to complete
• The most commonly referred to type of evidence synthesis. Sometimes confused as a blanket term for other types of reviews

Gascon, M., Triguero-Mas, M., Martínez, D., Dadvand, P., Forns, J., Plasència, A., & Nieuwenhuijsen, M. J. (2015). Mental health benefits of long-term exposure to residential green and blue spaces: a systematic review.  International Journal of Environmental Research and Public Health ,  12 (4), 4354–4379.  https://doi.org/10.3390/ijerph120404354

"Systematized reviews attempt to include one or more elements of the systematic review process while stopping short of claiming that the resultant output is a systematic review" (Grant & Booth, 2009, p. 102). When a systematic review approach is adapted to produce a more manageable scope, while still retaining the rigor of a systematic review such as risk of bias assessment and the use of a protocol, this is often referred to as a  structured review  (Huelin et al., 2015).

• Typically conducted by postgraduate or graduate students
• Often assigned by instructors to students who don't have the resources to conduct a full systematic review

Salvo, G., Lashewicz, B. M., Doyle-Baker, P. K., & McCormack, G. R. (2018). Neighbourhood built environment influences on physical activity among adults: A systematized review of qualitative evidence.  International Journal of Environmental Research and Public Health ,  15 (5), 897.  https://doi.org/10.3390/ijerph15050897

Huelin, R., Iheanacho, I., Payne, K., & Sandman, K. (2015). What’s in a name? Systematic and non-systematic literature reviews, and why the distinction matters. https://www.evidera.com/resource/whats-in-a-name-systematic-and-non-systematic-literature-reviews-and-why-the-distinction-matters/

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Evidence on the ecological and physical effects of built structures in shallow, tropical coral reefs: a systematic map

• Avery B. Paxton   ORCID: orcid.org/0000-0002-4871-9167 1 ,
• Iris R. Foxfoot   ORCID: orcid.org/0009-0005-8950-9632 2 , 3 ,
• Christina Cutshaw   ORCID: orcid.org/0009-0008-5098-4892 1 , 4 ,
• D’amy N. Steward   ORCID: orcid.org/0000-0001-6816-0658 4 ,
• Leanne Poussard   ORCID: orcid.org/0000-0001-9992-7874 1 ,
• Trevor N. Riley   ORCID: orcid.org/0000-0002-6834-9802 5 ,
• Todd M. Swannack   ORCID: orcid.org/0000-0003-4261-9621 2 ,
• Candice D. Piercy   ORCID: orcid.org/0000-0001-9493-0775 2 ,
• Safra Altman   ORCID: orcid.org/0009-0004-3297-3488 2 ,
• Brandon J. Puckett   ORCID: orcid.org/0000-0001-9615-6242 1 ,
• Curt D. Storlazzi   ORCID: orcid.org/0000-0001-8057-4490 6 &
• T. Shay Viehman   ORCID: orcid.org/0000-0001-8505-665X 1  

Environmental Evidence volume  13 , Article number:  12 ( 2024 ) Cite this article

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Shallow, tropical coral reefs face compounding threats from climate change, habitat degradation due to coastal development and pollution, impacts from storms and sea-level rise, and pulse disturbances like blast fishing, mining, dredging, and ship groundings that reduce reef height and complexity. One approach toward restoring coral reef physical structure from such impacts is deploying built structures of artificial, natural, or hybrid (both artificial and natural) origin. Built structures range from designed modules and repurposed materials to underwater sculptures and intentionally placed natural rocks. Restoration practitioners and coastal managers increasingly consider incorporating – and in many cases have already begun to incorporate – built structures into coral reef-related applications, yet synthesized evidence on the ecological (coral-related; e.g., coral growth, coral survival) and physical performance of built structures in coral ecosystems across a variety of contexts (e.g., restoration, coastal protection, mitigation, tourism) is not readily available to guide decisions. To help fill this gap and inform management decisions, we systematically mapped the global distribution and abundance of published evidence on the ecological (coral-related) and physical performance of built structure interventions in shallow (≤ 30 m), tropical (35°N to 35°S) coral ecosystems.

To identify potentially relevant articles, we used predefined and tested strategies to search two indexing platforms, one bibliographic database, two open discovery citation indexes, one web-based search engine, one novel literature discovery tool, 19 organizational websites, and information requested from stakeholders. Discovered articles were screened according to preset eligibility criteria first by title and abstract and second by full text. Articles included during full text screening were coded to extract metadata following a predefined framework. We analyzed and visualized the evidence base to answer our primary and secondary research questions and to identify knowledge clusters and gaps. Findings are reported in a narrative synthesis.

Our search discovered > 20,000 potentially relevant unique articles, of which 258 were included in the systematic map. The evidence base spans 50 countries, and the volume of evidence increased over the past five decades. Built structures were most commonly installed for coral restoration (61%) or coastal protection (12%). Structures were predominately characterized as artificial (87%), with fewer hybrid or natural interventions. Evidence clusters existed for intentionally designed artificial structures and outcomes associated with coral-related ecological performance, including coral mortality, growth, recruitment, cover, and diversity. Pronounced evidence gaps occurred at the intersection of several ecological coral-related performance outcomes (e.g., connectivity, microbiome) across all types of built structures; gaps also existed across most ecological coral-related outcomes for artwork and repurposed artificial structures. Physical performance of built structures was most frequently evaluated for outcomes related to waves ( n  = 14) and sediment and morphology ( n  = 11) with pervasive evidence gaps across other outcomes like storm surge and water level.

Conclusions

While the systematic map highlighted several evidence clusters, it also revealed pronounced evidence gaps surrounding the coral-related ecological and physical performance of built structures in coral ecosystems. The compiled evidence base will help inform policy, management, and future consideration of built structures in reef-related applications, including habitat restoration, environmental mitigation, and coastal protection. Map findings also point to promising future research avenues, such as investigating seascape-scale ecological effects of and the physical performance of built structures.

Coral reefs provide extensive ecosystem services, including biodiversity benefits, coastal protection, and fisheries provisioning [ 1 ], yet face global declines from multiple threats [ 2 , 3 ]. Local threats include those from habitat degradation often linked to coastal development [ 4 ], overfishing [ 5 ], and pollution [ 6 , 7 , 8 ], as well as from disturbances like blast fishing [ 9 ], coral mining [ 10 ], dredging [ 11 ], and ship groundings [ 12 ]. Global impacts from climate change include coral mortality from ocean warming and associated bleaching [ 13 ], disease [ 14 ], and ocean acidification [ 15 ]. Climate change is also increasing the severity and frequency of storms that can further degrade coral reefs by breaking and dislodging coral [ 16 ] and increasing sedimentation, which reduces the potential for successful coral recruitment [ 17 , 18 ].

Strategies to slow or reverse declines in coral reefs often include restoration, such as direct transplantation of corals or larval enhancement [ 19 ]. Coastal managers and restoration practitioners are increasingly considering the incorporation of built structures into coral restoration design and implementation [ 20 ]. Here, we define built structures as those that have been engineered, designed, created, built, or constructed using artificial, hybrid, or natural materials. We define restoration broadly, following the UN Decade on Ecosystem Restoration, as “efforts to prevent, halt, or reverse the degradation of ecosystems” [ 21 , 22 ]. For coral reefs, this definition includes partial and holistic ecosystem recovery and thus actions aimed towards returning reefs to a historical state or creating new reefs [ 20 , 23 ]. Built structures have a centuries-long history of being deployed in the seascape for multiple objectives. For example, artificial reefs have been purposely sunk since the 1600s [ 24 ] to increase fishing yield, provide recreation opportunities, and conduct scientific research experiments, but in select cases have also been used specifically to restore coral reefs by creating, replacing, supplementing, enhancing, or stabilizing structured habitat [ 25 , 26 ]. These intentionally deployed structures include those that have been repurposed from their original uses (e.g., concrete pipes originally used in construction), as well as modules designed for particular contexts, such as restoration of target coral species or specific seascape settings [ 27 , 28 ]. In the past decade, underwater artwork installations have grown in popularity, as artwork and sculpture gardens have been commissioned and implemented to help restore corals and generate locations for recreational divers to enjoy [ 29 , 30 ] (1,000 Mermaids Artificial Reef Project, https://1000mermaids.com/ ).

Built structures have also been used for environmental mitigation and coastal protection purposes. Structures installed for environmental mitigation seek to address impacts from disturbances like blast fishing, ship grounding, coral mining, dredging, and storms, which can reduce reef height and complexity and create excess amounts of rubble that prevent survival of coral recruits [ 31 , 32 ]. In these instances, natural rock, hybrid structures (e.g., rock with cement, rock with mesh net), or human-made structures (e.g., concrete) have been deployed to provide habitat [ 33 ], stabilize rubble, and allow for recruit survival [ 31 ]. The role of coral reefs in providing coastal protection benefits has become increasingly apparent, as coral reefs can reduce wave energy by up to ∼ 97% where present [ 34 ] and thus provide ∼ $1.8 billion in hazard risk reduction benefits per year in the U.S. alone [ 35 , 36 ]. New initiatives have been launched to design engineered reefs for coastal protection. In Grenada, modular engineered structures were deployed to help reduce coastal erosion and flooding [ 37 ], whereas in southeast India, trapezoidal artificial modules were deployed to dissipate wave energy [ 38 ]. Newly funded Department of Defense projects in the U.S. aim to create hybrid reef structures that incorporate artificial (e.g., “gray) elements and natural (e.g., “green”) elements to mitigate flooding, erosion, and storm damage (Reefense, https://www.darpa.mil/program/reefense ).

Despite the history and increasing consideration of built structures for coral restoration and related applications like environmental mitigation and coastal protection, questions remain regarding how built structures should be considered in management and restoration decisions. For instance, how do built structures relate to coral growth, cover, and condition, and how do built structures relate to wave energy and storm surge? Central to these questions is that the global evidence base regarding the use and performance of built structures has not been collated or synthesized; but see syntheses for particular contexts, such as artificial reefs [ 26 ], substrate stabilization [ 31 ], and 3D technology for reef structures [ 39 ]. The lack of broadly synthesized evidence presents barriers to implementing management and policy decisions regarding future use of built structures in coral reef systems. Without synthesized evidence, it is more challenging for decision makers to rigorously and reproducibly evaluate the appropriateness of built structures for providing restorative, mitigative, or protective ecological outcomes in particular seascape settings.

The goal of this study was to collate evidence on coral-related ecological performance, as well as the physical performance, of built structure interventions in shallow, tropical coral reef settings. We use “built structures” as an umbrella term encompassing structures of artificial, hybrid, or natural origin. We use “hybrid” to describe structures that have both artificial (i.e., “gray”) and natural (i.e., “green) elements. This synthesis of knowledge will help inform practice for built structure design, siting, and implementation, including for nature-based solutions that can help address societal and ecological challenges, such as those related to scaling up and achieving successful habitat restoration and environmental mitigation, in coral reef settings. Because built structures have been used for multiple applications related to tropical coral reefs, such as for restoration, coastal protection, and environmental mitigation, we included evidence from these diverse bodies of literature. This will ensure that our synthesis stems from the most comprehensive body of relevant literature and will help ensure that findings from our synthesis can be used to help guide management decisions regarding the design, siting, and implementation of built structures in coral reef settings.

Stakeholder engagement

This systematic map was a joint effort by scientists from the National Oceanic and Atmospheric Administration (NOAA) National Centers for Coastal Ocean Science (NCCOS), the U.S. Army Corps of Engineers (USACE) Engineer Research and Development Center (ERDC), and the U.S. Geological Survey (USGS) Coastal and Marine Hazards and Resources Program (CMHRP). The core team of scientists from NOAA, USACE, and USGS developed the systematic map protocol to address stakeholder needs [ 40 ]. During the mapping process, we consulted additional stakeholders and scientists from the U.S. and internationally to ensure that international sources of primary literature were incorporated into the map.

Objective of the review

The objective of this systematic map was to document the global evidence base on the ecological and physical performance of built structures in shallow, tropical coral reef settings. The systematic map also aimed to summarize how evidence differs by built structure qualities, such as the type and material of intervention, as well as the goal and seascape setting.

The primary research question for the systematic map was: What is the distribution and abundance of evidence on the ecological and physical performance of built structures in shallow, tropical coral reef systems? The components of this primary question are:

Population : Coral reefs located in shallow, tropical coastal environments (≤ 30 m depth, 35 o N to 35 o S latitude).

Intervention : Built structures of artificial, hybrid, or natural origin established in coral systems.

Comparator : Studies that include a spatial or temporal comparator (presence vs. absence of built structure intervention, before vs. after built structure intervention, different types of built structure interventions, etc.) were included. Articles without comparators, but that did have qualifying outcomes measured at one point in time or at one spatial location, could be included because they provided valuable “snapshot” evidence. See ‘eligibility criteria’ for additional information.

Outcome : Ecological (coral-related – e.g., coral recruitment, coral mortality) or physical (e.g., waves, current, flooding) performance outcomes associated with built structure intervention.

Study type : Experimental, observational, or modeling studies with quantitative data on ecological or physical outcomes associated with the intervention. Studies could be conducted in the field or lab settings.

The evidence base used to answer the primary question also allowed us to investigate the following secondary questions:

How does the distribution and abundance of evidence on the performance of built structures used in coral reef-related applications differ by intervention type (e.g., artificial – designed structures, artificial – repurposed structures, artificial – artwork, hybrid structures of artificial and natural origin, and natural structures of geologic origin)?

For which materials (e.g., concrete, metal, rock, fiberglass) and types (e.g., reef modules, concrete pipes, natural rock, mesh over rubble) of built structures has the performance been evaluated?

For which ecological and physical outcomes has the performance of built structures used in coral reef-related applications been evaluated?

How does the distribution and abundance of evidence on built structures differ by intervention goal or context (e.g., restoration, environmental mitigation, coastal protection, tourism), seascape setting (e.g., depth, energetic environment, relative location on reef), spatial scale, and geographic region?

The protocol for this systematic map was published in Environmental Evidence in 2023 [ 40 ]. There were two deviations from the protocol. First, we conducted the database search following the initial round of peer-review but prior to protocol final acceptance and publication. Specifically, we received the initial peer-reviews of the systematic map protocol on April 7, 2023. Because the peer-reviews indicated that no changes to our search string would be required for mapping, we conducted the database search shortly thereafter from April 30, 2023 to May 3, 2023. We received a second round of protocol peer-reviews on July 25, 2023, which also required no changes to the database search. The protocol was officially accepted on August 10, 2023. We made the decision to execute the database search prior to final acceptance and publication of the protocol manuscript due to project timeline and staffing constraints but were prepared to modify the search strategy and rerun the search should any concerns or issues have been found during the peer-review process. We understood that this was a risk; however, we were confident with the quality of the search and that this had been confirmed in the initial round of the protocol peer-review process. Second, the organizational website Reef Base was not searched because the website was inaccessible. The systematic map followed evidence synthesis standards from the Collaboration for Environmental Evidence [ 41 ] and used the RepOrting standards for Systematic Evidence Synthesis (ROSES) [ 42 ] (Additional File 1 ).

Search for articles

The search for articles was conducted from April 30, 2023 to May 3, 2023 in Web of Science, Scopus, Lens, Dimensions, ProQuest, Google Scholar, and Inciteful. Organizational website searches were conducted during September 2023. All searches were performed in English. The geographic scope was global. There were no temporal scope constraints.

Search string

The search string was created using Web of Science syntax. The search string syntax was adapted for the other sources (Additional File 2 ). See the protocol [ 40 ] for details of search string development and testing.

Population terms: coral * AND Intervention terms: artificial* OR gray* OR grey* OR engineer* OR hybrid* OR design* OR construct* OR install* OR built* OR build* OR deploy* OR sink* OR sunk* OR sank* OR modul* OR structur* OR biorock* OR concrete* OR “reef ball*” OR ecoreef* OR “eco reef*” OR “eco-reef*” OR “mars assisted reef restoration*” OR “mineral accretion*” OR tetrapod* OR tetrahedron* OR trapezoid* OR “reef mattress*” OR “reef unit*” OR “reef star*” OR “reef spider*” OR print* OR fabricat* OR rebar* OR artwork* OR sculpt* OR monument* OR decommission* OR ship* OR pipe* OR tire* OR tyre* OR bridge* OR repurpose* OR “re-purpose*” OR eternal* OR “self-healing*” OR “self healing*” OR terracotta* OR clay* OR ceramic* OR tile* OR “human-made*” OR “human made*” OR “man-made*” OR “man made*” OR manmade* OR biomimic* OR mimic* OR “biogenic structure*” OR “biogenic material*” OR limestone* OR boulder* OR rubble* OR cobble* OR rock* OR unconsolidate* OR “natural material*” OR “natural structure*” OR “natural reef*” OR “nature based solution*” OR “nature based strateg*” OR “nature based defen$e*” OR “nature based protection*” OR “nature based coastal” OR “nature based shoreline*” OR “nature based mitigation” OR infrastructure* OR “nature based infrastructure” OR “hybrid infrastructure” OR “hybrid technique*” OR “natural climate solution*” OR “natural infrastructure” OR “eco* engineer*” OR “eco-engineer*” OR ecoengineer* OR “eco* friendly engineering” OR “ecosystem friendly engineering” OR bioengineer* OR “blue engineering” OR “green engineering” OR “building with nature” OR “engineering with nature” OR “working with nature” OR “nature derived solution*” OR “nature based feature*” OR “nature inspired solution*” OR “nature inclusive design*” OR “nature inspired design*” OR “nature derived design*” OR “ecosystem* based adaptation*” OR “ecosystem* based mitigation” OR “disaster risk reduction” OR “coastal defen$e*” OR “blue infrastructure” OR “green infrastructure” OR “ecosystem based disaster risk reduction” OR “hazard* mitigation*” OR “hazard* risk*” OR “coast* protect*” OR “reefense” OR “x-reef*” OR stabili$* AND restor* OR mitig* OR enhanc* OR creat* OR supplement* OR rehabilitat* OR protect* OR “damage reduc*” OR “risk reduc*” OR attenuat* OR “coastal defen$e*” OR stabili$* OR recover* OR resilienc* OR “hazard risk*” OR conserv* OR infrastructure* OR “nature based*” OR engineer* OR recreat* OR touris* OR dredg* OR ground* OR “blast fish*” OR mining* AND Ecological outcome terms: grow* OR cover* OR communit* OR rich* OR divers* OR surviv* OR settle* OR dens* OR recruit* OR abund* OR size* OR coloniz* OR rugos* OR complexit* OR “surface area*” OR volume* OR connectiv* OR dispers* OR disease* OR mortalit* OR fragment* OR breakage* OR condition* OR bleach* OR succession* OR bioaccumul* OR “bio-accumul*” OR “chemical concentrat*” OR “biological interact*” OR succession* OR competit* OR predat* OR mutual* OR commensal* OR facilitat* OR parasit* OR omniv* OR zooplank* OR herbiv* OR piscivor* OR invasiv* OR invad* OR calcific* OR skelet* OR accret* OR gene OR genes OR genetic* OR corridor* OR distribut* OR composit* OR tissue* OR extens* OR zooxanth* OR symbio* OR microb* OR microorgan* OR “micro organ*” OR physiol* OR respir* OR photosynth* OR photopigm* OR histol* OR metabol* OR friction* OR bathy* OR curv* OR aspect* OR slop* OR fertiliz* OR embryo* OR planulat* OR health* OR diamet* OR “coral watch” OR stabili$* OR struct* OR Physical outcome terms: wave* OR current* OR friction* OR rough* OR flood* OR inundat* OR protect* OR forc* OR eros* OR erod* OR “storm surge*” OR break* OR sediment* OR attenuat* OR energ* OR flux* OR reduc* OR mitig* OR defen* OR tide* OR tidal* OR “sea level*” OR “water level*” OR elevat* OR shoreline* OR scour* OR damp* OR amplif* OR expos* OR circulat* OR fetch* OR buffer* OR stress* OR velocit* OR speed* OR direction* OR magnitud* OR redistribut* OR compact* OR consolid* OR trap* OR retain* OR retent*

Comprehensiveness of the search

We identified 21 benchmarking articles to test against the search string in Web of Science and estimate the comprehensiveness of our search string. These articles were sourced from subject matter experts and our core research team. Of the 21 articles, 18 were indexed and thus available in Web of Science (Additional File 3 ). The three articles that were not indexed in Web of Science were found in other databases [ 43 , 44 , 45 ]. Our search string found 16 of the 18 articles that were indexed in Web of Science. The two articles that were indexed in Web of Science but were unable to be identified with our search string did not include terms related to the intervention in the title or abstract and so were thus undetectable. These two articles had been provided by the synthesis team and had case studies embedded within them. See the protocol for additional details on benchmarking [ 40 ].

Indexing platforms

We searched two indexing platforms, Web of Science (WOS) Core Collection and Scopus. The WOS search was conducted with five indexes:

SCI-Expanded (1980 - present).

SSCI (1980 - present).

CPCI-S (1990 - present).

CPCI-SSH (1990 - present).

ESCI (2018 - present).

Document types searched included articles, proceedings papers, early access, and data papers. The Duke University subscription was used for the WOS search. The Scopus search was conducted using the Duke University subscription with no filters.

Bibliographic databases

We searched the bibliographic database ProQuest Earth, Atmospheric and Aquatic Sciences Collection. Search indexes were.

Aquatic Sciences and Fisheries Abstracts.

Meteorological and Geoastrophysical Abstracts.

Earth, Atmospheric, and Aquatic Sciences Database.

Oceanic Abstracts.

Source types included scholarly journals, dissertations and theses, conference papers and proceedings, and reports. The Duke University subscription was used.

Open discovery citation indexes

Two open discovery citation indexes, LENS and Dimensions, were searched. The LENS search (lens.org) included four indexes:

Microsoft Academic.

LENS was searched for journal articles, conference proceeding articles, conference proceedings, dissertations, and reports. Dimensions was searched for articles and proceedings. No subscription was required for either.

Web-based search engine

We searched Google Scholar using Publish or Perish version 8 [ 46 ]. The simplified search string used for Google Scholar, due to limitations of this search engine, was:

(coral AND reef) AND (artificial OR gray OR grey OR engineer OR hybrid OR design OR construct OR install OR built OR build OR deploy OR infrastructure OR “nature based solution” OR “nature inspired design”).

We conducted a title search for up to 1,000 articles, as per guidance from Haddaway, Collins, Coughlin and Kirk [ 47 ].

Novel literature discovery tool

We searched Inciteful, an online novel literature discovery tool [ 48 ], to find additional articles. Inciteful was seeded using a .RIS file of the benchmarking articles, and the tool returned up to 1,000 most similar papers.

Organizational websites

Searches were conducted in the following 19 organizational websites from September 12–21, 2023:

Conservation International: https://www.conservation.org/ .

Coral Reef Alliance: https://coral.org/en/ .

Florida Department of Environmental Protection: https://floridadep.gov/ .

Global Coral Reef Alliance: https://www.globalcoral.org/ .

International Union for Conservation of Nature: https://www.iucn.org/ .

National Oceanic and Atmospheric Administration: https://www.noaa.gov/ .

Sea Grant: https://seagrant.noaa.gov/ .

The Nature Conservancy: https://www.nature.org/ .

United Nations Decade on Restoration: https://www.decadeonrestoration.org/ .

United Nations Development Programme: https://www.undp.org/ .

United Nations Environment Programme: https://www.unep.org/ .

United Nations Environment Programme World Conservation Monitoring Center: https://resources.unep-wcmc.org/ .

U.S. Army Corps of Engineers: https://www.usace.army.mil/ .

U.S. Geological Survey: https://www.usgs.gov/ .

U.S. Fish and Wildlife Service: https://www.fws.gov/ .

Wildlife Conservation Society: https://library.wcs.org/ .

World Bank: https://www.worldbank.org .

World Resources Institute: https://www.wri.org/ .

World Wildlife Fund: https://www.worldwildlife.org/ .

These searches were conducted using adapted and simplified search strings matching search functionality of each website (Additional File 4 ). The first 100 results from each website were screened in situ. In cases where articles were in a series and published the same data with updates over time, we included the most recent article only.

Call for literature

We conducted a call for literature by reaching out to 57 stakeholders, including resource managers, to request gray literature. These calls for literature were sent to experts in the US and US territories (Puerto Rico, US Virgin Islands), Australia, Spain, United Kingdom, France, Monaco, Israel, Saudi Arabia, and several international organizations between September 26 - October 2, 2023. In several instances, stakeholders shared reference libraries (e.g., .bib, .ris) with over 100 references; in these cases, we screened the first 100 results from each reference library in situ.

Assembling and managing search results

Search results from the indexing platforms, bibliographic database, open discovery citation indexes, web-based search engine, and novel literature discovery tool were downloaded as .RIS files. All .RIS files were imported into R version 4.2.2 [ 49 ], assigned a source (e.g., Web of Science, Scopus, LENS), and deduplicated using CiteSource [ 50 ]. The deduplicated references were exported from R as a .RIS file, which was then imported to EndNote version 21.2 [ 51 ] for manual deduplication. Deduplication was conducted following steps in McKeown and Mir [ 52 ]. Duplicates were merged but the record ID of the discarded duplicate was collated to the record ID of the retained duplicate for tracking. Articles from organizational websites and the call for literature were deduplicated during in situ screening and added to the final map .RIS file.

Article screening and study eligibility criteria

Screening process.

Screening was conducted in two stages, first by title and abstract and second by full text.

We used the software Swift-Active Screener (henceforth Swift) [ 53 ] for title and abstract screening. Swift uses a combination of screener feedback and a type of machine learning termed “active learning.” The active learning algorithm continuously incorporates screener feedback on which articles should be included or excluded based on the title and abstract screening decisions. The software then ranks the remaining unscreened articles in order of relevance. The most relevant articles are then prioritized for screening. We conducted title and abstract screening in Swift until the software’s “recall rate” reached 95%. The “recall rate” is the running estimate of the percentage of relevant articles that have been screened from the original set.

Four screeners (ABP, CC, DNS, LP) conducted title and abstract screening in Swift. Prior to screening, all screeners attended a training session (led by ABP) that provided background on the project and taught them how to screen and use Swift. During the session, 10 articles were screened together. Following the training session, everyone screened 10 articles independently; we then compared responses and discussed and resolved inconsistencies. The team then conducted a third screening exercise, where everybody screened an additional 30 articles independently, and again compared responses and discussed inconsistencies. Next, we evaluated inter-reviewer consistency on a set of 100 randomly selected articles. We used percent agreement to evaluate consistency, and each pair of reviewers achieved 95% or higher agreement, suggesting that single-screening was sufficient. Screeners were then authorized to begin screening in earnest; if a screener was unsure whether an article should be included or excluded, they marked the article as requiring a second opinion from another screener.

Following the completion of title and abstract screening in Swift, we randomly selected 500 articles using a custom R code to be rescreened for quality assurance and quality control. We manually rescreened the selected 500 articles at the title and abstract level. This number of articles was equivalent to 2.5% of the total number of deduplicated articles from database searches (19,434 articles, including those manually included, manually excluded, and excluded by the active learning algorithm) or 7.5% of the manually screened articles (6,643 articles manually included or excluded). There was one article that was originally excluded during title and abstract screening that we deemed potentially relevant and so changed to include. When we changed this article to include within Swift, the recall rate fell slightly below the 95% threshold, so we screened additional articles until our recall rate returned to ≥ 95%.

Full text screening was conducted in an online spreadsheet (detailed description below) so that our multi-institutional team could simultaneously screen individual articles. Full texts were stored in and accessed via EndNote. Screening was conducted by five screeners (ABP, CC, IF, DNS, LP). All screeners attended a training session (led by ABP) to learn how to conduct full text screening and to practice screening articles together. During full text screening, if a reviewer encountered uncertainties, the reviewer discussed these uncertainties with at least one other reviewer or in some cases the whole team to resolve the problem. Lessons learned from these discussions were noted and provided for the whole team. Following full text screening, we conducted quality assurance and quality control by independently rescreening 25 articles (5%). The 25 articles were randomly selected using a custom R code. This number of articles was equivalent to 5% of the total number of full text articles for which full texts (499) could be retrieved; it did not include articles from organizational websites or stakeholder contributed literature. During rescreening, the full texts were screened independently by a second reviewer. Any inconsistences were noted, discussed, and resolved. There were two articles that required changes to the full text screening decision; one article had a qualitative outcome in the discussion section, and the other had a nursery structure that reported on fish but also coral.

Eligibility criteria

Articles were screened using the following eligibility criteria.

Relevant population : The relevant population was coral reefs located in shallow tropical waters. We define shallow as ≤ 30 m. We define tropical waters as those between 35 o N and 35 o S latitude; this may include some water typically designated as subtropical depending on the latitudinal classification scheme. Reef types include atolls, fringing reefs, barrier reefs, and generic reefs. If a coral reef was created by a built structure intervention on sand, then it was included. Coral reefs located in deep waters or mesophotic zones were excluded. Reefs with substrate other than carbonate deposited by coral, such as rocky reefs or sponge reefs, were also excluded. All other marine, coastal, terrestrial, freshwater, and subterranean ecosystems were also excluded.

Relevant intervention : Relevant interventions used a built structure, such as those of: (1) Artificial or human-made origin, including structures engineered or designed for reef contexts with or without electricity, structures repurposed from their primary use, and those structures created as artwork; (2) Hybrid origin that are created from a combination of artificial and natural material, such as cement plus natural rock; (3) Natural origin from geologic sources, such as mined rock, limestone, or boulders. These interventions were related to coral reef-related applications, including restoration, remediation, mitigation, enhancement, rehabilitation, rebuilding, stabilization, providing coastal protection or defense, tourism and recreation, research, etc. These interventions were established in response to general habitat degradation and chronic disturbances or in response to pulse disturbances, like storms, blast fishing, dredging, mining, and ship groundings. Interventions using electrification and a built structure were included. Built interventions that were unintentional coral habitat were also included (see refined eligibility criteria below).

Relevant comparator : Studies with comparators over time or space. Comparators included: presence vs. absence of built structure intervention, before vs. after built structure intervention, different types of built structure interventions, different projects or sites with the same built structure intervention type, different reef types (e.g., built structure on fore- vs. back reef), built structure vs. natural coral reef. If articles did not have comparators, however, they could also be included. For instance, if an article measured coral cover on a built structure once but did not compare over space or time, the study contained valuable evidence and was thus eligible for inclusion.

Relevant outcome : Ecological and physical performance outcomes of built structure interventions that are measured, observed, or modeled. Ecological outcomes relate to coral and coral reef metrics, such as recruitment, growth, mortality, condition, rugosity, and cover. Ecological metrics related to biological interactions with coral were included. Physical outcomes relate to waves, currents, erosion, flooding, and other coastal processes. Performance outcomes could be related to the built structure or adjacent areas. For example, ecological outcomes like coral growing on the built structure or coral growing adjacent to the built structure were both be included.

Relevant study type : Experimental, modeling (statistical, theoretical, simulation), or observational studies with quantitative data. Field and lab studies were included. Reviews, meta-analyses, theoretical studies, commentaries, editorials, opinions, and perspectives were excluded. If lab studies occurred, the country where the laboratory was located could fall outside of the 35 o N and 35 o S latitude range.

Several special cases arose for which we refined eligibility criteria. For example, if nursery corals were outplanted onto a bare substrate or dead corals, this was excluded because the substrate was not considered built unless it was purposely placed. If a study examined coral recruitment on natural substrate but used settlement tiles to do so, it was excluded because the settlement tiles were used to measure natural recruitment rather than effects from a built structure; if settlement tiles were used on a built structure, however, they were included. We also refined our inclusion criteria to encompass interventions that were unintentional coral habitat. Unintentional built structures included accidental or historic shipwrecks. The unintentional category also included built structures, such as aquaculture infrastructure, that were not designed for coral reef-related applications but formed de facto coral habitat. Other unintentional examples that were included were seawalls or jetties not originally intended for restoration or other reef-related applications but that did contain measurements of coral growth, coral settlement, or other coral metrics. Additionally, if a study examined the performance of a built structure in a laboratory environment but did not feature coral, then it was excluded.

Study validity assessment

Study validity was not systematically assessed because this systematic map aimed to collate and summarize the distribution and abundance of evidence. During data coding, however, attributes were extracted that can be used for follow-up assessments of study validity for subsets of the evidence base.

Data coding strategy

Metadata from studies that passed full text screening were entered into a data “coding” spreadsheet. Each study corresponded to one row in the spreadsheet. These attributes included bibliographic information, as well as those related to the population, intervention, study type, comparator, and outcome (Additional File 5 ) and associated typologies (Additional File 6 ). Details of each attribute were provided in a code book that describes each attribute, instructions for data entry, and levels of categorical attributes that screeners could select from dropdown menus (Additional File 5 ). Data were coded according to information in the full text and supplementary materials; we did not contact authors to request missing information.

Three researchers (ABP, CC, DNS) piloted the codebook on 10 articles and discussed challenges and inconsistencies. The five data coders (ABP, CC, DNS, IF, LP) were trained on metadata extraction during the full text training session (led by ABP). We did not conduct double extraction because of the high number of articles that required coding. Instead, we discussed articles that were unclear or challenging. The coding tool was deployed in an online spreadsheet. After completing data coding, spot checks were conducted for 100% of the included coded articles discovered during the full database searches, call for literature, and organizational website searches. During spot checks, we checked for and corrected dissimilarities in spelling, deviations from pre-defined factor levels, ambiguous metadata, and any other uncertainties. Following spot checking, coded data were exported from the online spreadsheet as a .csv and imported to R for analysis and visualization.

Data mapping method

Coded data were analyzed in R version 4.2.2 [ 49 ] to answer the primary and secondary research questions. We provided an overview of the review process using the ROSES flow diagram [ 54 ]. We then visualized the evidence base by descriptive information (e.g., publication type, publication date, geography), coral reef types, seascape settings, built structure intervention types, study types, and ecological and physical outcomes. We also compiled heatmaps where ecological and physical outcomes (rows) were mapped against built structure intervention types (columns) to assess evidence clusters and evidence gaps. All visualizations were created using ggplot2 [ 55 ].

Review findings

Systematic mapping process.

The number of articles returned during each stage in the systematic map process is reported in the ROSES flowchart (Fig.  1 ). Database searches returned 50,480 potentially relevant records. Scopus returned the highest number of records ( n  = 11,226), followed by Dimensions ( n  = 10,896), LENS ( n  = 9,723), Web of Science ( n  = 9,227), and ProQuest ( n  = 7,924). The web-based search engine Google Scholar yielded 990 records, and the novel search tool Inciteful [ 48 ] discovered 494 records. After deduplicating articles across the databases, 19,494 articles remained ( n  = 30,986 duplicates) and were screened at the level of title and abstract. During title and abstract screening, 536 articles were included, and a high proportion of articles were excluded ( n  = 18,958) either by manual screening ( n  = 6,107) or machine learning ( n  = 12,851) using Swift Active Screener [ 53 ]. Of the 536 articles that passed title and abstract screening, full texts were retrievable for 499 ( n  = 37 unretrievable; Additional File 8 ). During full text screening, 188 articles were included and 311 were excluded. Articles were excluded during full text screening because they were not in English ( n  = 76), did not meet our criteria for a coral reef population ( n  = 68), did not have a built structure intervention ( n  = 63), were the improper study type ( n  = 37), were duplicates that had been missed at the previous step or reported on the same content using a slightly different title or format (e.g., report vs. journal article) ( n  = 36), or did not have eligible ecological or physical outcome ( n  = 31).

ROSES flowchart depicting the number of articles returned from the initial search and included during each stage in the map process. Flowchart from Haddaway, Macura, Whaley and Pullin [ 54 ]

Outside of database searches, articles were sourced from organizational website searches and a call for stakeholder contributed literature. Organizational website searches yielded 1,242 potentially relevant articles; 11 articles were included based on in situ screening. Calls for literature contributions from stakeholders retuned 281 potentially relevant articles, of which 59 were included based on in situ screening.

In total, 258 articles ( n  = 188 from databases, n  = 11 from organizational websites, and n  = 59 from stakeholder-contributed literature; full bibliography Additional File 7 ) were included in the systematic map after full text screening; these articles are included in the systematic map database and narrative synthesis. The bibliography of excluded articles and their exclusion reasons is in Additional File 8 . Coded data for included articles is in Additional File 9 . The ROSES reporting form is in Additional File 1 . In the descriptive results reported below on publication information, reef type, seascape setting, intervention types, study types, and outcomes, articles can appear in more than one category (e.g., an article can contribute to the sample size for multiple categories, so the total sample size can be greater than the number of total articles (258)).

Descriptive information

Publication type.

The majority (72.1%) of articles in the map were peer-reviewed publications ( n  = 186; Fig.  2 A). Reports comprised 13.6% ( n  = 35) of the evidence base and proceedings 4.3% ( n  = 11). The remaining 10.0% were several MS theses, PhD dissertations, white papers, and book chapters.

Number of articles by ( A ) publication type, ( B ) publication year, and ( C ) country. For ( B ), Red asterisk in panel B denotes a partial year for 2023, which is when the search was conducted. For ( C ), countries that are not in blue denote 0 articles. Dashed lines indicate 35°N to 35°S latitudes, as well as the equator. Some European countries that are outside of the 35°N to 35°S latitudinal range contain evidence either because ex-situ studies were conducted in these countries or because in-situ studies occurred in associated locations, such as Little Cayman for the United Kingdom; see Table  1 for additional details

Publication year

The number of articles published per year increased over the past five decades (Fig.  2 B); the earliest published article was from 1974. There were 3 articles published in the 1970s, zero in the 1980s, and 8 in the 1990s. At the turn of the century, the number of published articles grew, totaling 69 in the 2000s and 104 in the 2010s; there have been 73 publications so far in the 2020s. The two most recent years, 2021 and 2022, had the highest annual number of publications to date, 28 and 18, respectively. The year 2023 is incomplete because the search ended before the end of the calendar year; database searches were completed in April 2023 and organizational websites were searched in September 2023.

Publication geography

The evidence base stemmed from 50 countries (Fig.  2 C; Table  1 ). The countries where the research occurred with the most articles were the United States ( n  = 68), Indonesia ( n  = 30), Israel ( n  = 18), Singapore ( n  = 12), Australia ( n  = 10), and Philippines ( n  = 10). These top six countries represent  ∼  56% of the total evidence base.

Coral reef types examined

Coral reefs populations were classified by reef type, reef geological zone, and reef geomorphological zone according to a USGS and NOAA coral reef classification scheme based on Coyne, et al. [ 56 ], Kendall, et al. [ 57 ], and Cochran et al. [ 58 ]. The majority of articles did not report reef type ( n  = 224), geological zone ( n  = 221), or geomorphological zone ( n  = 166) (Fig.  3 ). Of the articles that did specify, most evidence stemmed from reef types classified as fringing reefs ( n  = 24) (Fig.  3 A) and geological zones classified as reef flats ( n  = 19) (Fig.  3 B). The geomorphological structures were commonly sand ( n  = 56), reef rubble ( n  = 28), or patch reef ( n  = 23) (Fig.  3 C).

Number of articles by coral reef population characteristics: ( A ) reef type, ( B ) reef geological zone, ( C ) reef morphological structure. Some articles contained more than one population, so articles can appear in more than one category within each panel. “N/A” indicates the number of articles where the reef characteristic was unspecified; for reef type (A), sand is included within “N/A”

Seascape settings of studies

The seascape setting of the coral reefs and their built structure interventions included the water depth, reef vertical relief, and reef energy regime (Fig.  4 ). The majority of articles reported on reefs that were at depths ≤ 10 m ( n  = 155; Fig.  4 A). There were 45 articles on reefs 11–20 m deep, and 13 articles on reefs 21–30 m deep (Fig.  4 A); we selected three equally divided depth bins based on our predefined maximum eligible reef depth of ≤ 30 m. Most studies did not report either the reef vertical relief ( n  = 236) or reef energy regime ( n  = 245). Of studies that did report the relief and energy regime, more occurred on low relief ( n  = 21) than high relief reefs ( n  = 5) (Fig.  4 B); more studies also took place on high energy reefs ( n  = 9) than low energy reefs ( n  = 3) (Fig.  4 C). The reef relief and reef energy categories were assigned based on qualitative descriptors in the articles.

Number of articles by seascape setting: ( A ) depth (m), ( B ) reef vertical relief, and ( C ) reef energy regime. Some articles contained more than one population, so articles can appear in more than one category within each panel. If a study reported more than one depth or depth range, then depths were averaged. “N/A” indicates the number of articles where the seascape setting was unspecified

Characteristics of built structure interventions

Built structure interventions spanned a variety of goals, structure types, structure materials, and proprietary structure names (Fig.  5 ).

Number of articles by built structure intervention characteristics: ( A ) context, ( B ) type, ( C ) material, and ( D ) proprietary name. Some articles contained more than one built structure intervention, so articles can appear in more than one category within each panel. “N/A” indicates the number of articles where the intervention characteristic was unspecified. Abbreviations for the proprietary names are defined as: HSAR = Hemispherical Shape Artificial Reefs, WAD = Wave Attenuation Device, SHED = Sheppard Hill Energy Dissipator, MARRS = Mars Assisted Reef Restoration System

Most of the interventions were installed for coral restoration ( n  = 156; 60.7%; Fig.  5 A). Another common intervention goal was to achieve coastal protection ( n  = 30; 11.7%) against waves energy and sediment changes. Other interventions were unintentional and so had no specific goal ( n  = 30; e.g., ship sunk accidentally), whereas some were installed for environmental mitigation ( n  = 26), habitat creation ( n  = 7), tourism and recreation ( n  = 6), or artwork ( n  = 2).

Built structures were classified as either artificial ( n  = 224), hybrid ( n  = 28), or natural ( n  = 22) (Fig.  5 B). Of the artificial structures, most were designed ( n  = 172), but some were unintentional so lacked a priori design for reef-related applications ( n  = 28), such as historic shipwrecks and aquaculture infrastructure; others were designed and supplemented with electricity ( n  = 19; e.g., mineral accretion technology). Hybrid structures were mainly designed ( n  = 25), but several ( n  = 3) [ 59 , 60 , 61 ] were unintentional. One structure was called an artificial reef, but it was unclear whether it was artificial, hybrid, or natural in origin ( n  = 1 for unspecified – n/a).

The most common built structure materials were concrete ( n  = 132), followed by metal ( n  = 96), rock ( n  = 69), and plastic ( n  = 53) (Fig.  5 C). Natural built structures were rocks and boulders, primarily composed of limestone.

Proprietary name

Some of the built structures were proprietary, such as Reef Balls ( n  = 16), Biorock ( n  = 8), and MARRS Reef Spiders ( n  = 7) (Fig.  5 D).

Study types

The evidence base contained a high number of observational studies ( n  = 174) and experimental studies ( n  = 126). Modeling or simulation studies were less common ( n  = 10) (Fig.  6 A). Some studies did not have comparators ( n  = 64; Fig.  6 B). Of the studies with comparators, most compared different types of built structure interventions to each other ( n  = 73), the presence or absence of built structures ( n  = 54), or tracked built structures over time ( n  = 45). Other studies compared the same types of built structures across spatial scales ( n  = 23), built structures to natural or green systems ( n  = 18, e.g., reef module versus natural coral reef), built structures in different habitat types ( n  = 11; e.g., reef modules in high energy environment vs. low energy environment or reef modules in urban versus natural settings), before versus after built structures ( n  = 9), and built versus fully gray infrastructure ( n  = 1; e.g., reef module versus bulkhead not intended for coral reef-related applications). The geographic scale of the studies was frequently local ( n  = 234), although there were several regional ( n  = 21), global ( n  = 3), and national ( n  = 2) studies (Fig.  6 C). Only 23 studies or 8.9% reported the cost of the built structure intervention (Fig.  6 D).

Number of articles by for ( A ) study type, ( B ) study comparator type, ( C ) study geographic scale, and ( D ) whether study reported cost. Some articles contained more than one study type or comparator, so articles can appear in more than one category within each panel. Comparators are: “structure type” compares different types of built structure interventions, “presence v. absence” compares the presence or absence of built structure; “temporal” tracks built structures over time, “none” is no comparator, “spatial” compares built structures at different sites or from different projects, “built v. green” compares a built structure intervention to a green or natural structure, “before v. after” compares before built structure construction to after, “habitat type” compares built structures in different habitat types, “built v. gray” compares a built structure to a fully gray intervention

Ecological and physical performance outcomes examined

More articles examined the coral ecological performance outcomes of built structures ( n  = 431) than physical performance outcomes ( n  = 27). The most frequently studied coral ecological outcomes were coral growth ( n  = 90), coral mortality ( n  = 88), coral cover ( n  = 69), coral recruitment ( n  = 68), and coral diversity ( n  = 57; Fig.  7 A). Several coral ecological outcomes – physiology, microbiome, connectivity, calcification, bioaccumulation – were not represented in the evidence base. Only three types of physical performance outcomes were studied – those related to waves ( n  = 13), sediment and morphology ( n  = 11), and currents ( n  = 3). Wind, water level, and storm surge were not assessed in the identified evidence base.

Number of articles by ( A ) outcome category and ( B ) outcome evaluation time. Outcome types for coral ecological outcomes and physical outcomes ( A ) are colored by the outcome directionality and faceted by whether the outcome is ecological (top panel) or physical (bottom panel). Outcome directionality (e.g., positive and negative) does not infer statistical significance. Outcome evaluation times ( B ) are relative to built structure construction, where time periods are the number of years following construction. Some articles contained more than one outcome, so articles can appear in more than one category within each panel. “N/A” indicates the number of articles where the outcome evaluation time period was unspecified

Performance outcomes were evaluated using multiple metrics common to ecology and to physical sciences (Table  2 ). Popular metrics used to quantify ecological diversity, for example, included species diversity, species evenness, species richness, and community composition. For currents, current speed and magnitude were commonly evaluated physical metrics. The methods used to evaluate ecological outcomes often relied upon in situ visual transects, photograph surveys, and video surveys (Table  3 ). Several studies used settlement tiles and microscope analysis. Some studies employed less common evaluation methods like habitat mapping and eDNA sampling.

Most articles reported on outcome evaluations within a year of construction ( n  = 139) or up to five years following construction ( n  = 110; Fig.  7 B). Fewer articles presented longer-term outcome evaluations up to 10 years post construction ( n  = 27) or more than 10 years post construction ( n  = 43). Outcome evaluations indicate that the directionality of evidence (e.g., positive, negative, neutral, or mixed) varied (Fig.  7 A). In some cases, the performance of the structure was positive, whereas in others it was negative, neutral, or mixed (both positives and negatives reported). For instance, if there were enhanced ecological outcomes (e.g., increased growth, decreased mortality, increased diversity), then the directionality of evidence was coded as “positive.” Following this coding approach, evidence related to coral mortality was mixed in 50 cases, positive in 29, negative in 4, and neutral in 5. Likewise, if there were enhanced physical outcomes (e.g., reduced wave attenuation, reduced erosion) then the outcome was coded as “positive.” For waves, evidence was mixed in 7 instances and positive in 6.

Intersection of built structure interventions and ecological performance outcomes

Evidence clusters were most pronounced for coral ecological performance outcomes on artificial structures that were designed (without electricity or mineral accretion technology) for reef-related applications (Fig.  8 ). For example, the largest evidence clusters on artificial designed structures were for coral mortality ( n  = 66), growth ( n  = 64), recruitment ( n  = 57), cover ( n  = 40), and diversity ( n  = 26). Artificial structures that were designed with electricity had a moderate amount of evidence for coral growth ( n  = 13) and mortality ( n  = 10); artificial unintentional structures had a moderate amount of evidence for cover ( n  = 13) and diversity ( n  = 13). Hybrid structures had a moderate amount of evidence for diversity ( n  = 9), recruitment ( n  = 9), and growth ( n  = 8). The most pronounced gaps were for particular outcomes (e.g., connectivity, physiology, bioaccumulation, calcification) without evidence across all built structure types, as well as for artificial artwork ( n  = 2 outcomes), artificial repurposed ( n  = 6 outcomes), and hybrid unintentional ( n  = 4) outcomes.

Distribution of evidence (number of articles) across built structure intervention types and coral ecological outcomes. Some articles contained more than one intervention or outcome, so articles can appear in more than one cell. Blank cells have zero articles. Top row and far right column provide total values across intervention types and coral ecological outcomes, respectively

Intersection of built structure interventions and physical performance outcomes

Evidence on the physical performance of built structures was relatively sparse (Fig.  9 ). Most evidence stemmed from outcomes related to waves ( n  = 8) and sediment and morphology ( n  = 6) on artificial built structures designed for reef-related applications. There was sparse evidence related to currents ( n  = 2) on artificial built structures, as well as for wave outcomes ( n  = 3) on hybrid structures. Unintentional artificial built structures were rarely evaluated for sediment and morphology ( n  = 1) and current ( n  = 1) outcomes, as were artificial structures designed with electricity (waves n  = 2, sediment and morphology n  = 2). Similarly, natural structures were rarely evaluated for waves ( n  = 1) and sediment and morphology ( n  = 2). Complete gaps in evidence exist at all other intersections of built intervention types and physical outcomes.

Distribution of evidence (number of articles) across built structure intervention types and physical outcomes. Some articles contained more than one intervention or outcome, so articles can appear in more than one cell. Blank cells have zero articles. Top row and far right column provide total values across intervention types and physical outcomes, respectively

Evidence clusters and gaps

The systematic map provides an up-to-date published evidence base on the ecological (coral-related) and physical performance of built structures for reef-related applications in shallow coral ecosystems through 2022 and partially through 2023, when the search was conducted. Map findings highlight the distribution and abundance of evidence by publication type, year, and country, as well as characteristics of the coral reef population, built structure intervention, comparator, and outcomes. Taken together, our findings highlight several evidence clusters related to the ecological performance of designed artificial structures for coral, but also a multitude of evidence gaps. Evidence gaps were most pronounced across physical outcomes on all types of built structures, as well as for some ecological outcomes especially on artwork and repurposed structures. The compiled evidence base can help guide manager consideration of whether and how to incorporate built structures into coral-reef related applications, such as restoration, coastal protection, and environmental mitigation. Here, we discuss implications of our findings on the evidence base related to the built structure goal, structure type, and materials. We then highlight the ecological and physical gaps and limitations of the map.

Goal of built structures

The abundance of evidence differed according to the intervention goal. Most built structures were installed to meet coral restoration goals. These goals largely match those reported for broader coral restoration by Bayraktarov, et al. [ 62 ], such as to experimentally test restoration approaches and their effectiveness. For example, designed artificial structures called Reef Balls were deployed in the Netherlands Antilles [ 45 ], and three-dimensional printed ceramic tiles were deployed in Israel [ 44 ] to evaluate coral recruitment and thus explore the potential of built structures to serve as restoration tools. The abundance of evidence related to coral restoration is not surprising since our eligibility criteria required that ecological outcomes relate to coral or coral reef metrics, which are often measured in restoration projects. The moderate amount of evidence related to coastal protection mainly stemmed from laboratory experiments or modeling (e.g., [ 63 , 64 , 65 , 66 ]). with the exception of several field studies (e.g., [ 65 , 67 , 68 ]). This demonstrates a gap in scaling up built structures for coastal protection in coral ecosystems, similarly highlighted by Viehman, et al. [ 20 ]. Built structures related to environmental mitigation, such as in the aftermath of blast fishing, ship grounding, or dredging, accounted for fewer articles than expected. We hypothesize that this is because many environmental mitigation articles exist only in white papers. We were able to discover some of these through our literature solicitation to stakeholders (e.g., [ 69 , 70 ]), but others likely exist that were not captured in our map. Few articles included interventions related to artwork or tourism and recreation, suggesting that when built structures are installed for these purposes, they may not be monitored at all, or may be monitored for other outcomes (social, economic, ecological – fish; for example) rather than ecological (coral) or physical outcomes (e.g., [ 71 , 72 ]). Unintentionally deployed structures were also included in the map and provided a moderate amount of evidence; these often included ships sunk accidentally (e.g., [ 60 , 73 ]); see Lemasson, et al. [ 74 ] for a meta-analysis on ecological effects of anthropogenic structures, including accidental shipwrecks.

Type and material of built structures

The distribution of evidence varied by built structure type, but the overwhelming majority of evidence was from artificial structures. This may relate to the historic use of artificial reefs for habitat enhancement in coral ecosystems and other ecosystems [ 25 , 75 , 76 ] and the rising amount of artificial or gray infrastructure across coastal habitats [ 77 ]. However, growing calls for incorporation of nature-inspired and gray-green (i.e., hybrid with both artificial and natural elements) designs have produced a moderate amount of evidence on hybrid structures to date [ 78 , 79 , 80 , 81 ]. For example, Miller, et al. [ 82 ] evaluated the ecological performance of hybrid restoration structures in the Florida Keys that were created from limestone and concrete, and Blakeway et al. [ 83 ] assessed the ecological performance of limestone and concrete reef modules following nearby land reclamation. Despite these case studies, the overall abundance of evidence on hybrid structures was eight times less than that of artificial evidence. Natural structures had the least amount of evidence; when evidence existed, it usually related to the introduction of structures of geological origin, such as limestone rocks or boulders (e.g., [ 84 , 85 ]).

The most common built structure materials for artificial and hybrid interventions were concrete and metal, which matches a recent analysis of materials used in U.S. ocean artificial reefs managed by states [ 86 ]. We did find evidence that three-dimensional printed materials, often composed of plastic, are becoming more common [ 87 , 88 , 89 ]. This likely reflects recent innovations in the interdisciplinary engineering of built structures for coral restoration and related applications. There were multiple articles that evaluated proprietary structures, such as Reef Balls or Biorock, but overall, there was a diversity of structures that varied in size, shape, and material reflecting a mix of established structures and more recently developed structures.

Ecological and physical performance of built structures

Ecological evaluations of coral primarily focused on several outcomes with the complete absence of others. Outcomes such as coral mortality, coral growth, coral cover, and coral recruitment were studied repeatedly using metrics like percent cover, percent mortality, growth rate, and coral size and methods like video, photo, or visual transect surveys. The coral outcomes that were not evaluated were largely broader seascape outcomes, such as connectivity, or fine scale outcomes, such as microbiome, physiology, and calcification. This suggests that the evidence base on the ecological performance of built structures for coral is concentrated on population or community level outcomes and that gaps exist in seascape level, and in some cases, individual level outcomes. Multiple studies have been conducted on how built structures relate to fish population or community seascape patterns [ 90 , 91 , 92 ], and so this could be extended to examine coral seascape outcomes associated with built structures. Additionally, whereas the microbiome of epifauna on artificial reefs [ 93 ] and the microbiome of bacteria in the sediment surrounding artificial reefs [ 94 ] have been investigated, there is a lack of information on coral microbiomes on built structures. Our systematic map focused on ecological outcomes of built structures associated with coral, but there are other coral-reef related organisms and associated metrics across ecological scales that were beyond the scope of this map.

The pronounced evidence gaps in physical outcomes associated with built structures fits with recent calls for increased consideration of the physical performance of coral reefs, especially within coastal resilience frameworks [ 20 ]. Our systematic map findings reinforce the need for additional research on physical performance of built structures for reef-related applications. During article screening, we did find numerous studies that evaluated the physical performance of built structures in lab settings; however, because these studies often did not include corals, they did not meet the coral ecosystem requirement and were thus excluded (e.g., [ 95 , 96 ]). This highlights a gap, where built structure physical performance is often monitored in lab settings without coral, whereas field studies typically focus on ecological coral-associated outcomes rather than physical outcomes. Future research could consider expanding our map to examine physical outcomes of built structures without coral in lab settings. Moreover, built structures are often evaluated solely for ecological or solely for physical outcomes; additional research could harness interdisciplinary collaborations to examine both ecological and physical outcomes simultaneously [ 20 ].

Limitations of the map

We recognize several potential sources of bias in our systematic map. First, we restricted our search to English language due to resource constraints. Although our map includes evidence from 50 countries, we were unable to conduct full text screening on 76 articles because they were not in English. To help reduce bias, we ensured that our solicitation for contributed literature was shared outside of English-speaking countries with stakeholders from Spain, France, Monaco, Israel, Saudi Arabia, and several international organizations. Despite these measures, there is likely bias in our map towards English-speaking countries. Future efforts could broaden the evidence base by incorporating non-English language articles.

Second, we conducted single screening, which may have introduced bias into the systematic map. Single screening was necessary because of resource constraints and the high number of expected articles ( ∼  20,000 after deduplication). We took several steps to maximize inter-reviewer consistency, including holding rigorous screening training sessions, evaluating inter-reviewer consistency with a random selection of articles, conducting double screening on a subset of articles, and flagging articles for a second opinion when a screener was unsure whether to include or exclude. These measures likely helped reduce bias.

Third, we used software with a machine learning algorithm to assist with title and abstract screening. The algorithm in the software Swift Active Screener incorporates screener feedback on which articles are marked as relevant or irrelevant [ 53 ]. The algorithm then ranks and shuffles unscreened articles in order of relevance for priority screening. We conducted screening until the software “recall rate” reached 95%. This approach has been tested and accepted in medical science evidence syntheses [ 97 , 98 ]. It is possible, however, that using Swift Active Screener introduced bias into the systematic map if articles were overlooked by the algorithm and ranking system.

Implications for policy and management

Our map highlights several evidence clusters that can be used to help guide management decisions related to the use of built structures in coral reef ecosystems. For example, clusters of evidence on coral outcomes associated with designed artificial structures can be used by stakeholders including coral restoration managers and practitioners, environmental mitigation teams, coastal protection and resilience specialists, and artificial reef managers to help inform decisions. We caution, however, that the coral-related ecological performance of built structures is likely location-specific, as has been found for fish communities [ 75 ]. Managers should take utmost caution when extrapolating results from one geographic location to another or from one built structure material or type to another. Our map also reveals that the lack of information on the physical performance of coral reefs may impede the ability of the management community to make informed decisions. The type of decisions that may be impeded by the lack of evidence relate to the potential of built structures in coral ecosystems to provide coastal protection services, such as attenuating wave energy, reducing current magnitude, or decreasing storm surge. There is a great push, however, to utilize coral reef restoration for coastal protection [ 99 , 100 ], which has large financial implications as it would allow for millions of dollars in pre-disaster mitigation or billions of dollars of post-disaster recovery funding for coral reef restoration. Despite this push, additional evidence stemming from lab and field studies will be needed to help better inform decisions on how to actively use built structures for coastal protection purposes. A systematic review and accompanying meta-analysis could also help determine the potential study bias and effect sizes associated with built structures and ecological and physical performance outcomes.

Implications for research

Our systematic map findings can be used for a systematic review. There may be sufficient evidence to evaluate the ecological performance of artificial designed structures for coral mortality ( n  = 66), coral growth ( n  = 64), coral recruitment ( n  = 57), coral cover ( n  = 40), coral diversity ( n  = 26). A systematic review could also evaluate the ecological performance of coral diversity, recruitment, and cover across different types of built structures. There is likely not enough evidence to conduct a quantitative synthesis, such as a meta-analysis, on physical performance of built structures, as the highest concentration of evidence was 14 studies for outcomes related to waves. Future research could combine ecological and physical performance assessments of built structures and should focus on understanding effects of built structures across broader spatial and temporal scales. Key gaps remain in our understanding of how built structures perform across seascape scales, for example, but gaps also remain in our understanding of individual coral outcomes like microbiome and physiology. Future efforts can help strategically fill gaps in understanding physical outcomes of built structures by installing built structures as part of scaled field experiments and conducting in situ monitoring to determine changes in waves, currents, wind, and water level that may relate to the built structure. Study designs could compare different types of built structures but could also compare the presence vs. absence of built structures to help disentangle performance. Such studies could include teams with diverse subject matter expertise and skillsets to study both ecological and physical performance of built structures.

Data availability

Not applicable.

Woodhead AJ, et al. Coral reef ecosystem services in the Anthropocene. Funct Ecol. 2019. https://doi.org/10.1111/1365-2435.13331 .

Article   Google Scholar  

Eddy TD, et al. Global decline in capacity of coral reefs to provide ecosystem services. One Earth. 2021;4:1278–85.

Hughes TP, et al. Coral reefs in the Anthropocene. Nature. 2017;546:82–90.

Article   CAS   Google Scholar  

Heery EC, et al. Urban coral reefs: degradation and resilience of hard coral assemblages in coastal cities of East and Southeast Asia. Mar Pollut Bull. 2018;135:654–81.

Zaneveld JR, et al. Overfishing and nutrient pollution interact with temperature to disrupt coral reefs down to microbial scales. Nat Commun. 2016;7:11833.

Lapointe BE, Brewton RA, Herren LW, Porter JW, Hu C. Nitrogen enrichment, altered stoichiometry, and coral reef decline at Looe Key, Florida Keys, USA: a 3-decade study. Mar Biol 166 (2019).

Zhao H et al. Impacts of nitrogen pollution on corals in the context of global climate change and potential strategies to conserve coral reefs. Sci Total Environ 774 (2021).

Nalley EM, et al. Water quality thresholds for coastal contaminant impacts on corals: a systematic review and meta-analysis. Sci Total Environ. 2021;794:148632.

Williams SL, et al. Large-scale coral reef rehabilitation after blast fishing in Indonesia. Restor Ecol. 2018;27:447–56.

Clark S, Edwards AJ. Use of artificial reef structures to rehabilitate reef flats degraded by coral mining in the Maldives. Bull Mar Sci. 1994;55:724–44.

Google Scholar  

Erftemeijer PL, Riegl B, Hoeksema BW, Todd PA. Environmental impacts of dredging and other sediment disturbances on corals: a review. Mar Pollut Bull. 2012;64:1737–65.

Raymundo LJ, Licuanan WY, Kerr AM. Adding insult to injury: ship groundings are associated with coral disease in a pristine reef. PLoS ONE. 2018;13:e0202939.

Hughes TP, et al. Global warming and recurrent mass bleaching of corals. Nature. 2017;543:373–7.

Howells EJ, Vaughan GO, Work TM, Burt JA, Abrego D. Annual outbreaks of coral disease coincide with extreme seasonal warming. Coral Reefs. 2020;39:771–81.

Cornwall CE et al. Global declines in coral reef calcium carbonate production under ocean acidification and warming. Proceedings of the National Academy of Sciences 118 (2021).

Fabricius KE, et al. Disturbance gradients on inshore and offshore coral reefs caused by a severe tropical cyclone. Limnol Oceanogr. 2008;53:690–704.

Edmunds PJ, Gray SC. The effects of storms, heavy rain, and sedimentation on the shallow coral reefs of St. John, US Virgin Islands. Hydrobiologia. 2014;734:143–58.

Tuttle LJ, Donahue MJ. Effects of sediment exposure on corals: a systematic review of experimental studies. Environ Evid. 2022;11:4.

Bostrom-Einarsson L, et al. Coral restoration - A systematic review of current methods, successes, failures and future directions. PLoS ONE. 2020;15:e0226631.

Viehman TS et al. Coral restoration for coastal resilience: integrating ecology, hydrodynamics, and engineering at multiple scales. Ecosphere 14 (2023).

United Nations General Assembly. Resolution adopted by the General Assembly on 1 March 2019. A/RES/73/284, United Nations Decade on Ecosystem Restoration (2021–2039). (2019).

Gann GD et al. International principles and standards for the practice of ecological restoration. Second edition. Restoration Ecology 27 (2019).

Vardi T et al. Six priorities to advance the science and practice of coral reef restoration worldwide. Restor Ecol 29 (2021).

Stone RB, McGurrin JM, Sprague LM, Seaman WJ. In: Seaman WJ, Sprague LM, editors. Artificial habitats of the world: synopsis and major trends in Artificial habitats for marine and freshwater fisheries. Academic; 1991. pp. 31–60.

Becker A, Taylor MD, Folpp H, Lowry MB. Managing the development of artificial reef systems: the need for quantitative goals. Fish Fish. 2018;19:740–52.

Higgins E, Metaxas A, Scheibling RE. A systematic review of artificial reefs as platforms for coral reef research and conservation. PLoS ONE. 2022;17:e0261964.

Steward DaN et al. Quantifying spatial extents of artificial versus natural reefs in the seascape. Front Mar Sci 9 (2022).

Keenan SF, Switzer TS, Knapp A, Weather EJ, Davis J. Spatial dynamics of the quantity and diversity of natural and artificial hard bottom habitats in the eastern Gulf of Mexico. Cont Shelf Res 233 (2022).

Beans C. Science and Culture: artistic endeavors strive to save coral reefs. Proc Natl Acad Sci. 2018;115:5303–5.

Smith A et al. Engineering, ecological and social monitoring of the largest underwater sculpture in the world at John Brewer Reef, Australia. J Mar Sci Eng 10 (2022).

Ceccarelli DM, et al. Substrate stabilisation and small structures in coral restoration: state of knowledge, and considerations for management and implementation. PLoS ONE. 2020;15:e0240846.

Viehman TS, et al. Understanding differential patterns in coral reef recovery: chronic hydrodynamic disturbance as a limiting mechanism for coral colonization. Mar Ecol Prog Ser. 2018;605:135–50.

Jaap WC. Coral reef restoration. Ecol Eng. 2000;15:345–64.

Ferrario F, et al. The effectiveness of coral reefs for coastal hazard risk reduction and adaptation. Nat Commun. 2014;5:3794.

Reguero BG, et al. The value of US coral reefs for flood risk reduction. Nat Sustain. 2021;4:688–98.

Storlazzi CD et al. (2019) Rigorously valuing the role of U.S. coral reefs in coastal hazard risk reduction. U.S. Geological Survey Open-File Report 2019–1027. p 42.

Reguero BG, Beck MW, Agostini VN, Kramer P, Hancock B. Coral reefs for coastal protection: a new methodological approach and engineering case study in Grenada. J Environ Manage. 2018;210:146–61.

Jayanthi M, et al. Perforated trapezoidal artificial reefs can augment the benefits of restoration of an island and its marine ecosystem. Restor Ecol. 2019;28:233–43.

Levy N, et al. Emerging 3D technologies for future reformation of coral reefs: enhancing biodiversity using biomimetic structures based on designs by nature. Sci Total Environ. 2022;830:154749.

Paxton AB et al. What evidence exists on the ecological and physical effects of built structures in shallow, tropical coral reefs? A systematic map protocol. Environ Evid 12 (2023).

Collaboration for Environmental Evidence. In: Pullin AS, Frampton GK, Livoreil B, editors. Guidelines and standards for evidence synthesis in environmental management. Version 5.1. G. Petrokofsky; 2022.

Haddaway NR, Macura B, Whaley P, Pullin AS. ROSES RepOrting standards for systematic evidence syntheses: pro forma, flow-diagram and descriptive summary of the plan and conduct of environmental systematic reviews and systematic maps. Environ Evid 7 (2018).

Mendoza E, Ríos A, Mariño-Tapia I, Silva R. Modular coral shaped artificial reefs acting as beach protection barriers. Coastal Struct. 2019;989–97. https://doi.org/10.18451/978-3-939230-64-9_099 .

Berman O, et al. Design and application of a novel 3D printing method for bio-inspired artificial reefs. Ecol Eng. 2023;188:106892.

Hylkema A, et al. The effect of artificial reef design on the attraction of herbivorous fish and on coral recruitment, survival and growth. Ecol Eng. 2023;188:106882.

Harzing AW. (2007) Publish or perish. https://harzing.com/resources/publish-or-perish .

Haddaway NR, Collins AM, Coughlin D, Kirk S. The role of Google Scholar in evidence reviews and its applicability to grey literature searching. PLoS ONE. 2015;10:e0138237.

Weishuhn M. (2022) Inciteful: citation network exploration.

R Development Core Team. R: a language and environment for statistical computing. Vienna, Austria.): R Foundation for Statistical Computing; 2022.

Riley T et al. (2022) CiteSource: analyze the utility of information sources and retrieval methodologies for evidence synthesis.

The EndNote Team. EndNote. Philadelphia, PA: Clarivate; 2013.

McKeown S, Mir ZM. Considerations for conducting systematic reviews: evaluating the performance of different methods for de-duplicating references. Syst Rev. 2021;10:38.

Howard BE, et al. SWIFT-Active screener: accelerated document screening through active learning and integrated recall estimation. Environ Int. 2020;138:105623.

Haddaway N, Macura B, Whaley P, Pullin A. (2018) ROSES Flow Diagram for systematic reviews. Version 1.0. (figshare).

Wickham H. ggplot2: elegant graphics for data analysis. New York: Springer-; 2016.

Book   Google Scholar  

Coyne MS, et al. NOAA Technical Memorandum NOS NCCOS CCMA 152. Benthic habitats of the Main Hawaiian Islands. (also available on U.S. National Oceanic and Atmospheric Administration. National Ocean Service, National Centers for Coastal Ocean Science. Biogeography Program. 2003. (CD-ROM). Benthic habitats of the Main Hawaiian islands. Silver Spring, MD: National Oceanic and Atmospheric Administration.); 2023.

Kendall MS, the U.S. Virgin Islands. (2021) Methods Used to Map the Benthic Habitats of Puerto Rico and. (Also available on U.S. National Oceanic and Atmospheric Administration. National Ocean Service, National Centers for Coastal Ocean Science Biogeography Program. 2001. (CD-ROM). Benthic Habitats of Puerto Rico and the U.S. Virgin Islands. Silver Spring, MD: National Oceanic and Atmospheric Administration.).

Cochran SA, Gibbs AE, White DJ. (2014) Benthic habitat map of the U.S. Coral Reef Task Force Watershed Partnership Initiative Kā’anapali priority study area and the State of Hawai’i Kahekili Herbivore Fisheries Management Area, west-central Maui, Hawai’i. in Open-File Report (Reston, VA), p 52.

Gilbert A, et al. Endangered New Caledonian endemic mushroom coral Cantharellus noumeae in turbid, metal-rich, natural and artificial environments. Mar Pollut Bull. 2015;100:359–69.

Hill CEL, Lymperaki MM, Hoeksema BW. A centuries-old manmade reef in the Caribbean does not substitute natural reefs in terms of species assemblages and interspecific competition. Mar Pollut Bull. 2021;169:112576.

Team FOSPBCRR. (2006) Florida Fish and Wildlife Conservation Commisssion Grant No. 04030 Annual Report for December 2004 to November 2006 Grant Period.

Bayraktarov E, et al. Motivations, success, and cost of coral reef restoration. Restor Ecol. 2019;27:981–91.

Ghiasian M, Carrick J, Bisson C, Haus BK. Laboratory quantification of the relative contribution of staghorn coral skeletons to the total wave-energy dissipation provided by an artificial coral reef. J Mar Sci Eng 9 (2021).

Ghiasian M, et al. Dissipation of wave energy by a hybrid artificial reef in a wave simulator: implications for coastal resilience and shoreline protection. Limnol Oceanography: Methods. 2021;19:1–7.

Roelvink FE, Storlazzi CD, van Dongeren AR, Pearson SG. Coral reef restorations can be optimized to reduce coastal flooding hazards. Front Mar Sci 8 (2021).

Storlazzi CD et al. (2021) Rigorously valuing the coastal hazard risks reduction provided by potential coral reef restoration in Florida and Puerto Rico: U.S. Geological Survey Open-File Report 2021–1054. p 35.

Reguero BG, Beck MW, Agostini VN, Kramer P. Coral reefs for coastal protection: a new methodological approach and engineering case study in Grenada. J Environ Manage. 2018;210:146–61.

Jayanthi M, et al. Perforated trapezoidal artificial reefs can augment the benefits of restoration of island and its marine ecosystem. Restor Ecol. 2020;28:233–43.

Eco-Group IC. Town of Palm Beach coral nursery mitigation and Port of Palm Beach Slip 3 coral relocation project – year 2 post-transplant monitoring report. (2016).

Prekel SE, Craft J, Carter AP. U.S. Army Corps of Engineers Palm Beach Harbor maintenance dredging program, town of Palm Beach mitigative artificial reef, 1-year post-mitigation biological monitoring report. Boca Raton, FL): Coastal Planning and Engineering, Inc.; 2008. p. 30.

Kotb M. Coral colonization and fish assemblage on an artificial reef off Hurghada, Red Sea, Egypt. Egypt J Aquat Biology Fisheries. 2013;17:71–81.

Smith A, et al. Engineering, ecological and social monitoring of the largest underwater sculpture in the world at John Brewer Reef, Australia. J Mar Sci Eng. 2022;10:1617–1617.

Kumar JSY, Geetha S. Fouling communities on ship wreck site in the Gulf of Mannar, India. Int J Appl Biology Pharm Technol (2012).

Lemasson AJ, et al. A global meta-analysis of ecological effects from offshore marine artificial structures. Nat Sustain. 2024. https://doi.org/10.1038/s41893-024-01311-z .

Paxton AB et al. Meta-analysis reveals artificial reefs can be effective tools for fish community enhancement but are not one-size-fits-all. Front Mar Sci 7 (2020).

Ramm LAW, Florisson JH, Watts SL, Becker A, Tweedley JR. Artificial reefs in the Anthropocene: a review of geographical and historical trends in their design, purpose, and monitoring. Bull Mar Sci. 2021;97:699–728.

Bugnot AB, et al. Current and projected global extent of marine built structures. Nat Sustain. 2020;4:33–41.

Feagin RA, et al. Infrastructure investment must incorporate Nature’s lessons in a rapidly changing world. One Earth. 2021;4:1361–4.

Sutton-Grier A et al. Investing in natural and nature-based infrastructure: building better along our coasts. Sustainability 10 (2018).

Executive Office of the President. (2022) Strengthening the Nation’s forests, communities, and local economies. Executive Order 14072. 87 FR 24851. p 5.

Firth LB et al. Coastal greening of grey infrastructure: an update on the state-of-the-art. Proceedings of the Institution of Civil Engineers - Maritime Engineering https://doi.org/10.1680/jmaen.2023.003 , 1–69. Emerald Publishing LImited (2024).

Miller MW, et al. Alternate benthic assemblages on reef restoration structures and cascading effects on coral settlement. Mar Ecol Prog Ser. 2009;387:147–56.

Blakeway D, Byers M, Stoddart J, Rossendell J. Coral colonisation of an artificial reef in a turbid nearshore environment, Dampier Harbour, Western Australia. PLoS ONE. 2013;8:e75281.

Deb K, McCarthy A. (2014) Coral relocation as habitat mitigation for impacts from the Barzan gas project pipeline construction offshore eastern Qatar: Survey IV update. pp 127–155.

Abelson A, Shlesinger Y. Comparison of the development of coral and fish communities on rock-aggregated artificial reefs in Eliat, Red Sea. ICES J Mar Sci. 2002;59:S122–6.

Paxton AB et al. Artificial reef footprint in the U.S. ocean. Nature Sustainability ( In press ).

Pérez-Pagán BS, Mercado-Molina AE. Evaluation of the effectiveness of 3D-printed corals to attract coral reef fish at Tamarindo Reef, Culebra, Puerto Rico. Conserv Evid. 2018;15:43–7.

Leonard C et al. Performance of innovative materials as recruitment substrates for coral restoration. Restor Ecol 30 (2022).

Randall CJ, Giuliano C, Heyward AJ, Negri AP. Enhancing coral survival on deployment devices with microrefugia. Front Mar Sci. 2021;8:662263.

Ajemian MJ, et al. Movement patterns and habitat use of tiger sharks ( Galeocerdo cuvier ) across ontogeny in the Gulf of Mexico. PLoS ONE. 2020;15:e0234868.

Paxton AB, et al. Artificial reefs facilitate tropical fish at their range edge. Commun Biology. 2019;2:168.

Airoldi L, Turon X, Perkol-Finkel S, Rius M. Corridors for aliens but not for natives: effects of marine urban sprawl at a regional scale. Divers Distrib. 2015;21:755–68.

Babcock KK, et al. Changing biogeochemistry and invertebrate community composition at newly deployed artificial reefs in the Northeast Gulf of Mexico. Estuaries Coasts. 2020;43:680–92.

Tong F, Chen G, Feng X, Liu Y, Chen P. The effect of the artificial reef on the structure and function of sediment bacterial community. Sustainability 14 (2022).

Rossignol G, Sous D. Coastal defences on low-lying reef flats: a laboratory study of seawall shape and position. J Mar Sci Eng. 2022;10:1652.

Liu Y et al. Random wave overtopping of vertical seawalls on coral reefs. Applied Ocean Research 100, 102166 – 102113 (2020).

DeLuca NM, Angrish M, Wilkins A, Thayer K, Cohen EA, Hubal. Human exposure pathways to poly- and perfluoroalkyl substances (PFAS) from indoor media: a systematic review protocol. Environ Int. 2021;146:106308.

Gardner B, et al. Mapping the evidence of the effects of environmental factors on the prevalence of antibiotic resistance in the non-built environment: protocol for a systematic evidence map. Environ Int. 2023;171:107707.

Stovall A, et al. Coral reef restoration for risk reduction (CR4): a guide to project design and proposal development. University of California Santa Cruz); 2022.

USCRTF Resolution 47.2. (2023) Coral reefs as national natural infrastructure.

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Acknowledgements

We thank the US Army Corps of Engineers Engineering With Nature® for supporting the protocol. We thank S. Jones from the NOAA Central Library for support finding full texts. We thank S. Cheng for methodological guidance. We thank J. Rudebusch, K. Cushway, A. Yarnall, and T. Barnes, for thoughtful reviews of the manuscript. The views and conclusions contained in this document are those of the authors and should not be interpreted as representing the opinions or policies of NOAA and USACE. The mention of trade names or commercial products does not constitute U.S. Government endorsement or recommendation for use.

This study was supported by the NOAA National Centers for Coastal Ocean Science and the USACE Engineering With Nature® Program, and the USGS Coastal and Marine Hazards and Resources Program.

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TSV and TMS acquired funding for the synthesis. ABP, TSV, TMS, CDP, SA, BJP, and TSV conceptualized the project scope. ABP developed search strings with feedback from coauthors and assistance and review from TNR. ABP developed the protocol, including the search strategy, article screening and eligibility criteria, data extraction and coding strategy, and the study mapping and presentation vision with assistance and review from TNR. ABP implemented the search strategy. CC, DNS, LP, and ABP conducted title and abstract screening. CC, DNS, IRF, LP, and ABP conducted full-text screening and coding. ABP and IRF conducted gray literature screening and coding. ABP, IRF, and LP screened stakeholder-contributed articles. ABP analyzed and visualized data. ABP drafted the map manuscript. All authors helped refine the manuscript. All authors read, reviewed, and approved the final manuscript.

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Paxton, A.B., Foxfoot, I.R., Cutshaw, C. et al. Evidence on the ecological and physical effects of built structures in shallow, tropical coral reefs: a systematic map. Environ Evid 13 , 12 (2024). https://doi.org/10.1186/s13750-024-00336-3

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Systematic Reviews and Meta-analysis: Understanding the Best Evidence in Primary Healthcare

S. gopalakrishnan.

Department of Community Medicine, SRM Medical College, Hospital and Research Centre, Kattankulathur, Tamil Nadu, India

P. Ganeshkumar

Healthcare decisions for individual patients and for public health policies should be informed by the best available research evidence. The practice of evidence-based medicine is the integration of individual clinical expertise with the best available external clinical evidence from systematic research and patient's values and expectations. Primary care physicians need evidence for both clinical practice and for public health decision making. The evidence comes from good reviews which is a state-of-the-art synthesis of current evidence on a given research question. Given the explosion of medical literature, and the fact that time is always scarce, review articles play a vital role in decision making in evidence-based medical practice. Given that most clinicians and public health professionals do not have the time to track down all the original articles, critically read them, and obtain the evidence they need for their questions, systematic reviews and clinical practice guidelines may be their best source of evidence. Systematic reviews aim to identify, evaluate, and summarize the findings of all relevant individual studies over a health-related issue, thereby making the available evidence more accessible to decision makers. The objective of this article is to introduce the primary care physicians about the concept of systematic reviews and meta-analysis, outlining why they are important, describing their methods and terminologies used, and thereby helping them with the skills to recognize and understand a reliable review which will be helpful for their day-to-day clinical practice and research activities.

Introduction

Evidence-based healthcare is the integration of best research evidence with clinical expertise and patient values. Green denotes, “Using evidence from reliable research, to inform healthcare decisions, has the potential to ensure best practice and reduce variations in healthcare delivery.” However, incorporating research into practice is time consuming, and so we need methods of facilitating easy access to evidence for busy clinicians.[ 1 ] Ganeshkumar et al . mentioned that nearly half of the private practitioners in India were consulting more than 4 h per day in a locality,[ 2 ] which explains the difficulty of them in spending time in searching evidence during consultation. Ideally, clinical decision making ought to be based on the latest evidence available. However, to keep abreast with the continuously increasing number of publications in health research, a primary healthcare professional would need to read an insurmountable number of articles every day, covered in more than 13 million references and over 4800 biomedical and health journals in Medline alone. With the view to address this challenge, the systematic review method was developed. Systematic reviews aim to inform and facilitate this process through research synthesis of multiple studies, enabling increased and efficient access to evidence.[ 1 , 3 , 4 ]

Systematic reviews and meta-analyses have become increasingly important in healthcare settings. Clinicians read them to keep up-to-date with their field and they are often used as a starting point for developing clinical practice guidelines. Granting agencies may require a systematic review to ensure there is justification for further research and some healthcare journals are moving in this direction.[ 5 ]

This article is intended to provide an easy guide to understand the concept of systematic reviews and meta-analysis, which has been prepared with the aim of capacity building for general practitioners and other primary healthcare professionals in research methodology and day-to-day clinical practice.

The purpose of this article is to introduce readers to:

• The two approaches of evaluating all the available evidence on an issue i.e., systematic reviews and meta-analysis,
• Discuss the steps in doing a systematic review,
• Introduce the terms used in systematic reviews and meta-analysis,
• Interpret results of a meta-analysis, and
• The advantages and disadvantages of systematic review and meta-analysis.

Application

What is the effect of antiviral treatment in dengue fever? Most often a primary care physician needs to know convincing answers to questions like this in a primary care setting.

To find out the solutions or answers to a clinical question like this, one has to refer textbooks, ask a colleague, or search electronic database for reports of clinical trials. Doctors need reliable information on such problems and on the effectiveness of large number of therapeutic interventions, but the information sources are too many, i.e., nearly 20,000 journals publishing 2 million articles per year with unclear or confusing results. Because no study, regardless of its type, should be interpreted in isolation, a systematic review is generally the best form of evidence.[ 6 ] So, the preferred method is a good summary of research reports, i.e., systematic reviews and meta-analysis, which will give evidence-based answers to clinical situations.

There are two fundamental categories of research: Primary research and secondary research. Primary research is collecting data directly from patients or population, while secondary research is the analysis of data already collected through primary research. A review is an article that summarizes a number of primary studies and may draw conclusions on the topic of interest which can be traditional (unsystematic) or systematic.

Terminologies

Systematic review.

A systematic review is a summary of the medical literature that uses explicit and reproducible methods to systematically search, critically appraise, and synthesize on a specific issue. It synthesizes the results of multiple primary studies related to each other by using strategies that reduce biases and random errors.[ 7 ] To this end, systematic reviews may or may not include a statistical synthesis called meta-analysis, depending on whether the studies are similar enough so that combining their results is meaningful.[ 8 ] Systematic reviews are often called overviews.

The evidence-based practitioner, David Sackett, defines the following terminologies.[ 3 ]

• Review: The general term for all attempts to synthesize the results and conclusions of two or more publications on a given topic.
• Overview: When a review strives to comprehensively identify and track down all the literature on a given topic (also called “systematic literature review”).
• Meta-analysis: A specific statistical strategy for assembling the results of several studies into a single estimate.

Systematic reviews adhere to a strict scientific design based on explicit, pre-specified, and reproducible methods. Because of this, when carried out well, they provide reliable estimates about the effects of interventions so that conclusions are defensible. Systematic reviews can also demonstrate where knowledge is lacking. This can then be used to guide future research. Systematic reviews are usually carried out in the areas of clinical tests (diagnostic, screening, and prognostic), public health interventions, adverse (harm) effects, economic (cost) evaluations, and how and why interventions work.[ 9 ]

Cochrane reviews

Cochrane reviews are systematic reviews undertaken by members of the Cochrane Collaboration which is an international not-for-profit organization that aims to help people to make well-informed decisions about healthcare by preparing, maintaining, and promoting the accessibility of systematic reviews of the effects of healthcare interventions.

Cochrane Primary Health Care Field is a systematic review of primary healthcare research on prevention, treatment, rehabilitation, and diagnostic test accuracy. The overall aim and mission of the Primary Health Care Field is to promote the quality, quantity, dissemination, accessibility, applicability, and impact of Cochrane systematic reviews relevant to people who work in primary care and to ensure proper representation in the interests of primary care clinicians and consumers in Cochrane reviews and review groups, and in other entities. This field would serve to coordinate and promote the mission of the Cochrane Collaboration within the primary healthcare disciplines, as well as ensuring that primary care perspectives are adequately represented within the Collaboration.[ 10 ]

Meta-analysis

A meta-analysis is the combination of data from several independent primary studies that address the same question to produce a single estimate like the effect of treatment or risk factor. It is the statistical analysis of a large collection of analysis and results from individual studies for the purpose of integrating the findings.[ 11 ] The term meta-analysis has been used to denote the full range of quantitative methods for research reviews.[ 12 ] Meta-analyses are studies of studies.[ 13 ] Meta-analysis provides a logical framework to a research review where similar measures from comparable studies are listed systematically and the available effect measures are combined wherever possible.[ 14 ]

The fundamental rationale of meta-analysis is that it reduces the quantity of data by summarizing data from multiple resources and helps to plan research as well as to frame guidelines. It also helps to make efficient use of existing data, ensuring generalizability, helping to check consistency of relationships, explaining data inconsistency, and quantifies the data. It helps to improve the precision in estimating the risk by using explicit methods.

Therefore, “systematic review” will refer to the entire process of collecting, reviewing, and presenting all available evidence, while the term “meta-analysis” will refer to the statistical technique involved in extracting and combining data to produce a summary result.[ 15 ]

Steps in doing systematic reviews/meta-analysis

Following are the six fundamental essential steps while doing systematic review and meta-analysis.[ 16 ]

Define the question

This is the most important part of systematic reviews/meta-analysis. The research question for the systematic reviews may be related to a major public health problem or a controversial clinical situation which requires acceptable intervention as a possible solution to the present healthcare need of the community. This step is most important since the remaining steps will be based on this.

Reviewing the literature

This can be done by going through scientific resources such as electronic database, controlled clinical trials registers, other biomedical databases, non-English literatures, “gray literatures” (thesis, internal reports, non–peer-reviewed journals, pharmaceutical industry files), references listed in primary sources, raw data from published trials and other unpublished sources known to experts in the field. Among the available electronic scientific database, the popular ones are PUBMED, MEDLINE, and EMBASE.

Sift the studies to select relevant ones

To select the relevant studies from the searches, we need to sift through the studies thus identified. The first sift is pre-screening, i.e., to decide which studies to retrieve in full, and the second sift is selection which is to look again at these studies and decide which are to be included in the review. The next step is selecting the eligible studies based on similar study designs, year of publication, language, choice among multiple articles, sample size or follow-up issues, similarity of exposure, and or treatment and completeness of information.

It is necessary to ensure that the sifting includes all relevant studies like the unpublished studies (desk drawer problem), studies which came with negative conclusions or were published in non-English journals, and studies with small sample size.

Assess the quality of studies

The steps undertaken in evaluating the study quality are early definition of study quality and criteria, setting up a good scoring system, developing a standard form for assessment, calculating quality for each study, and finally using this for sensitivity analysis.

For example, the quality of a randomized controlled trial can be assessed by finding out the answers to the following questions:

• Was the assignment to the treatment groups really random?
• Was the treatment allocation concealed?
• Were the groups similar at baseline in terms of prognostic factors?
• Were the eligibility criteria specified?
• Were the assessors, the care provider, and the patient blinded?
• Were the point estimates and measure of variability presented for the primary outcome measure?
• Did the analyses include intention-to-treat analysis?

Calculate the outcome measures of each study and combine them

We need a standard measure of outcome which can be applied to each study on the basis of its effect size. Based on their type of outcome, following are the measures of outcome: Studies with binary outcomes (cured/not cured) have odds ratio, risk ratio; studies with continuous outcomes (blood pressure) have means, difference in means, standardized difference in means (effect sizes); and survival or time-to-event data have hazard ratios.

Combining studies

Homogeneity of different studies can be estimated at a glance from a forest plot (explained below). For example, if the lower confidence interval of every trial is below the upper of all the others, i.e., the lines all overlap to some extent, then the trials are homogeneous. If some lines do not overlap at all, these trials may be said to be heterogeneous.

The definitive test for assessing the heterogeneity of studies is a variant of Chi-square test (Mantel–Haenszel test). The final step is calculating the common estimate and its confidence interval with the original data or with the summary statistics from all the studies. The best estimate of treatment effect can be derived from the weighted summary statistics of all studies which will be based on weighting to sample size, standard errors, and other summary statistics. Log scale is used to combine the data to estimate the weighting.

Interpret results: Graph

The results of a meta-analysis are usually presented as a graph called forest plot because the typical forest plots appear as forest of lines. It provides a simple visual presentation of individual studies that went into the meta-analysis at a glance. It shows the variation between the studies and an estimate of the overall result of all the studies together.

Forest plot

Meta-analysis graphs can principally be divided into six columns [ Figure 1 ]. Individual study results are displayed in rows. The first column (“study”) lists the individual study IDs included in the meta-analysis; usually the first author and year are displayed. The second column relates to the intervention groups and the third column to the control groups. The fourth column visually displays the study results. The line in the middle is called “the line of no effect.” The weight (in %) in the fifth column indicates the weighting or influence of the study on the overall results of the meta-analysis of all included studies. The higher the percentage weight, the bigger the box, the more influence the study has on the overall results. The sixth column gives the numerical results for each study (e.g., odds ratio or relative risk and 95% confidence interval), which are identical to the graphical display in the fourth column. The diamond in the last row of the graph illustrates the overall result of the meta-analysis.[ 4 ]

Interpretation of meta-analysis[ 4 ]

Thus, the horizontal lines represent individual studies. Length of line is the confidence interval (usually 95%), squares on the line represent effect size (risk ratio) for the study, with area of the square being the study size (proportional to weight given) and position as point estimate (relative risk) of the study.[ 7 ]

For example, the forest plot of the effectiveness of dexamethasone compared with placebo in preventing the recurrence of acute severe migraine headache in adults is shown in Figure 2 .[ 17 ]

Forest plot of the effectiveness of dexamethasone compared with placebo in preventing the recurrence of acute severe migraine headache in adults[ 17 ]

The overall effect is shown as diamond where the position toward the center represents pooled point estimate, the width represents estimated 95% confidence interval for all studies, and the black plain line vertically in the middle of plot is the “line of no effect” (e.g., relative risk = 1).

Therefore, when examining the results of a systematic reviews/meta-analysis, the following questions should be kept in mind:

• Heterogeneity among studies may make any pooled estimate meaningless.
• The quality of a meta-analysis cannot be any better than the quality of the studies it is summarizing.
• An incomplete search of the literature can bias the findings of a meta-analysis.
• Make sure that the meta-analysis quantifies the size of the effect in units that you can understand.

Subgroup analysis and sensitivity analysis

Subgroup analysis looks at the results of different subgroups of trials, e.g., by considering trials on adults and children separately. This should be planned at the protocol stage itself which is based on good scientific reasoning and is to be kept to a minimum.

Sensitivity analysis is used to determine how results of a systematic review/meta-analysis change by fiddling with data, for example, what is the implication if the exclusion criteria or excluded unpublished studies or weightings are assigned differently. Thus, after the analysis, if changing makes little or no difference to the overall results, the reviewer's conclusions are robust. If the key findings disappear, then the conclusions need to be expressed more cautiously.

Advantages of Systematic Reviews

Systematic reviews have specific advantages because of using explicit methods which limit bias, draw reliable and accurate conclusions, easily deliver required information to healthcare providers, researchers, and policymakers, help to reduce the time delay in the research discoveries to implementation, improve the generalizability and consistency of results, generation of new hypotheses about subgroups of the study population, and overall they increase precision of the results.[ 18 ]

Limitations in Systematic Reviews/Meta-analysis

As with all research, the value of a systematic review depends on what was done, what was found, and the clarity of reporting. As with other publications, the reporting quality of systematic reviews varies, limiting readers’ ability to assess the strengths and weaknesses of those reviews.[ 5 ]

Even though systematic review and meta-analysis are considered the best evidence for getting a definitive answer to a research question, there are certain inherent flaws associated with it, such as the location and selection of studies, heterogeneity, loss of information on important outcomes, inappropriate subgroup analyses, conflict with new experimental data, and duplication of publication.

Publication Bias

Publication bias results in it being easier to find studies with a “positive” result.[ 19 ] This occurs particularly due to inappropriate sifting of the studies where there is always a tendency towards the studies with positive (significant) outcomes. This effect occurs more commonly in systematic reviews/meta-analysis which need to be eliminated.

The quality of reporting of systematic reviews is still not optimal. In a recent review of 300 systematic reviews, few authors reported assessing possible publication bias even though there is overwhelming evidence both for its existence and its impact on the results of systematic reviews. Even when the possibility of publication bias is assessed, there is no guarantee that systematic reviewers have assessed or interpreted it appropriately.[ 20 ]

To overcome certain limitations mentioned above, the Cochrane reviews are currently reported in a format where at the end of every review, findings are summarized in the author's point of view and also give an overall picture of the outcome by means of plain language summary. This is found to be much helpful to understand the existing evidence about the topic more easily by the reader.

A systematic review is an overview of primary studies which contains an explicit statement of objectives, materials, and methods, and has been conducted according to explicit and reproducible methodology. A meta-analysis is a mathematical synthesis of the results of two or more primary studies that addressed the same hypothesis in the same way. Although meta-analysis can increase the precision of a result, it is important to ensure that the methods used for the reviews were valid and reliable.

High-quality systematic reviews and meta-analyses take great care to find all relevant studies, critically assess each study, synthesize the findings from individual studies in an unbiased manner, and present balanced important summary of findings with due consideration of any flaws in the evidence. Systematic review and meta-analysis is a way of summarizing research evidence, which is generally the best form of evidence, and hence positioned at the top of the hierarchy of evidence.

Systematic reviews can be very useful decision-making tools for primary care/family physicians. They objectively summarize large amounts of information, identifying gaps in medical research, and identifying beneficial or harmful interventions which will be useful for clinicians, researchers, and even for public and policymakers.

Source of Support: Nil

Conflict of Interest: None declared.

Leadership and the Process of Internationalization of Family Businesses: A Systematic Review of Literature

• First Online: 17 May 2024

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• Juliana R. Baltazar 6  

Part of the book series: Contributions to Management Science ((MANAGEMENT SC.))

The leaders of family businesses have a great impact on the decision-making that the company decides to make, so the leadership presented by these managers impacts the company’s processes, one of which is the internationalization of companies. The aim of this research is to discover how leadership influences the process of internationalization of family businesses, and in order to achieve this objective, we conducted a systematic review of the literature, using the Web of Science database. The 96 articles selected in the database were analyzed with the VOSviewer software , which shows the dispersion of the theme of leadership and internationalization of family businesses. This research contributes to the construction of an agenda on the process of internationalization of family businesses, and how this is influenced by leadership.

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Abdellatif, M., Amann, B., & Jaussaud, J. (2010). Family versus nonfamily business: A comparison of international strategies. Journal of Family Business Strategy, 1 (2), 108–116.

Article   Google Scholar  

Barac, M., & Moner-Colonques, R. (2022). Leadership in internationalization strategies . Manchester School.

Book   Google Scholar  

Baranyai, T., & Kozma, M. (2019). Family firms with new leaders in the global market- A potential success story? Acta Oeconomica, 69 , 131–162.

Barney, J. (1991). Firm resources and sustained competitive advantage. Journal of Management, 17 (1), 99–120.

Belderbos, R., Lykogianni, E., & Veugelers, R. (2008). Strategic R&D location by multinational firms: Spillovers, technology sourcing, and competition. Journal of Economics & Management Strategy, 17 (3), 759–779.

Google Scholar  

Berrone, P., Cruz, C., & Gomez-Mejia, L. R. (2012). Socioemotional wealth in family firms. Family Business Review, 25 (3), 258–279.

Boubaker, S., Nguyen, P., & Rouatbi, W. (2016). Multiple large shareholders and corporate risk taking: Evidence from French family firms. European Financial Management, 22 (4), 697–745.

Cesinger, B., Bouncken, R., Fredrich, V., & Kraus, S. (2014). The alchemy of family enterprises’ internationalisation: Dexterous movers or prodigal laggards? European Journal of International Management, 8 (6), 671–696.

Chhotray, S., Sivertsson, O., & Tell, J. (2018). The roles of leadership, vision, and empowerment in born global companies. Journal of International Entrepreneurship, 16 (1), 38–57.

Cho, J., & Lee, J. (2018). Internationalization and performance of Korean SMEs: The moderating role of competitive strategy. Asian Business & Management, 17 (2), 140–166.

Chrisman, J. J., Chua, J. H., & Sharma, P. (2005). Trends and directions in the development of a strategic management theory of the family firm. Entrepreneurship Theory Practice, 29 (5), 555–576.

Christensen-Salem, A., Mesquita, L. F., Hashimoto, M., Hom, P. W., & Gomez-Mejia, L. R. (2021). Family firms are indeed better places to work than non-family firms! Socioemotional wealth and employees’ perceived organizational caring. Journal of Family Business Strategy, 12 (1), Article 100412. https://doi.org/10.1016/j.jfbs.2020.100412

Cruz, C., & Justo, R. (2017). Portfolio entrepreneurship as a mixed gamble: A winning bet for family entrepreneurs in SMEs. Journal of Small Business Management, 55 (4), 571–593.

Cruz, C., Firfiray, S., Makri, M., & Gomez-Mejia, L. R. (2015). Socioemotional wealth: An obstacle or a springboard to creativity, innovation, and entrepreneurship in family firms? In C. E. Shalley, M. Hitt, & J. Zhou (Eds.), Oxford handbook of creativity, innovation, and entrepreneurship: Multilevel linkages (pp. 509–521). Oxford University Press.

Cui, L., Li, Y., Meyer, K. E., & Li, Z. J. (2015). Leadership experience meets ownership structure: Returnee managers and internationalization of emerging economy firms. Management International Review, 55 (3), 355–387.

D’Angelo, A., Majocchi, A., & Buck, T. (2016). External managers, family ownership and the scope of SME internationalization. Journal of World Business, 51 (4), 534–547.

Davis, J. H., Allen, M. R., & Hayes, H. D. (2010). Is blood thicker than water? A study of stewardship perceptions in family business. Entrepreneurship: Theory and Practice, 34 (6), 1093–1116.

De Massis, A., & Foss, N. J. (2018). Advancing family business research: The promise of microfoundations. Family Business Review, 31 (4), 386–396.

Demirtas, O. (2015). Ethical leadership influence at organizations: Evidence from the field. Journal of Business Ethics, 126 , 273–284.

Den Hartog, D. N., & Verburg, R. M. (1997). Charisma and rhetoric: Communicative techniques of international business leaders. Leadership Quarterly, 8 (4), 355–391.

Denyer, D., & Tranfield, D. (2009). Producing a systematic review. In D. Buchanan & A. Bryman (Eds.), Handbook of organizational research methods (pp. 671–689). Sage Publications Ltd.

Donckels, R., & Fröhlich, E. (1991). Are family businesses really different? European experiences from STRATOS. Family Business Review, 4 (2), 149–160.

Dung, L. T., & Giang, H. T. T. (2022). The effect of international intrapreneurship on firm export performance with driving force of organizational factors. Journal of Business & Industrial Marketing, 37 (11), 2185–2204.

Eisenhardt, K. M. (1989). Building theories from case study research. The Academy of Management Review, 14 (4), 532.

Eisenhardt, K. M., & Graebner, M. E. (2007). Theory building from cases: Opportunities and challenges. Academy of Management Journal, 50 (1), 25–32.

Eisenhardt, K. M., & Martin, J. A. (2000). Dynamic capabilities: What are they? Strategic Management Journal, 21 (10–11), 1105–1121.

Esteban-Jardim, P., & Urraca- Ruiz, A. (2018). Does internationalization matter? Comparing the innovative performance of Brazilian multinational and non-multinational companies. Transnational Corporations Review, 10 (4), 33–358.

Fernández, Z., & Nieto, M. J. (2005). Internationalization strategy of small and medium-sized family businesses: Some influential factors. Family Business Review, 18 (1), 77–89.

Ferraris, A., Giachino, C., Ciampi, F., & Couturier, J. (2021). R&D internationalization in medium-sized firms. The moderating role of knowledge management in enhancing innovation performances. Journal of Business Research, 128 , 711–718.

Ferreira, J. J. M., Ferreira, F. A. F., Fernandes, C. I. M. A. S., Jalali, M. S., Raposo, M. L., & Marques, C. S. (2015). What do we [not] know about technology entrepreneurship research? International Entrepreneurship and Management Journal, 12 (3), 713–733.

Fries, A., Kammerlander, N., & Leitterstorf, M. (2021). Leadership styles and leadership behaviors in family firms: A systematic literature review. Journal of Family Business Strategy, 12 (1), 100374.

Gao, G. Y., Murray, J. Y., Kotabe, M., & Lu, J. Y. (2010). A strategy tripod perspective on export behaviors: Evidence from domestic and foreign firms based in an emerging economy. Journal of International Business Studies, 41 (3), 377–396.

García-Morales, V. J., Jiménez-Barrionuevo, M. M., & Gutiérrez-Gutiérrez, L. (2012). Transformational leadership influence on organizational performance through organizational learning and innovation. Journal of Business Research, 65 (7), 1040–1050.

Giang, H. T. T., & Dung, L. T. (2021). Transformational leadership dimensions and dimensions and job-based psychological ownership as facilitators in international intrapreneurship of family firms. South East Asian Journal of Management, 15 (2), 188–211.

Glinkowska, B. (2017). Features of the international manager-leader of the near future-findings of the research. Management-Poland, 21 (1), 120–132.

Gomez-Mejia, L. R., Makri, M., & Kintana, M. L. (2010). Diversification decisions in family-controlled firms. Journal of Management Studies, 47 (2), 223–252.

Gomez-Mejia, L. R., Cruz, C. C., Berrone, P., & De Castro, J. (2011). The bind that ties: Socioemotional wealth preservation in family firms. The Academy of Management Annals, 5 (1), 653–707.

Gomez-Mejia, L. R., Patel, P. C., & Zellweger, T. M. (2018). In the horns of the dilemma: Socioemotional wealth, financial wealth, and acquisitions in family firms. Journal of Management, 44 (4), 1369–1397.

Gonçales Filho, M., de Campos, F. C., & Assumpção, M. R. P. (2016). Revisão sistemática da literatura com analise bibliométrica sobre estratégia e Manufatura Enxuta em segmentos da indústria. Gestão & Produção, 23 (2), 408–418.

Hambrick, D. C., & Mason, P. A. (1984). Upper echelons: The organization as a reflection of its top managers. The Academy of Management Review, 9 (2), 193.

Hitt, M. A., Hoskisson, R. E., & Kim, H. (1997). International diversification: Effects on innovation and firm performance in product-diversified firms. Academy of Management Journal, 40 (4), 767–798.

Hoskisson, R., Eden, L., Lau, C., & Wright, M. (2000). Strategy in emerging economies. Academy of Management Journal, 43 , 249–267. https://doi.org/10.5465/1556394

Huang, X. Y., Chen, H. Q., Wang, L. Y., & Zeng, S. X. (2020). How does leader narcissism influence firm internationalization? IEEE Transactions on Engineering Management, 67 (3), 683–696.

Ireland, R. D., Hitt, M. A., Camp, S. M., & Sexton, D. L. (2001). Integrating entrepreneurship and strategic management actions to create firm wealth. Academy of Management Executive, 15 (1), 49–63.

Johanson, J., & Vahlne, J.-E. (1977). The internationalization process of the firm-a model of knowledge development and increasing foreign market commitments. Journal of International Business Studies, 8 (1), 23–32.

Johanson, J., & Vahlne, J.-E. (2009). The Uppsala internationalization process model revisited: From liability of foreignness to liability of outsidership. Journal of International Business Studies, 40 (9), 1411–1431.

Kaiser, R. B., Hogan, R., & Craig, S. B. (2008). Leadership and the fate of organizations. American Psychologist, 63 (2), 96–110.

Khan, Z., & Lew, Y. K. (2018). Post-entry survival of developing economy international new ventures: A dynamic capability perspective. International Business Review, 27 (1), 149–160.

Kim, J., & McLean, G. N. (2015). An integrative framework for global leadership competency: Levels and dimensions. Human Resource Development International, 18 (3), 235–258.

Knight, G. A., & Cavusgil, S. T. (2004). Innovation, organizational capabilities, and the born-global firm. Journal of International Business Studies, 35 (2), 124–141.

König, A., Graf-Vlachy, L., & Schöberl, M. (2021). Opportunity/threat perception and inertia in response to discontinuous change: Replicating and extending Gilbert (2005). Journal of Management, 47 (3), 771–816. https://doi.org/10.1177/0149206320908630

Kontinen, T., & Ojala, A. (2010). The internationalization of family businesses: A review of extant research. Journal of Family Business Strategy, 1 (2), 97–107.

Kraus, S., Niemand, T., Besler, M., Stieg, P., & Martinez-Ciment, C. (2018). The influence of leadership styles on the internationalisation of ‘born-global’ firms and traditionally global-expanding firms. European Journal of International Management, 12 (5–6), 554–575.

Kuivalainen, O., Sundqvist, S., Puumalainen, K., & Cadogan, J. W. (2004). The effect of environmental turbulence and leader characteristics on international performance: Are knowledge-based firms different? Canadian Journal of Administrative Sciences-Revue Canadienne des Sciences de L Administration, 21 (1), 35–50.

Lee, S. B., Kotabe, M., Yoon, A. H., & Kwon, K. H. (2013). Export strategies and performance of Small and medium-sized enterprises: Evidence from Korean manufacturing SMEs. Journal of Korea Trade, 17 (1), 1–24.

Lim, S. L., & Wu, M. F. (2010). Family ownership and risk-taking: Exploring nonlinear effects in financial industry. African Journal of Business Management, 4 (17), 3738–3751.

Lu, J. W., & Beamish, P. W. (2001). The internationalization and performance of SMEs. Strategic Management Journal, 22 (6–7), 565–586.

Luo, Y., & Tung, R. L. (2007). International expansion of emerging market enterprises: A springboard perspective. Journal of International Business Studies, 38 (4), 481–498.

Martin, G., Campbell, J., & Gomez-Mejia, L. R. (2016). Family control, socioemotional wealth and earnings management in publicly traded firms. Journal of Business Ethics, 133 (3), 453–469.

McDougall, P. P., & Oviatt, B. M. (2000). International entrepreneurship: The intersection of two research paths. Academy of Management Journal, 43 (5), 902–906.

Morgan, T., & Gomez-Mejia, L. R. (2014). Hooked on a feeling: The affective component of socioemotional wealth in family firms. Journal of Family Business Strategy, 5 , 280–294.

Muralidharan, A., & Pathak, S. (2017). Informal institutions and international entrepreneurship. International Business Review, 26 (2), 288–302.

Oviatt, B. M., & McDougall, P. P. (1994). Toward a theory of international new ventures. Journal of International Business Studies, 25 (1), 45–64.

Pearson, A. W., & Marler, L. E. (2010). A leadership perspective of reciprocal stewardship in family firms. Entrepreneurship Theory and Practice, 34 (6), 1117–1124.

Podsakoff, P. M., MacKenzie, S. B., Lee, J.-Y., & Podsakoff, N. P. (2003). Common method biases in behavioral research: A critical review of the literature and recommended remedies. Journal of Applied Psychology, 88 (5), 879–903. https://doi.org/10.1037/0021-9010.88.5.879

Porter, M. E. (1980). Competitive strategy: Techniques for analyzing industries and competitors . Free Press.

Prasetyo, A. H. (2016). What drives international competitiveness? An empirical test in emerging Indonesian market. Journal of Competitiveness, 8 (4), 124–139.

Pulido, L. S., Gene, J. M., & Larraz, J. L. G. (2021). Internationalization of family firms: The effect of CEO attributes. Journal of Management & Governance.

Ramon-Llorens, M. C., Garcia-Meca, E., & Durendez, A. (2017). Influence of CEO characteristics in family firms internationalization. International Business Review, 26 (4), 786–799.

Ratajczak-Mrozek, M. (2015). The aspect of time in research on the internationalization of companies, Gospodarka Narodowa. The Polish Journal of Economics, GNPJE 2015, 278 (4), 49–67. https://doi.org/10.33119/GN/100821

Ronen, S., & Shenkar, O. (2013). Mapping world cultures: Cluster formation, sources and implications. Journal of International Business Studies, 44 (9), 867–897.

Rovelli, P., Ferasso, M., De Massis, A., & Kraus, S. (2022). Thirty years of research in family business journals: Status quo and future directions. Journal of Family Business Strategy, 13 (3), 100422.

Shen, C., Nguyen, D. T., & Hsu, P.-Y. (2019). Bibliometric networks and analytics on gerontology research. Library Hi Tech, 37 (1), 88–100.

Sirmon, D., & Hitt, M. (2003). Managing resources: Linking unique resources, management, and wealth creation in family. Entrepreneurship Theory and Practice, 27 (4), 339–358.

Small, H. (1973). Co-citation in the scientific literature: A new measure of the relationship between two documents. Journal of the American Society for Information Science, 24 (4), 265–269.

Smith, L. (1981). Citation analysis. Library Trends, 30 (1), 83–106.

Smuttrasen, K., & Heo, D. (2020). The impact of leader roles on cross-border knowledge management and the development of boundaryless business models: A case study of Thai construction companies. Knowledge and Process Management, 27 (1), 53–62.

Sullivan, D. (1994). Measuring the degree of internationalization of a firm. Journal of International Business Studies, 25 (2), 325–342.

Szymanski, M., Villar, F. V., & Zepeda, M. C. (2021). Multicultural individuals and theirs potential to become international entrepreneurs. Thunderbird International Business Review, 63 (6), 735–749.

Teece, D. J. (2017). Dynamic capabilities and (digital) platform lifecycles. Entrepreneurship, Innovation, and Platforms (Advances in Strategic Management, Vol. 37) , Emerald Publishing Limited, Leeds, pp. 211–225. https://doi.org/10.1108/S0742-332220170000037008

Teece, D. J., Pisano, G., & Shuen, A. (1997). Dynamic capabilities and strategic management. Strategic Management Journal, 18 (7), 509–533.

Tranfield, D., Denyer, D., & Smart, P. (2003). Towards a methodology for developing evidence-informed management knowledge by means of systematic review. British Journal of Management, 14 , 207–222.

Wang, X. T., & Jiang, M. S. (2018). Learning alongside and learning apart: Successor nurturing styles in family business succession. Knowledge Management Research & Practice, 16 (2), 258–266.

Wernerfelt, B. (1984). A resource-based view of the firm. Strategic Management Journal, 5 (2), 171–180.

White, H., & McCain, K. (1998). Visualizing a discipline: An author co-citation analysis of information science 1972–1995. Journal of the American Society for Information Science, 49 (4), 327–355.

Xie, L. (2019). Leadership and organizational learning culture: A systematic literature review. European Journal of Training and Development, 43 (1/2), 76–104.

Yoon, J., & Suh, M. G. (2021). The key elements of strategic leadership capabilities to the latecomer firm: The case of RT Mart’s success in the Chinese retail industry. Asia Pacific Business Review, 27 (1), 29–52.

Zaheer, S. (1995). Overcoming the liability of foreignness. Academy of Management Journal, 38 (2), 341–363.

Zahra, S. A., & Garvis, D. M. (2000). International corporate entrepreneurship and firm performance. Journal of Business Venturing, 15 (5–6), 469–492.

Zahra, S. A., & Sharma, P. (2004). Family business research: A strategic reflection. Family Business Review, 17 (4), 331–346.

Zitt, M., & Bassecoulard, E. (1994). Development of a method for detection and trend analysis of research fronts built by lexical or cocitation analysis. Scientometrics, 30 (1), 333–351.

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Baltazar, J.R. (2024). Leadership and the Process of Internationalization of Family Businesses: A Systematic Review of Literature. In: Schlyakhto, E., Ilin, I., Devezas, T., Correia Leitão, J.C., Cubico, S. (eds) Innovations for Healthcare and Wellbeing. Contributions to Management Science. Springer, Cham. https://doi.org/10.1007/978-3-031-53614-4_22

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

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

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

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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.

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Immunotherapy combined with apatinib in the treatment of advanced or metastatic gastric/gastroesophageal tumors: a systematic review and meta-analysis

• Jincheng Wang 1 ,
• Jie Lin 2 ,
• Ruimin Wang 3 ,
• Ti Tong 1 &
• Yinghao Zhao 1  

BMC Cancer volume  24 , Article number:  603 ( 2024 ) Cite this article

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Immunotherapy or apatinib alone has been used as third-line adjuvant therapy for advanced or metastatic gastric/gastroesophageal junction (G/GEJ) tumors, but the efficacy of combining them with each other for the treatment of patients with advanced or metastatic G/GEJ is unknown; therefore, we further evaluated the efficacy and safety of immunotherapy combined with apatinib in patients with advanced or metastatic G/GEJ.

The main search was conducted on published databases: Embase, Cochrane library, PubMed.The search was conducted from the establishment of the database to December 2023.Clinical trials with patients with advanced or metastatic G/GEJ and immunotherapy combined with apatinib as the study variable were collected. Review Manager 5.4 software as well as stata 15.0 software were used for meta-analysis.

A total of 651 patients from 19 articles were included in this meta-analysis. In the included studies, immunotherapy combined with apatinib had a complete response (CR) of 0.03 (95% CI: 0.00 -0.06), partial response (PR) of 0.34 (95% CI: 0.19–0.49), stable disease (SD) of 0.43 (95% CI: 0.32–0.55), objective response rate (ORR) was 0.36 (95% CI: 0.23–0.48), disease control rate (DCR) was 0.80 (95% CI: 0.74–0.86), and median progression-free survival (PFS) was 4.29 (95% CI: 4.05–4.52), median Overall survival (OS) was 8.79 (95% CI: 7.92–9.66), and the incidence of grade ≥ 3 TRAEs was 0.34 (95% CI: 0:19-0.49). PR, ORR, DCR, median PFS and median OS were significantly higher in the immunotherapy and apatinib combination chemotherapy group (IAC) than in the immunotherapy combination apatinib group (IA). And the difference was not significant in the incidence of SD and grade ≥ 3 TRAEs.

This meta-analysis shows that immunotherapy combined with apatinib is safe and effective in the treatment of advanced or metastatic G/GEJ, where IAC can be a recommended adjuvant treatment option for patients with advanced or metastatic G/GEJ. However, more large multicenter randomized studies are urgently needed to reveal the long-term outcomes of immunotherapy combined with apatinib treatment.

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Introduction

Gastric or gastroesophageal junction (G/GEJ) tumors are a common malignancy with a rather poor prognosis, which ranks as the fifth most common malignancy and the third leading cause of cancer deaths, and the majority of cases are diagnosed at an advanced stage [ 1 , 2 ]. With respect to advanced or metastatic G/GEJ adenocarcinomas that do not express HER2, fluoropyrimidine plus platinum-based systemic chemotherapy regimens remain the mainstay of first-line treatment [ 3 ]. The second-line treatment of advanced gastric cancer with paclitaxel, irinotecan, doxorubicin, or combination paclitaxel. The Chinese Society of Clinical Oncology (CSCO) guidelines for third-line treatment recommend the use of apatinib, nivulizumab, pembrolizumab, or a rational choice of chemotherapy regimen with reference to the second-line recommended modality [ 4 ]. Nevertheless, there are study data suggesting objective remission rates (ORR) of 6.8–25% and progression-free survival (PFS) of 1.5–5.3 months in second or second-line therapy [ 5 , 6 , 7 ]. At the same time, with the development of the patient’s condition, the drug resistance of conventional chemotherapy drugs gradually increased, and the clinical application effect decreased significantly [ 8 ]. There is an urgent need to develop more effective therapeutic options for the follow-up of patients with advanced or metastatic G/GEJ.

With the emergence of checkpoint inhibitors has led to fundamental changes in the treatment of a number of tumors. Anti-programmed death-1 (anti -programmed death-1,PD-1) antibodies and their ligand, PD-L1 antibodies, have shown antitumor efficacy in a variety of cancers, of which, pembrolizumab has been approved as a third-line treatment for PD-L1-expressing advanced GC [ 9 ]. On the other hand, only about 10% of patients with advanced GC/ GEJ benefit from monotherapy [ 10 , 11 ]. A number of studies have revealed that combining immunotherapy with other treatments could produce a substantial impact on patients with advanced cancer [ 12 , 13 , 14 ]. There has been much interest in recent years in the efficacy of anti-pd -1 combined with molecular antiangiogenic drugs. Antiangiogenesis is an established tumor microenvironment (TME)-targeted therapy for GC/GEJ. It may be possible to overcome primary resistance in patients with advanced GC/GEJ by combining PD-1/PD-L1 blockade with agents capable of eliminating pre-existing immunosuppression in the TME [ 15 , 16 , 17 ]. Recent studies of the selective VEGFR1-3 inhibitor axitinib in combination with pembrolizumab for the treatment of patients with advanced renal cell carcinoma have reported promising antitumor activity and an acceptable safety profile [ 18 ]. Another study of the combination of an anti-pd - l1 antibody (atezolizumab) and a vegf antibody (bevacizumab) also showed encouraging response rates in patients with advanced HCC who tolerated the toxicity [ 19 ].

Apatinib is a selective VEGFR2 TKI approved for the treatment of advanced gastric cancer in China [ 20 ]. A potential additive or synergistic anti-tumor effect between anti-pd-1 antibodies and VEGF/VEGFR2 inhibitors as demonstrated in vitro and phase I clinical studies [ 21 , 22 ]. The aim of this meta-analysis is to demonstrate the efficacy and safety of immunotherapy in combination with apatinib in the treatment of advanced or metastatic G/GEJ based on the available data, and to provide further therapeutic options for better survival benefit in advanced or metastatic G/GEJ in the future. Until now, there is no published meta-analysis on a similar topic.

Data sources and search strategy

We conducted an independent systematic literature search mainly in PubMed, Embase, Cochrane Library and Web of Science databases. Recent unpublished clinical trials of immunotherapy combined with apatinib for advanced or metastatic G/GEJ tumors from the American Society of Clinical Oncology (ASCO), the European Society for Medical Oncology (ESMO), and other international oncology congresses were included. The time span was from the inception of the database to December 1, 2023. All keywords were searched by MeSH, mainly including “immunologic agents”, “apatinib”, “advanced or metastatic”, " gastric cancer” and “gastroesophageal junction tumor”. This systematic evaluation and meta-analysis followed the Preferred Reporting Items for Systematic Evaluation and Meta-Analysis (PRISMA) statement [ 23 ]. The systematic evaluation and meta-analysis is registered with PROSPERO (registration number: CRD42023491167).

Inclusion and exclusion criteria

In this meta-analysis, the inclusion criteria were as follows: (1) patients with histopathologically confirmed advanced or metastatic G/GEJ; (2) immunotherapy combined with apatinib as the primary therapeutic agent; and (3) reported at least one of the following primary outcomes: incidence of CR, PR, SD, ORR, DCR, median PFS, median OS, and ≥ 3TRAEs. Exclusion criteria were as follows: (1) patients with resectable or locally advanced G/GEJ; (2) case reports, reviews, or commentaries; (3) multiple articles published by different authors with overlapping or duplicated data; (4) articles not in English; and (5) studies that did not address the key findings of the current meta-analysis.

Data extraction and quality assessment

Two authors (JCW and JL) independently filtered the titles and abstracts of all included studies. The abstracts of all potentially eligible trials were read independently by the same authors who decided whether the study was selected. The full text of all selected papers was then analyzed by the same author to select all trials that were ultimately included in the combined analysis. When discrepancies in trial search or selection arose, they were discussed with a third researcher (RMW) to reach a final consensus. Data were recorded and archived in an Excel spreadsheet. In addition, parameters were extracted in a uniform format, including first author, year of publication, study type (single-arm or RCT), approval number, dMMR/pMMR, HER2, PD-L1 expression, pathologic typing, pathologic staging, treatment modality, number of enrollees, age, incidence of ≥ grade 3 TRAEs, CR, PR, ORR, SD, DCR, median PFS, and median OS. The partial MINORS tool was used to evaluate the study quality. The items are scored 0 (not reported), 1 (reported but inadequate), or 2 (reported and adequate) [ 24 ].

Statistical analysis

Meta-analysis of non-comparative binary outcomes was mainly applied because most of the included studies were single-arm clinical studies and the outcome indicators were mainly expressed as proportions. The combined odds ratios (OR) and 95% confidence intervals (CI) were converted into incidence rates to assess the efficacy and safety of immunotherapy in combination with apatinib in the treatment of advanced/metastatic G/GEJ. q-tests of P  < 0.05 or I2 > 50% were used to consider that there was significant heterogeneity in the literature, and a random-effects model was used; otherwise, a fixed-effects model was applied. In addition, sensitivity analyses were performed by sequentially removing individual studies to assess the stability of the combined results of these studies. For studies with significant heterogeneity that could not be reduced using sensitivity analyses, further subgroup analyses were performed to explore the sources of heterogeneity. A funnel plot test for publication bias was used. p  < 0.05 was considered a statistically significant difference. In addition, as median PFS and median OS were continuous variables that could not be calculated using incidence for analysis, further analysis using stata 15.0 software was required. All analyses were performed using Review Manager 5.4/stata 15.0 software.

The characteristics of the included studies

There is a PRISMA diagram of the study selection process as shown in Fig.  1 . According to the search strategy, a total of 705 publications were included (118 PubMed, 463 Embase, and 124 Web of science), and 19 studies [ 21 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ] with a total of 651 patients were eligible for inclusion in the final meta-analysis. meta-analysis included a total of 16 single-arm cohort studies, and three randomized controlled studies. The main immunotherapeutic agents were SHR-1210, JS001, Camrelizumab, Pembrolizumab, sintilmab, Tislelizumab, and Nivolumab.Depending on the treatment regimen, we can categorize them into 2 main therapeutic modalities, namely, immunotherapy combined with apatinib (IA) and immunotherapy and apatinib combined with chemotherapy (IAC). The main characteristics of the included studies are shown in Table  1 , and the main outcomes are shown in Table  2 . Supplementary Table 1 shows the overall low risk of bias of the included studies.

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) diagram of the study selection

Evaluation of efficacy outcomes

In this study, CR, PR, SD, ORR and DCR were used to evaluate the efficacy of immunoapatinib treatment. CR is when a tumor has been treated so that all previously detectable tumors have disappeared and there is no clinical or imaging evidence of tumor presence. Of all the included studies, CR was not assessed in 4 studies, CR was not achieved in 11 studies, and CR in the remaining studies ranged from 2.2 to 5.3%. In the four eligible studies, the combined CR was 0.03 (95% CI: 0.00 -0.06), a statistically significant difference ( p  = 0.03). Using a fixed-effects model, there was no significant heterogeneity among the 4 studies ( P  = 0.91, I 2  = 0%; Fig.  2 A). PR was defined as a ≥ 30% reduction in the sum of the largest diameters of the tumor target lesions, maintained for at least 4 weeks. Meanwhile, among the 15 eligible studies, the combined PR was 0.34 (95% CI: 0.19–0.49), a statistically significant difference ( P  < 0.00001). Using a random-effects model, there was significant heterogeneity among the 15 studies ( p  < 0.00001, I 2  = 94%; Fig.  2 B). SD is defined as shrinkage of the sum of the largest diameters of the tumor target lesions without PR, or enlargement without disease progression. Among the 19 eligible studies, the combined SD was 0.43 (95% CI: 0.32–0.55), a statistically significant difference ( p  < 0.00001). Using a random-effects model, there was similarly significant heterogeneity among the 15 studies ( p  < 0.00001, I 2  = 91%; Fig.  2 C).

Immunotherapy combined with apatinib forest plot. ( A ): CR; ( B ): PR. ( C ): SD

ORR is the proportion of patients whose tumor volume shrinks to a pre-specified value and maintains the minimum timeframe requirement, and is the sum of the CR and PR proportions. In addition, the 19 included studies reported ORR rates ranging from 5.9 to 90.9%. The joint ORR was 0.36 (95% CI: 0.23–0.48), a statistically significant difference ( p  < 0.0001). Using a random-effects model, there was significant heterogeneity among the 19 studies ( p  < 0.0001, I 2  = 94%; Fig.  3 ). DCR is the number of cases that achieved remission (PR + CR) and lesion stabilization (SD) after treatment as a percentage of the number of evaluable cases. In contrast, a total of 18 studies could be included in the DCR for single-arm Meta-analysis, with a joint DCR of 0.80 (95% CI: 0.74–0.86), a statistically significant difference ( p  < 0.0001). Using a random-effects model, there was similarly significant heterogeneity among the 18 studies ( p  < 0.0001, I 2  = 86%; Fig.  4 ).

Immunotherapy combined with apatinib forest plot.:(ORR)

Immunotherapy combined with apatinib forest plot.:(DCR)

The same was true for median PFS and median OS, with 16 and 11 studies included, respectively. The median PFS (month) ranged from 2.47 to 11, and the OR of the combined median PFS was 4.29 (95% CI:4.05–4.52, I 2  = 92.3%, P  = 0.000, Fig.  5 A). Due to the large heterogeneity of the 16 studies, a random effects model was used. The median OS (month) of course also ranged from 5.2 to 20, and the OR of the combined median OS was 8.79 (95% CI:7.92–9.66, I 2  = 81.1%, P  = 0.000, Fig.  5 B). Again, due to the large heterogeneity of the 11 included studies, a random effects model was used.

Immunotherapy combined with apatinib forest plot. ( A ): Median PFS; ( B ): Median OS

Evaluation of safety outcomes

The safety of immunotherapy in combination with apatinib for the treatment of patients with advanced or metastatic G/GEJ was evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE16; version 4.0) [ 43 ]. A total of 10 of the included clinical studies reported the incidence of grade ≥ 3 and higher treatments, totaling 118 patients. The incidence of combined grade ≥ 3 TRAEs was 0.34 (95% CI: 0:19-0.49, I 2  = 93%, P  < 0.00001) (Fig.  6 ). Only 1 patient [ 35 ] patient died due to grade ≥ 3 TRAEs (abnormal liver function and interstitial lung disease). Other mainly controllable adverse events such as thrombocytopenia, anemia, neutropenia, leukopenia, pruritus, rash, hand-foot syndrome, elevated AST/ALT, fatigue, nausea and vomiting, diarrhea, hypertension, proteinuria, and reactive cutaneous capillary endothelial cell proliferation, among others, did not result in serious adverse outcomes or lead to mortality.

Immunotherapy combined with apatinib forest plot: (≥ 3 TRAEs)

Sensitivity analysis and subgroup analysis

Reconsideration of study search, selection, and inclusion criteria did not reduce heterogeneity. To determine that the joint results were not heavily influenced by individual trials, the included studies were taken out of sequence for sensitivity analysis. We found that this did not significantly reduce heterogeneity. To further identify possible sources of heterogeneity, immunotherapy combined with apatinib was grouped according to whether it was combined with other treatment modalities. In the subgroup analysis, significant differences in PR, SD, ORR, DCR, median PFS and median OS were found. Among them, PR, ORR, DCR, median PFS and median OS were much higher in the IAC group than in the IA group (0.54 vs. 0.15, Fig.  7 A.58 vs. 0.18, Fig.  8 A.94 vs. 0.71, Fig.  8 B.67 vs. 3.35, Fig.  9 .85 vs. 15.79, Fig.  10 ). In terms of the incidence of SD, the IAC group group was slightly lower than the IA group, but the difference was not significant (0.33 vs. 0.52, Fig.  7 B). And there was no significant difference between the IAC group and the IA group in terms of grade ≥ 3 TRAEs (0.31 vs. 0.27, I 2  = 5.8%, P  = 0.30, Fig.  11 ). This showed that the IAC group both improved the effectiveness of the treatment without increasing the incidence of adverse events, implying that the combination of immunotherapy and apatinib with chemotherapy may be somehow superior to immunotherapy alone combined with apatinib.

Subgroup analysis. ( A ): PR. ( B ): SD

Subgroup analysis. ( A ): ORR. ( B ): DCR

Subgroup analysis of Median PFS. ( A ): IA; ( B ): IAC

Subgroup analysis of Median OS ( A ): IA; ( B ): IAC

Subgroup analysis of ≥ 3 TRAEs

Publication bias

Due to the high degree of heterogeneity, most of the above results were obtained using random-effects models, and therefore future phase 3 and large-scale randomized controlled trials are needed for further assessment. Funnel plots were used to analyze possible publication bias for immunotherapy combined with apatinib in 19 clinical studies. Most of the data collected were single-arm clinical trials without controls, but there was no significant publication bias (Supplementary Fig.  1 ).

Approximately half of the world’s new cases of gastric cancer are detected in China each year, and half of all Chinese patients are diagnosed at an advanced stage. It is recommended in the 2021 CSCO guidelines that fluorouracil in combination with platinum (or) paclitaxel is the first-line standard chemotherapy regimen for patients with her2 negative advanced gastric cancer [ 4 ]. But in clinical practice, there are still a large number of patients failing first-line treatment. As a maintenance or sequential treatment chemo-free strategy is constantly being explored. Immunotherapy or apatinib alone has been used in the third-line treatment of advanced or metastatic G/GEJ, but the results remain suboptimal. Regardless of PD-L1 status in the ATTRACTION-2 trial, nivolumab monotherapy improved overall survival in patients with advanced gastric cancer by 5.26 months (95% CI 4.60–6.37), but the ORR was only 11.2% (95% CI: 7.77–15.6) [ 10 ]. Based on previous studies, the median PFS and OS of mGC patients receiving third-line treatment with apatinib monotherapy were 2.70  ∼  4.47 months and 4.27–6.51 months, respectively [ 20 , 44 , 45 ]. Some findings suggest that combination therapy with PD-1 inhibitors and apatinib improves therapeutic efficacy, mainly because tumor angiogenesis inhibits the extravasation of reactive T-cells, which form an immunosuppressive microenvironment, leading to tumor evasion of immune surveillance. Combination therapy enhances t-cell infiltration and activation, thereby eliminating tumor cells [ 46 , 47 , 48 , 49 ]. A combination study of PD-1 monoclonal antibodies and angiogenesis inhibitors has been initially validated in several clinical trials. Ramucirumab in combination with nivolumab or pembrolizumab has shown promising efficacy in AGC patients in several phase I/II trials [ 50 , 51 , 52 ].

As far as we know, this is the first meta-analysis evaluating the efficacy and safety of immunotherapy combined with apatinib for the treatment of patients with advanced or metastatic G/GEJ. Our analysis is based on 19 small studies, including 651 patients, quantitatively and synthetically analyzing the efficacy and safety of immunotherapy combined with apatinib treatment. There is great excitement about the results of the current meta-analysis study. The aggregated CR, PR, SD, ORR and DCR for immunotherapy combined with apatinib were 0.03 (95% CI: 0.00 -0.06), 0.34 (95% CI: 0.19–0.49), 0.43 (95% CI: 0.32–0.55), 0.36 (95% CI: 0.23–0.48), 0.80 (95% CI: 0:74-0.86). And the median PFS and median OS reached 4.29 (95% CI:4.05–4.52), 8.79 (95% CI:7.92–9.66), respectively. Subgroup analysis showed significant differences in PR, ORR, DCR, median PFS, and median OS, with the IAC group being significantly better than the IA group as well as the IAC group being slightly lower than the IA group in terms of SD. The IAC group had an ORR of 0.58 (95% CI: 0.42–0.74, Fig.  8 A), a DCR of 0.94 (95% CI: 0.89–0.98, Fig.  8 B) a median PFS of 6.67 months (95% CI: 6.23–7.12, Fig.  9 B) and a median OS of 15.47 months (95% CI. 13.00-17.93, Fig.  10 B), which was higher than the ORR (about 40%), PFS (5.5 months) and OS (11.5 months) of fluorouracil-platinum regimen [ 53 ]. This suggests that combination chemotherapy with immunotherapy and apatinib is superior to adjuvant chemotherapy in terms of effectiveness. In the IAC group, the L. Su et al. study achieved a 100% DCR as well as the highest median PFS of 11.0 (95% CI: 7.0–15.0) months [ 41 ]. In addition, there was the highest median OS of 20.0 months (95% CI: 13.6–26.4) in the study by Kunpeng Wu et al [ 37 ]. And from the 3 RCT trials we included, we found that immunotherapy combined with apatinib treatment was superior to immuno/apatinib alone, apatinib combined with chemotherapy, and immuno combined with chemotherapy in terms of median PFS and median OS [ 32 , 33 , 34 ].

Considering the safety of immunotherapy combined with apatinib, the combined OR for the incidence of grade ≥ 3 TRAEs was 0.34 (95% CI: 0:19-0.49), which was not significantly different between the IAC and IA groups (0.31 vs. 0.27). Among the studies we included, only 2 studies explicitly stated that a total of 6 and 12 patients, respectively, discontinued their medication because of TRAE due to immunologic agents or apatinib [ 26 , 36 ]. Only one patient also died from grade ≥ 3 TRAEs, and other adverse events were manageable. In conclusion, combination therapy with immunotherapy and apatinib has shown encouraging clinical activity in patients with advanced or metastatic G/GEJ, which may improve survival and show tolerable toxicity as second- or third-line therapy.

On the other hand, however, the current meta-analysis still has some limitations. First, the small number of included studies, insufficient sample size, and mostly single-arm clinical trials, the lack of randomized controlled trials, and the single type of study may lead to bias. Therefore, more multicenter, large-sample phase III randomized controlled trials and subsequent meta-analysis are needed to further validate the results of this study. Second, more predictive biomarkers are urgently needed to identify patients who benefit most from immunotherapy combined with apatinib treatment. Despite the heterogeneity, the results suggest that adjuvant therapy based on immunotherapy combined with apatinib is safe and feasible with a favorable improvement in survival, pointing the way to the future development of adjuvant therapy for advanced or metastatic G/GEJ.

Data availability

The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author.

Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359–386.

Article   CAS   PubMed   Google Scholar  

Catalano V, Labianca R, Beretta GD, Gatta G, de Braud F, Van Cutsem E. Gastric cancer. Crit Rev Oncol Hematol. 2009;71(2):127–64.

Article   PubMed   Google Scholar  

Wagner AD, Syn NL, Moehler M, Grothe W, Yong WP, Tai BC, Ho J, Unverzagt S. Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev. 2017;8(8):Cd004064.

PubMed   Google Scholar  

Wang FH, Zhang XT, Li YF, Tang L, Qu XJ, Ying JE, Zhang J, Sun LY, Lin RB, Qiu H et al. The Chinese Society of Clinical Oncology (CSCO): clinical guidelines for the diagnosis and treatment of gastric cancer, 2021. Cancer communications (London, England) 2021, 41(8):747–95.

Chan WL, Yuen KK, Siu SW, Lam KO, Kwong DL. Third-line systemic treatment versus best supportive care for advanced/metastatic gastric cancer: a systematic review and meta-analysis. Crit Rev Oncol Hematol. 2017;116:68–81.

Galdy S, Cella CA, Spada F, Murgioni S, Frezza AM, Ravenda SP, Zampino MG, Fazio N. Systemic therapy beyond first-line in advanced gastric cancer: an overview of the main randomized clinical trials. Crit Rev Oncol Hematol. 2016;99:1–12.

Takahari D. Second-line chemotherapy for patients with advanced gastric cancer. Gastric Cancer. 2017;20(3):395–406.

Shitara K, Takashima A, Fujitani K, Koeda K, Hara H, Nakayama N, Hironaka S, Nishikawa K, Makari Y, Amagai K, et al. Nab-paclitaxel versus solvent-based paclitaxel in patients with previously treated advanced gastric cancer (ABSOLUTE): an open-label, randomised, non-inferiority, phase 3 trial. Lancet Gastroenterol Hepatol. 2017;2(4):277–87.

Fuchs CS, Doi T, Jang RW, Muro K, Satoh T, Machado M, Sun W, Jalal SI, Shah MA, Metges JP, et al. Safety and Efficacy of Pembrolizumab Monotherapy in patients with previously treated Advanced gastric and gastroesophageal Junction Cancer: phase 2 clinical KEYNOTE-059 trial. JAMA Oncol. 2018;4(5):e180013.

Article   PubMed   PubMed Central   Google Scholar  

Kang YK, Boku N, Satoh T, Ryu MH, Chao Y, Kato K, Chung HC, Chen JS, Muro K, Kang WK, et al. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;390(10111):2461–71.

Fashoyin-Aje L, Donoghue M, Chen H, He K, Veeraraghavan J, Goldberg KB, Keegan P, McKee AE, Pazdur R. FDA approval Summary: Pembrolizumab for recurrent locally Advanced or metastatic gastric or gastroesophageal Junction Adenocarcinoma expressing PD-L1. Oncologist. 2019;24(1):103–9.

Janjigian YY, Shitara K, Moehler M, Garrido M, Salman P, Shen L, Wyrwicz L, Yamaguchi K, Skoczylas T, Campos Bragagnoli A, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. 2021;398(10294):27–40.

Article   CAS   PubMed   PubMed Central   Google Scholar  

Powles T, Csőszi T, Özgüroğlu M, Matsubara N, Géczi L, Cheng SY, Fradet Y, Oudard S, Vulsteke C, Morales Barrera R, et al. Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(7):931–45.

Zhou C, Wang Y, Zhao J, Chen G, Liu Z, Gu K, Huang M, He J, Chen J, Ma Z, et al. Efficacy and Biomarker Analysis of Camrelizumab in Combination with Apatinib in patients with Advanced Nonsquamous NSCLC previously treated with chemotherapy. Clin Cancer Res. 2021;27(5):1296–304.

Vanneman M, Dranoff G. Combining immunotherapy and targeted therapies in cancer treatment. Nat Rev Cancer. 2012;12(4):237–51.

Hamzah J, Jugold M, Kiessling F, Rigby P, Manzur M, Marti HH, Rabie T, Kaden S, Gröne HJ, Hämmerling GJ, et al. Vascular normalization in Rgs5-deficient tumours promotes immune destruction. Nature. 2008;453(7193):410–4.

Tartour E, Pere H, Maillere B, Terme M, Merillon N, Taieb J, Sandoval F, Quintin-Colonna F, Lacerda K, Karadimou A, et al. Angiogenesis and immunity: a bidirectional link potentially relevant for the monitoring of antiangiogenic therapy and the development of novel therapeutic combination with immunotherapy. Cancer Metastasis Rev. 2011;30(1):83–95.

Atkins MB, Plimack ER, Puzanov I, Fishman MN, McDermott DF, Cho DC, Vaishampayan U, George S, Olencki TE, Tarazi JC, et al. Axitinib in combination with pembrolizumab in patients with advanced renal cell cancer: a non-randomised, open-label, dose-finding, and dose-expansion phase 1b trial. Lancet Oncol. 2018;19(3):405–15.

Stein S, Pishvaian MJ, Lee MS, Lee K-H, Hernandez S, Kwan A, Liu B, Grossman W, Iizuka K, Ryoo B-Y. Safety and clinical activity of 1L atezolizumab + bevacizumab in a phase ib study in hepatocellular carcinoma (HCC). J Clin Oncol. 2018;36(15suppl):4074–4074.

Article   Google Scholar  

Li J, Qin S, Xu J, Xiong J, Wu C, Bai Y, Liu W, Tong J, Liu Y, Xu R, et al. Randomized, Double-Blind, placebo-controlled phase III trial of apatinib in patients with chemotherapy-refractory Advanced or metastatic adenocarcinoma of the stomach or Gastroesophageal Junction. J Clin Oncol. 2016;34(13):1448–54.

Xu J, Zhang Y, Jia R, Yue C, Chang L, Liu R, Zhang G, Zhao C, Zhang Y, Chen C, et al. Anti-PD-1 antibody SHR-1210 combined with apatinib for Advanced Hepatocellular Carcinoma, gastric, or Esophagogastric Junction Cancer: an Open-label, dose escalation and expansion study. Clin Cancer Res. 2019;25(2):515–23.

Yasuda S, Sho M, Yamato I, Yoshiji H, Wakatsuki K, Nishiwada S, Yagita H, Nakajima Y. Simultaneous blockade of programmed death 1 and vascular endothelial growth factor receptor 2 (VEGFR2) induces synergistic anti-tumour effect in vivo. Clin Exp Immunol. 2013;172(3):500–6.

Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, Shamseer L, Tetzlaff JM, Akl EA, Brennan SE, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ (Clinical Res ed). 2021;372:n71.

Google Scholar  

Slim K, Nini E, Forestier D, Kwiatkowski F, Panis Y, Chipponi J. Methodological index for non-randomized studies (minors): development and validation of a new instrument. ANZ J Surg. 2003;73(9):712–6.

Wei Q, Yuan X, Li J, Xu Q, Ying J. PD-1 inhibitor combined with apatinib for advanced gastric or esophagogastric junction cancer: a retrospective study. Translational cancer Res. 2020;9(9):5315–22.

Article   CAS   Google Scholar  

Li LH, Chen WC, Wu G. Feasibility and tolerance of apatinib plus PD-1 inhibitors for previously treated Advanced Gastric Cancer: a real-world exploratory study. Disease markers 2022, 2022:4322404.

Ma N, Qiao H, Tao H, Gan X, Shan Z, Chen X, Zhou X. Treatment response, survival, and safety profile of camrelizumab plus apatinib regimen as third-line treatment in metastatic gastric cancer patients. Clin Res Hepatol Gastroenterol. 2022;46(7):101962.

Gao L, Tang L, Li X, Peng J, Hu Z, Liu B. Efficacy and safety of sintilimab combined with apatinib as third-line or above therapy for patients with advanced or metastatic gastric cancer. Anti-cancer drugs; 2023.

Xiao L, Zhang Y, Lin Q. Camrelizumab combined with apatinib in the treatment of patients with advanced gastric cancer and colorectal cancer: one-arm exploratory clinical trial. Ann Oncol. 2020;31:S429.

Chen B, Zhao H, Wang S, Lv H, Xu W, Nie C, Wang J, Zhao J, He Y, Chen X. PD-1 inhibitors combined with apatinib for advanced diffuse gastric cancer: a retrospective study. J Clin Oncol 2022, 40(16).

Hou XF, Zhang XX, Li S, Wu C, Chen XB. A Retrospective Cohort Study examining the effects of Anti-PD-1 antibody in combination with apatinib in patients previously treated for Her2-Negative Advanced Gastric/Gastroesophageal Junction Cancer. J Clin Pharmacol. 2023;63(7):769–75.

Cui Q, Mao Y, Wu D, Hu Y, Ma D, Zhang L, Liu H. Apatinib combined with PD-1 antibody for third-line or later treatment of advanced gastric cancer. Front Oncol. 2022;12:952494.

Nie C, Xu W, Lv H, Gao X, Li G, Chen B, Wang J, Liu Y, Zhao J, He Y, et al. Tailoring second-line or above therapy for patients with advanced or metastatic gastric cancer: a multicenter real-world study. Front Pharmacol. 2022;13:1043217.

Gou M, Zhang Y, Wang Z, Dai G. PD-1 inhibitors-based second-line therapy for metastatic gastric cancer. Front Immunol 2023, 14.

Peng Z, Wei J, Wang F, Ying J, Deng Y, Gu K, Cheng Y, Yuan X, Xiao J, Tai Y, et al. Camrelizumab combined with chemotherapy followed by camrelizumab plus apatinib as first-line therapy for advanced gastric or gastroesophageal junction adenocarcinoma. Clin Cancer Res. 2021;27(11):3069–78.

Jing C, Wang J, Zhu M, Bai Z, Zhao B, Zhang J, Yin J, Yang X, Liu Z, Zhang Z, et al. Camrelizumab combined with apatinib and S-1 as second-line treatment for patients with advanced gastric or gastroesophageal junction adenocarcinoma: a phase 2, single-arm, prospective study. Cancer Immunol Immunother. 2022;71(11):2597–608.

Wu K, Li Y, Li Z, Zhou Z, Ge X, Li Y, Han X, Chen P, Ren K. Transcatheter arterial chemoembolization combined with apatinib and camrelizumab for unresectable advanced gastric or gastroesophageal junction cancer: a single-arm, single-center, retrospective study. Front Oncol. 2023;13:1143578.

Zhang L, Wang W, Ge S, Li H, Bai M, Duan J, Yang Y, Ning T, Liu R, Wang X, et al. Sintilimab Plus Apatinib and Chemotherapy as Second–/Third-Line treatment for Advanced Gastric or Gastroesophageal Junction Adenocarcinoma: a prospective, Single-Arm, phase II trial. BMC Cancer. 2023;23(1):211.

Deng T, Zhang L, Duan J, Li H, Ge S, Bai M, Ning T, Yang Y, Ji Z, Liu R et al. Chemothery (pacitaxol or irinotecan), plus apatinib and sintilimab as second-/third-line treatment for advanced gastric cancer. J Clin Oncol 2021, 39(15 SUPPL).

Gou M, Qian N, Wang Z, Yan H, Zhang Y, Si H, Dai G. A phase II single-center single-arm study of PD-1 inhibitor in combination with albumin paclitaxel and apatinib as second-line treatment of metastatic gastric cancer (mGC). J Clin Oncol 2022, 40(16).

Su L, Zhao S, Lin P, Yin Y, Lin R. 1250P camrelizumab plus apatinib combined with POF in patients with untreated advanced gastric cancer (UAGC): a single-center, open-label, single-arm, phase II trial (SYLT-017). Ann Oncol. 2022;33:S1119–20.

Chen X, Xu H, Wang D, Chen X, Wang K, Jin G, Ding Y, Tang J, Fang Y, Sun H, et al. Camrelizumab plus low-dose apatinib and SOX in the first-line treatment of advanced gastric/gastroesophageal junction (G/GEJ) adenocarcinoma: a single-arm, dose escalation and expansion study (SPACE study). J Clin Oncol. 2023;41(4):365.

Wang J, Zhang K, Liu T, Song Y, Hua P, Chen S, Li J, Liu Y, Zhao Y. Efficacy and safety of neoadjuvant immunotherapy combined with chemotherapy in locally advanced esophageal cancer: a meta-analysis. Front Oncol. 2022;12:974684.

Peng W, Zhang F, Wang Z, Li D, He Y, Ning Z, Sheng L, Wang J, Xia X, Yu C, et al. Large scale, Multicenter, prospective study of apatinib in Advanced Gastric Cancer: a real-world study from China. Cancer Manage Res. 2020;12:6977–85.

Li J, Qin S, Xu J, Guo W, Xiong J, Bai Y, Sun G, Yang Y, Wang L, Xu N, et al. Apatinib for chemotherapy-refractory advanced metastatic gastric cancer: results from a randomized, placebo-controlled, parallel-arm, phase II trial. J Clin Oncol. 2013;31(26):3219–25.

Motz GT, Coukos G. Deciphering and reversing tumor immune suppression. Immunity. 2013;39(1):61–73.

Allen E, Jabouille A, Rivera LB, Lodewijckx I, Missiaen R, Steri V, Feyen K, Tawney J, Hanahan D, Michael IP et al. Combined antiangiogenic and anti-PD-L1 therapy stimulates tumor immunity through HEV formation. Sci Transl Med 2017, 9(385).

Lanitis E, Irving M, Coukos G. Targeting the tumor vasculature to enhance T cell activity. Curr Opin Immunol. 2015;33:55–63.

Tang H, Wang Y, Chlewicki LK, Zhang Y, Guo J, Liang W, Wang J, Wang X, Fu YX. Facilitating T cell infiltration in Tumor Microenvironment overcomes resistance to PD-L1 blockade. Cancer Cell. 2016;29(3):285–96.

Chau I, Penel N, Soriano AO, Arkenau HT, Cultrera J, Santana-Davila R, Calvo E, Le Tourneau C, Zender L, Bendell JC et al. Ramucirumab in Combination with Pembrolizumab in Treatment-Naïve Advanced gastric or GEJ Adenocarcinoma: Safety and Antitumor Activity from the phase 1a/b JVDF Trial. Cancers 2020, 12(10).

Herbst RS, Arkenau HT, Santana-Davila R, Calvo E, Paz-Ares L, Cassier PA, Bendell J, Penel N, Krebs MG, Martin-Liberal J, et al. Ramucirumab plus Pembrolizumab in patients with previously treated advanced non-small-cell lung cancer, gastro-oesophageal cancer, or urothelial carcinomas (JVDF): a multicohort, non-randomised, open-label, phase 1a/b trial. Lancet Oncol. 2019;20(8):1109–23.

Nakajima TE, Kadowaki S, Minashi K, Nishina T, Yamanaka T, Hayashi Y, Izawa N, Muro K, Hironaka S, Kajiwara T, et al. Multicenter Phase I/II study of Nivolumab Combined with Paclitaxel Plus Ramucirumab as second-line treatment in patients with Advanced Gastric Cancer. Clin Cancer Res. 2021;27(4):1029–36.

Van Cutsem E, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C, Rodrigues A, Fodor M, Chao Y, Voznyi E, et al. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol. 2006;24(31):4991–7.

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Jincheng Wang, Ti Tong & Yinghao Zhao

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Jincheng Wang , Ti Tong and Yinghao Zhao: Conceptualization, Methodology. Jincheng Wang , Jie Lin and Ruimin Wang: Software, Formal analysis, Investigation, Resources, Data Curation, extracted data from studies, and matched inclusion and exclusion criteria. Jincheng Wang: Writing - Original Draft, Writing - Review & Editing. Ti Tong and Yinghao Zhao: Visualization, Project administration, Supervision.All authors had full access to all data, critically revised the paper, approved the final analysis, and took responsibility for all aspects of the work to ensure that issues relating to the accuracy or integrity of any part of the work could be appropriately investigated and resolved. We warrant that the article is the original work, hasn’t received prior publication.

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Wang, J., Lin, J., Wang, R. et al. Immunotherapy combined with apatinib in the treatment of advanced or metastatic gastric/gastroesophageal tumors: a systematic review and meta-analysis. BMC Cancer 24 , 603 (2024). https://doi.org/10.1186/s12885-024-12340-4

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Received : 28 February 2024

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Published : 17 May 2024

DOI : https://doi.org/10.1186/s12885-024-12340-4

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