journals on systematic literature review

How to Do a Systematic Review: A Best Practice Guide for Conducting and Reporting Narrative Reviews, Meta-Analyses, and Meta-Syntheses

Affiliations.

• 1 Behavioural Science Centre, Stirling Management School, University of Stirling, Stirling FK9 4LA, United Kingdom; email: [email protected].
• 2 Department of Psychological and Behavioural Science, London School of Economics and Political Science, London WC2A 2AE, United Kingdom.
• 3 Department of Statistics, Northwestern University, Evanston, Illinois 60208, USA; email: [email protected].
• PMID: 30089228
• DOI: 10.1146/annurev-psych-010418-102803

Systematic reviews are characterized by a methodical and replicable methodology and presentation. They involve a comprehensive search to locate all relevant published and unpublished work on a subject; a systematic integration of search results; and a critique of the extent, nature, and quality of evidence in relation to a particular research question. The best reviews synthesize studies to draw broad theoretical conclusions about what a literature means, linking theory to evidence and evidence to theory. This guide describes how to plan, conduct, organize, and present a systematic review of quantitative (meta-analysis) or qualitative (narrative review, meta-synthesis) information. We outline core standards and principles and describe commonly encountered problems. Although this guide targets psychological scientists, its high level of abstraction makes it potentially relevant to any subject area or discipline. We argue that systematic reviews are a key methodology for clarifying whether and how research findings replicate and for explaining possible inconsistencies, and we call for researchers to conduct systematic reviews to help elucidate whether there is a replication crisis.

Keywords: evidence; guide; meta-analysis; meta-synthesis; narrative; systematic review; theory.

• Guidelines as Topic
• Meta-Analysis as Topic*
• Publication Bias
• Review Literature as Topic
• Systematic Reviews as Topic*

• Open access
• Published: 29 March 2021

The PRISMA 2020 statement: an updated guideline for reporting systematic reviews

• Matthew J. Page   ORCID: orcid.org/0000-0002-4242-7526 1 ,
• Joanne E. McKenzie 1 ,
• Patrick M. Bossuyt 2 ,
• Isabelle Boutron 3 ,
• Tammy C. Hoffmann 4 ,
• Cynthia D. Mulrow 5 ,
• Larissa Shamseer 6 ,
• Jennifer M. Tetzlaff 7 ,
• Elie A. Akl 8 ,
• Sue E. Brennan 1 ,
• Roger Chou 9 ,
• Julie Glanville 10 ,
• Jeremy M. Grimshaw 11 ,
• Asbjørn Hróbjartsson 12 ,
• Manoj M. Lalu 13 ,
• Tianjing Li 14 ,
• Elizabeth W. Loder 15 ,
• Evan Mayo-Wilson 16 ,
• Steve McDonald 1 ,
• Luke A. McGuinness 17 ,
• Lesley A. Stewart 18 ,
• James Thomas 19 ,
• Andrea C. Tricco 20 ,
• Vivian A. Welch 21 ,
• Penny Whiting 17 &
• David Moher 22  

Systematic Reviews volume  10 , Article number:  89 ( 2021 ) Cite this article

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An Editorial to this article was published on 19 April 2021

The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement, published in 2009, was designed to help systematic reviewers transparently report why the review was done, what the authors did, and what they found. Over the past decade, advances in systematic review methodology and terminology have necessitated an update to the guideline. The PRISMA 2020 statement replaces the 2009 statement and includes new reporting guidance that reflects advances in methods to identify, select, appraise, and synthesise studies. The structure and presentation of the items have been modified to facilitate implementation. In this article, we present the PRISMA 2020 27-item checklist, an expanded checklist that details reporting recommendations for each item, the PRISMA 2020 abstract checklist, and the revised flow diagrams for original and updated reviews. In order to encourage its wide dissemination this article is freely accessible on BMJ, PLOS Medicine, Journal of Clinical Epidemiology and International Journal of Surgery journal websites.

Systematic reviews serve many critical roles. They can provide syntheses of the state of knowledge in a field, from which future research priorities can be identified; they can address questions that otherwise could not be answered by individual studies; they can identify problems in primary research that should be rectified in future studies; and they can generate or evaluate theories about how or why phenomena occur. Systematic reviews therefore generate various types of knowledge for different users of reviews (such as patients, healthcare providers, researchers, and policy makers) [ 1 , 2 ]. To ensure a systematic review is valuable to users, authors should prepare a transparent, complete, and accurate account of why the review was done, what they did (such as how studies were identified and selected) and what they found (such as characteristics of contributing studies and results of meta-analyses). Up-to-date reporting guidance facilitates authors achieving this [ 3 ].

The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement published in 2009 (hereafter referred to as PRISMA 2009) [ 4 , 5 , 6 , 7 , 8 , 9 , 10 ] is a reporting guideline designed to address poor reporting of systematic reviews [ 11 ]. The PRISMA 2009 statement comprised a checklist of 27 items recommended for reporting in systematic reviews and an “explanation and elaboration” paper [ 12 , 13 , 14 , 15 , 16 ] providing additional reporting guidance for each item, along with exemplars of reporting. The recommendations have been widely endorsed and adopted, as evidenced by its co-publication in multiple journals, citation in over 60,000 reports (Scopus, August 2020), endorsement from almost 200 journals and systematic review organisations, and adoption in various disciplines. Evidence from observational studies suggests that use of the PRISMA 2009 statement is associated with more complete reporting of systematic reviews [ 17 , 18 , 19 , 20 ], although more could be done to improve adherence to the guideline [ 21 ].

Many innovations in the conduct of systematic reviews have occurred since publication of the PRISMA 2009 statement. For example, technological advances have enabled the use of natural language processing and machine learning to identify relevant evidence [ 22 , 23 , 24 ], methods have been proposed to synthesise and present findings when meta-analysis is not possible or appropriate [ 25 , 26 , 27 ], and new methods have been developed to assess the risk of bias in results of included studies [ 28 , 29 ]. Evidence on sources of bias in systematic reviews has accrued, culminating in the development of new tools to appraise the conduct of systematic reviews [ 30 , 31 ]. Terminology used to describe particular review processes has also evolved, as in the shift from assessing “quality” to assessing “certainty” in the body of evidence [ 32 ]. In addition, the publishing landscape has transformed, with multiple avenues now available for registering and disseminating systematic review protocols [ 33 , 34 ], disseminating reports of systematic reviews, and sharing data and materials, such as preprint servers and publicly accessible repositories. To capture these advances in the reporting of systematic reviews necessitated an update to the PRISMA 2009 statement.

Development of PRISMA 2020

A complete description of the methods used to develop PRISMA 2020 is available elsewhere [ 35 ]. We identified PRISMA 2009 items that were often reported incompletely by examining the results of studies investigating the transparency of reporting of published reviews [ 17 , 21 , 36 , 37 ]. We identified possible modifications to the PRISMA 2009 statement by reviewing 60 documents providing reporting guidance for systematic reviews (including reporting guidelines, handbooks, tools, and meta-research studies) [ 38 ]. These reviews of the literature were used to inform the content of a survey with suggested possible modifications to the 27 items in PRISMA 2009 and possible additional items. Respondents were asked whether they believed we should keep each PRISMA 2009 item as is, modify it, or remove it, and whether we should add each additional item. Systematic review methodologists and journal editors were invited to complete the online survey (110 of 220 invited responded). We discussed proposed content and wording of the PRISMA 2020 statement, as informed by the review and survey results, at a 21-member, two-day, in-person meeting in September 2018 in Edinburgh, Scotland. Throughout 2019 and 2020, we circulated an initial draft and five revisions of the checklist and explanation and elaboration paper to co-authors for feedback. In April 2020, we invited 22 systematic reviewers who had expressed interest in providing feedback on the PRISMA 2020 checklist to share their views (via an online survey) on the layout and terminology used in a preliminary version of the checklist. Feedback was received from 15 individuals and considered by the first author, and any revisions deemed necessary were incorporated before the final version was approved and endorsed by all co-authors.

The PRISMA 2020 statement

Scope of the guideline.

The PRISMA 2020 statement has been designed primarily for systematic reviews of studies that evaluate the effects of health interventions, irrespective of the design of the included studies. However, the checklist items are applicable to reports of systematic reviews evaluating other interventions (such as social or educational interventions), and many items are applicable to systematic reviews with objectives other than evaluating interventions (such as evaluating aetiology, prevalence, or prognosis). PRISMA 2020 is intended for use in systematic reviews that include synthesis (such as pairwise meta-analysis or other statistical synthesis methods) or do not include synthesis (for example, because only one eligible study is identified). The PRISMA 2020 items are relevant for mixed-methods systematic reviews (which include quantitative and qualitative studies), but reporting guidelines addressing the presentation and synthesis of qualitative data should also be consulted [ 39 , 40 ]. PRISMA 2020 can be used for original systematic reviews, updated systematic reviews, or continually updated (“living”) systematic reviews. However, for updated and living systematic reviews, there may be some additional considerations that need to be addressed. Where there is relevant content from other reporting guidelines, we reference these guidelines within the items in the explanation and elaboration paper [ 41 ] (such as PRISMA-Search [ 42 ] in items 6 and 7, Synthesis without meta-analysis (SWiM) reporting guideline [ 27 ] in item 13d). Box 1 includes a glossary of terms used throughout the PRISMA 2020 statement.

PRISMA 2020 is not intended to guide systematic review conduct, for which comprehensive resources are available [ 43 , 44 , 45 , 46 ]. However, familiarity with PRISMA 2020 is useful when planning and conducting systematic reviews to ensure that all recommended information is captured. PRISMA 2020 should not be used to assess the conduct or methodological quality of systematic reviews; other tools exist for this purpose [ 30 , 31 ]. Furthermore, PRISMA 2020 is not intended to inform the reporting of systematic review protocols, for which a separate statement is available (PRISMA for Protocols (PRISMA-P) 2015 statement [ 47 , 48 ]). Finally, extensions to the PRISMA 2009 statement have been developed to guide reporting of network meta-analyses [ 49 ], meta-analyses of individual participant data [ 50 ], systematic reviews of harms [ 51 ], systematic reviews of diagnostic test accuracy studies [ 52 ], and scoping reviews [ 53 ]; for these types of reviews we recommend authors report their review in accordance with the recommendations in PRISMA 2020 along with the guidance specific to the extension.

How to use PRISMA 2020

The PRISMA 2020 statement (including the checklists, explanation and elaboration, and flow diagram) replaces the PRISMA 2009 statement, which should no longer be used. Box  2 summarises noteworthy changes from the PRISMA 2009 statement. The PRISMA 2020 checklist includes seven sections with 27 items, some of which include sub-items (Table  1 ). A checklist for journal and conference abstracts for systematic reviews is included in PRISMA 2020. This abstract checklist is an update of the 2013 PRISMA for Abstracts statement [ 54 ], reflecting new and modified content in PRISMA 2020 (Table  2 ). A template PRISMA flow diagram is provided, which can be modified depending on whether the systematic review is original or updated (Fig.  1 ).

 PRISMA 2020 flow diagram template for systematic reviews. The new design is adapted from flow diagrams proposed by Boers [ 55 ], Mayo-Wilson et al. [ 56 ] and Stovold et al. [ 57 ] The boxes in grey should only be completed if applicable; otherwise they should be removed from the flow diagram. Note that a “report” could be a journal article, preprint, conference abstract, study register entry, clinical study report, dissertation, unpublished manuscript, government report or any other document providing relevant information

We recommend authors refer to PRISMA 2020 early in the writing process, because prospective consideration of the items may help to ensure that all the items are addressed. To help keep track of which items have been reported, the PRISMA statement website ( http://www.prisma-statement.org/ ) includes fillable templates of the checklists to download and complete (also available in Additional file 1 ). We have also created a web application that allows users to complete the checklist via a user-friendly interface [ 58 ] (available at https://prisma.shinyapps.io/checklist/ and adapted from the Transparency Checklist app [ 59 ]). The completed checklist can be exported to Word or PDF. Editable templates of the flow diagram can also be downloaded from the PRISMA statement website.

We have prepared an updated explanation and elaboration paper, in which we explain why reporting of each item is recommended and present bullet points that detail the reporting recommendations (which we refer to as elements) [ 41 ]. The bullet-point structure is new to PRISMA 2020 and has been adopted to facilitate implementation of the guidance [ 60 , 61 ]. An expanded checklist, which comprises an abridged version of the elements presented in the explanation and elaboration paper, with references and some examples removed, is available in Additional file 2 . Consulting the explanation and elaboration paper is recommended if further clarity or information is required.

Journals and publishers might impose word and section limits, and limits on the number of tables and figures allowed in the main report. In such cases, if the relevant information for some items already appears in a publicly accessible review protocol, referring to the protocol may suffice. Alternatively, placing detailed descriptions of the methods used or additional results (such as for less critical outcomes) in supplementary files is recommended. Ideally, supplementary files should be deposited to a general-purpose or institutional open-access repository that provides free and permanent access to the material (such as Open Science Framework, Dryad, figshare). A reference or link to the additional information should be included in the main report. Finally, although PRISMA 2020 provides a template for where information might be located, the suggested location should not be seen as prescriptive; the guiding principle is to ensure the information is reported.

Use of PRISMA 2020 has the potential to benefit many stakeholders. Complete reporting allows readers to assess the appropriateness of the methods, and therefore the trustworthiness of the findings. Presenting and summarising characteristics of studies contributing to a synthesis allows healthcare providers and policy makers to evaluate the applicability of the findings to their setting. Describing the certainty in the body of evidence for an outcome and the implications of findings should help policy makers, managers, and other decision makers formulate appropriate recommendations for practice or policy. Complete reporting of all PRISMA 2020 items also facilitates replication and review updates, as well as inclusion of systematic reviews in overviews (of systematic reviews) and guidelines, so teams can leverage work that is already done and decrease research waste [ 36 , 62 , 63 ].

We updated the PRISMA 2009 statement by adapting the EQUATOR Network’s guidance for developing health research reporting guidelines [ 64 ]. We evaluated the reporting completeness of published systematic reviews [ 17 , 21 , 36 , 37 ], reviewed the items included in other documents providing guidance for systematic reviews [ 38 ], surveyed systematic review methodologists and journal editors for their views on how to revise the original PRISMA statement [ 35 ], discussed the findings at an in-person meeting, and prepared this document through an iterative process. Our recommendations are informed by the reviews and survey conducted before the in-person meeting, theoretical considerations about which items facilitate replication and help users assess the risk of bias and applicability of systematic reviews, and co-authors’ experience with authoring and using systematic reviews.

Various strategies to increase the use of reporting guidelines and improve reporting have been proposed. They include educators introducing reporting guidelines into graduate curricula to promote good reporting habits of early career scientists [ 65 ]; journal editors and regulators endorsing use of reporting guidelines [ 18 ]; peer reviewers evaluating adherence to reporting guidelines [ 61 , 66 ]; journals requiring authors to indicate where in their manuscript they have adhered to each reporting item [ 67 ]; and authors using online writing tools that prompt complete reporting at the writing stage [ 60 ]. Multi-pronged interventions, where more than one of these strategies are combined, may be more effective (such as completion of checklists coupled with editorial checks) [ 68 ]. However, of 31 interventions proposed to increase adherence to reporting guidelines, the effects of only 11 have been evaluated, mostly in observational studies at high risk of bias due to confounding [ 69 ]. It is therefore unclear which strategies should be used. Future research might explore barriers and facilitators to the use of PRISMA 2020 by authors, editors, and peer reviewers, designing interventions that address the identified barriers, and evaluating those interventions using randomised trials. To inform possible revisions to the guideline, it would also be valuable to conduct think-aloud studies [ 70 ] to understand how systematic reviewers interpret the items, and reliability studies to identify items where there is varied interpretation of the items.

We encourage readers to submit evidence that informs any of the recommendations in PRISMA 2020 (via the PRISMA statement website: http://www.prisma-statement.org/ ). To enhance accessibility of PRISMA 2020, several translations of the guideline are under way (see available translations at the PRISMA statement website). We encourage journal editors and publishers to raise awareness of PRISMA 2020 (for example, by referring to it in journal “Instructions to authors”), endorsing its use, advising editors and peer reviewers to evaluate submitted systematic reviews against the PRISMA 2020 checklists, and making changes to journal policies to accommodate the new reporting recommendations. We recommend existing PRISMA extensions [ 47 , 49 , 50 , 51 , 52 , 53 , 71 , 72 ] be updated to reflect PRISMA 2020 and advise developers of new PRISMA extensions to use PRISMA 2020 as the foundation document.

We anticipate that the PRISMA 2020 statement will benefit authors, editors, and peer reviewers of systematic reviews, and different users of reviews, including guideline developers, policy makers, healthcare providers, patients, and other stakeholders. Ultimately, we hope that uptake of the guideline will lead to more transparent, complete, and accurate reporting of systematic reviews, thus facilitating evidence based decision making.

Box 1 Glossary of terms

Systematic review —A review that uses explicit, systematic methods to collate and synthesise findings of studies that address a clearly formulated question [ 43 ]

Statistical synthesis —The combination of quantitative results of two or more studies. This encompasses meta-analysis of effect estimates (described below) and other methods, such as combining P values, calculating the range and distribution of observed effects, and vote counting based on the direction of effect (see McKenzie and Brennan [ 25 ] for a description of each method)

Meta-analysis of effect estimates —A statistical technique used to synthesise results when study effect estimates and their variances are available, yielding a quantitative summary of results [ 25 ]

Outcome —An event or measurement collected for participants in a study (such as quality of life, mortality)

Result —The combination of a point estimate (such as a mean difference, risk ratio, or proportion) and a measure of its precision (such as a confidence/credible interval) for a particular outcome

Report —A document (paper or electronic) supplying information about a particular study. It could be a journal article, preprint, conference abstract, study register entry, clinical study report, dissertation, unpublished manuscript, government report, or any other document providing relevant information

Record —The title or abstract (or both) of a report indexed in a database or website (such as a title or abstract for an article indexed in Medline). Records that refer to the same report (such as the same journal article) are “duplicates”; however, records that refer to reports that are merely similar (such as a similar abstract submitted to two different conferences) should be considered unique.

Study —An investigation, such as a clinical trial, that includes a defined group of participants and one or more interventions and outcomes. A “study” might have multiple reports. For example, reports could include the protocol, statistical analysis plan, baseline characteristics, results for the primary outcome, results for harms, results for secondary outcomes, and results for additional mediator and moderator analyses

Box 2 Noteworthy changes to the PRISMA 2009 statement

• Inclusion of the abstract reporting checklist within PRISMA 2020 (see item #2 and Box 2 ).

• Movement of the ‘Protocol and registration’ item from the start of the Methods section of the checklist to a new Other section, with addition of a sub-item recommending authors describe amendments to information provided at registration or in the protocol (see item #24a-24c).

• Modification of the ‘Search’ item to recommend authors present full search strategies for all databases, registers and websites searched, not just at least one database (see item #7).

• Modification of the ‘Study selection’ item in the Methods section to emphasise the reporting of how many reviewers screened each record and each report retrieved, whether they worked independently, and if applicable, details of automation tools used in the process (see item #8).

• Addition of a sub-item to the ‘Data items’ item recommending authors report how outcomes were defined, which results were sought, and methods for selecting a subset of results from included studies (see item #10a).

• Splitting of the ‘Synthesis of results’ item in the Methods section into six sub-items recommending authors describe: the processes used to decide which studies were eligible for each synthesis; any methods required to prepare the data for synthesis; any methods used to tabulate or visually display results of individual studies and syntheses; any methods used to synthesise results; any methods used to explore possible causes of heterogeneity among study results (such as subgroup analysis, meta-regression); and any sensitivity analyses used to assess robustness of the synthesised results (see item #13a-13f).

• Addition of a sub-item to the ‘Study selection’ item in the Results section recommending authors cite studies that might appear to meet the inclusion criteria, but which were excluded, and explain why they were excluded (see item #16b).

• Splitting of the ‘Synthesis of results’ item in the Results section into four sub-items recommending authors: briefly summarise the characteristics and risk of bias among studies contributing to the synthesis; present results of all statistical syntheses conducted; present results of any investigations of possible causes of heterogeneity among study results; and present results of any sensitivity analyses (see item #20a-20d).

• Addition of new items recommending authors report methods for and results of an assessment of certainty (or confidence) in the body of evidence for an outcome (see items #15 and #22).

• Addition of a new item recommending authors declare any competing interests (see item #26).

• Addition of a new item recommending authors indicate whether data, analytic code and other materials used in the review are publicly available and if so, where they can be found (see item #27).

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Acknowledgements

We dedicate this paper to the late Douglas G Altman and Alessandro Liberati, whose contributions were fundamental to the development and implementation of the original PRISMA statement.

We thank the following contributors who completed the survey to inform discussions at the development meeting: Xavier Armoiry, Edoardo Aromataris, Ana Patricia Ayala, Ethan M Balk, Virginia Barbour, Elaine Beller, Jesse A Berlin, Lisa Bero, Zhao-Xiang Bian, Jean Joel Bigna, Ferrán Catalá-López, Anna Chaimani, Mike Clarke, Tammy Clifford, Ioana A Cristea, Miranda Cumpston, Sofia Dias, Corinna Dressler, Ivan D Florez, Joel J Gagnier, Chantelle Garritty, Long Ge, Davina Ghersi, Sean Grant, Gordon Guyatt, Neal R Haddaway, Julian PT Higgins, Sally Hopewell, Brian Hutton, Jamie J Kirkham, Jos Kleijnen, Julia Koricheva, Joey SW Kwong, Toby J Lasserson, Julia H Littell, Yoon K Loke, Malcolm R Macleod, Chris G Maher, Ana Marušic, Dimitris Mavridis, Jessie McGowan, Matthew DF McInnes, Philippa Middleton, Karel G Moons, Zachary Munn, Jane Noyes, Barbara Nußbaumer-Streit, Donald L Patrick, Tatiana Pereira-Cenci, Ba′ Pham, Bob Phillips, Dawid Pieper, Michelle Pollock, Daniel S Quintana, Drummond Rennie, Melissa L Rethlefsen, Hannah R Rothstein, Maroeska M Rovers, Rebecca Ryan, Georgia Salanti, Ian J Saldanha, Margaret Sampson, Nancy Santesso, Rafael Sarkis-Onofre, Jelena Savović, Christopher H Schmid, Kenneth F Schulz, Guido Schwarzer, Beverley J Shea, Paul G Shekelle, Farhad Shokraneh, Mark Simmonds, Nicole Skoetz, Sharon E Straus, Anneliese Synnot, Emily E Tanner-Smith, Brett D Thombs, Hilary Thomson, Alexander Tsertsvadze, Peter Tugwell, Tari Turner, Lesley Uttley, Jeffrey C Valentine, Matt Vassar, Areti Angeliki Veroniki, Meera Viswanathan, Cole Wayant, Paul Whaley, and Kehu Yang. We thank the following contributors who provided feedback on a preliminary version of the PRISMA 2020 checklist: Jo Abbott, Fionn Büttner, Patricia Correia-Santos, Victoria Freeman, Emily A Hennessy, Rakibul Islam, Amalia (Emily) Karahalios, Kasper Krommes, Andreas Lundh, Dafne Port Nascimento, Davina Robson, Catherine Schenck-Yglesias, Mary M Scott, Sarah Tanveer and Pavel Zhelnov. We thank Abigail H Goben, Melissa L Rethlefsen, Tanja Rombey, Anna Scott, and Farhad Shokraneh for their helpful comments on the preprints of the PRISMA 2020 papers. We thank Edoardo Aromataris, Stephanie Chang, Toby Lasserson and David Schriger for their helpful peer review comments on the PRISMA 2020 papers.

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Patient and public involvement

Patients and the public were not involved in this methodological research. We plan to disseminate the research widely, including to community participants in evidence synthesis organisations.

There was no direct funding for this research. MJP is supported by an Australian Research Council Discovery Early Career Researcher Award (DE200101618) and was previously supported by an Australian National Health and Medical Research Council (NHMRC) Early Career Fellowship (1088535) during the conduct of this research. JEM is supported by an Australian NHMRC Career Development Fellowship (1143429). TCH is supported by an Australian NHMRC Senior Research Fellowship (1154607). JMT is supported by Evidence Partners Inc. JMG is supported by a Tier 1 Canada Research Chair in Health Knowledge Transfer and Uptake. MML is supported by The Ottawa Hospital Anaesthesia Alternate Funds Association and a Faculty of Medicine Junior Research Chair. TL is supported by funding from the National Eye Institute (UG1EY020522), National Institutes of Health, United States. LAM is supported by a National Institute for Health Research Doctoral Research Fellowship (DRF-2018-11-ST2–048). ACT is supported by a Tier 2 Canada Research Chair in Knowledge Synthesis. DM is supported in part by a University Research Chair, University of Ottawa. The funders had no role in considering the study design or in the collection, analysis, interpretation of data, writing of the report, or decision to submit the article for publication.

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Contributions

JEM and DM are joint senior authors. MJP, JEM, PMB, IB, TCH, CDM, LS, and DM conceived this paper and designed the literature review and survey conducted to inform the guideline content. MJP conducted the literature review, administered the survey and analysed the data for both. MJP prepared all materials for the development meeting. MJP and JEM presented proposals at the development meeting. All authors except for TCH, JMT, EAA, SEB, and LAM attended the development meeting. MJP and JEM took and consolidated notes from the development meeting. MJP and JEM led the drafting and editing of the article. JEM, PMB, IB, TCH, LS, JMT, EAA, SEB, RC, JG, AH, TL, EMW, SM, LAM, LAS, JT, ACT, PW, and DM drafted particular sections of the article. All authors were involved in revising the article critically for important intellectual content. All authors approved the final version of the article. MJP is the guarantor of this work. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

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All authors have completed the ICMJE uniform disclosure form at http://www.icmje.org/conflicts-of-interest/ and declare: EL is head of research for the BMJ ; MJP is an editorial board member for PLOS Medicine ; ACT is an associate editor and MJP, TL, EMW, and DM are editorial board members for the Journal of Clinical Epidemiology ; DM and LAS were editors in chief, LS, JMT, and ACT are associate editors, and JG is an editorial board member for Systematic Reviews . None of these authors were involved in the peer review process or decision to publish. TCH has received personal fees from Elsevier outside the submitted work. EMW has received personal fees from the American Journal for Public Health , for which he is the editor for systematic reviews. VW is editor in chief of the Campbell Collaboration, which produces systematic reviews, and co-convenor of the Campbell and Cochrane equity methods group. DM is chair of the EQUATOR Network, IB is adjunct director of the French EQUATOR Centre and TCH is co-director of the Australasian EQUATOR Centre, which advocates for the use of reporting guidelines to improve the quality of reporting in research articles. JMT received salary from Evidence Partners, creator of DistillerSR software for systematic reviews; Evidence Partners was not involved in the design or outcomes of the statement, and the views expressed solely represent those of the author.

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PRISMA 2020 checklist.

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PRISMA 2020 expanded checklist.

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Page, M.J., McKenzie, J.E., Bossuyt, P.M. et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Syst Rev 10 , 89 (2021). https://doi.org/10.1186/s13643-021-01626-4

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Synthesizing three decades of digital servitization: a systematic literature review and conceptual framework proposal

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• Pedro E. Minaya   ORCID: orcid.org/0000-0002-1179-9378 1 ,
• Lucía Avella   ORCID: orcid.org/0000-0003-2598-7318 2 &
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This study, through a systematic literature review spanning 1990 to 2023, interrogates how servitization, and nowadays digital servitization, enhances manufacturing competitiveness. It introduces the DASOBI (Drivers, Actors, Strategies, Obstacles, Benefits, and Impact) framework for navigating the digital servitization transition, emphasizing strategic adaptability and technological alignment. Analysis of 157 articles reveals a significant increase in research, highlighting digital servitization’s role in competitive enhancement and customer engagement. The DASOBI framework offers manufacturers a novel approach for managing this transition, marking a unique contribution by distilling extensive literature into actionable insights for both theory and practice in the evolving field of digital servitization.

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1 Introduction

1.1 context, motivation, and research topic.

In today’s dynamic manufacturing sector, companies are increasingly acknowledging the importance of complementing their product offerings with value-added services. This strategic shift, known as servitization—and more specifically digital servitization—marks a fundamental turn in the contemporary business paradigm. This transformation involves not only a shift from a product-centric to a service-centric focus but also a deep integration of advanced digital technologies. While considerable research has been conducted on individual aspects of servitization, a comprehensive analysis that encompasses all essential facets of this phenomenon, from its motivations to its final outcomes, remains relatively unexplored. This research proposal aims to develop a holistic conceptual framework that synthesizes and extends existing knowledge, thereby providing a more complete and nuanced understanding of digital servitization. This exhaustive review examines this evolving business model, highlighting its key benefits and challenges, its intersection with digital technologies, and its theoretical and practical implications.

The foundational premise, supported by Bustinza et al. ( 2015 ), suggests that manufacturing companies can achieve higher returns by offering services in conjunction with their products, a claim echoed in seminal works by Davies et al. ( 2007 ), Johnstone et al. ( 2009 ), Martín-Peña et al. ( 2017 ), and Leoni and Aria ( 2021 ). These services, ranging from maintenance and support to more sophisticated and customized solutions, expand the revenue streams of these firms. In this context, the contributions of Baines et al. ( 2007 ) and Neely et al. ( 2011 ) are pivotal, as they underscore how transitioning to a service-oriented market is driving strategic transformations in manufacturing firms, emphasizing value creation and differentiation in increasingly competitive markets (Brady et al. 2005 ).

The current market dynamics almost make this shift imperative. As noted by Sandström et al. ( 2008 ) and Tukker ( 2015 ), companies that limit their offerings to products alone face formidable challenges in maintaining profitability, driving them toward business model innovation that incorporates services into their product portfolios, as discussed in the literature by Gebauer and Fleisch ( 2007 ), Visnjic and Van Looy ( 2013 ), and Díaz-Garrido et al. ( 2018 ).

Servitization requires effective coordination among multiple stakeholders. Alghisi and Saccani ( 2015 ) address the critical importance of internal and external alignment, while Ayala et al. ( 2019 ) highlight the essential role of service providers in the successful adoption of servitization strategies. Moreover, Baines et al. ( 2011 ) and Lightfoot et al. ( 2013 ) explore how manufacturing firms can effectively integrate services into their product portfolio, emphasizing the importance of a strategically well-planned approach.

Beyond being a customer-facing strategy, the internal benefits are equally compelling. As delineated by Kamp and Alcalde ( 2014 ), servitization facilitates process optimization and extends the lifespan of machinery. These advantages are further enhanced with the incorporation of digital technologies, particularly in the era of Industry 4.0 (Kamp and Perry 2017 ). This digital servitization, explored in studies by Lee et al. ( 2014 ), Kans and Ingwald ( 2016 ), and Paiola and Gebauer ( 2020 ), offers an enhanced layer of value, encompassing innovative goods and services.

Researchers such as Favoretto et al. ( 2022 ) and Rabetino et al. ( 2023 ) have elucidated how technological advancements act as catalysts for developing differentiated products and services, thereby enhancing competitiveness (Müller et al. 2021 ). This leads to the formulation of hybrid business models, termed Product-Service Systems (PSS), which are economically, socially, and environmentally sustainable. This PSS model provides a more holistic solution, meeting specific customer needs beyond just providing functional products (Barquet et al. 2013 ).

In this process, a demand for specific organizational and technological capabilities is identified. Coreynen et al. ( 2017 ) and Schroeder et al. ( 2022 ) have pinpointed the importance of organizational structure and technological capabilities, particularly in the context of digitalization, as key factors for a successful transition to digital servitization (Parida et al. 2014 ; Kanninen et al. 2017 ).

Implementing servitization, as highlighted by Mathieu ( 2001 ) and Yu and Sung ( 2023 ), is not without its challenges, ranging from internal organizational resistance to external factors, such as customer reluctance. Brax ( 2005 ) and Benedettini et al. ( 2015 ) provide a comprehensive analysis of these risks, emphasizing the importance of effective management to navigate potential obstacles in achieving successful servitization (Windahl and Lakemond 2006 ; Pessôa and Becker 2017 ). The process demands a well-structured and strategically informed approach, incorporating both business and customer perspectives. Proper implementation of servitization can lead to substantial benefits, as demonstrated by Baines et al. ( 2009b , 2017 ) and Wang et al. ( 2018 ), highlighting its potential for long-term value creation (Brady et al. 2005 ).

The phenomenon of servitization, particularly in its digital form, has emerged as a prominent area of study, characterized by its complexity and multidimensionality. Academic literature has thoroughly explored this concept, from underlying motivations to implementation strategies, examining both inherent challenges and potential benefits (Raddats et al. 2016 ; Rabetino et al. 2021 ).

1.2 Research gap

Despite the extensive body of knowledge on servitization amassed by previous studies, there remains a discernible gap characterized by fragmented examinations rather than a consolidated analytical approach. This study pinpoints a need for a unified framework that can effectively guide servitization strategies, addressing this lacuna as a pivotal area for forthcoming research (Calabrese et al. 2019 ; Kohtamäki et al. 2020a ). The advent of the digital era has precipitated transformative shifts, underscoring the servitization concept—the transition from purely selling products to offering integrated product-service solutions. Nevertheless, the interaction between servitization and digital technologies, a realm referred to as digital servitization, remains a relatively uncharted territory. This area lacks a systematic and thorough review spanning the last three decades. This omission highlights the imperative need for an in-depth understanding of how servitization has evolved and the essential development of a framework to adeptly navigate the intricacies involved in implementing these strategies effectively.

1.3 Methodology proposed

To address the identified research gap, our study employs a comprehensive, multi-phased methodology structured as follows: Initially, we conduct an in-depth examination of the literature on servitization and digital servitization. This phase aims to develop an integrative theoretical framework that captures the evolution of servitization over the past three decades, emphasizing the shift toward digital service delivery within the manufacturing sector. Subsequently, the study undertakes a systematic literature review to classify the existing body of work. This review specifically focuses on selecting pertinent studies that encompass both traditional and digital servitization, aiming to identify trends, patterns, and existing research gaps. Following the review, we perform a detailed analysis of the selected articles to explore how various aspects of servitization and digital servitization interact and influence each other. In the final phase, we synthesize the findings from the study to deepen the conceptual understanding of the servitization phenomenon, including its digital components. This synthesis will provide valuable insights into effectively managing the transition toward servitization and digital servitization, highlighting its practical applicability in a business context.

1.4 Expected contributions

The primary goal of this research is to construct an integrative framework that captures the evolution, current state, and future trajectory of servitization and digital servitization. This framework will delineate both the theoretical underpinnings and practical ramifications of servitization, illuminating the challenges and opportunities that have surfaced. Particularly, it will explore the transformative influence of Industry 4.0 technologies—such as the Internet of Things, Big Data analytics, and Artificial Intelligence—on traditional servitization models, steering them toward more advanced digital practices. This examination is crucial for understanding how digital technologies can enhance the competitiveness and value proposition of manufacturing firms engaged in servitization.

The overarching aim of this study is to deepen the comprehension of servitization by exploring its interplay with digitalization, thus broadening its theoretical and managerial relevance. The research intends to offer an integrated perspective that not only advances the academic discourse in this field but also aids manufacturing companies in adeptly navigating the complexities of servitization and digital servitization. Furthermore, this review will articulate a roadmap for manufacturers considering this transition, conceptually enriching a domain that, despite its increasing importance, remains underexplored in scholarly research. By highlighting the enduring interest in adopting servitization correctly and underscoring the necessity for a unified theoretical framework, this study responds to calls for theoretical consolidation and a more comprehensive research agenda (Pettigrew 1988 ; Pye and Pettigrew 2005 ).

In summary, our proposed study aims to provide a detailed analysis that integrates insights from various studies into a cohesive narrative, with a particular focus on the servitization and digital servitization processes within the manufacturing sector. This synthesis will significantly contribute to both academic knowledge and practical applications, emphasizing the complex and evolving nature of servitization in manufacturing, and marking a key conclusion of this thorough examination.

2 Research aims

This study is dedicated to a comprehensive analysis of the servitization phenomenon and its progression toward digital servitization within the manufacturing sector, meticulously examining the most significant research from the past 30 years. The aim is to understand the development and various applications of servitization, along with the challenges and obstacles it entails. The study seeks to identify the motivations driving companies toward servitization, examine the various actors involved in the process and their interplay, and explore the strategies necessary for successful implementation. Furthermore, the organizational and technological capabilities required for transitioning to servitization will be analyzed, as well as the associated risks and challenges, including both internal and external hurdles that companies must overcome to reap the potential benefits of servitization. This analysis is guided by key research in the field (Zhang and Banerji 2017 ; Khanra et al. 2021 ) offering a comprehensive perspective on this significant shift in business dynamics within the manufacturing sector.

Essentially, this study seeks to answer the main research question: To what extent do servitization and digital servitization provide benefits that contribute to enhancing a company’s competitiveness? Alongside this primary question, the study intends to address the following aspects related to the development of servitization and digital servitization:

RQ1. Implementation of a digital servitization strategy. How it should be affected by the company’s business environment? How it should be the co-creation process in an international context? Which new knowledge and new skills need to be developed to be implemented correctly? Which benefits can be obtained by implementing the digital enablers of Industry 4.0? Which changes could it involve in the internal structure of the business? Which changes could it involve in the company’s business environment (relations with suppliers or strategic partners)? How could it face the challenges and obstacles that arise during the transition process?

RQ2. Benefits of developing an effective digital servitization strategy. How it provides greater value to the customer? How can product customization be optimized? How it encourages access to new markets? How it promotes gaining new customers? How it allows innovation in ideas or business models? How it allows the development of goods with novel services? How it effectively allows greater returns to be achieved? How it improves competitiveness?

The focus of this study is not only on analyzing servitization as a strategic shift for manufacturing companies but also on exploring how the integration of digital technologies can enrich and complicate this process. Additionally, the aim is to synthesize existing knowledge to provide a broader and more nuanced understanding of digital servitization, highlighting its key advantages, challenges, and intersection with digital technologies.

Four stages were established for this systematic literature review (Tranfield et al. 2003 ), one for each of the four phases outlined in the first section.

This collection focuses on four fields of research: business administration, marketing, operations management, and administration of services. The studies from the two main databases were examined: Web of Science and Scopus, as they are considered reference sources for the topic being analyzed. Once the information was screened, the most-cited studies were selected, which formed the basis for the present study.

3.1 Review process

In conducting a systematic literature review to gain a profound understanding of servitization and digital servitization within the manufacturing sector, our approach integrated multiple rigorous methodologies (Thomé et al. 2016 ). Initially, following the method proposed by Hertzberg and Rudner ( 1999 ), we conducted a meticulous keyword search in the Web of Science and Scopus databases, aiming to identify pertinent literature using terms like “servitization,” “digital servitization,” and their variants. This was instrumental in capturing the subject’s breadth and depth, allowing for the creation of search strings using the Boolean connector OR. The search strings were incorporated in titles, abstracts, and/or keywords, adhering to the time span of 1990 to 2023 in major databases, thus fulfilling the guidelines set by Tranfield et al. ( 2003 ) for inclusion criteria.

To further refine the search and ensure a robust database, we applied additional parameters and restrictions post-establishing the primary search strings for both databases. We limited our search to open access and hybrid gold journals, focusing on high-quality, readily available research outputs. Additionally, we set a citation threshold to include articles with significant field impact, thereby ensuring the inclusion of seminal works and recent influential studies. This strategy was pivotal in developing a comprehensive, relevant collection of literature, ensuring the inclusion of the most pertinent works in the field of digital servitization.

The approach was enhanced by strictly adhering to three key inclusion criteria: (a) considering publications from 1990 to 2023, to ensure a contemporary and comprehensive review, (b) prioritizing articles from prestigious academic journals within the relevant study areas, thus ensuring source quality and relevance, and (c) selecting articles focusing explicitly on key aspects of servitization and digital servitization. This approach, aligned with the study’s objectives and research questions, ensures a holistic and detailed understanding of the phenomenon, accurately reflecting the dynamics and transformations in the manufacturing sector.

The present study aimed to answer the research question and the various related questions. This was done via the PRISMA method (Preferred Reporting Items for Systemic Reviews and Meta-Analyses). The selection criteria produced 647 articles (from Web of Science) and 630 articles (from Scopus). Once identified, the abstracts of each article were read to screen and select only those in line with the fourth study phase: to help properly understand the concept, how it is managed, and how it is applied. 157 articles were ultimately identified that met all of the inclusion criteria. Figure  1 outlines the PRISMA method used.

Source: Authors’ own work from Web of Science and Scopus databases

Flow diagram, based on the PRISMA Method, for the selection of relevant documents for the systematic literature review.

3.2 Descriptive analysis

Figure 2 offers an analytical synthesis of the publication trends within the realms of servitization and digital servitization over a span of more than three decades, utilizing data harvested from the Web of Science and Scopus databases. The blue bars across all three charts articulate the volume of literature pertaining to servitization, encompassing its theoretical underpinnings, industry applications, and cross-disciplinary studies. This scholarly corpus embodies the foundational and evolutionary aspects of servitization as a strategic paradigm shift in manufacturing and service industries.

Source: Web of Science and Scopus databases and authors’ own work

Evolution of publications on Servitization and Digital Servitization (1990–2023).

In parallel, the orange bars specifically chart the trajectory of literature focused on digital servitization. This subset of research delves into the intricacies of embedding digital technologies within traditional servitization frameworks. It illuminates the burgeoning intersection of digital innovation and service strategies, reflecting a vibrant and rapidly advancing frontier of research.

The upward trend of both blue and orange bars in the separate charts for Web of Science and Scopus indicates a robust increase in scholarly output. This not only testifies to the growing academic and practical significance of servitization concepts but also their digital counterparts, which are pivotal in today’s technology-driven marketplaces.

The application of inclusion and exclusion criteria to the study of servitization and digital servitization clarifies the focus of academic research, emphasizing the most relevant and impactful studies in these areas. This refined approach highlights the critical and emerging conversations shaping the future of manufacturing industries through servitization and its digital augmentation. The graph reflects the scholarly community’s increasing investment in understanding these concepts and their application, suggesting a dual focus: the persistent importance of servitization in strengthening the interplay between manufacturing and services, and the transformative potential of digital technologies within this framework. Serving both as a retrospective and a forecast, the visualization indicates key areas for future research that promise to advance industrial practices and academic thought.

Regarding the countries in which the identified studies have been carried out, the visual data presented in Fig.  3 captures a comprehensive view of the global research output on servitization and digital servitization from 1990 to 2023, as indexed by the Web of Science and Scopus databases and further refined by the application of inclusion and exclusion criteria. The top section, shown in blue, delineates the Web of Science data, indicating a prominent concentration of scholarly activity within certain countries, possibly linked to their robust research infrastructures, funding provisions, or strong manufacturing sectors that are conducive to studies in servitization.

Source: Web of Science and Scopus databases

Number of publications by country on Servitization and Digital Servitization (1990–2023).

The middle section, in orange, portrays the Scopus data, revealing a parallel distribution pattern to that of the Web of Science but with slight variances that may be indicative of the different regional research emphases or variations in the databases’ indexing methodologies. The countries with the highest volume of publications are recognized as potential centers of excellence and innovation in the field of servitization.

The bottom section of the graph, in green, represents the distilled essence of this academic output following the application of the inclusion and exclusion criteria. This section emphasizes the refined and concentrated scholarly work that aligns more closely with the specific nuances and requirements of servitization and digital servitization research as defined by the study. It presents a narrower but more focused spectrum of publications, suggesting a curated body of knowledge that serves as a critical resource for understanding the current state and future directions of servitization in the manufacturing sector.

Together, these three segments of Fig.  3 not only illustrate the quantitative aspects of the research output but also underscore the qualitative focus and depth of scholarly exploration achieved through rigorous selection. This tripartite analysis offers a lens through which to view the international dissemination and development of knowledge in servitization and digital servitization, highlighting established leaders in the field as well as regions with the potential for increased research activity, international collaboration, and contribution to the servitization discourse.

In Fig.  4 , the Web of Science data (represented by the blue graph) lists Oscar Bustinza as the author with the highest number of publications, closely followed by Marko Kohtamäki and Vinit Parida. In contrast, the Scopus data (illustrated by the orange graph) also positions Vinit Parida prominently, yet Marko Kohtamäki’s publication count is lower than that reported in the Web of Science, presenting a notable discrepancy.

Number of publications by author on Servitization and Digital Servitization (1990–2023).

When the inclusion and exclusion criteria are applied (as shown in the green graph), there is a decrease in the number of publications, which aligns with expectations, given that these criteria aim to omit publications failing to meet the predetermined standards of quality and relevance. Following this filtration, Tim Baines emerges as the author with the most publications, indicating the significant relevance of his research work to the focused aims of this systematic literature review. Consequently, the filtration process underscores those authors whose contributions are particularly central or foundational to the field.

The comparison across the three graphs demonstrates the influence of database selection and methodological rigor on the perceived prominence of authors within the academic community. This analysis goes beyond merely highlighting the leading figures in servitization research; it underscores the importance of thorough evaluation in literature reviews to identify research of substantial impact.

Thus, the filtration process distinctly recognizes authors whose contributions are considered pivotal to the discipline.

Figure  5 provides a succinct overview of journal publication volumes on servitization and digital servitization from 1990 to 2023, based on data from Web of Science and Scopus databases. Prior to applying inclusion and exclusion criteria, the journals listed in the Web of Science (blue) and Scopus (orange) indicate a diverse quantity of publications.

Number of publication volume in journals with the highest frequency of articles on Servitization and Digital Servitization (1990–2023).

Post-application (green), the data are refined to highlight the top ten journals that are most aligned with the research criteria. It is noteworthy that the application of these criteria significantly alters the landscape of the considered literature. Some journals that initially (in the Web of Science or Scopus databases) had a high volume of publications appear to have fewer articles meeting the requirements, which may reflect on the specificity and relevance of their contributions to the field.

The graphic serves as an insightful metric of the research landscape, indicating not only the journals that are most prolific in the domain but also the robustness of articles surviving rigorous scholarly scrutiny. This visual representation is integral to the academic discourse, as it not only informs researchers of the core journals within the field but also reflects the evolving standards and focal areas within the literature on servitization and digital servitization.

The descriptive analyses included in this section serve as a pivotal foundation for the authors’ elaboration, shedding light on the trajectory of academic inquiry into servitization and digital servitization. It encapsulates the dual analysis conducted using the Web of Science and Scopus databases and the meticulous selection process leading to the corpus of papers employed in the systematic literature review. The synthesis of these findings offers valuable insights into the progression of research in this domain, indicating a maturing yet dynamically expanding field of study.

3.3 Classification process

Upon identifying studies that met the established selection criteria, a thorough examination of each was conducted to categorize them according to specific themes. These encompassed the motivations driving companies toward servitization, namely the reasons why manufacturers transition from producing solely goods to combining these with services, including the anticipated benefits of such a transformation. The various actors involved in the servitization process and the nature of their interactions were scrutinized, as well as the strategies necessary for successful implementation, which entailed identifying potential needs for external partners, commonly service providers (Martínez et al. 2010 ; Bastl et al. 2012 ; Spring and Araujo 2013 ; Ziaee et al. 2018 ). The types of services commonly offered were analyzed, categorized as basic, intermediate, or advanced, along with the specific servitization strategies adopted by the companies. Furthermore, the study delved into the organizational and technological capabilities required for an effective transition to servitization (Momeni et al. 2023 ), as well as the potential risks and challenges arising in these transition processes, including both internal and external obstacles that must be overcome to fully capitalize on the potential benefits of servitization (Raddats et al. 2017 ; Reim et al. 2019 ; Minaya et al. 2023 ).

4 Results: theoretical background

4.1 from servitization to digital servitization.

The concept of servitization, which has significantly evolved over the years, has achieved solid recognition in both the academic and industrial spheres. Initially defined by Levitt ( 1972 ) and Vandermerwe and Rada ( 1988 ) as the process of adding value through services (Johnson and Mena 2008 ; Baines et al. 2011 ; Lindman et al. 2016 ; Ruiz-Martín and Díaz-Garrido 2021 ), servitization has expanded to encompass multiple strategic objectives, such as competitive advantage (Baines et al. 2009a ; Raddats et al. 2019 ), financial goals, and marketing benefits (Khanra et al. 2021 ).

The shift toward servitization entails a redefinition of traditional business models, focusing on innovation (Sandström et al. 2008 ; Martín-Peña et al. 2018 ; Qi et al. 2020 ; Xing et al. 2023 ), and transforming manufacturers into service-centric companies (Cusumano 2008 ; Santamaría et al. 2012 ; Mosch et al. 2021 ). In this regard, manufacturing companies are fundamentally reorienting their business models and operational strategies to include value-added services (Gebauer and Kowalkowski 2012 ; Hyun and Kim 2021 ). Baines and Lightfoot ( 2013 ) and Luoto et al. ( 2017 ) highlight the widespread changes this implies in management, marketing, and operations. The change is so substantial that over 50% of a company’s activities and personnel can be involved in providing these newly implemented services, as indicated by multiple studies cited by Martín-Peña and Ziaee ( 2016 ). This is because research has shown that servitization not only adds value but also increases profitability with relatively low asset investments (Davies et al. 2007 ; Kharlamov and Parry 2021 ).

The types of services offered range from basic to advanced (Gebauer et al. 2013 ; Kindström and Kowalkowski 2014 ; Sousa and Da Silveira 2017 ), with advanced services contributing to greater profitability (Eggert et al. 2014 ) and generating higher customer satisfaction (Mont 2002 ; Ostrom et al. 2010 ), leading to improved competitive positioning (Oliva and Kallenberg 2003 ; Durugbo 2014 ). Baines et al. ( 2011 ) argue that servitization involves creating distinctive and sustainable capabilities (Raddats 2011 ; Kimita et al. 2022 ), requiring not just the provision of goods, but also the innovation of value through added services (Tukker and Tischner 2006 ; García Martín et al. 2019 ; Zighan and Abualqumboz 2022 ), enabling companies to maintain their competitive edge (Tuli et al. 2007 ; Brax and Jonsson 2009 ; Nordin and Kowalkowski 2010 ).

While the goal of servitization is to enrich product offerings and drive competitiveness (Neely et al. 2011 ; Gaiardelli et al. 2014 ; Benedettini et al. 2015 ), companies must avoid the “service paradox,” where the focus on new services undermines existing production capabilities (Gebauer et al. 2005 ; Hyun and Kim 2021 ). To this end, various researchers advocate for a comprehensive analysis covering customer needs, pricing strategies, delivery infrastructure, and organizational change (Manzini and Vezzoli 2003 ; Kohtamäki and Partanen 2016 ; Ziaee et al. 2017 ). In summary, moving away from product-centric thinking and engaging in product and servitization logic.

In this context, Santamaría et al. ( 2012 ) and Rabetino et al. ( 2017 ) underscore three fundamental considerations for a successful servitization strategy: the content, process, and context of organizational change. This involves determining what to change, how to change, and why the change is necessary (Kreye et al. 2015 ).

The complexity of servitization also demands internal and external alignments within companies (Gebauer 2008 ; Alghisi and Saccani 2015 ; Kohtamäki et al. 2019a ; Zhang et al. 2023 ). Internally, this involves harmonizing the organization’s strategy with the service portfolio and aligning this strategy throughout the organization (Oliva and Kallenberg 2003 ; Yan et al. 2020 ). Externally, alignment extends to the service provider network and customer expectations (Ceci and Masini 2011 ; Paiola et al. 2013 ). Similarly, servitization applies in B2B and B2C domains, serving as a differentiator and pathway to future alliances and customer loyalty (Baines et al. 2017 ; Pombo and Franco 2023 ).

On the other hand, technological advancements act as significant facilitators in the transition toward servitization, particularly the digital elements of Industry 4.0 (Dalenogare et al. 2018 ; Paschou et al. 2020 ; Opazo-Basáez et al. 2021 ; Tian et al. 2022 ; Le-Dain et al. 2023 ). This involves both internal and external organizational changes, focusing on disruptive innovations and addressing legal and financial challenges (Bustinza et al. 2018 ; Tronvoll et al. 2020 ; Kolagar et al. 2022 ), leading to what is known as digital servitization.

Digital servitization represents the integration of enabling technologies from Industry 4.0 into the servitization process, generating additional benefits and creating value for the customer (Ibarra et al. 2018 ; Grandinetti et al. 2020 ; Ciasullo et al. 2021 ; Bettiol et al. 2022 ). This digital transformation expands the scope of traditional services, allowing for greater customization and efficiency (Frank et al. 2019 ; Chen et al. 2021 ).

Digitalization facilitates data collection and analysis, improving decision-making, and enabling more predictive and proactive services (Lee et al. 2014 ; Chen et al. 2022a ; Rakic et al. 2022 ). Moreover, data-based digital capabilities are fundamental for the success of digital servitization, as they enhance both product support services and customer support services (Chen et al. 2023 ).

Digital servitization also promotes value co-creation and collaboration among manufacturers, suppliers, and customers, optimizing service delivery and strengthening relationships (Coreynen et al. 2017 ; Vendrell-Herrero et al. 2017 ; Kohtamäki et al. 2020b ; Sjödin et al. 2020 ). The business models of digital servitization are also influenced by Industry 4.0 technologies, such as Internet of Things and Big Data, enabling the development of more integrated and customer-centric solutions (Naik et al. 2020 ; Bortoluzzi et al. 2022 ; Minaya et al.  2023 ).

Furthermore, an integral aspect of the servitization landscape, especially in the digital era, is the evolution of Product-Service Systems (PSS). PSS represents a strategic approach that shifts the focus from selling products to offering a combination of products and services designed to fulfill specific customer needs more efficiently (Tukker and Tischner 2006 ; Baines et al. 2017 ). This transition to PSS reflects a broader industry movement toward sustainable and customer-centric business models, where the value proposition extends beyond the physical product to include personalized services. The advent of Industry 4.0 technologies has further propelled this evolution, leading to the development of Smart PSS. Smart PSS integrates digital technologies, such as the Internet of Things, Big Data, and Artificial Intelligence to enhance service delivery, improve customer experience and enable new forms of value creation (Chowdhury et al. 2018 ; Bortoluzzi et al. 2022 ). The adoption of these advanced technologies within PSS frameworks represents a significant leap in how companies’ approach servitization, allowing for greater customization, efficiency, and proactive engagement with customers. Therefore, understanding the role and impact of PSS, particularly Smart PSS, is crucial for comprehending the full scope of digital servitization and its implications for future business strategies.

4.2 Integrating smart product-service systems (smart PSS) into digital servitization: evolution, challenges, and opportunities

Product-Service Systems (PSS) epitomize an evolution in business models, integrating goods and services to fulfill customer needs sustainably and effectively (Galbraith 2002 ; Gebauer et al. 2011 ; Oliveira et al. 2015 ; Haase et al. 2017 ; Gaiardelli et al. 2021 ; Zhou and Song 2021 ). Tukker ( 2004 ) categorizes PSS into product oriented, use oriented, and result oriented, with each type offering distinct benefits, such as improved profit margins and differentiation from competitors (Tukker and Tischner 2006 ; Reim et al. 2015 ; Baines et al. 2017 ; Rabetino et al. 2017 ). Service-oriented PSS prioritize personalized customer experiences, requiring greater customer involvement (Matthyssens and Vandenbempt 2010 ; Cusumano et al. 2014 ; Zighan and Abualqumboz 2022 ).

The advent of Industry 4.0 technologies has given rise to Smart PSS, enhancing traditional PSS frameworks with digital capabilities and aligning with digital servitization’s goals to maximize customer value and competitive advantage (Chowdhury et al. 2018 ; Zheng et al. 2019 ; Wang et al. 2021 ; Bortoluzzi et al. 2022 ; Chen et al. 2023 ). Smart PSS incorporate Internet of Things, Big Data, and Artificial Intelligence to offer tailored services and predictive maintenance, thus improving product reliability and customer experience. However, transitioning to Smart PSS necessitates overcoming internal challenges, such as developing digital capabilities and adapting organizational culture, and external challenges like aligning strategies with customer and supplier expectations (Alghisi and Saccani 2015 ; Baines and Shi 2015 ; Ceci and Masini 2011 ; Mosch et al. 2021 ).

Business models in the context of Smart PSS vary from product centered to service oriented, depending on the company’s servitization maturity and technological capacity, leading to greater competitive differentiation and new market opportunities (Kowalkowski et al. 2017 ; Zheng et al. 2019 ; Baines et al. 2020 ; Chen et al. 2021 ). Implementing Smart PSS calls for a holistic approach, from strategic planning to system design and operational management, with a focus on how digital capabilities enhance PSS offerings and the overall value chain (Coreynen et al. 2017 ; Zheng et al. 2018 ).

In sum, the transition from traditional servitization to digital servitization, through the deployment of Smart PSS, marks a critical shift in value creation and sustaining customer loyalty, propelled by Industry 4.0 innovations (Vandermerwe and Rada 1988 ; Frank et al. 2019 ; Pinillos et al. 2022 ; Raddats et al. 2022 ; Schroeder et al. 2022 ; Chen et al. 2023 ; Martín-Peña et al. 2023 ). Realizing the potential of digital servitization demands an understanding of technological capabilities, fostering innovation, and market adaptability (Kohtamäki et al. 2019b ; Zhang et al. 2023 ). Successful digital servitization and Smart PSS rely on integrating technology with strategic vision and customer centricity, cultivating a business model focused on collaboration, innovation, and value co-creation (Naik et al. 2020 ; Chen et al. 2021 ; Zhou et al. 2021 ; Kolagar et al. 2022 ).

4.3 Digital servitization: crafting superior value in the modern era

As previously noted, servitization, as it evolves into digital servitization, catalyzes a profound and strategic transformation of business models and operational paradigms, emphasizing the importance of both internal and external strategic alignments. This process not only optimizes existing service offerings but also unlocks significant potential for service innovation and market competitiveness. Specifically, the integration of advanced technologies in digital servitization allows companies to create superior and customized value for their customers. This expanded value creation is achieved through a synergistic combination of technological resources and human capabilities, facilitating more predictive, personalized, and proactive services. Thus, digital servitization emerges as an essential and transformative step in business strategy, driving not only efficiency and strategic alignment but also fostering innovation and strengthening competitive positioning in the market.

Digital servitization, a contemporary evolution of traditional servitization, integrates Industry 4.0 technologies into the service domain, creating significant value for the customer. This value manifests in several key dimensions, all driven by digitalization and the emerging capabilities it offers.

Enhanced personalization and customer experience. The ability to collect and analyze large volumes of data using digital technologies enables companies to better understand the needs and preferences of their customers (Tao and Qi 2017 ; Chen et al. 2023 ). This leads to the creation of more personalized service offerings, tailored specifically to individual customer requirements. For instance, data analytics capabilities enhance servitization by enabling service personalization, which is fundamental for improving customer satisfaction and fostering long-term loyalty (Chen et al. 2022b ).

Efficiency and proactivity in service delivery. Digital servitization allows companies to be more efficient and proactive in delivering services. Technologies like the Internet of Things and Artificial Intelligence facilitate remote monitoring and predictive maintenance, anticipating problems before they occur and minimizing downtime (Lee et al. 2014 ; Tao and Qi 2017 ; Raddats et al. 2022 ). This not only improves product reliability but also reduces costs for the customer.

Creation of new opportunities and business models. The integration of digital services opens new avenues for innovative business models. For example, companies can offer usage-based solutions or subscriptions, where customers pay for performance or outcomes rather than the product itself (Vendrell-Herrero et al. 2017 ; Martín-Peña et al. 2020 ; Bortoluzzi et al. 2022 ). This can result in greater flexibility and more attractive cost options for the customer.

Enhanced customer–supplier relationships. Digital servitization fosters greater collaboration and value co-creation between suppliers and customers (Coreynen et al. 2017 ; Sjödin et al. 2020 ; Harrmann et al. 2023 ). This is because digital capabilities enable smoother communication and more transparent information exchange, resulting in stronger and more reliable relationships (Davies et al. 2023 ).

Continuous improvement of products and services. Ongoing feedback and data analysis enable continuous improvement of the products and services offered. Companies can quickly adjust their offerings in response to customer feedback or market changes, ensuring that their services remain relevant and of high quality (Chen et al. 2021 ).

Access to new markets. Digital servitization enables companies to access new markets and customer segments. By offering digital solutions, companies can overcome geographical and logistical barriers, reaching customers who were previously inaccessible (Münch et al. 2022 ; Rakic et al. 2022 ).

In summary, digital servitization not only enhances existing service offerings but also opens new opportunities for service innovation, strategic alignment, and market competitiveness. Its successful implementation is key to creating substantial value for the customer, highlighting the importance of a well-planned and executed strategy in the context of modern servitization.

5 Proposed conceptual framework: guiding the transition to digital servitization

Digital servitization represents a pivotal shift in the business landscape, where manufacturing companies evolve into providers of comprehensive solutions that seamlessly integrate products and services, augmented by digital technologies. This transformation is driven by the need for enhanced competitiveness, customer engagement, and value creation in a rapidly changing digital economy.

The development of our DASOBI conceptual framework, designed to guide the transition to digital servitization, is grounded in a rigorous methodological approach, underpinned by a comprehensive systematic literature review. This review meticulously synthesized three decades of academic research and industry insights, incorporating a total of 157 articles. Our comprehensive review process involved a deep analysis of the most influential and relevant publications in the field, among which notable contributions include Alghisi and Saccani ( 2015 ); Ayala et al. ( 2017 , 2019 ); Coreynen et al. ( 2017 ); Tao and Qi ( 2017 ); Vendrell-Herrero et al. ( 2017 ); Bustinza et al. ( 2018 ); Frank et al. ( 2019 ); Baines et al. ( 2020 ); Martín-Peña et al. ( 2020 ); Naik et al. ( 2020 ); Brax et al. ( 2021 ); Gaiardelli et al. ( 2021 ); Kohtamäki et al. ( 2021 ); Bettiol et al. ( 2022 ); Bortoluzzi et al. ( 2022 ); Marcon et al. ( 2022 ); Münch et al. ( 2022 ); Brekke et al. ( 2023 ); Chen et al. ( 2023 ); Chirumalla et al. ( 2023 ); Shen et al. ( 2023 ). These articles were particularly significant for identifying emerging trends, key challenges, and effective strategies in digital servitization. By systematically analyzing this extensive body of literature, we identified critical themes, challenges, strategies, and outcomes associated with the digital servitization journey. This analysis not only highlighted the multifaceted nature of digital servitization but also emphasized the critical importance of aligning strategic considerations, technological capabilities, and stakeholder roles to successfully navigate this complex transition. The structured framework presented herein not only reflects the evolution of the field but also provides clear guidance for manufacturing companies advancing toward more sophisticated and digitalized servitization practices.

The DASOBI framework, while empirically grounded in a comprehensive literature review, also draws extensively on classical and emerging theories to provide a robust theoretical foundation. For instance, diffusion of innovations theory (Rogers 2003 ) elucidates the “Drivers” and “Obstacles” in the adoption of digital servitization by explaining the rate and process through which new technological innovations spread within industries. Furthermore, the resource-based view (Barney 1991 ) is instrumental in understanding the “Strategies” component of the framework, emphasizing the importance of internal capabilities and resources in gaining a competitive advantage through digital transformation. These theoretical integrations not only enhance the academic rigor of our framework but also offer a deeper understanding of the multifaceted nature of digital servitization.

Therefore, the proposed DASOBI (Drivers, Actors, Strategies, Obstacles, Benefits, and Impact) model emerges as a synthesis of empirical evidence and theoretical insights, designed to offer a coherent and actionable guide for organizations seeking to embrace digital servitization.

This conceptual framework delineates a roadmap for organizations to navigate this complex transition. The framework identifies the core components essential for a successful journey toward digital servitization:

Underlying reasons for the shift (Drivers). Recognizing the strategic imperatives for transitioning toward a digital servitization model is critical. This includes understanding market dynamics, competitive pressures, and technological advancements driving this change.

Key actors involved (Actors). Successful digital servitization necessitates the involvement and alignment of various stakeholders, including internal teams, customers, technology partners, and suppliers. Their roles, expectations, and contributions are pivotal in shaping the servitization journey.

Strategic considerations and tools (Strategies). This encompasses adopting strategic frameworks, methodologies, and digital tools that are conducive to servitization. These tools and strategies should facilitate the integration of digital technologies with traditional product-service offerings, ensuring a seamless transition.

Potential challenges and obstacles (Obstacles). Identifying and addressing challenges such as cultural resistance, skill gaps, technological complexities, and integration issues with existing processes is crucial. Proactive strategies and contingency plans are essential to mitigate these barriers.

Anticipated benefits of the transition (Benefits). The transition to digital servitization should bring about significant benefits, including enhanced customer value, increased revenue streams, and improved competitive positioning. This component focuses on quantifying these benefits and aligning them with organizational goals.

Expected outcomes and impact (Impact). The final component of the framework revolves around the tangible outcomes and impacts of digital servitization. This includes enhanced customer satisfaction, increased market share, and improved operational efficiency.

In the digital servitization framework, the transition toward digital servitization, driven by market dynamics, competitive pressures, and technological advancements, is intrinsically linked to the roles and contributions of key stakeholders, such as internal teams, customers, and technology partners. Strategic considerations and tools must be selected in light of potential challenges, like cultural resistance and skill gaps, ensuring alignment with stakeholder capabilities and expectations for a seamless integration of digital technologies with traditional offerings. This strategic alignment is pivotal in overcoming obstacles and realizing anticipated benefits, such as enhanced customer value and competitive positioning. These benefits, in turn, lead to tangible outcomes, like improved customer satisfaction and operational efficiency, which feedback into the market, influencing ongoing strategic imperatives and shaping the evolution of digital servitization strategies. This dynamic interplay highlights a continuous feedback loop where outcomes inform underlying reasons, reinforcing the need for adaptability and strategic foresight in the digital servitization journey.

The contribution of the DASOBI framework to the existing literature is manifold. By synthesizing empirical findings with theoretical insights from servitization and digital transformation research, this framework addresses identified gaps, such as the integration of digital technologies in traditional servitization models and the management of organizational changes associated with such transitions (Baines and Lightfoot 2013 ; Vargo and Lusch 2008 ). Specifically, the DASOBI framework aids in conceptualizing how companies can strategically navigate the complexities of digital servitization, providing a structured approach that is missing in previous studies. This not only extends the theoretical discourse around servitization but also sets a foundation for future research to explore the dynamic interactions between digital technologies and service strategies in manufacturing sectors.

In conclusion, this conceptual framework serves as a comprehensive guide for firms embarking on the digital servitization journey. It provides a structured approach to understanding and implementing the necessary changes, ensuring a smooth transition and realization of the potential benefits of digital servitization. Figure  6 summarizes this meticulously formulated model (DASOBI), referred to as the Drivers (underlying reasons for the shift), Actors (key actors involved), Strategies (strategic considerations and tools), Obstacles (potential challenges and obstacles), Benefits (anticipated benefits of the transition), and Impact (expected outcomes and impact) of Digital Servitization Strategy, offers a robust framework for scholarly exploration, grounded in an exhaustive review of extant literature.

Source: Authors’ own work

Conceptual theoretical model for the analysis of Digital Servitization.

The DASOBI framework orchestrates the shift from traditional service strategies to digitally-enhanced service offerings, underpinned by the alignment of core elements: Drivers, Actors, Strategy, Obstacles, Benefits, and Impact. The model emphasizes a strategic approach, incorporating digital catalytic factors to augment adaptability, customer-centric analytics, and the pursuit of novel revenue streams through digital innovations.

Within this framework, the digital knowledge and capability development are crucial. Firms must harness Big Data to distill customer insights, leverage Artificial Intelligence for identifying opportunities, and increase the flexibility of their service offerings via digital platforms. The role of digital service providers is pivotal, offering expertise to mitigate transition risks, assure service quality, and bolster productivity with cutting-edge technological solutions.

However, the shift is not without its challenges. The resistance to digital transformation and the complexity of measuring profitability in the digital service landscape can impede progress. Moreover, the implications of Industry 4.0 are profound, necessitating organizational restructuring, workforce upskilling, and technological investments to realize the potential of digital servitization.

The anticipated benefits of this digital shift are manifold. Enhanced customer understanding through sophisticated data analytics, improved market positioning through digital innovation, and elevated creative capability with advanced technology are but a few of the advantages. Furthermore, embracing Industry 4.0 technologies within digital servitization amplifies these benefits, leading to superior product quality via smart manufacturing, greater adaptability in production, and increased operational efficiency ensuring timely delivery.

In summary, the DASOBI model meticulously integrates the transition to digital servitization with the digital economy’s imperatives, presenting a coherent roadmap for firms aspiring to harness the full spectrum of benefits offered by Industry 4.0 innovations.

6 Conclusions, limitations, and further research

This study embarked on an exhaustive journey through three decades of literature on servitization and its evolution toward digital servitization within the manufacturing sector. Through a systematic literature review, we explored the strategic transformation that involves integrating advanced services and digital technologies into product offerings, a change driven by the need to enhance competitiveness, customer engagement, and value creation in a rapidly evolving digital economy.

Our research findings have identified key drivers, actors, strategies, challenges, and benefits associated with the transition toward digital servitization. The DASOBI conceptual framework tries to provide a structured guide for understanding and managing this complex transition. This framework emphasizes the importance of recognizing the underlying reasons for adopting digital servitization models, the necessity of aligning and collaborating with diverse stakeholders, and the use of specific strategies to overcome the inherent challenges of this process.

Despite this study’s contribution to the body of knowledge on digital servitization, we acknowledge several limitations. The geographical concentration of the research activity analyzed might limit the generalizability of our findings across diverse cultural and economic contexts. The rapid evolution of digital technologies and business models also suggests that the relevance of our discoveries could be challenged by future developments. Additionally, our research focused primarily on manufacturing firms, which limits the applicability of the findings to other sectors.

These limitations open several avenues for future research. It is imperative to validate and test the generalizability of the DASOBI framework across various organizational and industry contexts. Further research is also needed to develop specific metrics that can measure the impacts of digital servitization. Longitudinal studies could provide a deeper understanding of how servitization strategies influence business outcomes over time.

This study contributes to the academic discussion by clarifying and deepening the concept of servitization and its intersection with digitalization, offering an integrative view that can assist manufacturing firms in navigating the complex landscape of servitization and digital servitization. Although we have tried to establish a solid foundation for future research, it is evident that the field of digital servitization remains dynamic and evolving, requiring ongoing examination to fully comprehend its impact on business strategy and practice.

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Minaya, P.E., Avella, L. & Trespalacios, J.A. Synthesizing three decades of digital servitization: a systematic literature review and conceptual framework proposal. Serv Bus (2024). https://doi.org/10.1007/s11628-024-00559-x

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

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

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

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

Introduction

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

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

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

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

Materials and methods

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

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

Article Identification and Screening

Origin and etiology of CF

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

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

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

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

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

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

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

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

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

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

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

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

What is contained in CF?

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

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

Cell death and CF

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

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

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

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

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

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

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

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

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

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

Patient age and CF

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

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

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

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

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

IVF vs ICSI procedures and CF

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

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

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

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

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

Effect of CF on embryo development

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

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

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

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

Effect of CF on embryo implantation and pregnancy

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

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

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

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

Effect of CF removal on embryo development

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

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

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

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

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

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

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

CF and chromosomal abnormalities in embryo

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

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

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

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

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

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

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

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

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

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

Discussion and conclusion

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

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

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

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

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

Availability of data and materials

No datasets were generated or analysed during the current study.

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Ariella Yazdani, Catherine Boniface & Navid Esfandiari

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Financial hardship among patients suffering from neglected tropical diseases: A systematic review and meta-analysis of global literature

Roles Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Visualization, Writing – original draft

Affiliations Department of Pharmacotherapy, College of Pharmacy, University of Utah, Salt Lake City, Utah, United States of America, Department of Social and Administrative Pharmacy, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand

Roles Conceptualization, Data curation, Formal analysis, Investigation, Validation, Writing – review & editing

Affiliations Department of Pharmacotherapy, College of Pharmacy, University of Utah, Salt Lake City, Utah, United States of America, School of Pharmacy, Sungkyunkwan University, Suwon, South Korea

Roles Investigation, Writing – review & editing

Affiliation Corvaxan Foundation, Villanova, Pennsylvania, United States of America

Roles Conceptualization, Writing – review & editing

Affiliation Department of Global Programme for Neglected Tropical Diseases, World Health Organization, Geneva, Switzerland

Roles Conceptualization, Funding acquisition, Project administration, Writing – review & editing

* E-mail: [email protected]

Affiliations Department of Pharmacotherapy, College of Pharmacy, University of Utah, Salt Lake City, Utah, United States of America, IDEAS Center, Veterans Affairs Salt Lake City Healthcare System, Salt Lake City, Utah, United States of America

• Chanthawat Patikorn, 
• Jeong-Yeon Cho, 
• Joshua Higashi, 
• Xiao Xian Huang, 
• Nathorn Chaiyakunapruk

• Published: May 13, 2024
• https://doi.org/10.1371/journal.pntd.0012086
• Peer Review
• Reader Comments

Introduction

Neglected tropical diseases (NTDs) mainly affect underprivileged populations, potentially resulting in catastrophic health spending (CHS) and impoverishment from out-of-pocket (OOP) costs. This systematic review aimed to summarize the financial hardship caused by NTDs.

We searched PubMed, EMBASE, EconLit, OpenGrey, and EBSCO Open Dissertations, for articles reporting financial hardship caused by NTDs from database inception to January 1, 2023. We summarized the study findings and methodological characteristics. Meta-analyses were performed to pool the prevalence of CHS. Heterogeneity was evaluated using the I 2 statistic.

Ten out of 1,768 studies were included, assessing CHS (n = 10) and impoverishment (n = 1) among 2,761 patients with six NTDs (Buruli ulcer, chikungunya, dengue, visceral leishmaniasis, leprosy, and lymphatic filariasis). CHS was defined differently across studies. Prevalence of CHS due to OOP costs was relatively low among patients with leprosy (0.0–11.0%), dengue (12.5%), and lymphatic filariasis (0.0–23.0%), and relatively high among patients with Buruli ulcers (45.6%). Prevalence of CHS varied widely among patients with chikungunya (11.9–99.3%) and visceral leishmaniasis (24.6–91.8%). Meta-analysis showed that the pooled prevalence of CHS due to OOP costs of visceral leishmaniasis was 73% (95% CI; 65–80%, n = 2, I 2 = 0.00%). Costs of visceral leishmaniasis impoverished 20–26% of the 61 households investigated, depending on the costs captured. The reported costs did not capture the financial burden hidden by the abandonment of seeking healthcare.

NTDs lead to a substantial number of households facing financial hardship. However, financial hardship caused by NTDs was not comprehensively evaluated in the literature. To develop evidence-informed strategies to minimize the financial hardship caused by NTDs, studies should evaluate the factors contributing to financial hardship across household characteristics, disease stages, and treatment-seeking behaviors.

Author summary

Neglected tropical diseases (NTDs) mainly affect underprivileged populations, potentially resulting in catastrophic health spending (CHS) and impoverishment from out-of-pocket (OOP) costs. This systematic review aimed to summarize the financial hardship caused by NTDs. We found that NTDs lead to a substantial number of households facing financial hardship. CHS risk due to direct OOP costs was relatively low among patients with leprosy (0.0–11.0%), dengue (12.5%), and lymphatic filariasis (0.0–23.0%), and relatively high among patients with Buruli ulcers (45.6%). CHS risk varied widely among patients with chikungunya (11.9–99.3%) and visceral leishmaniasis (24.6–91.8%). Costs of visceral leishmaniasis impoverished 20–26% of 61 households, depending on the costs captured. Nevertheless, financial hardship caused by NTDs was not comprehensively evaluated in the literature. Therefore, to develop evidence-informed strategies to minimize the financial hardship caused by NTDs, studies should evaluate the factors contributing to financial hardship across household characteristics, disease stages, and treatment-seeking behaviors.

Citation: Patikorn C, Cho J-Y, Higashi J, Huang XX, Chaiyakunapruk N (2024) Financial hardship among patients suffering from neglected tropical diseases: A systematic review and meta-analysis of global literature. PLoS Negl Trop Dis 18(5): e0012086. https://doi.org/10.1371/journal.pntd.0012086

Editor: Yoel Lubell, Mahidol-Oxford Tropical Medicine Research Unit, THAILAND

Received: November 7, 2023; Accepted: March 20, 2024; Published: May 13, 2024

Copyright: © 2024 Patikorn et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files.

Funding: This study is funded by the Department of Control of Neglected Tropical Diseases, World Health Organization, Geneva, Switzerland. XXH, as an employee of the World Health Organization, contributed to this study in terms of study design, data interpretation, and report writing.

Competing interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests:XXH works for the World Health Organization. The author alone is responsible for the views expressed in this publication and does not necessarily represent the decisions, policies, or views of the World Health Organization.

In 2021, the World Health Organization (WHO) reported that 1.65 billion people required treatment and care for neglected tropical diseases (NTDs) as they faced humanistic, social, and economic burdens incurred by the diseases. NTDs are a diverse group of diseases that mainly affect underprivileged communities in tropical and subtropical areas [ 1 ]. NTDs predominantly affect disadvantaged populations in low- and middle-income countries (LMICs) due to the lack of timely access to affordable care. It has been reported that every low-income country is affected by at least five NTDs [ 2 ]. Even worse, impoverishment serves as a structural determinant. At the same time, it is a consequence of NTDs due to the direct and indirect costs incurred [ 3 ]. Therefore, the WHO has advocated in their recent NTDs 2021–2023 roadmap that NTDs must be overcome to attain Sustainable Development Goals (SDGs) and ensure Universal Health Coverage (UHC). The NTDs 2021–2030 roadmap targets that 90% of the population at risk are protected against catastrophic out-of-pocket (OOP) health spending caused by NTDs [ 1 ].

Financial hardship is usually quantified as catastrophic health spending (CHS) (as known as catastrophic health expenditure) and impoverishment. CHS is the proportion of households with OOP costs incurred by a specific disease that exceed a specific threshold of the total household income or expenditure (budget share approach) or non-subsistent household expenditure (capacity-to-pay approach). Impoverishment is when the OOP costs push households below the poverty line [ 4 – 6 ]. CHS and impoverishment are well-established indicators for the financial risk protection of the healthcare system, which was an essential dimension of the UHC as indicated under the SDG 3.8.2 indicators [ 1 , 7 ].

Financial hardship poses a greater challenge for individuals affected by NTDs, as they frequently reside in poverty before the onset of the disease. To evaluate the long-term economic risk imposed by health spending on NTDs, it is important to understand the coping strategies of this population. Literature has shown that coping strategies, such as seeking financial assistance through loans or selling their assets, could push households into or further into poverty if it impacts their productivity [ 8 ]. Thus, providing coverage to these groups effectively strengthens the financial risk protection of the health system [ 7 ]. Since some types of NTD are closely related to financial hardship, improving their financial protection may help attain UHC, especially for LMICs [ 9 ].

Financial protection is an essential indicator for NTDs and UHC; however, there was limited research on the financial hardship of NTDs. Although many studies addressed the question of the economic burden of NTDs, there is no systematic review and meta-analysis summarizing the financial hardship faced by the population affected by NTDs. Therefore, to fill this knowledge gap and build a baseline for the NTDs roadmap’s financial risk protection indicator, this study aimed to summarize the prevalence and magnitude of financial hardship among patients suffering from NTDs. Additionally, we assessed the methodologies of quantifying CHS and impoverishment incurred by NTDs.

Scope of the review

The protocol of this systematic review was registered with PROSPERO (CRD42023385627) [ 10 ]. This study was reported following the 2020 Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline ( S1 PRISMA Checklist) [ 11 ]. Differences from the original review protocol are described with rationale ( S1 Table ).

This systematic literature review focused on 20 diseases selected as NTDs by WHO: Buruli ulcer, Chagas disease, dengue and chikungunya, dracunculiasis (Guinea-worm disease), echinococcosis, foodborne trematodiases, human African trypanosomiasis (sleeping sickness), leishmaniasis, leprosy (Hansen’s disease), lymphatic filariasis, mycetoma, chromoblastomycosis and other deep mycoses, onchocerciasis (river blindness), rabies, scabies and other ectoparasitoses, schistosomiasis, soil-transmitted helminthiases, snakebite envenoming, taeniasis/cysticercosis, trachoma, and yaws and other endemic treponematoses [ 12 ].

Outcomes of interest of this systematic review were the prevalence and magnitude of victims who faced financial hardship caused by NTDs, including CHS, impoverishment, and coping strategies.

Search strategy and selection process

We searched three bibliographic databases, PubMed, EMBASE, and EconLit, to identify articles reporting financial hardship among patients suffering from NTDs from any country indexed from database inception to January 1, 2023. We also searched for grey literature in two databases, OpenGrey and EBSCO Open Dissertations. The search terms used were ( Disease name and its synonyms ) AND (catastroph* OR impoverish* OR coping OR economic consequence* OR out-of-pocket OR "out of pocket" OR ((household OR family OR patient AND (cost* OR spending OR expen*))), that was adapted to match the search techniques of each database. A full search strategy is shown in S2 Table . There was no language restriction applied in this systematic review. A supplemental search was performed by tracking citation and snowballing the eligible articles’ reference list.

Two reviewers (CP and JYC) independently performed the study selection. They screened the titles and abstracts of identified articles from database searches for relevance. Potentially relevant articles were sought for full-text articles. We requested the authors for full-text articles or reports of highly relevant articles without full-text articles, such as conference abstracts. The retrieved full-text articles were selected based on the eligibility criteria. Discrepancies arising during study selection were resolved by discussion with the third reviewer (NC).

Eligibility criteria

We included empirical studies reporting CHS, impoverishment, or coping strategies incurred by NTDs using primary data collection.

Data extraction

We developed a data extraction sheet by performing a pilot test of extracting five randomly selected articles and refining it until finalization. Two reviewers (CP and JYC) independently performed data extraction. Another reviewer (JH) checked the extracted data for correctness. Any discrepancies were resolved by discussion among reviewers.

Study findings and methodological characteristics extracted from the eligible articles are as follows: first author, publication year, NTDs, study setting, study design, sample characteristics, sample size, data collection period, data collection methods, time horizon, a perspective of the analysis, discount rate, costing year, reported currency, cost units, the definition of CHS and impoverishment, prevalence and magnitude of CHS and impoverishment incurred, economic consequences and coping strategies of financial hardship. Corresponding authors of the eligible articles were contacted to request individual patient-level data. However, we received no response.

The financial risk protection metric is intended to capture only the OOP costs for medical services (e.g., treatment and diagnosis costs). However, some studies considered certain types of direct non-medical costs (e.g., transportation, food, and accommodation costs) and indirect costs (e.g., productivity and income losses) when quantifying financial hardship. Some studies also included informal care costs, such as traditional medicine, as OOP costs [ 6 ]. Thus, our systematic review categorized costs extracted from the eligible studies as direct costs (OOP costs) and indirect costs. Direct costs were further categorized as direct medical costs and direct non-medical costs. The combination of direct costs and indirect costs was categorized as total costs.

Quality assessment

Two reviewers independently assessed the eligible articles’ quality (CP and JYC). Any discrepancies were resolved by consensus among the reviewers. To the best of our knowledge, there is no risk-of-bias assessment tool for economic burden studies. Hence, we assessed the quality of the eligible articles using the cost-of-illness evaluation checklist by Larg and Moss [ 13 ].

Data synthesis

A narrative synthesis was performed to summarize study findings, methodological characteristics, and the quality of the eligible studies. The identified countries were categorized based on the World Bank’s income levels and regions [ 14 ].

Statistical analysis

We performed meta-analyses to calculate the pooled prevalence of households experiencing financial hardship. However, this was possible only for studies that quantified financial hardship using the same measurement definition for a particular NTD. For example, we performed a meta-analysis to calculate the pooled prevalence of households experiencing CHS due to visceral leishmaniasis based on two studies that defined CHS as direct costs exceeding 10% of annual household income [ 8 , 15 ]. The remaining studies were not meta-analyzed due to the differences in the definitions of CHS. We estimated the pooled prevalence of CHS and 95% confidence intervals (CI) using a random-effects model under the DerSimonian and Laird approach [ 16 ]. Effect sizes were computed using each study’s Freeman–Tukey double-arcsine-transformed proportion. This variance-stabilizing transformation is particularly preferable when the proportions are close to 0 or 1 [ 17 ]. p < .05 was considered statistically significant in 2-sided tests.

Heterogeneity was evaluated by observing the forest plots and using the I 2 statistic that estimated the proportion of variability in a meta-analysis that is explained by differences between the included trials rather than by sampling error. Subgroup analyses were performed to explore possible causes of heterogeneity among study results. Publication bias was assessed using the funnel plot asymmetry test and the Egger regression asymmetry test [ 18 ]. Statistical analyses were conducted using Stata version 18.0 (Stata Corporation).

Patient and public involvement

Patients or the public were not involved in the design, or conduct, or reporting, or dissemination plans of our research.

Overall characteristics of the included studies

A total of 1,768 articles were identified from the search, of which 10 studies were included ( Fig 1 ) [ 8 , 15 , 19 – 26 ]. A list of excluded studies with reasons is presented in S3 Table . These studies quantified financial hardship among 2,761 patients in five LMICs (India, Nepal, Nigeria, Sudan, and Vietnam) who had been diagnosed with six out of the WHO’s 20 NTDs, including Buruli ulcer [ 20 ], chikungunya [ 21 , 26 ], dengue [ 22 ], visceral leishmaniasis [ 8 , 15 , 25 ], leprosy [ 19 , 23 ], and lymphatic filariasis [ 24 ]. Table 1 provides a summary of the study characteristics. We found no major concern in the quality of the included studies ( S4 Table )

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Financial hardship caused by NTDs was quantified as CHS (10 studies) [ 8 , 15 , 19 – 26 ], and impoverishment (1 study) [ 8 ]. All studies were conducted in LMICs with a focus on South Asia (7 studies) [ 8 , 19 , 21 , 23 – 26 ], Sub-Saharan Africa (2 studies) [ 15 , 20 ], East Asia & Pacific (1 study) [ 22 ]. Patients were mostly identified using a hospital-based approach (7 studies) [ 8 , 15 , 19 , 20 , 22 , 23 , 25 ], with active case-finding intervention implemented in two of those studies [ 20 , 23 ]. Five studies reported that patients sought informal healthcare, such as traditional healers, ayurveda, and homeopathy [ 19 – 21 , 25 , 26 ].

Costs captured in the financial hardship were direct medical costs (10 studies, 100%) [ 8 , 15 , 19 – 26 ], direct non-medical costs (9 studies, 90%) [ 8 , 15 , 19 – 21 , 23 – 26 ], and indirect costs (7 studies, 70%) [ 8 , 15 , 19 , 21 , 23 , 25 , 26 ], as summarized in Table 2 . These costs were captured with a different timeframe, including during a disease episode [ 8 , 15 , 20 , 21 , 25 , 26 ], during hospitalization in an intensive care unit [ 22 ], monthly costs with a maximum recall period of 3 years [ 19 ], per one outpatient visit in the last 6 months [ 23 ], and per one hospitalization episode in the last year and per one outpatient visit in the last 15 days [ 24 ]. Abandonment of healthcare seeking due to financial burden was not reflected in the reported costs as the included studies captured only patients who sought healthcare.

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The health insurance systems or special programs covered some of the costs. The costs for diagnosis and treatment of visceral leishmaniasis were provided free of charge to patients under the publicly financed health insurance system in Nepal [ 8 , 25 ] and Sudan [ 15 ]. In Nigeria, international development partners funded a special program that provided free diagnosis and treatment of Buruli ulcers, as well as accommodation, school funding, and basic allowance [ 20 ]. Additionally, the Indian government had a special program that provides financial assistance to families of patients affected by leprosy [ 19 ]. However, patients in India had to pay high OOP costs for medical services for leprosy [ 19 , 23 ], chikungunya [ 21 , 26 ], and lymphatic filariasis [ 24 ]. Similarly, patients in Vietnam also paid high OOP costs for the medical treatment of dengue [ 22 ]. For more details, refer to Table 3 .

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Financial hardship among patients suffering from NTDs

Catastrophic health spending..

CHS was variedly defined across studies in terms of types of costs (medical costs, medical and transportation costs, direct costs, indirect costs, or total costs), thresholds (5%, 10%, 15%, 25%, 30%, 40%, or 100%), timeframe (monthly, quarterly, or annual), household resources (income, consumption expenditure, national average annual household expenditure, or international poverty line) and perspective (household or individual). All studies used the budget share approach to quantify CHS. The most commonly used definitions of CHS caused by NTDs were direct costs of a disease episode exceeding 10% of annual household income (3 studies) [ 8 , 15 , 20 ] and total costs of a disease episode exceeding 10% of annual household income (3 studies) [ 8 , 15 , 25 ]. CHS that included only the direct medical costs was reported in two studies [ 8 , 22 ].

We summarized the prevalence of households experiencing CHS and the magnitude of CHS, determined as the percentage of the costs of NTDs as a share of income, in Table 4 . The prevalence and magnitude of CHS varied depending on the definitions of CHS, disease duration (episodic or chronic), and thresholds used (≤10% or >10%). Overall, the direct costs of NTDs resulted in a wide range of households experiencing CHS. CHS was generally low among patients with leprosy (0.0–11.0%) [ 19 , 23 ], dengue (12.5%) [ 22 ], and lymphatic filariasis (0.0–23.0%) [ 24 ], and relatively high among patients with Buruli ulcers (45.6%) [ 20 ]. CHS varied widely among patients with chikungunya (11.9–99.3%) [ 21 , 26 ] and visceral leishmaniasis (24.6–91.8%) [ 8 , 15 , 25 ].

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Meta-analyses were performed to pool the prevalence of CHS in studies reporting CHS using the same measurement definition in a particular CHS. This was only possible for visceral leishmaniasis, in which CHS was quantified as direct costs of a disease episode exceeding 10% of annual household income in two studies [ 8 , 15 ], and total costs exceeding 10% of annual household income in three studies [ 8 , 15 , 25 ].

The pooled prevalence of CHS, defined as direct costs exceeding 10% of annual household income, was 73% (95% CI; 65–80%, n = 2, I 2 = 0.00%), as shown in Fig 2A . Egger’s test (P = 0.80) indicated no evidence of small-study effects. Visual inspection of the funnel plot indicated no evidence of publication bias ( S1A Fig ).

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The pooled prevalence of CHS, defined as total costs exceeding 10% of annual household income, was 74% (95% CI; 49–93%, n = 3, I 2 = 94.72%), as shown in S2 Fig . We explored the source of heterogeneity by visual inspection of the forest plot. We found that the source of heterogeneity was the differences in the treatment of visceral leishmaniasis, where sodium stibogluconate was used in two studies [ 8 , 15 ], and miltefosine in one study [ 25 ]. Therefore, we performed a subgroup meta-analysis based on different treatments, as shown in Fig 2B . We removed one study [ 25 ] from the meta-analysis to investigate the publication bias without the presence of heterogeneity. Egger’s test (P = 0.81) indicated no evidence of small-study effects. Visual inspection of the funnel plot indicated no evidence of publication bias ( S1B Fig ).

Impoverishment.

Impoverishment was investigated in one study in patients with visceral leishmaniasis, which defined impoverishment as annual household income falling below the poverty line after paying for treatment [ 8 ]. Costs of visceral leishmaniasis impoverished 20–26% of the 61 households investigated, depending on the costs captured (20% medical costs, 21% medical and transportation costs, 26% direct costs), as shown in Table 2 .

Coping strategies

Four studies reported coping strategies used by patients to pay the costs of NTDs. These strategies included using savings (71–100% of patients), taking out loans (32–80%), selling livestock or other assets (17–32%), or borrowing money (0–23%), as shown in Table 2 . However, these studies did not distinguish between coping strategies used by patients who experienced CHS and those who did not [ 8 , 19 , 24 , 25 ].

Cost drivers and determinants of financial hardship

To understand the cost drivers of financial hardship caused by NTDs, we analyzed the percentage share of types of costs captured in the direct costs. The findings are presented in Fig 3 . Direct medical costs were the primary cost driver in nine studies [ 8 , 19 – 21 , 23 – 26 ]. However, one study identified food and transportation costs as the main cost drivers [ 15 ].

Abbreviation: ENL–erythema nodosum leprosum. Tripathy et al, 2020 [ 24 ]; Tiwari et al, 2018 [ 23 ]; Chandler et al, 2015 [ 19 ]; Uranw et al, 2013 [ 25 ], Meheus et al, 2013 [ 15 ], Adhikari et al, 2009 [ 8 ], McBride et al, 2019[ 22 ], Vijayakumar et al, 2013 [ 26 ], Gopalan et al, 2009 [ 21 ], Chukwu et al, 2017 [ 20 ] .

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Determinants of CHS were assessed in one study among patients with Buruli ulcers. The study concluded that neither age, gender, rural/urban location, education, occupation, religion, nor patient income group was a determinant of CHS [ 20 ]. There was no study investigating determinants of impoverishment.

NTDs primarily impact populations with limited financial means, yet the literature addressing the financial hardship caused by NTDs is relatively scarce. Our systematic review revealed that there were only ten studies covering six NTDs. We discovered that many households are facing financial hardship as a result of NTDs, despite having access to publicly funded healthcare systems or special NTD programs. The costs related to NTDs resulted in significant financial hardship for these households, mainly due to the high OOP costs associated with medical treatment. Even in situations where drugs used to treat NTDs were provided free of charge, the costs for supportive care, medical procedures, transportation, and food were still high and could have a devastating financial impact on these households. Moreover, these financial hardship indicators might not fully reflect the financial risk of the population affected by NTDs because many live in poverty or even extreme poverty. Victims of NTDs are usually those who are socially disadvantaged. They need to make trade-offs between suffering from the disease and seeking healthcare because not all victims can afford the costs of NTDs, especially OOP costs for medical treatment and transportation, which could lead to the abandonment of healthcare [ 1 – 3 ].

The research findings have shown that merely providing funding for treatments of NTDs is insufficient for protecting those affected by NTDs from financial hardship. Therefore, it is crucial to strengthen the entire healthcare system to effectively address the challenges of NTDs and provide financial protection to the victims. Additionally, it is important to encourage and engage communities to change the behavior of those affected by NTDs so that they seek medical assistance at appropriate healthcare facilities instead of relying on traditional healers or not seeking care at all. Our research also supports the need for an economic framework to guide NTD investments [ 27 ]. The ability to prioritize investments, informed partially by economic parameters, may appeal to a broad set of stakeholders and help facilitate the process of building coalitions to achieve the WHO’s goal that 90% of the at-risk population is protected against financial hardship caused by NTDs [ 1 ].

Although there is no consensus regarding the estimation approach and thresholds in quantifying CHS, it is important to note that these differences can significantly impact the findings and consequently impact the applications and implications of the findings [ 6 , 28 ]. We found that CHS was variedly defined across studies in terms of estimation approach, types of costs, thresholds, timeframe, household resources, and perspective. Our review revealed that 90% of the included studies captured direct non-medical costs as part of the OOP costs [ 8 , 15 , 19 – 21 , 23 – 26 ]. Furthermore, Seventy percent of the included studies considered indirect costs in quantifying financial hardship [ 8 , 15 , 19 , 21 , 23 , 25 , 26 ]. This approach aligned with an indicator called “catastrophic costs” that has emerged in tuberculosis studies. Catastrophic costs occur when the total healthcare costs, including direct and indirect costs, exceed 20% of the annual household income [ 28 ]. This indicator could be a more comprehensive measure of the overall financial burden of NTDs on the household beyond just the OOP costs which will be useful when evaluating and monitoring different healthcare policies and interventions to mitigate financial hardship caused by NTDs.

The findings of this systematic review and meta-analysis should be interpreted under the following limitations. The included studies in our review only focused on patients who sought healthcare, so the financial burden of those who did not seek healthcare was not captured in the reported OOP costs. This means that people who could not afford healthcare may have been excluded from these studies. Moreover, we could not perform meta-analyses of the prevalence of CHS on all identified NTDs due to differences in how CHS was quantified across studies and lack of access to individual patient-level data.

Hence, we highlighted some methodological considerations to guide future studies on financial hardship among households suffering from NTDs to gain a better understanding of the neglected public health issues and to inform the development of strategies of what to address to tackle the financial burden of NTDs. Firstly, methods to quantify financial hardship should be coherent to allow comparability across studies. For instance, CHS and impoverishment should be defined and measured in a relevant manner to the nature of the NTD, including estimation approach, thresholds, types of costs, timeframe, household resources, and perspective. Secondly, subgroup analyses should be conducted to evaluate the determinants of financial hardship across household characteristics (e.g., income, socioeconomic status) or phases of disease (e.g., disease onset, treatment seeking, diagnosis, treatment, post-treatment). Lastly, coping strategies should be assessed among those who did and did not experience financial hardship to understand the economic consequences of financial hardship across subgroups.

NTDs can be a devastating burden on households, not only in terms of physical and mental health but also financially. NTDs lead to a substantial number of households facing financial hardship. However, financial hardship caused by NTDs was not comprehensively evaluated in the literature. Furthermore, OOP costs represented only a partial picture of the financial hardship the population affected by NTDs faces. To mitigate this financial hardship, it is imperative to conduct thorough research to identify the factors contributing to it. Future research should consider various household characteristics, such as income, education level, and geographic location, as well as the different disease stages, from onset to treatment completion. Future studies should also investigate the hidden financial burden due to the abandonment of healthcare-seeking to capture the economic burden and opportunity costs of those who did not seek healthcare. By carefully examining these factors, researchers and decision-makers can gain insight into the specific challenges faced by households affected by NTDs and develop targeted interventions to alleviate financial hardships. Ultimately, these studies can help inform the development of strategies to reduce the burden of NTDs on households and improve overall health outcomes.

Supporting information

S1 prisma checklist. prisma checklist..

https://doi.org/10.1371/journal.pntd.0012086.s001

S1 Table. Differences from original review protocol.

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S2 Table. Full search strategy.

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S3 Table. Excluded studies with reasons.

https://doi.org/10.1371/journal.pntd.0012086.s004

S4 Table. Quality assessment using Larg, A., and Moss, J. R. (2011) Cost-of-illness studies: a guide to critical evaluation.

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S1 Fig. Assessment of publication bias.

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S2 Fig. Forest plot of pooled proportion of catastrophic health spending defined as total costs exceeding 10% of annual household income.

https://doi.org/10.1371/journal.pntd.0012086.s007

Acknowledgments

The authors alone are responsible for the views expressed in this article and they do not necessarily represent the views, decisions or policies of the institutions with which they are affiliated.

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SYSTEMATIC REVIEW article

The role of arts therapies in mitigating sleep initiation and maintenance disorders: a systematic review.

• 1 Faculty of Humanities and Arts, Macau University of Science and Technology, Macao, Macao SAR, China
• 2 State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macao, Macao SAR, China
• 3 Faculty of Chinese Medicine, Macau University of Science and Technology, Macao, Macao SAR, China
• 4 College of Computer Science and Technology Zhejiang University, Hangzhou, Zhejiang, China
• 5 Operation Management Centre, Guangzhou Wanqu Cooperative Institute of Design, Guangzhou, Guangdong, China
• 6 Qinghai Province Cardiovascular and Cerebrovascdular Disease Specialist Hospital, Xining, Qinghai, China
• 7 Centre for Epidemiology and Evidence-Based Practice, Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia

Introduction: Arts therapies offer effective non-pharmacological intervention for Sleep Initiation and Maintenance Disorders (SIMDs), encompassing both passive and active modalities. This review assesses their effectiveness and ethical considerations, focusing on music therapy, meditation, and Tai Chi.

Methods: Following PRISMA guidelines, a detailed search across PubMed, the Cochrane Library, Web of Science, and CNKI identified 17 relevant RCTs. Utilizing the Joanna Briggs Institute (JBI) quality criteria and the PICO(S) framework for data extraction ensured methodological integrity.

Results: Analysis shows arts therapies significantly improve sleep quality. Music therapy and meditation yield immediate benefits, while Tai Chi and Qigong require longer commitment for significant outcomes.

Discussion: The link between SIMDs and mental health issues like anxiety, stress, and depression suggests arts therapies not only enhance sleep quality but also address underlying mental health conditions. The evidence supports a wider adoption of arts therapies in treating SIMDs due to their dual benefits.

Systematic review registration: PROSPERO, ID: CRD42024506393.

1 Introduction

In the rapid pace of modern life, Sleep initiation and maintenance disorders (SIMDs) have emerged as a global health challenge, exacerbated by the aftereffects experienced by many in the wake of the pandemic, severely impacting physical health and daily routines ( 1 ). A study by the World Health Organization (WHO) estimates that approximately 1.7 billion people globally suffer from sleep disturbances, accounting for 27% of the world’s population ( 2 ). The Diagnostic and Statistical Manual of Mental Disorders (DSM-5) characterizes insomnia as a prevalent clinical condition, with approximately one-third of adults reporting symptoms of insomnia, and 6 to 10% meeting the diagnostic criteria for an insomnia disorder ( 3 ). SIMDs encompass a variety of abnormalities during sleep, including excessive daytime sleepiness, insomnia, abnormal movements or behaviors during sleep, and difficulty initiating sleep when desired ( 4 , 5 ), often accompanied by other physical conditions or mental health issues, including insomnia, obstructive sleep apnea, somnambulism, narcolepsy, and restless legs syndrome among different types ( 6 , 7 ). More than 50% of adults globally have experienced a sleep disorder at least once in their lives ( 8 ). The distribution of sleep problems across certain age groups and populations is even broader, becoming a significant and growing public health issue ( 9 ). Sleep, as a fundamental human need, plays a crucial role in maintaining overall health, cognitive function, and quality of life ( 10 ). Research indicates that most SIMDs are preventable or treatable ( 11 ), yet the majority of sufferers do not seek professional help. The consequences of SIMDs are wide-ranging, adversely affecting individual health and socioeconomic well-being. Conditions such as insomnia, obstructive sleep apnea (OSA), and restless legs syndrome (RLS) continue to have high prevalence rates and exert profound effects on physical and mental health ( 12 – 14 ). Studies have shown a close correlation between sleep and an increased risk of obesity, diabetes, cardiovascular diseases, and mental health disorders, including depression and anxiety ( 15 – 17 ). Sleep issues not only have a strong bidirectional relationship with mood disorders such as depression and anxiety but are also associated with cognitive decline, physical health problems, and decreased work efficiency ( 18 – 21 ). Particularly among the elderly, over 50% suffer from sleep issues, impacting their physical and mental well-being ( 22 ). Furthermore, approximately 80% of individuals with clinical depression experience sleep disturbances ( 23 ). Research also reveals that sleep problems are prevalent in high-stress groups, such as college students ( 24 ). Traditional sleep interventions have relied on pharmacological treatments, which may come with side effects that limit their long-term application ( 25 ), such as residual drowsiness, tolerance, dependence, altered sleep architecture, and rebound insomnia ( 26 – 29 ). Common medications used in traditional treatments include sleep aids like zopiclone, zolpidem, and eszopiclone, as well as medications used to alleviate anxiety or depression associated with sleep issues, such as alprazolam, quetiapine, and fluoxetine ( 30 , 31 ). These medications often result in side effects during the medication-induced sleep process, such as nasal congestion, convulsions, nightmares or hallucinations, and breathing difficulties, and are accompanied by side effects such as dizziness, nausea, dry mouth, muscle weakness, and headache upon waking. Moreover, these drugs carry the risk of dependency and resistance, often leading to withdrawal reactions upon cessation, and place significant financial stress on many patients over the long term ( 32 , 33 ). This has paved the way for non-pharmacological interventions ( 34 ), given the burdens of pharmacotherapy, exploring benign non-pharmacological interventions for sleep issues becomes the focus of this article.

Among the numerous methods for sleep healing, various forms of arts therapies as non-pharmacological treatments have shown unique advantages and potential. To refine and expand our definition of arts within arts therapies, it’s crucial to adopt a nuanced and comprehensive perspective that acknowledges the wide array of non-pharmacological therapeutic arts as defined by the five senses: visual, auditory, olfactory, gustatory, and tactile. For example, visual art and color therapy utilize form, color, and imagery to engage the visual sense, potentially evoking feelings of calmness and relaxation that can improve sleep quality ( 35 ). Similarly, music therapy leverages auditory stimuli to influence emotional states and stress levels, indirectly promoting healthier sleep patterns ( 36 ). Aromatherapy, targeting the olfactory sense, uses essential oils and fragrant extracts to harmonize the mind and body, with certain scents known for their sedative properties that aid sleep. While gustatory arts, such as culinary arts therapy, may indirectly influence sleep through mood and wellbeing improvements, tactile forms of therapy like body movement and dance therapy emphasize physical expression and the tactile experience to relieve stress and enhance sleep quality ( 37 , 38 ). This inclusive approach not only broadens the review’s scope but also underscores the multifaceted nature of arts therapies in mitigating sleep initiation and maintenance disorders by alleviating mental stress and emotional tension. Moreover, arts therapies promote and encourage individuals to actively manage their own health, placing a greater emphasis on intrinsic motivation and personal involvement. By engaging with art, individuals improve their mood and mental health, releasing inner stress and uneasy emotions, which in turn reduces levels of anxiety and depression ( 39 ). This engagement in creative activities provides an outlet for emotional release and self-exploration, not only offering immediate relief from sleep issues but also increasing individual life satisfaction and happiness over the long term. As a non-pharmacological treatment, arts therapies not only highlights its uniqueness in addressing sleep problems but also robustly supports the improvement of sleep quality, promising to become an important tool for enhancing individual and community health ( 40 ).

Therefore, this review explores a gentler approach to improving sleep health through non-pharmacological interventions. Focusing on various art forms, this review examines diversified alternative therapies including mindfulness-based stress reduction (MBSR) ( 41 ), yoga ( 42 ), music therapy ( 43 ), virtual reality (VR) ( 44 ), and meditation ( 45 ) that offer sensory engagement. Studies indicate that these therapies assist in regulating both physiological and psychological states, thus improving sleep quality. These arts therapies not only eliminate the need for injections or oral medications but also provide multidimensional benefits unreachable by traditional treatment methods ( 46 ). For instance, group yoga not only promotes relaxation and improves sleep quality but also enhances social interaction, boosts self-esteem, and positively affects posture ( 47 ). Beyond sleep, these interventions also include stress reduction, enhanced emotional regulation, and improved cognitive function ( 48 , 49 ). These intervention methods offer assistance not just to the elderly but have also shown potential in ICU patients, college students, and other populations affected by high stress levels.

This review aims to comprehensively examine and compare evidence supporting various non-pharmacological interventions for SIMDs, delving into how these measures can improve sleep issues across different populations and assessing their benefits and potential limitations in clinical practice. Specifically, this review will focus on the following research questions:

1) Which arts therapies have been effective in addressing SIMDs?

2) How do different art forms and practices leverage their unique advantages in the intervention of SIMDs?

3) What are the mechanisms of effect when these arts therapies are used as alternative treatments, and what hypotheses can be explored?

This review intends to provide healthcare professionals with practical guidelines to make more informed decisions in treating SIMDs and offer value to patients seeking alternative and complementary treatments. By considering the multidimensional benefits of arts therapies, this article aims to present a new perspective and direction for the management of SIMDs within the healthcare system.

This systematic review adheres to the PRISMA statement for systematic reviews and meta-analyses (PRISMA) ( 50 , 51 ) and is registered with PROSPERO ( 52 ) under the registration number CRD42024506393. We developed the research question using the PICOS acronym, as follows:

• P: Any patient associated with SIMDS.

• I: Interventional arts therapies.

• C: Conventional therapy.

• O: Improved clinical and/or mental health outcomes.

• S: randomized controlled trials, quasi experimental studies (non-randomized controlled trials), and single-arm, pre-test/post-test studies.

2.1 Study inclusion and exclusion criteria

In the systematic review, we rigorously defined the inclusion and exclusion criteria to ensure a thorough examination of the impact of arts therapies on Sleep Initiation and Maintenance Disorders (SIMDs). Studies eligible for inclusion are those that adhere to the Joanna Briggs Institute (JBI) research design guidelines, involve participants diagnosed with SIMDs, and implement arts therapies, including but not limited to music, visual arts, dance/movement, drama therapy, and bibliotherapy as a primary intervention. The interventions could be carried out across various settings and delivered by arts therapy professionals. These studies should compare the outcomes against any type of control group and report on sleep quality indicators such as sleep latency and efficiency. Our focus is on gathering empirical evidence from randomized controlled trials, quasi-experimental studies, and analytical cross-sectional studies that meet ethical and methodological standards.

Conversely, the review excludes non-peer-reviewed documents, studies not employing art-based interventions, and those concerning individuals without SIMDs diagnoses. Additionally, research designs such as non-experimental studies, narrative reviews, animal studies, and publications not in English are omitted to maintain the review’s integrity and manageability. This selectivity ensures the inclusion of studies with robust methodologies and relevant outcomes, thereby providing reliable evidence on the effectiveness of arts therapies in treating sleep disorders. The exclusion of non-English articles and grey literature is acknowledged as a limitation but is necessary for ensuring thorough analysis and interpretation within the language proficiency of the review team.

2.2 Electronic databases

This systematic search was conducted across five electronic databases: PubMed, Cochrane Library, Web of Science, Embase, and the Chinese database CNKI, for publications spanning from 2004 to 2024.

2.3 Search strategy

A meticulously structured search strategy was implemented by a team of three independent researchers. This strategy aimed to capture a wide array of studies that investigate the intersection of arts therapies and sleep disorders. Table 1 of the original article delineates the search strategy, highlighting the employment of specific keywords and Medical Subject Headings (MeSH) to guide the literature search. The primary keywords included ‘Arts Therapies’ and ‘Sleep Disorders,’ which were chosen for their broad applicability to studies exploring the therapeutic use of art in the context of sleep-related issues.

Table 1 Search strategies for English databases or Chinese databases.

To ensure a comprehensive gathering of relevant literature, various forms of art therapy were considered, encompassing visual arts and color-related therapies, auditory music-related therapies, and tactile movement-related therapies. This approach acknowledges the multifaceted nature of arts therapies and their potential impact on sleep disorders across different sensory modalities. Furthermore, to mitigate the risk of overlooking pertinent studies, a manual search was conducted through the reference lists of key reviews and articles identified during the initial search phase. This dual-faceted search strategy, combining both electronic database searches with manual reference checking, was aimed at creating a thorough and all-encompassing review of the literature available on the subject matter, enhancing the reliability and depth of the systematic review.

2.4 Study selection

Three independent reviewers, LXX, HL, and AJZ, engaged in the screening, eligibility, and selection review processes. LXX was tasked with downloading and reviewing the filtered articles, excluding those deemed irrelevant. Subsequently, pertinent literature was forwarded to HL for an eligibility review. Upon determining the eligibility of 17 documents, AJZ conducted a meticulous evaluation and scoring based on JBI’s critical appraisal tools ( 53 , 54 ). These instruments are designed to assess the methodological quality of the studies and ascertain the extent to which the studies address the potential for bias in their design, execution, and analysis. Moreover, literature meeting the eligibility criteria was subjected to a dual examination by LXX and HL. Every one of the 17 included studies, particularly those identified as randomized controlled trials, underwent a thorough data extraction process using the PICO(S) framework ( 55 ). This approach allowed for the systematic organization and assessment of pertinent information extracted from the documents, enhancing the clarity and conciseness of the analysis.

2.5 Data extraction

In the systematic review process, the task of data extraction was meticulously planned and executed by three independent researchers, ensuring a thorough and unbiased collection of data from the selected studies. This critical phase was structured around the creation of four distinct tables, each designed with a specific function to aid in the systematic organization and analysis of the collected data.

The first table was developed to provide a clear visualization of the core content extracted from each piece of literature, organized into categories such as Study Aims, Participants, Methods, Results, and Discussion. This table aimed to facilitate an immediate understanding of each study’s key components, allowing for a quick yet comprehensive overview of the collected data. The second table was tailored to display subgroups of different arts therapies, enabling the researchers to categorize and compare the results and author names within specific therapeutic groups, thereby highlighting the diversity and specific outcomes associated with each art therapy type.

To ensure the quality and reliability of the included studies, a third table was utilized for conducting a quality review of the literature. This table employed checklists derived from the Joanna Briggs Institute (JBI) guidelines, which are renowned for their robustness in assessing the methodological quality of research. The fourth table was dedicated to extracting detailed data about patient samples, intervention and control group methodologies, and outcomes, specifically from randomized controlled trials (RCTs). For this purpose, the researchers adopted the PICOS (Population, Intervention, Comparator, Outcomes, and Study Design) model, which facilitated a structured and comprehensive analysis of the RCTs. This strategic approach to data extraction not only enhanced the clarity and organization of the data but also laid a solid foundation for the systematic review’s subsequent analysis and discussions.

2.6 Quality appraisal of the included studies

The initial comprehensive search yielded 17,262 publications, from which irrelevant studies were excluded through a meticulous screening of titles and abstracts, followed by a detailed full-text review as required. This rigorous selection process leveraged the PICO(S) framework (Population, Intervention, Comparison, Outcome, and Study design) to systematically define inclusion and exclusion criteria, ensuring focus and relevance in the selection of studies, to uphold the methodological integrity of the review, the Joanna Briggs Institute (JBI) critical appraisal tools were employed, facilitating the evaluation of the studies’ quality. This approach underlined our commitment to incorporating only the most methodologically sound literature into our analysis ( 53 – 56 ).

The quality appraisal of randomized controlled trials (RCTs) within our dataset was conducted using a scoring system informed by JBI guidelines. This involved assigning a score of one point for each criterion adequately met ‘yes’, zero points for unmet criteria ‘no’ and ‘unclear’. This scoring facilitated a horizontal comparison of study quality, ranking them based on their aggregate scores. A score of ≤6 was considered as low quality, from 7 to 9 as moderate and ≥ 10 as high quality. No studies were excluded based on methodological quality. Vertically, this method allowed for the assessment of commonalities across the reviewed literature, evaluating the proportion of studies that successfully met each quality criterion.

Furthermore, the application of the PICO(S) framework extended beyond initial study selection, informing the structured tabulation of the research data. This included organizing studies and ranking them by the number of participants, recognizing that larger sample sizes typically contribute to a stronger evidence base.

3.1 Study characteristics

This manuscript incorporates 17 studies focusing on experimental design, wherein 10 studies juxtapose art therapy with a standard routine, and three compare art therapy to sleep hygiene education, see in Figure 1 . The control groups in other investigations employed a variety of methods including daily routine sleep intervention, self-monitoring, low-impact exercise, and health education, see in Figure 2 , primarily encompassing Virtual Reality (VR) ( 57 ), meditation ( 58 – 60 ), qigong ( 61 ), tai chi ( 62 , 63 ), Biodanza ( 64 ), music therapy ( 65 – 70 ), yoga ( 71 , 72 ), and Mindfulness-Based Stress Reduction (MBSR)/Mindfulness-Based Cognitive Therapy (MBCT) ( 73 ).

Figure 1 Flow diagram for the included and excluded articles.

Figure 2 Types of arts therapies with Sleep Initiation and Maintenance Disorders (SIMDs).

Tables 2 , 3 synthesize the principal characteristics of the qualifying studies. The 17 included studies comprise 1,300 participants (treatment conditions= 694, control conditions= 606) hailing from South Korea ( 57 ), the USA ( 58 – 60 , 62 , 63 , 71 , 72 ), China ( 61 , 65 – 67 , 70 ), Spain ( 64 ), Hungary ( 68 ), Singapore ( 69 ), and Iran ( 73 ), with the largest sample consisting of 237 individuals ( 58 ) and the smallest of 18 ( 71 ). The age range of participants was broad, from teenagers aged 19 to senior citizens aged 92, encompassing healthy individuals ( 61 – 63 , 66 , 69 , 72 ), cardiac patients ( 57 ), those with chronic insomnia and moderate SIMDs ( 58 – 60 , 65 – 68 , 70 , 71 ), stressed university students ( 64 ), and individuals with depression ( 73 ).

Table 2 Record of citations and full text reviewed.

Table 3 Principal characteristics of all included RCTs in this review.

Regarding the evaluation of study outcomes, the research included varied in their focus on therapeutic outcomes, hence employing diverse testing methodologies. The studies measured characteristics related to sleep quality ( 57 , 59 – 73 ), or outcomes in other categories such as anxiety ( 58 , 65 ), depression ( 58 , 64 , 68 ), stress ( 64 ), heart rate ( 71 ), electroencephalography ( 65 , 71 ), or mood ( 73 ). The Pittsburgh Sleep Quality Index and scales were the most frequently utilized measures for assessing sleep quality. Additionally, the activity tracker FitBit Charge 2 ( 57 ), electroencephalography ( 65 , 71 ), and heart rate variability ( 71 ) represented the latest measurement techniques.

An analysis using the JBI Critical Appraisal Checklist indicates that the quality of evidence from the included studies is relatively high. However, nearly all studies did not rigorously implement a double-blind experimental methodology ( Table 4 ).

Table 4 Quality of evidence in the included 17 reports based on JBI’s critical appraisal tools.

3.2 Description of the population

The comprehensive review of literature on the application of arts therapies in addressing Sleep Initiation and Maintenance Disorders (SIMDs) culminated in the selection of 17 pivotal papers. These studies are meticulously tabulated in Tables 3 , 5 , adhering to the PICOs methodological framework, thereby illustrating the core experimental data extracted from each randomized controlled trial (RCT) article. Collectively, these papers encapsulate a population of 1,300 patients, underscoring the substantial empirical effort directed toward exploring the efficacy of diverse art therapy interventions in mitigating SIMDs.

Table 5 Clinical setting, country, and characteristics of the participants.

Among this aggregation of research, the RCTs conducted by Jason, Chiung-Yu, and László are particularly notable for their methodological rigor. By segregating patients into three distinct groups, these studies not only facilitated a nuanced examination of the therapeutic outcomes attributable to various arts interventions and settings but also implemented strategic measures to curtail potential data bias (references 59 , 65 , 68 ). Contrasting with these, the remainder of the corpus, comprising 14 papers, predominantly adopted a dual-group treatment versus control design, which is a conventional approach within clinical trial methodologies.

Within this diverse array of studies, Jennifer’s research stands out due to its scale, encompassing a total of 237 patients divided into two groups (124:113), marking it as the study with the highest number of trials among the 17 papers reviewed (reference 58 ). Following closely, the works of Fuzhong and Michael also contribute significantly to the dataset with totals of 118 and 112 patients, respectively (references 62 , 63 ). Conversely, the study led by Erica, involving a comparatively modest cohort of 18 patients, commands attention not for its volume but rather for its profound implications. Despite its smaller scale, the depth of insights and the meticulous attention to minimizing data bias within Erica’s study necessitate a detailed examination of its experimental outcomes and methodological strengths (reference 71 ).

3.3 Analysis the function with arts therapies

The main effects of each art therapy on sleep quality are shown in Table 6 . In modern society, sleep issues have become a common health concern, not only affecting the quality of individual lives but also leading to a range of physical and mental health problems ( 74 ). As research into non-pharmacological treatments for SIMDs deepens, art therapy has gained attention as an alternative method. This review aims to explore the effectiveness and mechanisms of various arts therapies in improving sleep quality through a systematic analysis of 17 research articles.

Table 6 Comparative analysis of results across modalities.

With technological advancements, meditation practices using virtual reality (VR) technology have become feasible ( 75 ). By simulating natural environments and combining deep breathing and guided meditation, VR meditation has shown significant effects in shortening the time to fall asleep, reducing the number of awakenings during the night, and increasing deep sleep duration, offering a new perspective and method for sleep therapy ( 57 , 76 ).

Meditation, especially mindfulness meditation, has proven to be an effective self-regulation method for chronic insomnia sufferers by reducing anxiety and stress before sleep, shortening the time to fall asleep, and improving sleep quality ( 77 ). Research indicates that meditation not only alleviates SIMDs but also reduces negative emotions such as anxiety and depression, thereby enhancing daytime function and quality of life. These multiple benefits make meditation a powerful tool for treating SIMDs ( 59 ).

Qigong and Tai Chi, ancient Chinese mind-body practices ( 78 ), improve sleep quality through a series of slow, orderly movements and breathing techniques. These practices not only promote physical relaxation and reduce psychological stress but also regulate the endocrine system, effectively improving SIMDs ( 79 ). For example, a 12-week Qigong training for premenopausal women successfully improved their sleep quality and daytime drowsiness ( 61 ). Similarly, Tai Chi practice has been shown to enhance self-reported sleep quality and physical function in the elderly, indicating its positive effect on sleep improvement ( 62 ).

Biodanza therapy, a dance movement therapy that integrates music, movement, and emotional expression ( 64 ), did not show significant differences in directly improving sleep quality but effectively alleviated stress and depression, indirectly promoting a better rest state. Its significant effect in relieving stress, anxiety, and depression indirectly helps attain better sleep ( 80 ). Music therapy, including listening to soothing music and music videos, has also shown potential in improving sleep quality in adults and the elderly ( 65 ). Music can extend subjective sleep duration, shorten stage two sleep duration, prolong rapid eye movement sleep, and overall improve participants’ sleep experience ( 67 , 81 ). These studies emphasize music as a non-pharmacological intervention that improves sleep quality by reducing stress responses, relaxing the body and mind, and diverting attention ( 82 ).

Yoga therapy, particularly Kundalini yoga and Yoga Nidra, has been proven to have a positive impact on improving sleep quality ( 71 , 72 ). By improving physical flexibility, enhancing muscle strength, deep breathing, and meditation practices, it not only improves sleep quality but also has a significant therapeutic effect on emotional disorders such as depression and anxiety ( 83 ). These improvements suggest that yoga can be an effective treatment method for SIMDs. This effectiveness is not only immediate at the end of yoga practice but can last up to six months after the practice has ended ( 84 ), implying that the improvement in sleep quality through yoga is not temporary but has a certain durability. This underscores yoga practice as a long-term effective non-pharmacological treatment method, not just a short-term intervention.

Mindfulness-Based Stress Reduction (MBSR)/Mindfulness-Based Cognitive Therapy (MBCT) courses have had a positive effect on improving emotional regulation and sleep problems ( 73 ), significantly reducing depressive symptoms and improving sleep quality in the elderly population with depression.

Overall, these arts therapies provide a diverse range of non-pharmacological treatment options for SIMDs. They significantly improve sleep issues through various mechanisms such as emotional regulation, stress reduction, improving the wakefulness state before sleep, and enhancing sleep quality. Future research should further explore the specific mechanisms of action, sustained effects, and how these arts therapies can be effectively integrated into existing sleep disorder treatment frameworks.

3.4 Literature quality assessment

Leveraging Table 4 , our analysis meticulously appraised the comprehensive quality of each study through the Joanna Briggs Institute (JBI) methodology, assigning a one-point increment for every “Yes” response, culminating in an aggregate score out of 13. Within this cohort of 17 randomized controlled trials (RCTs), the paper authored by Sat Bir distinguished itself with a high-quality score of 12 (reference 72 ), closely trailed by the contributions from En-Ting, László, and Erica, each securing a commendable score of 11 (references 67 , 68 , 72 ). This echelon of papers stands apart for their rigorous alignment with quality parameters, whereas the corpus of remaining studies predominantly manifested moderate quality, with the exception of Shu-chuan’s work, which uniquely aligns with the aforementioned group by also securing a score of 11 (references 67 , 68 , 72 ). One RCT article notably diverged from this trend, recording a modest score of 6 (reference 61 ) upon JBI evaluation.

A deeper dive into the JBI quality assessment criteria across these 17 RCT articles revealed that questions 3, 9, 10, 11, and 12 witnessed unanimous affirmative responses. This uniformity underscores a foundational concordance among the studies with regards to the critical aspects of including treatment groups based on clear baseline characteristics, ensuring randomness in subgroup allocations, maintaining uniformity and authenticity in measurement techniques, and employing appropriate statistical analyses. Such consistency is pivotal for establishing the foundational integrity of trial methodologies.

Conversely, a nuanced examination reveals that questions 4 and 5, which probe the implementation of double-blind or single-blind protocols in RCTs, presented a spectrum of “No” and “Unclear” responses across all examined literature. This variance highlights a prevalent methodological vulnerability within the domain, signifying a crucial area for future methodological refinement and adherence to ensure the elimination of bias and elevation of research quality standards.

3.5 Description of the control intervention

According to Table 3 , within the ambit of the 17 randomized controlled trials (RCTs) scrutinized in the presented literature, a discernible allocation of control group methodologies is observed. Notably, a majority, specifically 10 RCTs, embraced a ‘Normal Routine’ strategy for their control groups, an approach characterized by the absence of any specialized methodological intervention for participants afflicted with sleep disorders ( 58 , 61 , 64 , 65 , 67 – 71 , 73 ). This strategy ostensibly serves to mirror the unaltered daily routines of individuals, thereby establishing a baseline for comparative analysis. An integrative approach was adopted in three RCTs, employing ‘Sleep Hygiene Education’ as the control group intervention. This methodological choice is predicated on the dissemination of essential medical knowledge, aiming to cultivate an awareness among patients regarding the principles conducive to healthy sleep patterns ( 60 , 66 , 72 ).

Complementing these, the remainder of the dataset, comprising four RCTs, instituted a varied spectrum of control conditions, specifically ‘Daily Routine Sleep Intervention,’ ‘Self-Monitoring,’ ‘Low-Impact Exercise,’ and ‘Health Education.’ These interventions ( 57 , 59 , 62 , 63 ) were distinctively implemented.

3.6 Main results on the primary outcomes

Under PICO(S) design in Table 3 , In the analytical examination of 17 randomized controlled trials (RCTs) delineated in our systematic review, the utilization of the Pittsburgh Sleep Quality Index (PSQI) emerged as the predominant tool for outcome measurement, with an overwhelming 14 studies ( 57 , 60 – 70 , 72 , 73 ) electing the PSQI as their principal evaluative instrument. This universal adoption underscores the PSQI’s acknowledged efficacy in gauging the multifaceted aspects of sleep quality within clinical research paradigms. The Pre-Sleep Arousal Scale (PSAS) was employed as the measurement methodology in two distinct RCTs ( 59 , 72 ), signifying its specialized application in assessing pre-sleep cognitive and somatic arousal levels. Of note, one study ( 57 ) innovatively combined the PSQI with both the Sleep Scale A (SSA) and an activity tracker (FitBit Charge 2, ATFC2), thus broadening the spectrum of sleep-related data acquisition. Similarly, an additional study ( 59 ) integrated Total Wake Time (TWT) alongside the PSQI, thereby enriching the dimensional coverage of sleep disturbances being investigated.

The Epworth Sleepiness Scale (ESS), a tool designed to measure daytime sleepiness, was cohesively utilized across three studies ( 62 , 68 , 70 ). Notably, the sophisticated technology of electroencephalography (EEG) was harnessed for data collection in two studies ( 65 , 71 ).

3.7 Therapeutic with SIMDs

Music therapy, featured prominently as the most frequently cited intervention method among the 17 studies reviewed, distinguishes itself from other modalities by its passive nature, as opposed to the active engagement required by the others ( 65 – 70 ). This form of therapy, characterized by the passive auditory reception of music, serves to alleviate emotional tension and soothe neural stress without necessitating physical movement, making it particularly well-suited for improving sleep disturbances among the elderly with limited mobility. According to Table 4 of the PICO(S) framework, in the elderly population, two randomized controlled trials (RCTs), each involving around 60 participants split into two groups, conducted interventions over periods of 3 and 6 weeks. The pre and post-intervention data, gauged by the Pittsburgh Sleep Quality Index (PSQI), demonstrated a comprehensive amelioration of SIMDs in the elderly ( 69 , 70 ). In studies targeting younger demographics, such as college students, La´szlo´ divided participants into three groups of 35, 30, and 29. After a 3-week intervention, data from the PSQI and Beck Depression Inventory (BDI) indicated that music therapy could concurrently suppress depressive symptoms and sleep disorder manifestations ( 68 ). A 3-day experiment focusing on adults with chronic insomnia revealed that listening to soothing music for 45 minutes before sleep significantly prolonged the rapid eye movement (REM) sleep phase ( 67 ). As a form of passive intervention, music therapy, a non-pharmacological measure, has been shown to effectively enhance sleep initiation and maintenance in patients with sleep quality issues ( 85 ), particularly benefiting those who prefer natural remedies or are concerned about the side effects of sleep medications, without requiring physical movement ( 86 ). Allowing participants to select their preferred music enhances the effectiveness of the intervention, as personal preference plays a critical role in the therapeutic impact of music. However, choices in music can vary greatly, and there is no standardized method for selecting the type or duration of music to be used for sleep therapy. Nevertheless, according to Table 4 of the PICO(S) framework, most studies on music therapy interventions had short durations, lacking data on the long-term efficacy and sustainability of music therapy for treating SIMDs ( 65 , 67 , 68 , 70 ).

Besides music therapy’s passive interventions, all other methods included in the 17 studies fall under active interventions, with meditation and mindfulness being primary modalities ( 57 – 60 , 73 ), followed by physical movement-based interventions like Qigong, Tai Chi, dance, and yoga ( 61 – 64 , 71 , 72 ). Tai Chi and Qigong therapies, among these active interventions, had the longest durations of engagement, spanning 2 months, 3 months, and 6 months, utilizing slow, rhythmic movements and deep breathing to achieve relaxation and equilibrium of body and mind. Studies have shown that Qigong improved menopausal symptoms and sleep quality in the intervention group after 6 and 12 weeks compared to the control group, while Tai Chi required long-term intervention, such as more than 24 weeks, to exhibit a significant improvement in sleep, with the Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS) serving as primary measurement tools ( 61 – 63 ). Meditation is a commonly employed method in the treatment of SIMDs, typically involving 6–8 week interventions focused primarily on elderly individuals, especially those experiencing sleep disturbances. Research suggests that mindfulness meditation may correlate with reduced concentrations of NF-κB (a transcription factor associated with inflammatory responses), indicating a potential anti-inflammatory effect beneficial to seniors. Furthermore, meditation therapy has been found to improve mental health issues in the elderly, alleviating depression, anxiety, and feelings of loneliness. Meditation, often linked to Buddhism or yoga, typically incorporates techniques such as silence, breath counting, and visualization during training, aimed at reducing stress and intrusive thoughts, thereby psychologically remedying non-organic insomnia ( 58 – 60 , 73 ). Yoga and dance, requiring some degree of physical effort, have shown varying impacts. Despite no significant intergroup differences in EEG alpha-wave power, heart rate variability (HRV), or sleep latency observed with Yoga Nidra (a form of guided meditation practice), a statistically significant difference in respiratory rate between the Yoga Nidra group and the control group suggests that Yoga Nidra may aid in relaxation, though further research is necessary to confirm ( 71 ). The effects of Kundalini yoga and Sleep Hygiene Education (SH) on chronic primary insomnia showed the yoga group had greater improvements in sleep onset latency (SOL), total sleep time (TST), and sleep efficiency (SE), with these improvements persisting at a 6-month follow-up. Over 50% of participants in the yoga group reported a decrease of at least 8 points in the Insomnia Severity Index (ISI) at the end of treatment and during the follow-up period ( 72 ). The dance therapy Biodanza, after a 4-week intervention among university students, significantly reduced stress, tension, and depressive moods, indirectly ameliorating sleep issues to some extent ( 64 ).

Virtual reality (VR) devices, with their immersive capabilities, offer a promising complement to meditation or mindfulness therapies. However, caution is warranted when applying this emerging technology to older populations, as it may induce fear, stress, and anxiety, potentially exacerbating sleep disorder issues ( 57 ).

In conclusion, music therapy emerges as the most extensively documented passive intervention within the study, utilizing auditory reception to mitigate emotional and stress-related issues. It has proven effective in improving sleep disturbances among both the elderly and younger populations, requiring no physical exertion and allowing for personalized music selection to enhance intervention outcomes. Despite the absence of data on long-term effectiveness, music therapy remains a beneficial non-pharmacological intervention ( 87 ). Concurrently, the study also explores active interventions such as meditation, Qigong, Tai Chi, yoga, and dance, which are also effective in improving sleep quality among specific groups. The nascent combination of VR technology with meditation shows potential therapeutic effects but should be approached cautiously when applied to older individuals to avoid eliciting adverse emotional responses.

4 Discussion

Given the comprehensive analysis of the results surrounding different arts therapies for mitigating SIMDs, our discussion will explore the optimal combination of these therapies to achieve maximum effectiveness for various demographics. The results highlight the varying benefits of passive and active interventions, including music therapy, meditation, Tai Chi, Qigong, Yoga, and Biodanza, as well as emerging technologies like virtual reality (VR) meditation. By understanding the unique advantages of each method, we can propose tailored, multimodal therapy regimens that cater to specific needs.

The evidence strongly suggests that a combination of passive and active therapies might offer a synergistic effect on improving sleep quality and duration ( 88 – 90 ). Music therapy, the most extensively studied passive intervention in the included literature, demonstrated significant potential in improving sleep quality for both elderly and younger populations without the necessity of physical movement ( 91 , 92 ). This points to the utility of integrating music therapy into the bedtime routine of individuals across different age groups, particularly those with limited physical mobility or preference for less physically demanding interventions ( 93 , 94 ).

On the other hand, active therapies like Meditation, Tai Chi, Qigong, and Yoga, have shown promise in not only improving sleep quality but also enhancing psychological well-being and reducing stress, anxiety, and depressive symptoms. These findings suggest that active interventions, which often incorporate elements of mindfulness, physical movement, and breathwork, can address both the physiological and psychological contributors to SIMDs.

The diversity in demographics across the studies, including varying age groups, health statuses, and cultural backgrounds, underscores the necessity of personalized therapy plans. For instance, older adults may benefit more from a combination of music therapy with gentle Qigong exercises, which mitigate the risk of falls while promoting relaxation and improving sleep ( 95 ). Conversely, younger individuals, particularly those experiencing stress and anxiety (e.g., college students), might find a combination of high-intensity Biodanza and meditation more effective, leveraging the physical exertion of dance to alleviate stress and the mindfulness aspect of meditation to prepare the mind for rest ( 96 , 97 ).

Additionally, for those experiencing more profound psychological issues, such as depression, integrating therapies that specifically target emotional well-being—like meditation with music therapy ( 98 )—can be particularly beneficial. This combination can leverage the stress-reducing and mood-enhancing benefits of music alongside the mindfulness and self-awareness cultivated through meditation, offering a holistic approach to treating SIMDs.

The integration of VR technology into meditation practices presents an innovative approach to enhancing the immersion and effectiveness of mindfulness exercises for SIMDs. However, given the potential for VR to induce anxiety or discomfort in certain populations, its application should be carefully considered. Tailoring VR experiences to match individual preferences and introducing these technologies gradually can mitigate potential adverse reactions. Furthermore, combining VR-enhanced meditation with more traditional, familiar therapeutic practices like music therapy could offer a balanced approach, providing the novel benefits of VR while ensuring comfort and accessibility ( 99 ).

For the integration of arts therapies to be most effective, ongoing assessment and adaptation of therapy plans are crucial. This includes regular monitoring of individual responses to therapy, readiness to modify or switch therapies based on efficacy and preference, and continually updating the therapy plan as new evidence emerges. Future research should focus on longitudinal studies to better understand the long-term effectiveness of combined therapies and to refine these recommendations further.

SIMDs frequently coexist with, or are exacerbated by, psychological conditions such as anxiety, depression, and stress, suggesting a bidirectional relationship between sleep disturbances and mental health issues ( 100 ). The complex interplay between these factors highlights the importance of emotional regulation in the effective management of SIMDs. As sleep problems often serve as both a symptom and a contributor to mental health issues, addressing the psychological underpinnings is paramount ( 101 ). This underscores the necessity for therapeutic approaches that not only target the physiological aspects of SIMDs but also focus on psychological de-escalation. Arts therapies, with their inherent capacity for emotional expression and regulation, offer a unique conduit for this purpose ( 102 ). In the forward trajectory of research, it is imperative that experimental designs embody stringent rigor, with the incorporation of single-blind and double-blind methodologies in randomized controlled trials (RCTs) being non-negotiable to mitigate the potential for data skewness. Furthermore, the endeavor to extend art therapy over protracted durations for the amelioration of sleep disorders poses a formidable challenge in the context of healthcare personnel ratios. The paucity of healthcare professionals in numerous developing nations presents a tangible barrier to the scalable application of art therapy to a broad demographic afflicted with sleep disturbances. This scenario necessitates a considerable investment of resources and dedication, thereby underscoring the exploration of artificial intelligence (AI) as a plausible adjunct or enhancer of art therapy practices. The potential for AI to bridge the gap in patient care and augment the efficacy of arts therapies represents a nascent yet promising paradigm, meriting earnest scholarly attention.

5 Limitations

The systematic review of randomized controlled trials (RCTs) evaluating the efficacy of arts therapies in addressing SIMDs provides strong evidence supporting the potential advantages of these interventions. Nonetheless, the presence of several methodological limitations within the analyzed studies necessitates thorough scrutiny, as it could affect the interpretation of results and guide the trajectory of subsequent research in this domain.

The systematic review highlights a prevalent issue in the included randomized controlled trials (RCTs) regarding participant blinding and the blinding of individuals administering treatments. As identified using the Joanna Briggs Institute (JBI) critical appraisal tool, a majority of the studies (11 out of 17) lacked participant blinding, raising serious concerns about bias in self-reporting of symptoms and treatment response. This lack of blinding could lead participants to have heightened expectations or placebo effects, which are well-documented phenomena in clinical research. These biases can significantly skew the reported efficacy of the arts therapies, leading to potentially inflated outcomes.

The absence of blinding among treatment administrators in 16 out of the 17 reviewed studies poses a critical threat to the validity of the study findings. Unblinded facilitators might unconsciously convey their expectations to participants, affecting the latter’s responses and engagement. This methodological oversight complicates the interpretation of the efficacy of arts therapies, as the observed benefits could be attributed to non-specific effects rather than the therapeutic intervention itself. Restricting the systematic review to English-language studies introduces another significant limitation by potentially overlooking valuable research conducted in other languages. This limitation not only restricts the diversity of the data but also introduces a cultural bias, limiting the generalizability of the findings to English-speaking populations. Art therapy practices, being deeply influenced by cultural contexts, might show different levels of efficacy and engagement in diverse cultural settings. Therefore, extending future systematic reviews to include multiple languages and cultural contexts could uncover more nuanced insights about the applicability and effectiveness of arts therapies across different global populations.

The short duration of interventions reported in four of the RCTs presents another limitation regarding the sustainability of the therapy benefits. While immediate improvements in sleep quality were noted, the long-term efficacy of these interventions remains uncertain. This limitation is significant as the chronic nature of SIMDs requires sustained management strategies. Future research should focus on longitudinal studies that assess the effects of arts therapies over extended periods to better understand and validate the longevity of the therapeutic benefits.

6 Conclusion

This comprehensive review, through an extensive analysis of 17 studies, examines the efficacy and mechanisms of arts therapies—including music therapy, meditation, Tai Chi, Qigong, yoga, Biodanza, and VR meditation—in improving Sleep Initiation and Maintenance Disorders (SIMDs). The findings reveal that these arts therapies, whether employed singularly or in conjunction, serve as effective non-pharmacological interventions to enhance sleep quality. Notably, music therapy, as a passive modality, significantly improves sleep quality in both elderly and younger populations, indicating its suitability as a pre-sleep routine across various age groups. Active therapies such as meditation, Tai Chi, Qigong, and yoga not only aid in augmenting sleep quality but also demonstrate positive effects on mental health, offering relief from stress, anxiety, and symptoms of depression. These active interventions, integrating mindfulness, physical movements, and breathing techniques, provide a holistic approach to addressing both physiological and psychological factors associated with SIMDs. The research underscores the importance of tailoring personalized arts therapy programs based on age, health status, and cultural backgrounds—for instance, combining music therapy and Qigong to improve sleep in the elderly, while Biodanza and meditation are more effective in stress relief among the younger demographic. Integrating new technologies like VR with traditional therapies offers innovative experiences in treating sleep disorders. Specific to practical applications in existing medical protocols, integration strategies such as professional training on arts therapies and infrastructural enhancements in healthcare settings can facilitate their adoption. Challenges such as cultural and institutional resistance, alongside hurdles in cost and resource allocation, may impede implementation, yet growing patient preference for non-drug treatments and supportive research outcomes provide favorable conditions for their integration. Future research should focus on the long-term effects of these interventions, integration of technological innovations like artificial intelligence, and the execution of cross-cultural studies to better understand global applicability and cultural influences on therapy effectiveness. Although this review confirms the effectiveness of arts therapies in treating SIMDs, future research should focus on the longevity of therapeutic outcomes, refinement of personalized treatment plans, and innovation through new technology integration, emphasizing longitudinal study designs to understand the long-term effects of combined therapies more comprehensively and further refine treatment recommendations.

Data availability statement

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

Author contributions

XL: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing. AZ: Writing – original draft, Writing – review & editing. HL: Writing – original draft, Writing – review & editing. YL: Conceptualization, Data curation, Formal analysis, Writing – review & editing. FY: Funding acquisition, Writing – review & editing. XW: Data curation, Software, Writing – review & editing. QY: Data curation, Software, Writing – review & editing. ZZ: Investigation, Writing – review & editing. GH: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing.

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the Macau University of Science and Technology’s Faculty Research Grant (No.: FRG-24–049-FA) and the Science and Technology Planning Project of Guangdong Province (2020B1212030008).

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Keywords: Arts Therapies, sleep disorders, psychotherapy, complementary interventions, mental health

Citation: Luo X, Zhang A, Li H, Li Y, Ying F, Wang X, Yang Q, Zhang Z and Huang G (2024) The role of arts therapies in mitigating Sleep Initiation and Maintenance Disorders: a systematic review. Front. Psychiatry 15:1386529. doi: 10.3389/fpsyt.2024.1386529

Received: 15 February 2024; Accepted: 01 May 2024; Published: 16 May 2024.

Reviewed by:

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

*Correspondence: Guanghui Huang, [email protected]

† These authors have contributed equally to this work

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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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.