secondary analysis of qualitative data a literature review

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Janet Heaton is a Research Fellow and a part-time DPhil student in the Social Policy Research Unit, Department of Social Policy and Social Work at the University of York. Her interest in secondary analysis of qualitative data developed through the intersection of these two roles. For her doctoral work she is re-analysing data from studies on which she worked as a primary researcher, focusing on the 'temporal imperatives' which characterise the discourses surrounding contemporary hospital discharge policy and practice.

Thorne, S. (1990) 'Secondary Analysis in Qualitative Research: issues and implications' in Morse, J.M. (Ed.) Critical Issues in Qualitative Research Methods . London: Sage.

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Living with diabetes: literature review and secondary analysis of qualitative data

Affiliations.

• 1 Department of Medicine, Public Health Sciences and Humanities, Penn State Milton S. Hershey Medical Center, Penn State College of Medicine, Hershey, PA.
• 2 Department of Sociology, Loyola University Maryland, Baltimore, MD, USA.
• 3 Department of Health and Social Science, Western Norway University of Applied Sciences, Bergen, Norway.
• PMID: 31984543
• DOI: 10.1111/dme.14255

Aim: To review the published qualitative literature on the lived experience of people with diabetes, describe the emerging findings and research methods over the last 25 years, and make recommendations for future research.

Methods: We describe a 'Next-Generation' mixed-method approach to reporting qualitative data that combines the advantages of traditional qualitative analysis (assessing depth of meaning from participants themselves) with those of descriptive analysis (assessing breadth and representativeness). We used our Next-Generation approach to conduct a secondary analysis of qualitative data derived from a systematic search of PubMed. A formal coding scheme was developed and systematically applied to 2050 respondent quotations contained in the 74 selected articles; inter-rater agreement was high (κ = 0.90). Quotations were aggregated at the level of the article and reported to assess both narratives and numerical counts of the data.

Results: The rate of qualitative research on the lived experience of diabetes has increased over the last 25 years. Both positive and negative aspects of lived experience were reported, although the former was less common. Data from many different populations were reported, but most studies emphasized breadth of coverage over depth. Some findings are well established and there is little benefit to repeating these studies. Best practices of qualitative methodology were often not utilized.

Conclusions: The amount of qualitative research in diabetes is substantial and increasing. We recommend that future research be focused on specific understudied topics rather than repeating existing research. We also provide recommendations for how qualitative study methodology can be improved by implementing the Next-Generation approach.

© 2020 Diabetes UK.

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• Diabetes Mellitus / psychology*
• Diabetes Mellitus / therapy
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• History, 21st Century
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• Self Care / history
• Self Care / psychology
• Self Care / trends

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Secondary research, also known as a literature review , preliminary research , historical research , background research , desk research , or library research , is research that analyzes or describes prior research. Rather than generating and analyzing new data, secondary research analyzes existing research results to establish the boundaries of knowledge on a topic, to identify trends or new practices, to test mathematical models or train machine learning systems, or to verify facts and figures. Secondary research is also used to justify the need for primary research as well as to justify and support other activities. For example, secondary research may be used to support a proposal to modernize a manufacturing plant, to justify the use of newly a developed treatment for cancer, to strengthen a business proposal, or to validate points made in a speech.

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Understanding referral of patients with cancer in rural Ethiopia: a qualitative study

• Josephin Trabitzsch 1 ,
• Morena Marquardt 1 ,
• Sarah Negash 1 ,
• Winini Belay 1 , 2 ,
• Yonas Abebe 2 , 3 ,
• Edom Seife 4 ,
• Kunuz Abdella 3 ,
• Muluken Gizaw 1 , 2 ,
• Sefonias Getachew 1 , 2 ,
• Adamu Addissie 1 , 2 ,
• Eva Johanna Kantelhardt 1 , 5 &
• Abigiya Wondimagegnehu 1 , 2  

BMC Cancer volume  24 , Article number:  553 ( 2024 ) Cite this article

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Cancer incidence is increasing in Ethiopia mainly due to increased life expectancy, while oncological capacities remain limited. Strong referral linkages between different levels of the healthcare system are key to provide timely access to cancer care. In this qualitative study, we assessed limitations and potential of cancer patient referral in the rural Southwest of Ethiopia.

We held four focus group discussions (FGD) with health professionals at one primary and three secondary hospitals and conducted eight in-depth interviews (IDI) with the hospitals´ medical executives and local health bureau representatives. Data was analysed inductively using thematic analysis and emerging themes were categorized within the revised concept of access by Penchansky and Saurman.

The inevitable referral of patients with cancer in the rural Southwest of Ethiopia is characterized by the absence of clear communication protocols and the lack of formal referral linkages. The newly implemented hub-system has improved emergency referrals and could be expanded to non-emergency referrals, sensitive to the needs of advanced oncological care. Liaison officers can pave the way but need to be trained and equipped adequately. Referred patients struggle with inadequate transportation systems, the lack of accommodation close to specialized facilities as well as the inability to navigate at those sites due to language barriers, illiteracy, and stigmatization. Few Non-Governmental Organizations (NGOs) help but cannot compensate the limited governmental support. The shortage of medications at public hospitals leads to patients being directed to costly private pharmacies. In the light of those challenges, cancer remains to be perceived as a “death sentence” within the rural communities.

Conclusions

Standardized referral linkages and a multi-faceted support network throughout the cancer care continuum are necessary to make oncology care accessible to Ethiopia´s large rural population.

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Introduction

Referral of cancer patients between healthcare levels in Sub-Saharan Africa has often been described to be poorly coordinated, resulting in extended time to diagnosis and treatment initiation and contributing to the region´s high cancer mortality [ 1 , 2 , 3 ]. In 2015, Ethiopia launched its first National Cancer Control Plan aiming to reduce cancer mortality in the country by 15% by 2020. Since then, the Ethiopian government has invested heavily into oncology services, implementing prevention and screening initiatives as well as expanding diagnostic and treatment capacities. However, the availability of advanced oncology services remains limited to tertiary-level specialized hospitals located in the larger cities. Considering that 80% of the Ethiopian population are living in rural areas, strong referral linkages between rural primary and general hospitals and tertiary specialized hospitals in the cities are of particular importance to provide access to oncology care to Ethiopia´s large rural population [ 4 , 5 ].

Ethiopia´s healthcare system is divided into three tiers: Health posts, health centres and primary hospitals on the lowest level, general hospitals on the secondary level and specialized hospitals on the tertiary healthcare level [ 1 ]. In terms of cancer care, at primary- and secondary-level hospitals, cancer diagnosis mostly relies on clinical findings. An affirmative diagnosis is often only possible in cooperation with pathology facilities or specialized hospitals. Primary- and secondary-level hospitals provide basic surgery for common cancers, and some offer hormonal therapy (Tamoxifen) for breast cancer patients. For advanced surgery or chemotherapy patients have to be referred to tertiary-level specialized hospitals. At time of data collection, there was only one hospital (Tikur Anbessa Specialized Hospital) providing radiotherapy.

While literature on access to oncology care in Ethiopia is increasing, referral linkages specifically have rarely been studied [ 6 ]. Furthermore, most studies addressing access to cancer care in Ethiopia have been conducted at tertiary-level cancer centres, missing out on perspectives of primary and secondary level healthcare institutions [ 7 ].

In this study we aimed to achieve a comprehensive understanding of factors influencing referral of cancer patients from primary and secondary hospitals in the rural Southwest of Ethiopia. We included healthcare professionals and representatives from local health bureaus to capture their perceptions on the existing referral system and assessed their ideas for its development in the future.

Study design and ethical approval

This qualitative study was conducted in December 2020 at primary and secondary hospitals in the rural Southwest of Ethiopia. It is part of a larger project aiming to design, implement, and evaluate decentralized cancer care in Ethiopia. In the writing of this manuscript we followed the Consolidated criteria for reporting qualitative research (COREQ) [ 8 ].

The study was approved by the Institutional Review Board of the Addis Ababa University College of Health Science (ref: 041/20/SPH). Study participants gave their written informed consent before each interview or discussion. All data were handled confidentially and participants´ data were pseudonymized within the transcripts.

Participant selection and setting

The study took place at one primary and three secondary hospitals in the region of Southern Nations, Nationalities, and Peoples (Table  1 ).

On each site, we conducted one focus group discussions (FGD) among health professionals. Participants were sampled purposefully, based on their involvement into oncology care and patient referral. Six to ten healthcare professionals participated in each FGD. In addition, we conducted in-depth interviews (IDIs) with the medical executives of each hospital, as well as with representatives from the affiliated health bureaus. Participants were approached via phone-calls prior to the interviews. All but one of the priorly arranged discussions and interviews took place; one medical executive dropped out just before the interview due to time constraints. His deputy took part in the in-depth interview instead. The FGDs took place in selected rooms within the hospital compounds while the IDIs were conducted in the participants´ private offices.

Data collection

Discussions and interviews were conducted by two well-trained and experienced data collectors, who were one female and one male masters-level graduates. During the interviews one principal data collector acted as interviewer and moderator, while the other quietly observed the discussion taking notes.

Individualized topic guides were used to conduct interviews and focus group discussions (see Additional file 1 ). They were partially adapted by the data collectors to capture emerging themes as the process of data collection evolved. Interview guides were designed in English. They were translated and back translated to Amharic to ensure coherence. All interviews were conducted in Amharic. After four focus group discussions and eight in-depth interviews with key informants, data saturation was judged to have been reached. All discussions and interviews were audio-recorded, and those recordings were transcribed and translated into English by the two principal data collectors.

Data analysis

We applied thematic framework analysis to analyse the data [ 9 ]. As suggested by Ritchie et al. we followed five analytical steps during analysis: (1) familiarisation, (2) constructing an initial framework, (3) indexing and sorting, (4) data summary and display and (5) abstraction and interpretation. We judged this to be the best suitable approach to analysis as it had been developed to be used in healthcare policy development and has since then become an often referred to approach in healthcare research. The initial framework was designed by the first author based on emerging themes and then applied parallelly by two authors to the same three transcripts. Results were discussed and the framework was adapted accordingly to ensure similar indexing and sorting. The finalized framework was then applied to all transcripts. MAXQDA 2023 was used for software support during analysis.

We used the modified “Concept of Access” to categorize our emerging findings [ 10 , 11 ]. The concept was originally designed by Penchansky et al. in 1981 to describe access to healthcare within five dimensions (availability, accessibility, accommodation, affordability and acceptability) [ 10 ]. As suggested by Saurman we added awareness as a sixths dimension to mirror the total width of our data [ 11 ].

Socio-demographics

Thirty-eight medical professionals and four health bureau representatives took part in our interviews and focus group discussions. FGDs took between 50 and 60 min, while IDIs lasted between 22 and 46 min. Participants in the FGDs were mostly nurses (15) and physicians (7). More than half of the participants had been working at the hospital for less than five years, there were 18 women and 16 men (Table  2 ). Participants in IDIs were predominantly male and all but one below the age of forty years. Among the medical executives were two general practitioners, one surgeon and one gynaecologist. Health bureau representatives were two non-communicable diseases focal persons, one medical service coordinator and one disease prevention team leader (Table  3 ).

Perceptions on cancer patient referrals

Across all interviews and focus group discussions, participants described the need to strengthen referral linkages between primary and secondary as well as tertiary healthcare institutions. Acknowledging the major challenges referred cancer patients faced at time of this study, perceptions on the patients´ determination to overcome those barriers differed: Some participants reported that most cancer patients refused referral, while others stated patients mostly accepted the advice, eager to follow referral. Participants ideas on how to improve the referral for patients with cancer in the rural Southwest of Ethiopia are presented in the Additional file 2 .

The reason [for refusing referral] is mainly the low economical capacity of these patients and also, once they know it is cancer, they get discouraged because of what they heard about the disease. They claim that they have almost no time left to live, and it is [therefore] no use to go to the referral hospitals or it [following the referral advice] has no advantage over staying here. (FGD participant, female, nurse, age group 30–39 years)

It is a life and death condition for them, therefore they will go. As long as they have money, they will go. (FGD participant, female, health officer, age group 40–49 years).

Availability of oncology service

Limited oncological capacities at all levels of the healthcare system.

Participants consistently identified the limited oncological capacities at all levels of the healthcare system as a major barrier to successful referral. At most sites, patients had to be referred upon suspected diagnosis or after surgery and morphological cancer verification. However, referring hospitals struggled to fulfil the receiving hospitals´ referral criteria, such as prior advanced diagnostics, that often were not available at their institution. Organizing the diagnostic workup via private diagnostic services was reported to increase costs for the patients as well as time to referral.

Regarding capacities at tertiary specialized hospitals, participants reported of patients who waited in the capital city for weeks for a preliminary appointment and were then sent back home to await their treatment initiation, which could take months.

Sometimes they come back because the appointment for radiation is in six months, seven months or more…And they are discouraged by going up and down and I put them on my palliative care list. I just give them anti-pain. You know until then [until the reception of an appointment for treatment] they are already dead. (Hospital executive, age group ≥ 50 years)

Lack of oncology specialists and training

Participants also mentioned the lack of oncology specialists at primary and secondary healthcare level. Next to the call for increased speciality and subspecialty training in oncology, health bureau representatives repeatedly mentioned the inability of rural facilities to bind trained specialists. Medical staff and health bureau representatives alike experienced that once trained adequately, oncology specialists would move to the larger cities and specialized cancer centres. Participants suggested to address the lack of oncological expertise in rural areas by establishing formal teachings from specialists to healthcare professionals from lower-level hospitals.

Accessibility

Road infrastructure and transport.

Due to the limited number of cancer centres throughout the country, referred patients often had to travel far to receive adequate treatment. Ethiopia´s road infrastructure was perceived to challenge patients substantially, hindering them to receive services and travel back home in one day.

Most cancer cases were non-emergency referrals and therefore patients had to organize their own transport. Besides the associated costs, patients weakened by the disease and associated treatment often were too sick to endure travelling with public transport.

Accommodation

Protocols and communication within referring hospitals.

In all settings, medical seniors were the ones deciding to refer patients. They would also be the ones writing the referral letter or communicating with the liaisons´ office in case of emergencies. Even though health bureau representatives highlighted the sites´ obligation to have appropriate protocols in place, formal referral protocols were only implemented at one site.

In two FGDs, the topic of unclear communication among professionals within the hospital emerged. This could lead to different parties making differing referral arrangements and resulted in patients being referred inadequately.

Liaisons and the hub-system for emergency referrals

At all sites, emergency referrals were organized via the formal liaison system. Nurses designated as liaisons were in charge of calling the receiving hospital in advance to check for availability of beds and announce the patients´ arrival. Even though participants agreed that the implementation of liaisons had brought major improvements to the system of emergency referrals, shortcomings of the system were discussed across all interviews and focus group discussions:

Liaisons, both at the referring as well as at the receiving institution, were perceived as not well trained to fulfil their responsibilities. They often did not grasp the urgency of the referral, or in case of cancer patient referrals, would refer patients to sites that did not offer cancer treatment.

Another perceived barrier to efficient referral of cancer patients was the newly implemented “hub system”. All primary and secondary hospitals had predefined “hub hospitals”, which were tertiary specialized hospitals acting as the first site to address when referring emergencies to a higher level. However, many of those hub hospitals did not offer oncology services, resulting in referring hospitals omitting the hub system to find adequate care for their patients with cancer. However, patients would often be rejected from hospitals other than the official hub hospital. One positive aspect of the system was the establishment of command posts: Those were interposed, site-independent units facilitating emergency referrals from lower-level hospitals to specialized facilities. Their implementation was perceived to have smoothened communication between referring and receiving hospitals.

Most of the cancer referrals at the study sites were non-emergencies. The extent to which the liaisons´ office was involved into their organization differed between hospitals. Two sites did not involve liaisons into non-emergency referrals at all. Referral letters were written by a senior doctor and patients had to organize their travels by themselves. At other sites referral letters written by doctors had to be signed and registered by the liaisons office who then supported patients in organizing their travels. In some cases, prior phone-calls were made by the health professionals to receiving institutions checking for capacities. However, this was not the norm. Participants consented that non-emergency referral via a well-equipped liaisons office, with the referring site checking for capacity and communicating the referral to the receiving site, would have a substantial impact on cancer patient referral.

Data management

Data management was perceived to play another important role in cancer patient referral. At time of data collection, patients carrying a referral letter were often the only form of communication between hospitals. However, professionals generally judged hand-written referral letters to be an unreliable source of data transmission. Participants from one hospital reported, that the strengthening of the liaison system had improved referral writing practices at their institution, because liaisons would no longer accept imprecise entries on the referral letter. Furthermore, there was a collective call for digital data management between hospitals, allowing for the transfer of patient data.

Participants also hoped that a digital form of data management would improve the feedback system regarding referred patients. Even though health bureau representatives described an official feedback system to be in place, currently hospitals only heard back from referred patients, when they had relatives working in the hospitals or if patients came back for further treatment. Health bureaus stated to be aware of the problem regarding the management of data and highlighted the governments ambitions to improve data quality in health facilities.

If you would only know how people for example get a chance for radiation. Like a feed-back of how meaningful this referral was, whether it makes sense to refer people or whether they are just spending their money and time for nothing…so just simple feed-back on what is possible and what is not possible, would be nice. (Hospital executive, age group ≥ 50 years)

Communication between hospitals

Poor communication between primary- and secondary-level hospitals on one side and tertiary hospitals on the other side was consistently lamented. The formal line of communication via liaisons offices was described to be unreliable due to lack of equipment and congestion.

Informal communication on the other side mostly relied on personal connections between health professionals: At referring sites where professionals knew staff from receiving sites personally, communication worked better than at sites without personal connection.

Besides communication, participants repeatedly regretted the lack of a formal way of receiving updates on services offered at receiving institution. For instance, one medical director did not know about a second hospital having recently started chemotherapy in the capital city. Health bureau representatives confirmed this observation, adding that even in health bureaus they often were not up-to-date regarding services being offered in their catchment area. As a result, patients were referred to hospitals with inadequate treatment capacities.

In the absence of well-functioning formal referral linkages, at some sites a non-governmental cancer organisation acted as the major link between the hospitals. They ensured patients met all the requirements for acceptance at the receiving institution and communicated with receiving hospitals about the referred patients. Multiple participants suggested panel discussions with members from all healthcare levels to establish personal connections and improve communication between hospitals.

And nationally, it would be better if there was a forum prepared for hospitals to exchange their experience and discuss ways to ease treatment for referral patients. For example, a forum between our hospital and TASH [Tikur Anbessa Specialized Hospital]. I believe the health system has many stakeholders such as government organizations, government bodies and so on, so there needs to be a regular forum which includes all the stakeholders. (FGD participant, female, midwife, age group < 30)

Patient navigation

Across all interviews and discussions participants highlighted, that patients with cancer were often severely ill and therefore needed much support with the facilitation of their referral. Existing projects proving the success of “patient navigators” assisting patients throughout their pathways were discussed: At one hospital site a “cancer nurse” was responsible for accompanying patients with cervical cancer to the receiving institutions. Other participants reported of an NGO providing similar services for patients with cancer. Besides establishing skilled hospital personnel or volunteers from NGOs as patient navigators, one participant suggested the introduction of so called “case managers” (former cancer patients) accompanying patients throughout their journey. In the past, this approach had proven to be successful in the context of the referral of patients with HIV.

If the patient links with Mathiwos Wondu Ethiopian Cancer Society then things going smoothly because they receive the patient [in Addis Ababa] and facilitate processes, including cost coverage. But this association cannot reach to all cancer patients, so it is better to expand such kind of program. (Health bureau representative, age group 30–39)

Reception at receiving institutions

Finding the correct services at the receiving institution could be a challenge to referred patients. Many patients were not able to read and could therefore not follow signs at the receiving institution. Furthermore, some patients did not speak Amharic, the language spoken in the capital city.

At the time of the study, patients that were not referred by ambulance had to go through the receiving hospital´s OPD before getting connected to the oncology unit. A fast-track system, channelling referred patients with cancer directly to the oncology unit was thought to decrease waiting times at the receiving institution.

Finding the unit at the hospital compound is also other challenge. I heard there was a patient who came back from the hospital, where he had been referred to, without getting the investigation and management, because he did not find the exact room. So, it’s better to modernize the reception and assign individuals to show the way to the units to which they [the patients] were referred to. (Hospital executive, age group < 30 years)

Affordability

Patients handling of costs.

Participants discussed how the patients’ economic status directly affected their ability to follow the referral advice. It determined not only where they would be referred to (more costly private institutions offered treatment with substantially shorter waiting times), but also whether they could follow the referral at all. Healthcare workers emphasized the efforts patients made to comply with the referral. Because of the disease, patients often were unable to work and cover the costs themselves. Mostly, costs were arranged with the family or within the communities. Some patients rented their land or sold their property. However, facing the uncertainty of surviving the disease even if they followed the referral, many patients refused referral. Those patients then turned to cultural healers or went back home, possibly preparing for death.

Governmental support

In the absence of universal health insurance, the Ethiopian government provides free cancer treatment at public hospitals for patients with a low economic background. However, participants reported regular shortages of medications at tertiary public hospitals. In those occasions, even patients eligible for free treatment were told to buy medication at private pharmacies – leading to them having to pay for treatment which was supposed to be free. In addition, the governments´ support did not cover expenses for food and accommodation before and during the treatment. Patients relied on having relatives in the city. Participants agreed that those factors often resulted in patients not being able to afford following the referral advice, even though they were eligible for free treatment.

Non-governmental support

Compensating for the lack of governmental aid, all study sites had support mechanisms in place trying to enable patients financially to follow the referral advice. Those mechanisms included social workers assisting the patients in raising the necessary money as well as the provision of free transport. However, the hospital´s ability to support was perceived to be insufficient, often resulting in staff personally donating money for patient referrals. Again, NGOs were also perceived to play an important role in decreasing direct and indirect costs for patients. They paid for travel expenses and offered food and accommodation in staying houses close to the receiving hospitals.

Health education

There was large consent on the importance of educating patients about their cancer disease. Participants highlighted, that patients would only follow the referral advice, if they were informed properly about their disease and its possible outcomes. The provision of health education was described to take place on different levels: On community-level (health extension workers, public gatherings, and mass media), hospital-level (lectures on health-related topics in the waiting areas each morning) as well as on a one-on-one level during appointments. There was a general perception, that educated and well-informed patients were more likely to follow the referral advice. Uneducated and uninformed patients would often turn to traditional medicine instead.

Most of the time people tend to do what they believe. So, if they understand well, they don’t hesitate to follow a referral process unless they may have financial problem. (Hospital executive, age group < 30 years)

Availability of public information on services

In addition to information about the cancer disease, participants agreed on the importance of providing patients with information on costs and waiting times. They regretted not being able to give patients the numbers on how much money they needed at the receiving institution. This led to referred patients having to return home without any treatment, because they ran out of money while waiting.

Acceptability

Trust in the health system.

The patients´ perception of referral as a “death sentence” was one more emerging theme. Even though, knowledge about cancer in rural communities was perceived to have increased over the last years, cancer was still reported to have a fatal reputation. Rumors of rejection and long waiting times at the specialized hospitals added to the patients´ believe that once referred, they would never come back alive.

Healthcare professionals suggested to learn from the countries´ experiences with HIV which also used to be perceived as “death sentence”. Participants suggested to extend existing cancer awareness campaigns and include education about cancer into the curriculum of health extension workers. Establishing cancer as a treatable disease in communities and families was felt to be essential to convince patients of the significance of following the referral.

So likewise, when we come to cancer, it follows a similar pattern as when HIV first came to Ethiopia. HIV patients used to feel hopeless and likewise cancer patients are feeling like that now. Secondly, the status of HIV reached what it has today due to integrated relent less effort, so if we do the same with cancer, I bet we could save lots of lives. (FGD participant, female, nurse, age group 40–49 years)

Stigmatization

One more barrier to successful referral was reported to be the stigmatization patients from rural areas experienced at tertiary hospitals. Patients often returned to referring hospitals complaining of having been handled badly at the receiving institution. Establishing a welcoming environment at receiving hospitals was regarded to contribute to the patients´ successful treatment initiation at the tertiary healthcare level.

They [referred cancer patients] come [back] and complain “We would rather die here than go there [again], they don’t accept us as you do, they don’t talk to us as you do, they harass us saying ‘people who come from rural areas’, the place they give [us] is not good.’ They also complain like ‘they host those who come from near that area, and they only give distant appointments to us.’ (FGD participant, female, nurse in a leadership position, age group < 30) .

Patients with cancer referred from primary and secondary hospitals to tertiary specialized care face challenges in all dimensions of Penchansky´s revised concept of access. We found a broad range of experiences among medical and local health bureau representatives on how to address those challenges aiming to provide access to cancer care in rural Ethiopia.

Participants felt strongly about the need to increase oncological capacities throughout the country as a foundation for successful referral. Expanding specialized training and connecting specialists in oncological societies are tools to strengthen a nation´s expertise in oncology care [ 12 ]. Ethiopia´s first clinical oncology residency program was initiated at Tikur Anbessa Hospital in 2013. Since 2019, the “Ethiopian Society of Haemato-Oncology” serves as a national platform for knowledge exchange. One intervention suggested by participants of the study was the training of non-oncology-specialists to provide oncological diagnostics and treatment. Experiences with this task shifting model from other countries in Sub-Saharan Africa are promising: An example could be the training of non-oncologists (internists, paediatricians, general practitioners, and nurses) in delivering cancer care, as it has been successfully done in Rwanda over the past year [ 13 ].

We identified three possible ways patients with cancer were referred: non-emergency referral via referral letter only, non-emergency referral via the liaisons´ office and emergency referrals. Most cancer patients were non-emergencies and mostly referred via referral letters only. Standardized referral letters had been introduced by the Ministry of Health in 2010 and were used in all four hospitals [ 14 ].

While oncological emergency referrals were organized via the official hub-system, for non-emergency referrals there were no inter-hospital referral protocols. An intra-institutional protocol for cancer patient referral was in place at only one of our study sites. Knowledge on where to refer patients with cancer relied on the health professionals´ personal experiences and expertise. Even though the hub-system for emergency referrals was perceived to be a barrier to the referral of patients with cancer, participants consented, that having a set system defining where to refer patients had improved emergency referrals in general. Expanding the system to include non-emergency referrals, sensitive to the availability of advanced oncological care, could improve referral of patient with cancer substantially.

In its “Guideline for implementation of a patient referral system” the Ethiopian Ministry of Health foresaw a “referral coordinator” at each hospital - responsible for the facilitation of emergency as well as non-emergency referrals [ 14 ]. In our study, only one hospital reported organizing non-emergency referrals via the liaisons´ office (which served as referral coordinator). Training and equipping designated personnel at the liaisons´ office, enabling them to organize both emergency and non-emergency referrals in a reliable manner emerged to be of substantial significance when improving cancer patient referral.

An important aspect in strengthening the referral linkage between healthcare levels is the standardization of data management. At the time of our study, patient data was collected in paper files and referral-letters were hand-written. Currently the Ministry of Health is developing a standardized electronic health record system to “strengthen digitization of routine and non-routine data collection, management, analysis and use” [ 15 ].

To enable patients to follow referral advice, participants also suggested the implementation of patient navigators. In high-income countries patient navigation programs are a well-established tool to promote access to cancer care [ 16 ]. Nurses or lay persons, who have been trained to be “patient navigators”, accompany patients with cancer throughout their diagnostic and treatment journey. Depending on the extent of the program, patient navigators provide patients with health education, facilitate appointments, and arrange linkages to follow-up services. In countries without universal health coverage, the navigation services often also include stipends for transport, accommodation, and treatment [ 17 , 18 ]. In the past years, the concept of patient navigation has been increasingly adapted in low- and middle-income countries, showing positive effects on outcomes like treatment initiation and adherence [ 19 ]. Initiatives such as the BEACON Initiative (Building expertise, advocacy, and capacity for oncology navigation) launched by the American Cancer Society implementing patient navigation programs at national referral hospitals in Uganda and Kenya serve as examples [ 20 ].

Furthermore, a smooth reception of referred patients at the receiving institutions was identified to be key for a successful referral. Participants suggested to address the patients´ difficulties in finding the correct units at the receiving hospitals by establishing an easy-to-follow signposting, as well as staffed info-points. Such low-cost concepts, sensitive to the patients´ different language and educational backgrounds, have previously shown to improve the patients´ experiences at receiving institutions substantially [ 21 ].

A current project addressing the need for “fast-track” pathways for patients with cancer at receiving institutions is the “Walk-in-Clinic” at the Else-Kroener-Center for Cancer Care in Addis Ababa. In collaboration with the surgical and oncology units at Tikur Anbessa Hospital the centre enables women with suspected cancer to omit the usual out-patient department pathways and be directly seen by gynaeco-oncologists and breast surgeons [ 22 ].

Direct and indirect costs were perceived to be a major barrier to successful referral. Patients with sufficient financial means could visit private hospitals or receive care in countries with better access to high-quality healthcare. However, with an income per capita of 940$ and approximately one quarter of the population living below the international poverty line, most patients in Ethiopia rely on the public healthcare sector [ 23 , 24 ]. Ethiopia aims to establish a universal health coverage by 2030 [ 1 ]. To reach this ambitious goal, the government has established multiple channels to increase access to healthcare for its population: Social health insurance is currently being implemented for people working in the formal sector, while community-based health insurance schemes are successfully expanded within the large informal sector [ 1 ]. In addition, certain oncology-associated interventions were recently added to the “Essential Health Services Package”, guaranteeing their provision free of charge, or with cost-sharing and cost-recovery mechanisms in place at public hospitals [ 25 ]. Patients who cannot afford care are eligible for free treatment, provided they receive a “fee waiver” from their local health bureau [ 1 , 26 ].

Nevertheless, the multitude of unofficial financial support mechanisms in place at all study sites demonstrates that patients with cancer in rural Ethiopia still face substantial financial challenges. Unavailability of necessary medications in public institutions (resulting in patients having to buy treatment at private pharmacies) as well as the costs for transport and accommodation associated with the treatment, emerged to be major barriers to oncology care. These findings are confirmed by previous studies [ 26 , 27 , 28 , 29 ]. Reliable mechanisms for the procurement and financing of cancer drugs at public hospitals are needed to decrease direct costs of treatment. Indirect costs could be tackled by the provision of governmental travel stipends for those in need as well as the establishment of staying houses close to the cancer centres.

We found high awareness regarding the significance of health education in the provision of cancer care among health professionals and health bureau representatives. This mirrors the governments´ focus on health education since the launch of Ethiopia´s Health Extension Program in 2003. Core of the program are health extension workers who promote primary healthcare on the community level. A study by Funga et al. found health extension workers to be the main source of information on cancer for most of the rural population [ 30 ]. However, even though the Health Extension Program has proven to be highly successful in providing health education to Ethiopia´s rural population, awareness on cancer is still insufficient and the perception of cancer as a “death sentence” common [ 30 , 31 , 32 , 33 ]. Expansion of existing and initiation of new cancer awareness programs is therefore essential to increase knowledge about cancer in rural communities. In addition, the implementation of survivor groups could contribute to change the patients´ attitude towards cancer and improve trust into the healthcare system [ 34 ]. Establishing cancer as a curable disease is important to convince patients to follow the referral advice.

Interestingly, while much reported previously in the context of access to cancer care, stigmatization of patients in their community did not emerge to be a major barrier to successful referral in our study [ 35 ]. This might be explained by the healthcare professionals´ and health bureau representatives´ perspective of the study. A recent study on the perceptions of cervical cancer care among Ethiopian women and their providers supports this explanation: While patients discussed the role of stigmatization within their communities vividly, providers did not mention stigma as a major barrier to care [ 35 ]. On the other hand, participants did report about patients feeling stigmatized at receiving institutions due to their rural background. While we could not find any literature on stigmatization of rural patients in specialized hospitals in Ethiopia, poor handling and disrespectful communication at tertiary hospitals has been described before [ 35 , 36 ]. Further research on patients´ experiences at tertiary hospitals as well as health professionals´ training is needed to guarantee culturally sensitive access to cancer care.

We believe it a great strength of this study to have captured a broad variety of perspectives of healthcare professionals and health bureau representatives who are involved into cancer care at the primary and secondary level of the healthcare system. However, our study has certain limitations: First and foremost, our results are limited by the participants´ provider perspective. To receive a comprehensive understanding of the cancer patient referral in rural Ethiopia, perspectives of referred patients have to be considered. In terms of sample size, the number of IDIs and FGDs conducted for this study falls within the lower end of what is typically considered adequate in qualitative research. However, while we cannot exclude the possibility that an increased sample size would have contributed new data, after four FGDs and eight IDIs we felt we had reached data saturation. Working with a small sample size increases the importance of thorough purposive sampling. Following the guidance of Ritchie et al., we ensured best possible representation and diversity within the sample with regards to variables such as age, years of experience, field of expertise, healthcare level, and hospital size [ 9 ]. This approach also helped to minimize, however not eliminate, a potential sampling bias.

Furthermore, we did not use a formal protocol regarding the triangulation of data collected by different methods and from different participant groups. However, in the final phases of analysis we did colour-code different origins of elements within themes and subthemes to be aware of consent and contradictions between the different participant groups.

In the rural Southwest of Ethiopia, decision makers are aware of multi-factorial challenges cancer patients face when being referred from lower-level hospitals to tertiary-level oncology care. A way forward requires a multi-faceted approach involving capacity building, improved coordination between different levels of the healthcare system, standardized protocols and data management, financial and social support mechanisms, as well as awareness programs. Lay persons as patient navigators could be involved. Establishing an environment for inter-institutional exchange and integrating stakeholders´ broad experiences from the primary and secondary healthcare level into future policy making is a key to reduce disparities in cancer care and make oncology care available to Ethiopia´s large rural population.

Data availability

The datasets used and analysed during the presented study are available from the corresponding author on reasonable request.

Abbreviations

Consolidated criteria for reporting qualitative research

focus group discussion

in-depth interview

non-governmental organization

outpatient department

fine needle aspiration cytology

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Acknowledgements

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Funding was provided by Else-Kroener-Fresenius-Foundation (HA18_31SP), Bundesministerium für Bildung und Forschung Germany (01KA2220B), and the Wellcome Trust (Del-22-008). The Funders had no role in the design and conduct of the study, collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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Josephin Trabitzsch, Morena Marquardt, Sarah Negash, Winini Belay, Muluken Gizaw, Sefonias Getachew, Adamu Addissie, Eva Johanna Kantelhardt & Abigiya Wondimagegnehu

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JT: conception and design of study, collection and assembly of data, analysis and interpretation of data, drafting of the work; MM: analysis and interpretation of data, drafting of the work; SN: conception and design of study, revision of the manuscript; WB: collection and assembly of data, analysis and interpretation of data; YA: collection and assembly of data, analysis and interpretation of data; ES: analysis and interpretation of data, revision of the manuscript; KA: analysis and interpretation of data, revision of the manuscript; MG: conception and design of study, revision of the manuscript; SG: conception and design of study, revision of the manuscript; AA: conception and design of study, revision of the manuscript; EJK: conception and design of study, revision of the manuscript; AW: conception and design of study, collection and assembly of data, revision of the manuscript. All authors read and approved the final manuscript.

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Trabitzsch, J., Marquardt, M., Negash, S. et al. Understanding referral of patients with cancer in rural Ethiopia: a qualitative study. BMC Cancer 24 , 553 (2024). https://doi.org/10.1186/s12885-024-12294-7

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Efficacy of psilocybin for treating symptoms of depression: systematic review and meta-analysis

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Psilocybin for depression

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• EXPRESSION OF CONCERN: Efficacy of psilocybin for treating symptoms of depression: systematic review and meta-analysis - May 04, 2024
• Athina-Marina Metaxa , masters graduate researcher 1 ,
• Mike Clarke , professor 2
• 1 Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford OX2 6GG, UK
• 2 Northern Ireland Methodology Hub, Centre for Public Health, ICS-A Royal Hospitals, Belfast, Ireland, UK
• Correspondence to: A-M Metaxa athina.metaxa{at}hmc.ox.ac.uk (or @Athina_Metaxa12 on X)
• Accepted 6 March 2024

Objective To determine the efficacy of psilocybin as an antidepressant compared with placebo or non-psychoactive drugs.

Design Systematic review and meta-analysis.

Data sources Five electronic databases of published literature (Cochrane Central Register of Controlled Trials, Medline, Embase, Science Citation Index and Conference Proceedings Citation Index, and PsycInfo) and four databases of unpublished and international literature (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, ProQuest Dissertations and Theses Global, and PsycEXTRA), and handsearching of reference lists, conference proceedings, and abstracts.

Data synthesis and study quality Information on potential treatment effect moderators was extracted, including depression type (primary or secondary), previous use of psychedelics, psilocybin dosage, type of outcome measure (clinician rated or self-reported), and personal characteristics (eg, age, sex). Data were synthesised using a random effects meta-analysis model, and observed heterogeneity and the effect of covariates were investigated with subgroup analyses and metaregression. Hedges’ g was used as a measure of treatment effect size, to account for small sample effects and substantial differences between the included studies’ sample sizes. Study quality was appraised using Cochrane’s Risk of Bias 2 tool, and the quality of the aggregated evidence was evaluated using GRADE guidelines.

Eligibility criteria Randomised trials in which psilocybin was administered as a standalone treatment for adults with clinically significant symptoms of depression and change in symptoms was measured using a validated clinician rated or self-report scale. Studies with directive psychotherapy were included if the psychotherapeutic component was present in both experimental and control conditions. Participants with depression regardless of comorbidities (eg, cancer) were eligible.

Results Meta-analysis on 436 participants (228 female participants), average age 36-60 years, from seven of the nine included studies showed a significant benefit of psilocybin (Hedges’ g=1.64, 95% confidence interval (CI) 0.55 to 2.73, P<0.001) on change in depression scores compared with comparator treatment. Subgroup analyses and metaregressions indicated that having secondary depression (Hedges’ g=3.25, 95% CI 0.97 to 5.53), being assessed with self-report depression scales such as the Beck depression inventory (3.25, 0.97 to 5.53), and older age and previous use of psychedelics (metaregression coefficient 0.16, 95% CI 0.08 to 0.24 and 4.2, 1.5 to 6.9, respectively) were correlated with greater improvements in symptoms. All studies had a low risk of bias, but the change from baseline metric was associated with high heterogeneity and a statistically significant risk of small study bias, resulting in a low certainty of evidence rating.

Conclusion Treatment effects of psilocybin were significantly larger among patients with secondary depression, when self-report scales were used to measure symptoms of depression, and when participants had previously used psychedelics. Further research is thus required to delineate the influence of expectancy effects, moderating factors, and treatment delivery on the efficacy of psilocybin as an antidepressant.

Systematic review registration PROSPERO CRD42023388065.

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Introduction

Depression affects an estimated 300 million people around the world, an increase of nearly 20% over the past decade. 1 Worldwide, depression is also the leading cause of disability. 2

Drugs for depression are widely available but these seem to have limited efficacy, can have serious adverse effects, and are associated with low patient adherence. 3 4 Importantly, the treatment effects of antidepressant drugs do not appear until 4-7 weeks after the start of treatment, and remission of symptoms can take months. 4 5 Additionally, the likelihood of relapse is high, with 40-60% of people with depression experiencing a further depressive episode, and the chance of relapse increasing with each subsequent episode. 6 7

Since the early 2000s, the naturally occurring serotonergic hallucinogen psilocybin, found in several species of mushrooms, has been widely discussed as a potential treatment for depression. 8 9 Psilocybin’s mechanism of action differs from that of classic selective serotonin reuptake inhibitors (SSRIs) and might improve the treatment response rate, decrease time to improvement of symptoms, and prevent relapse post-remission. Moreover, more recent assessments of harm have consistently reported that psilocybin generally has low addictive potential and toxicity and that it can be administered safely under clinical supervision. 10

The renewed interest in psilocybin’s antidepressive effects led to several clinical trials on treatment resistant depression, 11 12 major depressive disorder, 13 and depression related to physical illness. 14 15 16 17 These trials mostly reported positive efficacy findings, showing reductions in symptoms of depression within a few hours to a few days after one dose or two doses of psilocybin. 11 12 13 16 17 18 These studies reported only minimal adverse effects, however, and drug harm assessments in healthy volunteers indicated that psilocybin does not induce physiological toxicity, is not addictive, and does not lead to withdrawal. 19 20 Nevertheless, these findings should be interpreted with caution owing to the small sample sizes and open label design of some of these studies. 11 21

Several systematic reviews and meta-analyses since the early 2000s have investigated the use of psilocybin to treat symptoms of depression. Most found encouraging results, but as well as people with depression some included healthy volunteers, 22 and most combined data from studies of multiple serotonergic psychedelics, 23 24 25 even though each compound has unique neurobiological effects and mechanisms of action. 26 27 28 Furthermore, many systematic reviews included non-randomised studies and studies in which psilocybin was tested in conjunction with psychotherapeutic interventions, 25 29 30 31 32 which made it difficult to distinguish psilocybin’s treatment effects. Most systematic reviews and meta-analyses did not consider the impact of factors that could act as moderators to psilocybin’s effects, such as type of depression (primary or secondary), previous use of psychedelics, psilocybin dosage, type of outcome measure (clinician rated or self-reported), and personal characteristics (eg, age, sex). 25 26 29 30 31 32 Lastly, systematic reviews did not consider grey literature, 33 34 which might have led to a substantial overestimation of psilocybin’s efficacy as a treatment for depression. In this review we focused on randomised trials that contained an unconfounded evaluation of psilocybin in adults with symptoms of depression, regardless of country and language of publication.

In this systematic review and meta-analysis of indexed and non-indexed randomised trials we investigated the efficacy of psilocybin to treat symptoms of depression compared with placebo or non-psychoactive drugs. The protocol was registered in the International Prospective Register of Systematic Reviews (see supplementary Appendix A). The study overall did not deviate from the pre-registered protocol; one clarification was made to highlight that any non-psychedelic comparator was eligible for inclusion, including placebo, niacin, micro doses of psychedelics, and drugs that are considered the standard of care in depression (eg, SSRIs).

Inclusion and exclusion criteria

Double blind and open label randomised trials with a crossover or parallel design were eligible for inclusion. We considered only studies in humans and with a control condition, which could include any type of non -active comparator, such as placebo, niacin, or micro doses of psychedelics.

Eligible studies were those that included adults (≥18 years) with clinically significant symptoms of depression, evaluated using a clinically validated tool for depression and mood disorder outcomes. Such tools included the Beck depression inventory, Hamilton depression rating scale, Montgomery-Åsberg depression rating scale, profile of mood states, and quick inventory of depressive symptomatology. Studies of participants with symptoms of depression and comorbidities (eg, cancer) were also eligible. We excluded studies of healthy participants (without depressive symptomatology).

Eligible studies investigated the effect of psilocybin as a standalone treatment on symptoms of depression. Studies with an active psilocybin condition that involved micro dosing (ie, psilocybin <100 μg/kg, according to the commonly accepted convention 22 35 ) were excluded. We included studies with directive psychotherapy if the psychotherapeutic component was present in both the experimental and the control conditions, so that the effects of psilocybin could be distinguished from those of psychotherapy. Studies involving group therapy were also excluded. Any non-psychedelic comparator was eligible for inclusion, including placebo, niacin, and micro doses of psychedelics.

Changes in symptoms, measured by validated clinician rated or self-report scales, such as the Beck depression inventory, Hamilton depression rating scale, Montgomery-Åsberg depression rating scale, profile of mood states, and quick inventory of depressive symptomatology were considered. We excluded outcomes that were measured less than three hours after psilocybin had been administered because any reported changes could be attributed to the transient cognitive and affective effects of the substance being administered. Aside from this, outcomes were included irrespective of the time point at which measurements were taken.

Search strategy

We searched major electronic databases and trial registries of psychological and medical research, with no limits on the publication date. Databases were the Cochrane Central Register of Controlled Trials via the Cochrane Library, Embase via Ovid, Medline via Ovid, Science Citation Index and Conference Proceedings Citation Index-Science via Web of Science, and PsycInfo via Ovid. A search through multiple databases was necessary because each database includes unique journals. Supplementary Appendix B shows the search syntax used for the Cochrane Central Register of Controlled Trials, which was slightly modified to comply with the syntactic rules of the other databases.

Unpublished and grey literature were sought through registries of past and ongoing trials, databases of conference proceedings, government reports, theses, dissertations, and grant registries (eg, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, ProQuest Dissertations and Theses Global, and PsycEXTRA). The references and bibliographies of eligible studies were checked for relevant publications. The original search was done in January 2023 and updated search was performed on 10 August 2023.

Data collection, extraction, and management

The results of the literature search were imported to the Endnote X9 reference management software, and the references were imported to the Covidence platform after removal of duplicates. Two reviewers (AM and DT) independently screened the title and abstract of each reference and then screened the full text of potentially eligible references. Any disagreements about eligibility were resolved through discussion. If information was insufficient to determine eligibility, the study’s authors were contacted. The reviewers were not blinded to the studies’ authors, institutions, or journal of publication.

The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow diagram shows the study selection process and reasons for excluding studies that were considered eligible for full text screening. 36

Critical appraisal of individual studies and of aggregated evidence

The methodological quality of eligible studies was assessed using the Cochrane Risk of Bias 2 tool (RoB 2) for assessing risk of bias in randomised trials. 37 In addition to the criteria specified by RoB 2, we considered the potential impact of industry funding and conflicts of interest. The overall methodological quality of the aggregated evidence was evaluated using GRADE (Grading of Recommendations, Assessment, Development and Evaluation). 38

If we found evidence of heterogeneity among the trials, then small study biases, such as publication bias, were assessed using a funnel plot and asymmetry tests (eg, Egger’s test). 39

We used a template for data extraction (see supplementary Appendix C) and summarised the extracted data in tabular form, outlining personal characteristics (age, sex, previous use of psychedelics), methodology (study design, dosage), and outcome related characteristics (mean change from baseline score on a depression questionnaire, response rates, and remission rates) of the included studies. Response conventionally refers to a 50% decrease in symptom severity based on scores on a depression rating scale, whereas remission scores are specific to a questionnaire (eg, score of ≤5 on the quick inventory of depressive symptomatology, score of ≤10 on the Montgomery-Åsberg depression rating scale, 50% or greater reduction in symptoms, score of ≤7 on the Hamilton depression rating scale, or score of ≤12 on the Beck depression inventory). Across depression scales, higher scores signify more severe symptoms of depression.

Continuous data synthesis

From each study we extracted the baseline and post-intervention means and standard deviations (SDs) of the scores between comparison groups for the depression questionnaires and calculated the mean differences and SDs of change. If means and SDs were not available for the included studies, we extracted the values from available graphs and charts using the Web Plot Digitizer application ( https://automeris.io/WebPlotDigitizer/ ). If it was not possible to calculate SDs from the graphs or charts, we generated values by converting standard errors (SEs) or confidence intervals (CIs), depending on availability, using formulas in the Cochrane Handbook (section 7.7.3.2). 40

Standardised mean differences were calculated for each study. We chose these rather than weighted mean differences because, although all the studies measured depression as the primary outcome, they did so with different questionnaires that score depression based on slightly different items. 41 If we had used weighted mean differences, any variability among studies would be assumed to reflect actual methodological or population differences and not differences in how the outcome was measured, which could be misleading. 40

The Hedges’ g effect size estimate was used because it tends to produce less biased results for studies with smaller samples (<20 participants) and when sample sizes differ substantially between studies, in contrast with Cohen’s d. 42 According to the Cochrane Handbook, the Hedges’ g effect size measure is synonymous with the standardised mean difference, 40 and the terms may be used interchangeably. Thus, a Hedges’ g of 0.2, 0.5, 0.8, or 1.2 corresponds to a small, medium, large, or very large effect, respectively. 40

Owing to variation in the participants’ personal characteristics, psilocybin dosage, type of depression investigated (primary or secondary), and type of comparators, we used a random effects model with a Hartung-Knapp-Sidik-Jonkman modification. 43 This model also allowed for heterogeneity and within study variability to be incorporated into the weighting of the results of the included studies. 44 Lastly, this model could help to generalise the findings beyond the studies and patient populations included, making the meta-analysis more clinically useful. 45 We chose the Hartung-Knapp-Sidik-Jonkman adjustment in favour of more widely used random effects models (eg, DerSimonian and Laird) because it allows for better control of type 1 errors, especially for studies with smaller samples, and provides a better estimation of between study variance by accounting for small sample sizes. 46 47

For studies in which multiple treatment groups were compared with a single placebo group, we split the placebo group to avoid multiplicity. 48 Similarly, if studies included multiple primary outcomes (eg, change in depression at three weeks and at six weeks), we split the treatment groups to account for overlapping participants. 40

Prediction intervals (PIs) were calculated and reported to show the expected effect range of a similar future study, in a different setting. In a random effects model, within study measures of variability, such as CIs, can only show the range in which the average effect size could lie, but they are not informative about the range of potential treatment effects given the heterogeneity between studies. 49 Thus, we used PIs as an indication of variation between studies.

Heterogeneity and sensitivity analysis

Statistical heterogeneity was tested using the χ 2 test (significance level P<0.1) and I 2 statistic, and heterogeneity among included studies was evaluated visually and displayed graphically using a forest plot. If substantial or considerable heterogeneity was found (I 2 ≥50% or P<0.1), 50 we considered the study design and characteristics of the included studies. Sources of heterogeneity were explored by subgroup analysis, and the potential effects on the results are discussed.

Planned sensitivity analyses to assess the effect of unpublished studies and studies at high risk of bias were not done because all included studies had been published and none were assessed as high risk of bias. Exclusion sensitivity plots were used to display graphically the impact of individual studies and to determine which studies had a particularly large influence on the results of the meta-analysis. All sensitivity analyses were carried out with Stata 16 software.

Subgroup analysis

To reduce the risk of errors caused by multiplicity and to avoid data fishing, we planned subgroup analyses a priori and limited to: (1) patient characteristics, including age and sex; (2) comorbidities, such as a serious physical condition (previous research indicates that the effects of psilocybin may be less strong for such participants, compared with participants with no comorbidities) 33 ; (3) number of doses and amount of psilocybin administered, because some previous meta-analyses found that a higher number of doses and a higher dose of psilocybin both predicted a greater reduction in symptoms of depression, 34 whereas others reported the opposite 33 ; (4) psilocybin administered alongside psychotherapeutic guidance or as a standalone treatment; (5) severity of depressive symptoms (clinical v subclinical symptomatology); (6) clinician versus patient rated scales; and (7) high versus low quality studies, as determined by RoB 2 assessment scores.

Metaregression

Given that enough studies were identified (≥10 distinct observations according to the Cochrane Handbook’s suggestion 40 ), we performed metaregression to investigate whether covariates, or potential effect modifiers, explained any of the statistical heterogeneity. The metaregression analysis was carried out using Stata 16 software.

Random effects metaregression analyses were used to determine whether continuous variables such as participants’ age, percentage of female participants, and percentage of participants who had previously used psychedelics modified the effect estimate, all of which have been implicated in differentially affecting the efficacy of psychedelics in modifying mood. 51 We chose this approach in favour of converting these continuous variables into categorical variables and conducting subgroup analyses for two primary reasons; firstly, the loss of any data and subsequent loss of statistical power would increase the risk of spurious significant associations, 51 and, secondly, no cut-offs have been agreed for these factors in literature on psychedelic interventions for mood disorders, 52 making any such divisions arbitrary and difficult to reconcile with the findings of other studies. The analyses were based on within study averages, in the absence of individual data points for each participant, with the potential for the results to be affected by aggregate bias, compromising their validity and generalisability. 53 Furthermore, a group level analysis may not be able to detect distinct interactions between the effect modifiers and participant subgroups, resulting in ecological bias. 54 As a result, this analysis should be considered exploratory.

Sensitivity analysis

A sensitivity analysis was performed to determine if choice of analysis method affected the primary findings of meta-analysis. Specifically, we reanalysed the data on change in depression score using a random effects Dersimonian and Laird model without the Hartung-Knapp-Sidik-Jonkman modification and compared the results with those of the originally used model. This comparison is particularly important in the presence of substantial heterogeneity and the potential of small study effects to influence the intervention effect estimate. 55

Patient and public involvement

Research on novel depression treatments is of great interest to both patients and the public. Although patients and members of the public were not directly involved in the planning or writing of this manuscript owing to a lack of available funding for recruitment and researcher training, patients and members of the public read the manuscript after submission.

Figure 1 presents the flow of studies through the systematic review and meta-analysis. 56 A total of 4884 titles were retrieved from the five databases of published literature, and a further 368 titles were identified from the databases of unpublished and international literature in February 2023. After the removal of duplicate records, we screened the abstracts and titles of 875 reports. A further 12 studies were added after handsearching of reference lists and conference proceedings and abstracts. Overall, nine studies totalling 436 participants were eligible. The average age of the participants ranged from 36-60 years. During an updated search on 10 August 2023, no further studies were identified.

Flow of studies in systematic review and meta-analysis

After screening of the title and abstract, 61 titles remained for full text review. Native speakers helped to translate papers in languages other than English. The most common reasons for exclusion were the inclusion of healthy volunteers, absence of control groups, and use of a survey based design rather than an experimental design. After full text screening, nine studies were eligible for inclusion, and 15 clinical trials prospectively registered or underway as of August 2023 were noted for potential future inclusion in an update of this review (see supplementary Appendix D).

We sent requests for further information to the authors of studies by Griffiths et al, 57 Barrett, 58 and Benville et al, 59 because these studies appeared to meet the inclusion criteria but were only provided as summary abstracts online. A potentially eligible poster presentation from the 58th annual meeting of the American College of Neuropsychopharmacology was identified but the lead author (Griffiths) clarified that all information from the presentation was included in the studies by Davis et al 13 and Gukasyan et al 60 ; both of which we had already deemed ineligible.

Barrett 58 reported the effects of psilocybin on the cognitive flexibility and verbal reasoning of a subset of patients with major depressive disorder from Griffith et al’s trial, 61 compared with a waitlist group, but when contacted, Barrett explained that the results were published in the study by Doss et al, 62 which we had already screened and judged ineligible (see supplementary Appendix E). Benville et al’s study 59 presented a follow-up of Ross et al’s study 17 on a subset of patients with cancer and high suicidal ideation and desire for hastened death at baseline. Measures of antidepressant effects of psilocybin treatment compared with niacin were taken before and after treatment crossover, but detailed results are not reported. Table 1 describes the characteristics of the included studies and table 2 lists the main findings of the studies.

Characteristics of included studies

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Main findings of included studies

Side effects and adverse events

Side effects reported in the included studies were minor and transient (eg, short term increases in blood pressure, headache, and anxiety), and none were coded as serious. Cahart-Harris et al noted one instance of abnormal dreams and insomnia. 63 This side effect profile is consistent with findings from other meta-analyses. 30 68 Owing to the different scales and methods used to catalogue side effects and adverse events across trials, it was not possible to combine these data quantitatively (see supplementary Appendix F).

Risk of bias

The Cochrane RoB 2 tools were used to evaluate the included studies ( table 3 ). RoB 2 for randomised trials was used for the five reports of parallel randomised trials (Carhart-Harris et al 63 and its secondary analysis Barba et al, 64 Goodwin et al 18 and its secondary analysis Goodwin et al, 65 and von Rotz et al 66 ) and RoB 2 for crossover trials was used for the four reports of crossover randomised trials (Griffiths et al, 14 Grob et al, 15 and Ross et al 17 and its follow-up Ross et al 67 ). Supplementary Appendix G provides a detailed explanation of the assessment of the included studies.

Summary risk of bias assessment of included studies, based on domains in Cochrane Risk of Bias 2 tool

Quality of included studies

Confidence in the quality of the evidence for the meta-analysis was assessed using GRADE, 38 through the GRADEpro GDT software program. Figure 2 shows the results of this assessment, along with our summary of findings.

GRADE assessment outputs for outcomes investigated in meta-analysis (change in depression scores and response and remission rates). The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). BDI=Beck depression inventory; CI=confidence interval; GRADE=Grading of Recommendations, Assessment, Development and Evaluation; HADS-D=hospital anxiety and depression scale; HAM-D=Hamilton depression rating scale; MADRS=Montgomery-Åsberg depression rating scale; QIDS=quick inventory of depressive symptomatology; RCT=randomised controlled trial; SD=standard deviation

Meta-analyses

Continuous data, change in depression scores —Using a Hartung-Knapp-Sidik-Jonkman modified random effects meta-analysis, change in depression scores was significantly greater after treatment with psilocybin compared with active placebo. The overall Hedges’ g (1.64, 95% CI 0.55 to 2.73) indicated a large effect size favouring psilocybin ( fig 3 ). PIs were, however, wide and crossed the line of no difference (95% CI −1.72 to 5.03), indicating that there could be settings or populations in which psilocybin intervention would be less efficacious.

Forest plot for overall change in depression scores from before to after treatment. CI=confidence interval; DL=DerSimonian and Laird; HKSJ=Hartung-Knapp-Sidik-Jonkman

Exploring publication bias in continuous data —We used Egger’s test and a funnel plot to examine the possibility of small study biases, such as publication bias. Statistical significance of Egger’s test for small study effects, along with the asymmetry in the funnel plot ( fig 4 ), indicates the presence of bias against smaller studies with non-significant results, suggesting that the pooled intervention effect estimate is likely to be overestimated. 69 An alternative explanation, however, is that smaller studies conducted at the early stages of a new psychotherapeutic intervention tend to include more high risk or responsive participants, and psychotherapeutic interventions tend to be delivered more effectively in smaller trials; both of these factors can exaggerate treatment effects, resulting in funnel plot asymmetry. 70 Also, because of the relatively small number of included studies and the considerable heterogeneity observed, test power may be insufficient to distinguish real asymmetry from chance. 71 Thus, this analysis should be considered exploratory.

Funnel plot assessing publication bias among studies measuring change in depression scores from before to after treatment. CI=confidence interval; θ IV =estimated effect size under inverse variance random effects model

Dichotomous data

We extracted response and remission rates for each group when reported directly, or imputed information when presented graphically. Two studies did not measure response or remission and thus did not contribute data for this part of the analysis. 15 18 The random effects model with a Hartung-Knapp-Sidik-Jonkman modification was used to allow for heterogeneity to be incorporated into the weighting of the included studies’ results, and to provide a better estimation of between study variance accounting for small sample sizes.

Response rate —Overall, the likelihood of psilocybin intervention leading to treatment response was about two times greater (risk ratio 2.02, 95% CI 1.33 to 3.07) than with placebo. Despite the use of different scales to measure response, the heterogeneity between studies was not significant (I 2 =25.7%, P=0.23). PIs were, however, wide and crossed the line of no difference (−0.94 to 3.88), indicating that there could be settings or populations in which psilocybin intervention would be less efficacious.

Remission rate —Overall, the likelihood of psilocybin intervention leading to remission of depression was nearly three times greater than with placebo (risk ratio 2.71, 95% CI 1.75 to 4.20). Despite the use of different scales to measure response, no statistical heterogeneity was found between studies (I 2 =0.0%, P=0.53). PIs were, however, wide and crossed the line of no difference (0.87 to 2.32), indicating that there could be settings or populations in which psilocybin intervention would be less efficacious.

Exploring publication bias in response and remission rates data —We used Egger’s test and a funnel plot to examine whether response and remission estimates were affected by small study biases. The result for Egger’s test was non-significant (P>0.05) for both response and remission estimates, and no substantial asymmetry was observed in the funnel plots, providing no indication for the presence of bias against smaller studies with non-significant results.

Heterogeneity: subgroup analyses and metaregression

Heterogeneity was considerable across studies exploring changes in depression scores (I 2 =89.7%, P<0.005), triggering subgroup analyses to explore contributory factors. Table 4 and table 5 present the results of the heterogeneity analyses (subgroup analyses and metaregression, respectively). Also see supplementary Appendix H for a more detailed description and graphical representation of these results.

Subgroup analyses to explore potential causes of heterogeneity among included studies

Metaregression analyses to explore potential causes of heterogeneity among included studies

Cumulative meta-analyses

We used cumulative meta-analyses to investigate how the overall estimates of the outcomes of interest changed as each study was added in chronological order 72 ; change in depression scores and likelihood of treatment response both increased as the percentage of participants with past use of psychedelics increased across studies, as expected based on the metaregression analysis (see supplementary Appendix I). No other significant time related patterns were found.

We reanalysed the data for change in depression scores using a random effects Dersimonian and Laird model without the Hartung-Knapp-Sidik-Jonkman modification and compared the results with those of the original model. All comparisons found to be significant using the Dersimonian and Laird model with the Hartung-Knapp-Sidik-Jonkman adjustment were also significant without the Hartung-Knapp-Sidik-Jonkman adjustment, and confidence intervals were only slightly narrower. Thus, small study effects do not appear to have played a major role in the treatment effect estimate.

Additionally, to estimate the accuracy and robustness of the estimated treatment effect, we excluded studies from the meta-analysis one by one; no important differences in the treatment effect, significance, and heterogeneity levels were observed after the exclusion of any study (see supplementary Appendix J).

In our meta-analysis we found that psilocybin use showed a significant benefit on change in depression scores compared with placebo. This is consistent with other recent meta-analyses and trials of psilocybin as a standalone treatment for depression 73 74 or in combination with psychological support. 24 25 29 30 31 32 68 75 This review adds to those finding by exploring the considerable heterogeneity across the studies, with subsequent subgroup analyses showing that the type of depression (primary or secondary) and the depression scale used (Montgomery-Åsberg depression rating scale, quick inventory of depressive symptomatology, or Beck depression inventory) had a significant differential effect on the outcome. High between study heterogeneity has been identified by some other meta-analyses of psilocybin (eg, Goldberg et al 29 ), with a higher treatment effect in studies with patients with comorbid life threatening conditions compared with patients with primary depression. 22 Although possible explanations, including personal factors (eg, patients with life threatening conditions being older) or depression related factors (eg, secondary depression being more severe than primary depression) could be considered, these hypotheses are not supported by baseline data (ie, patients with secondary depression do not differ substantially in age or symptom severity from patients with primary depression). The differential effects from assessment scales used have not been examined in other meta-analyses of psilocybin, but this review’s finding that studies using the Beck depression inventory showed a higher treatment effect than those using the Montgomery-Åsberg depression rating scale and quick inventory of depressive symptomatology is consistent with studies in the psychological literature that have shown larger treatment effects when self-report scales are used (eg, Beck depression inventory). 76 77 This finding may be because clinicians tend to overestimate the severity of depression symptoms at baseline assessments, leading to less pronounced differences between before and after treatment identified in clinician assessed scales (eg, Montgomery-Åsberg depression rating scale, quick inventory of depressive symptomatology). 78

Metaregression analyses further showed that a higher average age and a higher percentage of participants with past use of psychedelics both correlated with a greater improvement in depression scores with psilocybin use and explained a substantial amount of between study variability. However, the cumulative meta-analysis showed that the effects of age might be largely an artefact of the inclusion of one specific study, and alternative explanations are worth considering. For instance, Studerus et al 79 identified participants’ age as the only personal variable significantly associated with psilocybin response, with older participants reporting a higher “blissful state” experience. This might be because of older people’s increased experience in managing negative emotions and the decrease in 5-hydroxytryptamine type 2A receptor density associated with older age. 80 Furthermore, Rootman et al 81 reported that the cognitive performance of older participants (>55 years) improved significantly more than that of younger participants after micro dosing with psilocybin. Therefore, the higher decrease in depressive symptoms associated with older age could be attributed to a decrease in cognitive difficulties experienced by older participants.

Interestingly, a clear pattern emerged for past use of psychedelics—the higher the proportion of study participants who had used psychedelics in the past, the higher the post-psilocybin treatment effect observed. Past use of psychedelics has been proposed to create an expectancy bias among participants and amplify the positive effects of psilocybin 82 83 84 ; however, this important finding has not been examined in other meta-analyses and may highlight the role of expectancy in psilocybin research.

Limitations of this study

Generalisability of the findings of this meta-analysis was limited by the lack of racial and ethnic diversity in the included studies—more than 90% of participants were white across all included trials, resulting in a homogeneous sample that is not representative of the general population. Moreover, it was not possible to distinguish between subgroups of participants who had never used psilocybin and those who had taken psilocybin more than a year before the start of the trial, as these data were not provided in the included studies. Such a distinction would be important, as the effects of psilocybin on mood may wane within a year after being administered. 21 85 Also, how psychological support was conceptualised was inconsistent within studies of psilocybin interventions; many studies failed to clearly describe the type of psychological support participants received, and others used methods ranging from directive guidance throughout the treatment session to passive encouragement or reassurance (eg, Griffiths et al, 14 Carhart-Harris et al 63 ). The included studies also did not gather evidence on participants’ previous experiences with treatment approaches, which could influence their response to the trials’ intervention. Thus, differences between participant subgroups related to past use of psilocybin or psychotherapy may be substantial and could help interpret this study’s findings more accurately. Lastly, the use of graphical extraction software to estimate the findings of studies where exact numerical data were not available (eg, Goodwin et al, 18 Grob et al 15 ), may have affected the robustness of the analyses.

A common limitation in studies of psilocybin is the likelihood of expectancy effects augmenting the treatment effect observed. Although some studies used low dose psychedelics as comparators to deal with this problem (eg, Carhart-Harris et al, 63 Goodwin et al, 18 Griffiths et al 14 ) or used a niacin placebo that can induce effects similar to those of psilocybin (eg, Grob et al, 15 Ross et al 17 ), the extent to which these methods were effective in blinding participants is not known. Other studies have, however, reported that participants can accurately identify the study groups to which they had been assigned 70-85% of the time, 84 86 indicating a high likelihood of insufficient blinding. This is especially likely for studies in which a high proportion of participants had previously used psilocybin and other hallucinogens, making the identification of the drug’s acute effects easier (eg, Griffiths et al, 14 Grob et al, 15 Ross et al 17 ). Patients also have expectations related to the outcome of their treatment, expecting psilocybin to improve their symptoms of depression, and these positive expectancies are strong predictors of actual treatment effects. 87 88 Importantly, the effect of outcome expectations on treatment effect is particularly strong when patient reported measures are used as primary outcomes, 89 which was the case in several of the included studies (eg, Griffiths et al, 14 Grob et al, 15 Ross et al 17 ). Unfortunately, none of the included studies recorded expectations before treatment, so it is not possible to determine the extent to which this factor affected the findings.

Implications for clinical practice

Although this review’s findings are encouraging for psilocybin’s potential as an effective antidepressant, a few areas about its applicability in clinical practice remain unexplored. Firstly, it is unclear whether the protocols for psilocybin interventions in clinical trials can be reliably and safely implemented in clinical practice. In clinical trials, patients receive psilocybin in a non-traditional medical setting, such as a specially designed living room, while they may be listening to curated calming music and are isolated from most external stimuli by wearing eyeshades and external noise-cancelling earphones. A trained therapist closely supervises these sessions, and the patient usually receives one or more preparatory sessions before the treatment commences. Standardising an intervention setting with so many variables is unlikely to be achievable in routine practice, and consensus is considerably lacking on the psychotherapeutic training and accreditations needed for a therapist to deliver such treatment. 90 The combination of these elements makes this a relatively complex and expensive intervention, which could make it challenging to gain approval from regulatory agencies and to gain reimbursement from insurance companies and others. Within publicly funded healthcare systems, the high cost of treatment may make psilocybin treatment inaccessible. The high cost associated with the intervention also increases the risk that unregulated clinics may attempt to cut costs by making alterations to the protocol and the therapeutic process, 91 92 which could have detrimental effects for patients. 92 93 94 Thus, avoiding the conflation of medical and commercial interests is a primary concern that needs to be dealt with before psilocybin enters mainstream practice.

Implications for future research

More large scale randomised trials with long follow-up are needed to fully understand psilocybin’s treatment potential, and future studies should aim to recruit a more diverse population. Another factor that would make clinical trials more representative of routine practice would be to recruit patients who are currently using or have used commonly prescribed serotonergic antidepressants. Clinical trials tend to exclude such participants because many antidepressants that act on the serotonin system modulate the 5-hydroxytryptamine type 2A receptor that psilocybin primarily acts upon, with prolonged use of tricyclic antidepressants associated with more intense psychedelic experiences and use of monoamine oxidase inhibitors or SSRIs inducing weaker responses to psychedelics. 95 96 97 Investigating psilocybin in such patients would, however, provide valuable insight on how psilocybin interacts with commonly prescribed drugs for depression and would help inform clinical practice.

Minimising the influence of expectancy effects is another core problem for future studies. One strategy would be to include expectancy measures and explore the level of expectancy as a covariate in statistical analysis. Researchers should also test the effectiveness of condition masking. Another proposed solution would be to adopt a 2×2 balanced placebo design, where both the drug (psilocybin or placebo) and the instructions given to participants (told they have received psilocybin or told they have received placebo) are crossed. 98 Alternatively, clinical trials could adopt a three arm design that includes both an inactive placebo (eg, saline) and active placebo (eg, niacin, lower psylocibin dose), 98 allowing for the effects of psilocybin to be separated from those of the placebo.

Overall, future studies should explore psilocybin’s exact mechanism of treatment effectiveness and outline how its physiological effects, mystical experiences, dosage, treatment setting, psychological support, and relationship with the therapist all interact to produce a synergistic antidepressant effect. Although this may be difficult to achieve using an explanatory randomised trial design, pragmatic clinical trial designs may be better suited to psilocybin research, as their primary objective is to achieve high external validity and generalisability. Such studies may include multiple alternative treatments rather than simply an active and placebo treatment comparison (eg, psilocybin v SSRI v serotonin-noradrenaline reuptake inhibitor), and participants would be recruited from broader clinical populations. 99 100 Although such studies are usually conducted after a drug’s launch, 100 earlier use of such designs could help assess the clinical effectiveness of psilocybin more robustly and broaden patient access to a novel type of antidepressant treatment.

Conclusions

This review’s findings on psilocybin’s efficacy in reducing symptoms of depression are encouraging for its use in clinical practice as a drug intervention for patients with primary or secondary depression, particularly when combined with psychological support and administered in a supervised clinical environment. However, the highly standardised treatment setting, high cost, and lack of regulatory guidelines and legal safeguards associated with psilocybin treatment need to be dealt with before it can be established in clinical practice.

What is already known on this topic

Recent research on treatments for depression has focused on psychedelic agents that could have strong antidepressant effects without the drawbacks of classic antidepressants; psilocybin being one such substance

Over the past decade, several clinical trials, meta-analyses, and systematic reviews have investigated the use of psilocybin for symptoms of depression, and most have found that psilocybin can have antidepressant effects

Studies published to date have not investigated factors that may moderate psilocybin’s effects, including type of depression, past use of psychedelics, dosage, outcome measures, and publication biases

What this study adds

This review showed a significantly greater efficacy of psilocybin among patients with secondary depression, patients with past use of psychedelics, older patients, and studies using self-report measures for symptoms of depression

Efficacy did not appear to be homogeneous across patient types—for example, those with depression and a life threatening illness appeared to benefit more from treatment

Further research is needed to clarify the factors that maximise psilocybin’s treatment potential for symptoms of depression

Ethics statements

Ethical approval.

This study was approved by the ethics committee of the University of Oxford Nuffield Department of Medicine, which waived the need for ethical approval and the need to obtain consent for the collection, analysis, and publication of the retrospectively obtained anonymised data for this non-interventional study.

Data availability statement

The relevant aggregated data and statistical code will be made available on reasonable request to the corresponding author.

Acknowledgments

We thank DT who acted as an independent secondary reviewer during the study selection and data review process.

Contributors: AMM contributed to the design and implementation of the research, analysis of the results, and writing of the manuscript. MC was involved in planning and supervising the work and contributed to the writing of the manuscript. AMM and MC are the guarantors. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

Funding: None received.

Competing interests: All authors have completed the ICMJE uniform disclosure form at https://www.icmje.org/disclosure-of-interest/ and declare: no support from any organisation for the submitted work; AMM is employed by IDEA Pharma, which does consultancy work for pharmaceutical companies developing drugs for physical and mental health conditions; MC was the supervisor for AMM’s University of Oxford MSc dissertation, which forms the basis for this paper; no other relationships or activities that could appear to have influenced the submitted work.

Transparency: The corresponding author (AMM) affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as registered have been explained.

Dissemination to participants and related patient and public communities: To disseminate our findings and increase the impact of our research, we plan on writing several social media posts and blog posts outlining the main conclusions of our paper. These will include blog posts on the websites of the University of Oxford’s Department of Primary Care Health Sciences and Department for Continuing Education, as well as print publications, which are likely to reach a wider audience. Furthermore, we plan to present our findings and discuss them with the public in local mental health related events and conferences, which are routinely attended by patient groups and advocacy organisations.

Provenance and peer review: Not commissioned; externally peer reviewed.

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

• ↵ World Health Organization. Depressive Disorder (Depression); 2023. https://www.who.int/news-room/fact-sheets/detail/depression .
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• Patient research partner involvement in rheumatology research: a systematic literature review informing the 2023 updated EULAR recommendations for the involvement of patient research partners
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• http://orcid.org/0000-0001-8708-9324 Krystel Aouad 1 ,
• http://orcid.org/0000-0002-8428-6354 Maarten de Wit 2 ,
• Muriel Elhai 3 ,
• http://orcid.org/0000-0001-9119-5330 Diego Benavent 4 ,
• Heidi Bertheussen 5 ,
• Condruta Zabalan 6 ,
• http://orcid.org/0000-0002-1049-4150 Jette Primdahl 7 ,
• http://orcid.org/0000-0002-8895-6941 Paul Studenic 8 , 9 ,
• http://orcid.org/0000-0002-4528-310X Laure Gossec 10 , 11
• 1 Rheumatology Division, Saint George University of Beirut , Saint George Hospital University Medical Center , Beirut , Lebanon
• 2 EULAR Study Group for collaborative research , Patient Research Partner , Amsterdam , The Netherlands
• 3 Rheumatology Department, University of Zurich , University Hospital Zurich , Zurich , Switzerland
• 4 Rheumatology Department , Hospital Universitari de Bellvitge , Barcelona , Spain
• 5 Patient Research Partner , Oslo , Norway
• 6 Patient Research Partner , Bucharest , Romania
• 7 Danish Hospital for Rheumatic Diseases , University Hospital of Southern Denmark , Sønderborg , Denmark
• 8 Rheumatology Division, Department of Medicine(Solna) , Karolinska Institutet , Stockholm , Sweden
• 9 Rheumatology Division, Internal Medicine Department , Medical University of Vienna , Vienna , Austria
• 10 Rheumatology Department , University Hospital Pitié Salpêtrière , Paris , France
• 11 INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique , Sorbonne Université , Paris , France
• Correspondence to Dr Krystel Aouad, Rheumatology Department, Saint George University of Beirut, Saint George Hospital University Medical Center, PO box 166378, Beirut, Lebanon; krystel.aouad{at}hotmail.com

Background Patient research partners (PRPs) are people with a disease who collaborate in a research team as partners. The aim of this systematic literature review (SLR) was to assess barriers and facilitators to PRP involvement in rheumatology research.

Methods The SLR was conducted in PubMed/Medline for articles on PRP involvement in rheumatology research, published between 2017 and 2023; websites were also searched in rheumatology and other specialties. Data were extracted regarding the definition of PRPs, their role and added value, as well as barriers and facilitators to PRP involvement. The quality of the articles was assessed. Quantitative data were analysed descriptively, and principles of thematic content analysis was applied to qualitative data.

Results Of 1016 publications, 53 articles were included; the majority of these studies were qualitative studies (26%), opinion articles (21%), meeting reports (17%) and mixed-methods studies (11%). Roles of PRPs ranged from research partners to patient advocates, advisors and patient reviewers. PRPs were reported/advised to be involved early in the project (32% of articles) and in all research phases (30%), from the conception stage to the implementation of research findings. The main barriers were challenges in communication and support for both PRPs and researchers. Facilitators of PRP involvement included more than one PRP per project, training of PRPs and researchers, a supportive environment for PRPs (including adequate communication, acknowledgement and compensation of PRPs) and the presence of a PRP coordinator.

Conclusion This SLR identified barriers and facilitators to PRP involvement, and was key to updating the European Alliance of Associations for Rheumatology recommendations for PRP–researcher collaboration based on scientific evidence.

• Health services research
• Health-Related Quality Of Life
• Outcome and Process Assessment, Health Care
• Quality Indicators, Health Care

Data availability statement

Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplemental information. Additional data are available on reasonable request.

This is an open access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0).

https://doi.org/10.1136/ard-2024-225567

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WHAT IS ALREADY KNOWN ON THIS TOPIC

Patient research partners (PRPs) are increasingly integrated into medical research, particularly in rheumatology.

Major global health organisations recognise the central role of PRPs’ involvement in research.

Previous recommendations have guided researchers and PRPs to build collaborative relations but lack a strong evidence base.

WHAT THIS STUDY ADDS

This systematic literature review provides for the first time a comprehensive overview of the emerging role of PRPs in rheumatology research, emphasising their expanding roles, contributions and the value they bring to the research process.

The review identified key barriers to PRP involvement, ranging from personal factors to challenges in training, communication and collaboration, and also identified strategies to enhance PRP involvement.

Early and sustained involvement of PRPs, as well as a supportive environment and effective communication, were found to be essential to enhance the relevance and impact of PRP contribution to research.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

Recognising and addressing the barriers to PRP involvement can lead to better support for PRPs, enhancing their involvement in research.

Some facilitators identified include involvement of PRPs since the early stages of research, a supportive environment for PRPs and encouraging researchers to adopt more flexible strategies and behaviours to maximise the benefit of PRP involvement.

This literature review informed European Alliance of Associations for Rheumatology recommendations, highlighting the importance of active collaboration, training, mutual respect, and transparent communication between PRPs and researchers.

Introduction

Patient research partners (PRPs) are described as individuals living with a health condition who ‘provide input to research, through active collaboration as equal partners with researchers’. 1 Their involvement is essential to make research more patient centred, for instance, by capturing outcomes that matter to patients. Over the past two decades, the magnitude of PRP involvement and their roles in research has grown substantially. 2–8 Patients have transitioned from passive subjects to active collaborators and equal partners, bringing their unique perspectives and valuable insights to the forefront of medical research. 5 This change has not only profoundly modified research practices but has also underscored the integral role PRPs play in shaping the future of medical practice. 9 The importance of PRP involvement in research has become widely recognised as an essential component of high-quality patient care, highlighted by organisations such as the WHO 4 and European Medicine Agency (EMA), 10 and is acknowledged across various medical specialties. 11–13

In rheumatology, this paradigm shift has been significant. In 2011, the European Alliance of Associations for Rheumatology (EULAR) developed recommendations for the involvement of patient representatives in scientific projects based on expert opinion. 14 These recommendations marked a pivotal step, setting the stage for the involvement of PRPs in research projects. Since then, these EULAR recommendations have guided other organisations such as Outcome Measures in Rheumatology (OMERACT), Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) and the Foundation for Research in Rheumatology (FOREUM), to recognise the important role of PRPs or to develop their own guidelines for collaborative research. 15–18

As the landscape of patient involvement in research evolves, the literature has witnessed a great surge in data and studies concerning PRP involvement. 2 4 5 15 19–25 These studies not only shed light on the benefits of PRP participation but also highlighted the challenges encountered in this collaborative effort and solutions proposed to overcome barriers. 21 22 25–29

In 2022, EULAR decided to update the 2011 recommendations for PRP involvement in research, focusing specifically on PRPs in the context of chronic conditions. 14 In accordance with the EULAR standardised operational procedures (SOPs) supporting this update, we conducted a systematic literature review (SLR) to inform the EULAR taskforce.

To support the update of the EULAR recommendations, we conducted in 2023 an SLR that encompassed both qualitative and semiquantitative analyses of recent publications in rheumatology, with the goal of identifying factors that affect PRP involvement, including barriers and facilitators.

Literature search

The SLR aimed to identify publications reporting PRP involvement in rheumatology research published between 1 January 2017 and 1 January 2023. We searched the electronic database PubMed MEDLINE using the terms “patient research partner”, “patient expert”, “patient and public involvement (PPI)”, their synonyms and related concepts. Details of the search terms and search strategy can be found in online supplemental table 1 . Two authors (KA, LG) independently assessed the title, abstract and keywords of every publication identified. In the event of disagreement between the reviewers, disparities were discussed and resolved. Additionally, we performed a scoping review of databases to assess PRP involvement and explored six websites from rheumatology: OMERACT, GRAPPA, American College of Rheumatology, EULAR, FOREUM and Osteoarthritis Research Society International. We also searched 2 regulator websites: Food and Drug Administration and EMA, and 10 websites of three selected specialties recognised for significant PRP involvement: cardiology, oncology, endocrinology (diabetes) ( online supplemental table 2 ). A specific search was done in two websites focusing on patient and public involvement: INVOLVE UK by the National Institute for Health Research and Education that empowers (European Patients’ Academy on Therapeutic Innovation), and in orphan diseases to answer specific research questions about training, involvement in grant applications and remuneration of PRPs ( online supplemental table 3 ).

Supplemental material

The scope of the literature search was defined by the EULAR taskforce steering group, 1 and addressed 11 specific research questions ( Box 1 ).

Research topics included in the systematic literature review

1. Definition of patient research partners (PRPs)

How to define a PRP? Is the current definition of PRPs still adequate?

2. Roles and activities undertaken by PRPs

What are the roles and activities of PRPs in rheumatic musculoskeletal disease research?

3. Benefits and added value of PRP involvement for PRPs themselves, researchers, the research itself

What is the added value of PRPs in different types of research and groups?

4. Types of scientific projects that involved PRPs and the stages of the projects in which they participated

What types of projects are (or should) PRPs (be) involved in?

What phases of a project are (or should) PRPs (be) involved in?

5. Selection and recruitment processes for PRPs

How are (or should) PRPs (be) recruited and selected?

How many PRPs are (or should be) involved in the research?

6. Insights into the experiences and feedback provided by PRPs

What are the PRP feedback and experiences, in terms of facilitators and barriers to PRP involvement?

How can we improve the PRP experience and involvement overall?

7. Roles of a coordinator for PRPs in research

Are PRP facilitators involved, if so how, and is it useful?

Is a facilitator/PRP coordinator recommended?

What is the reported usefulness of a facilitator ?

8. Training provided to PRPs or researchers

Do the PRPs involved have a specific training (previously/during the study)?

How should researchers be educated, trained, supported to enhance PRP involvement?

9. Evaluation and monitoring related to PRP involvement

How should PRP involvement be monitored or evaluated? At which time points and by whom?

How should PRP involvement evaluation/monitoring be reported?

10. Recognition, compensation and acknowledgement of PRPs during their involvement in a scientific project

How should PRP involvement be recognised and acknowledged?

Is (should) compensation (be) proposed?

11. Barriers encountered and proposed solutions to enhance PRP involvement

What are the barriers encountered during PRP involvement?

Which strategies and contextual factors enable optimal engagement of PRPs?

Inclusion and exclusion criteria

We included all types of articles reporting PRP involvement in all types of research, including trials and observational studies, qualitative studies, mixed-methods studies and reports of meetings, opinion papers and reviews. We did not exclude published articles from any country, aiming to enhance the generalisability of our findings. Recommendations and guidelines on PRPs were also analysed and were used as supportive information. Articles not focused on rheumatology research or not bringing any information on PRPs (ie, not answering one or more research questions), as well as not in English, were excluded. Articles only mentioning PRPs or their involvement, without providing any details (eg, on their roles, contributions or barriers/facilitators), were excluded as well. Articles with duplicate information (ie, multiple publications reporting on a single study) were excluded if they did not provide additional information relevant to our research questions.

We also identified relevant articles by hand search of the references cited in the included studies, extending the inclusion period to the date of publication of the previous recommendations (2011–2023).

Data extraction

Data collection encompassed both quantitative and qualitative data, addressing various aspects of PRP involvement and providing answers to our research questions ( Box 1 ). Data were extracted and checked independently by two authors (KA and MdW). Discrepancies were resolved by discussion among the core team (KA, MdW, PS, LG).

Quality assessment

Papers were assessed for quality only if they reported original data. Review papers, recommendation papers, opinion papers, case studies, study protocols, report papers and qualitative studies not primarily focused on PRPs were excluded from quality assessment. Given the diversity of study types, we used the Critical Appraisal Skills Programme (CASP) checklist for qualitative studies, literature reviews and cross-sectional studies as described in the EULAR SOP. 30 31 This tool, originally developed for qualitative studies, assesses elements such as the clarity of research aims, appropriateness of methodology, suitability of the research design, adequacy of data collection and clarity in reporting outcomes. For mixed-methods studies, we used the Mixed Methods Appraisal Tool (MMAT, a critical appraisal tool that is designed for the appraisal stage of systematic mixed-studies reviews, that is, reviews that include qualitative, quantitative and mixed-methods studies 32 (see online supplemental tables 4 and 5 for quality assessment). To facilitate interpretation, an overall quality assessment for the level of evidence (LoE) was conducted by evaluating the number of items on the score checklist and on the key items. Subsequently, the authors reached a consensus on classification of the articles’ quality as high, medium or low quality.

This SLR was not considered appropriate by PROSPERO for registration due to the mixed-methods study analyses involved.

Patient and public involvement

This SLR study is the result of a co-production of three PRPs (MdW, CZ, HB) and five researchers, all being members of the EULAR steering committee responsible for updating the EULAR recommendations on PRP involvement. 1 The three PRPs actively contributed to all meetings and discussions within the steering committee. They were involved at the early stage of formulating the research questions until reviewing and agreeing on the final manuscript. They were also actively engaged in planning dissemination and implementation of the study findings within the wider community and patient associations. The recruitment of the PRPs was coordinated by one of the PRPs (MdW), the convenor of the project.

For quantitative data, a descriptive analysis of findings is reported, including characteristics of studies (study design, population, country, study objectives), characteristics of PRPs, selection process of PRPs, type of involvement, phases of the research where their involvement occurred, with numbers and percentages using frequency tables and charts.

The number of PRPs involved in the studies was quantified using two distinct methods: first, coauthorship count: direct examination of the research articles’ authorship lists. PRPs were identified based on explicit mentioning of their role as ‘PRP’ or other specific identification. Second, participation count: this approach assessed the number of broader involvements of PRPs in activities of the research project. For instance, in a GRAPPA meeting report, the number of PRPs who actively participated was counted. 8

Qualitative data were analysed according to the principles of thematic content analysis (more details in online supplemental table 6 ). 33 The results were discussed within the EULAR taskforce, 1 and any disagreements on the interpretation of the findings were resolved by a consensus of the core group (MdW, LG, PS, KA).

Search strategy

The SLR yielded a total of 1016 records of which 941 (92.6%) were excluded based on titles and abstracts. We conducted a full-text screening of 75 papers and 46 (61.3%) were included. The main reasons for exclusion were papers not related to rheumatology, lacking reports of PRP involvement in research, being irrelevant to our research questions, or being duplicates or conference abstracts ( figure 1 ). Additionally, 7 papers were identified by hand search, resulting in a total number of 53 included articles.

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Flow chart of selected article search on PRP involvement in rheumatology research. PRP, patient research partner.

Quality assessment (LoE) of the papers

Nineteen articles were assessed for quality using the predefined scores according to the study type. Overall, 79% (15 of 19) were classified as high quality, 11% (2 of 19) as medium quality and 11% as low quality ( online supplemental table 4 ).

Study characteristics

The included studies were qualitative studies (14 of 53, 26%), opinion articles (11 of 53, 21%), meeting reports (9 of 53, 17%), mixed-methods studies (6 of 53, 11%), recommendation articles (4 of 53, 8%), reviews (SLR or scoping review; 3 of 53, 6%), cross-sectional (2 of 53, 4%), case studies (2 of 53, 4%), observational (1 of 53, 2%) and study protocol (1 of 53, 2%) ( online supplemental tables 4 and 5 ).

Overall, 62% were published in rheumatology journals. Geographically, most of the studies were from Europe (50%), followed by North America (31%).

Identification of barriers encountered and proposed solutions to enhance PRP involvement

Barriers to PRP involvement ( table 1 and online supplemental table 7 ) included emotional and personal factors, communication and relationship challenges, inadequate training and support, difficulties in the research process and pace, as well as collaboration and engagement issues. 2–4 21 22 24–27 34–42 Effective strategies to enhance PRP involvement ( table 1 ) included early involvement, a supportive environment, effective communication and trust, and providing support and training for PRPs and researchers. 7 21 22 26 29 38 40 43 44

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Barriers and strategies to enhance PRP involvement in rheumatology research

Definitions of PRP

Among the 53 included papers, 62% provided a definition of PRP. Importantly, a significant portion (30%) of these papers 4 6 15 26 27 34–36 45 46 adopted the 2011 EULAR definition of PRP as ‘persons with a relevant disease who operate as active research team members on an equal basis with professional researchers, adding the benefit of their experiential knowledge to any phase of the project’. 14 These papers consistently emphasised the importance of active involvement and fostering equal partnerships between PRP and researchers.

Additionally, seven papers (13%) expanded upon this definition by incorporating informal caregivers into the PRP definition, 20 28 37 38 47–49 known as persons, usually family members, who provide unpaid care to someone with whom they share a personal relationship.

The roles and activities of PRPs

The roles and activities of PRPs covered a wide spectrum, extending from research partners to patient advocates, advisory roles and participation as patient reviewers (as detailed in table 2 and online supplemental table 8 ). Their contributions encompassed a diverse range of activities, including providing input in guideline development, shaping research agendas, and actively advocating in scientific and clinical committees.

Activities and roles of PRPs

The added value of PRP involvement

The literature reported that PRPs added significant value across various aspects of research ( table 3 ). Specifically, 53% of the articles indicated that PRP involvement brought benefits for the PRP themselves, that is, better understanding of their medical condition, acquisition of practical skills, improved comprehension of the research process and increased self-confidence. 2 21 25 36 39 Furthermore, 26% of the articles highlighted advantages for the research process, that is, heightened relevance of the research, enhancement of its overall impact and enrichment of the results by adding experiential knowledge. 2 7 21 25 29 36 38 39 45 The positive impact on researchers, reported in 15% of the articles, encompassed deeper insights into research priorities, increased motivation, innovative ideas, awareness of the impact of their work, a comprehensive approach to addressing patients’ needs and improved communication in lay language ( table 3 ). 2 21 25 34 36 38 40 The added value of PRP involvement was also reported as advantageous for the wider community by enhancing the acceptance of research that prioritises community benefits. 2 21 25 36

Articles reporting on added value of PRP involvement in research for PRPs, for researchers and for the research

Types of research that involved PRPs

PRPs were actively involved in a wide range of scientific projects, including basic, translational and clinical research. 50 Although the benefits of PRP involvement were less apparent in basic and translational research, some researchers and PRPs recognised the substantial advantages of collaborative partnerships in this area. 3 25 34 A scoping review highlighted the benefits of PRP engagement in preclinical research, including enhanced understanding of basic science research for PRPs, broadened perspectives for researchers, and positive influence on study questions and methods, along with fostering mutual learning, new collaborations, and improved research quality and efficiency. 40 One study reported that researchers were committed to finding more meaningful ways to integrate PRPs into basic scientific research and dissemination of the project results. 3 Strategies to enhance PRP involvement (ie, training, support, PRP-focused tasks) were also reported. 3

Research phases in which PRP participated

Early involvement of PRPs in the research was reported or recommended in 32% of the included articles, emphasising engaging PRPs from the inception of a research project. 2 19–22 27–29 34 36–38 43 45 47 51 This early engagement was reported to enable PRPs to actively shape research questions and methodologies in line with their priorities. Additionally, 30% of the articles stressed the importance of PRPs’ continuous participation throughout all research stages ( table 4 ). 4 15 21 22 26 35 43 52–54

Articles reporting or recommending PRP involvement in different phases of the research project

Number of PRPs

The number of PRPs involved in research is shown in online supplemental figure 1 . When considering the coauthorship lists, the majority of articles clearly specified the name and identity of PRPs; subsequently, the number of PRPs involved in the writing and reviewing of the article could be easily deducted. Yet, in 19% of cases, the identification of a coauthor as a PRP was unclear. In cases where PRP involvement was explicitly highlighted by coauthorship, 34% of the articles included one or two PRPs per project, 17% of articles included three or four PRPs, and 25% of articles involved more than five PRPs. Notably, single-centre studies commonly involved one or two PRPs as coauthors. One study, which engaged four PRPs, found this number to be beneficial due to the diverse perspectives they brought. 45 Larger-scale international consortia projects recruited a higher number of PRPs, with around six PRPs being identified as an effective group size for facilitating participation and decision-making. 2

On the other hand, when reporting all PRP involvement and activities in a research project, 36% of the articles reported a number of PRP higher than nine ( online supplemental figure 1 ). Therefore, the number of PRPs involved in research can be higher than the number of PRPs mentioned as coauthors.

Selection and recruitment processes for PRPs

The selection process of PRPs was reported in 34% of articles ( figure 2 ). PRP selection criteria were mainly language proficiency (11%), research knowledge (6%), disease diagnosis (9%), communication skills and constructive assertiveness (9%), motivation (8%), educational background (6%), experiential knowledge and expertise (6%) as well as travel capability (4%). 2 3 15 19 21 23 24 27 34 35 55–58 Recruitment methods for PRPs were diverse, relying on patient organisations, marketing companies, rheumatology associations, social media, community outreach, clinic visits, personal connections with patients or researchers, word-of-mouth referrals and volunteering. 2 21 34 38 41 44 53 59 Furthermore, 28% of studies emphasised the importance of clarifying patient roles through clear goal-setting and exchanging mutual expectations early in the project initiation phase. 15 19–21 27 29 36 42 45 47 Additionally, 28% of studies highlighted the need for inclusivity and diverse representation in PRP recruitment. 2 4 15 35 41 42 52

The selection criteria of PRPs reported in the studies. PRP, patient research partner.

Creating a supportive environment for PRPs

A supportive environment for PRPs was reported to depend on several key principles ( table 1 ) 4 19 20 25 36 42 52 53 60 : ensuring a balanced and manageable workload that respects PRP abilities, providing adequate resources and time for PRP involvement, offering support to overcome language barriers, promoting flexibility and offering accessible accommodation to participate in meetings and scientific conferences. 7 21 38 40 43 44 Equal relationships and co-leadership between PRPs and researchers were cited in several papers as crucial, emphasising mutual respect, trust, and open, transparent communication. 7 15 19 Building strong team communication, and establishing informal personal relationships between PRPs and researchers were also found to be important factors to enhance collaboration. 20 38 47 Regular feedback and discussions about the quality of collaboration, combined with ongoing adjustments to meet the needs and preferences of PRPs, were proposed in two papers. 34 45

Roles of a PRP coordinator

A PRP ‘coordinator’ was defined in some papers, as an individual or a role within a research team responsible for facilitating and supporting the collaboration between researchers and PRPs. 2 20 25 47 61 The presence of a PRP coordinator was reported or advised in 29% of the included articles. 2 3 19 28 34 35 40 42 44 48 61 PRP coordinators were reported to be helpful in facilitating effective communication among PRPs, researchers and stakeholders, aligning expectations, organising logistics, moderating group discussions, providing ongoing education and support, and assisting in the recruitment and selection of PRPs in projects ( table 5 ). 2 20 25 35 36 42 47 This role was reported to be taken by a member of the research team, a PRP or a designated person within a patient organisation or academic institution. 2 38

Potential roles of a PRP coordinator

Training of researchers

We found that 34% of the included articles included in the SLR reported or advised training or education of researchers. 4 7 19 21 25 28 29 38–40 44 Researchers could receive training concerning various aspects of working with PRPs ( table 6 ).

Reported training content for researchers and PRPs

Training of PRPs

Educating and training PRPs was proposed in many papers to enhance the quality of their collaboration with researchers. Notably, nearly half of the publications emphasised the importance of training, with 21% recommending it and 25% providing it. 25 28 29 35 37 45 51 62–64 PRP training and support included various aspects ( table 6 ). Training of PRPs was reported to foster well-prepared and empowered PRPs ready to engage effectively in research collaborations. 22 26 29

Evaluation and monitoring related to PRP involvement

Around 21% of the included publications recommended or reported some form of evaluation, 3 4 15 19–21 25 34 35 with 28% collecting feedback from PRPs on their involvement. Regular discussions and evaluations of the quality and impact of PRPs’ collaboration and contributions were reported to enhance understanding, satisfaction and impact, allowing for adjustments and improvements as needed. 4 5 37 60 Some tools were reported for monitoring such as the Patient-Centered Outcomes Research Institute conceptual framework, an evaluative framework for research engagement, 19 surveys to evaluate the impact of PRPs in the project, 3 26 the Public Involvement Impact Assessment Framework Guidance, 53 and the Guidance for Reporting Involvement of Patients and the Public. 25 34

Recognition, compensation and acknowledgement of PRPs

Recognising, compensating and acknowledging the contributions of PRPs during their involvement in a scientific project were reported to be essential components of equal and meaningful partnerships. 27

In the context of recognition, coauthorship was cited as proof of PRP involvement and equality in research collaborations. 5 39 The SLR revealed a growing trend in recognising PRPs through coauthorship in 68% of articles, 2–6 8 15 19–21 23–26 28 29 34 36–40 42 43 45 47–50 52 54 56 58 60 63 65 and acknowledgement in 45% of articles. 3 6 7 25 27 28 34 37 43–45 48 51 53 56–61 63 65–67

Compensation refers to the payment of salary, wages, honorarium, fees or allowances for the time commitment and expertise of PRPs; this is different from reimbursing PRPs for expenses (eg, travel expenses and accommodation). 49 Non-compensation for PRPs was reported as a limitation and challenge for their effective involvement. 4 While PRPs can opt out of payment, several papers reported that researchers should consider compensation in their budget planning. 2 39 49 Some articles advised that institutions should simplify processes for fair PRP payment, and funders should enable researchers to allocate resources for PRP involvement. 5

The role of PRPs in rheumatology research has significantly expanded over recent years. The findings of this SLR underscore the important roles and contributions of PRPs in research projects, and the added value of PRP involvement, not only in clinical research, but also in basic, translational, registry and longitudinal observational studies. This review also highlighted current challenges and barriers, and pulled together proposals of strategies to overcome them.

The exact definition and roles of PRPs remain unclear for some researchers. A wide proportion of the reviewed studies had adopted the 2011 EULAR definition of PRP which reflects the global acknowledgement of the importance of PRP involvement in rheumatology research and the need for specific recommendations. 14 PRPs hold a crucial position in recognising and actively integrating the patient perspective, their voice and needs into research decision-making processes. Diverse roles and activities were undertaken by PRPs in this SLR, from research partners to patient advocates, reflecting the many ways PRPs can contribute. Their involvement, as evident in recent papers shaping research priorities, guideline development, and scientific and clinical committees, suggests a trend towards more inclusive and patient-centred research practices.

Our review revealed specific barriers and challenges in communication, training, research processes and collaboration. These challenges highlight difficulties in communication and relationship dynamics during research, the necessity for training and support for both PRPs and researchers, concerns about the research process and its pace, and obstacles in PRP collaboration, including issues of recognition and diversity. Inclusivity and diversity are important topics for future research. To address these challenges effectively, targeted strategies such as fostering open communication, creating a supportive environment, ensuring early and sustained involvement, using a PRP coordinator and providing appropriate training and support for PRPs and researchers are crucial. These findings underscore the ongoing need for refining and implementing these strategies to enhance PRP involvement more efficiently. 26

A key observation from the SLR is the importance of early and sustained PRP involvement in research projects. Engaging PRPs from the research project’s inception ensures that research questions and methodologies are aligned with patients’ priorities and perspectives right from the start. Sustained involvement further reinforces the trust and collaboration between PRPs and researchers, leading to research outcomes that are more relevant and impactful. The OMERACT recommendations proposed that the level and timing of PRP involvement should vary based on the scope and type of project, emphasising adaptability as a key factor for successful involvement. 15

Evaluation and monitoring are also integral aspects of PRP involvement. This ongoing reflection and feedback process is vital for fostering effective and meaningful PRP involvement in research. Recognition, compensation and acknowledgement of PRPs stand as key elements for fostering a meaningful partnership. Coauthorship serves not only to document the PRP’s contribution but also reinforces the idea of collaborative research. Of note, we observed disparity between the involvement of PRPs in research activities versus their acknowledgement as coauthors. This disparity may arise from some PRPs not prioritising or desiring coauthorship, or being unable to participate in producing and writing a research paper due to health-related challenges such as disease flare-ups or fatigue. In ensuring equitable recognition, a collective effort is essential to guarantee that PRPs receive due acknowledgement and compensation for their valuable contributions to scientific research.

Our study has strengths and weaknesses. One important strength of this SLR is that the findings will equip researchers, healthcare professionals and other stakeholders with evidence-based solutions to improve PRP involvement in medical research. To this end, the findings have supported the process of updating the EULAR recommendations for PRP involvement and made them more evidence based. 1 Another strength is the obtention of a more nuanced understanding of the challenges and complexities surrounding PRP involvement in rheumatology research. Furthermore, our study stands out for its comprehensive approach, analysing a broad spectrum of study types, including quantitative and qualitative studies, reviews, opinion pieces and information from websites. The inclusion of various rheumatic musculoskeletal disease conditions, encompassing both paediatric and adult populations, enhances the robustness of our findings. Another notable strength lies in the co-production of this work by three PRPs. The project was initiated and led by a PRP (MdW) who gave the work direction, participated in article screening, article analysis, overall interpretation and manuscript writing. The two other PRPs brought important insights into PRP roles, facilitators and barriers.

A limitation of the study might be the heterogeneity of the included papers. Because of the expected limited reporting of PRP involvement in rheumatology research, we decided to include a diversity of papers in the SLR, varying from qualitative studies, case studies and original research papers to conference reports and opinion articles. This heterogeneity did not allow for any form of meta-analysis, nor for identifying themes that would benefit individual groups of PRPs such as people with rare diseases, children or young adults, or people with different cultural or ethnic backgrounds. Furthermore, quality assessments could not be uniformly applied across all study types. It is important to note that the traditional evidence hierarchy may not be applicable to this SLR, given the expected absence of randomised controlled studies. Despite this, certain papers were assessed to be of high quality of evidence within their respective study types. While the systematic approach ensured a comprehensive gathering of data, there might be relevant grey literature or non-English-language publications that were not included. Another limitation might be the time period of the last 6 years, including data from articles published between January 2017 and January 2023. This time frame was chosen to reflect studies performed after the 2011 EULAR recommendations were published, taking into account the implementation time gap. 14 Furthermore, the chosen time span resulted in 53 articles which was deemed sufficient for gathering relevant data related to our research questions.

In conclusion, this SLR identified numerous publications reporting on PRP involvement in rheumatology research. Most authors reported that PRP involvement not only enriches the research process but also ensures that research outcomes are more relevant, meaningful and patient centred. However, for this involvement to be genuinely effective, it is essential to address the barriers and challenges that PRPs and researchers are facing. By updating the EULAR 2011 recommendations, based on the findings of this SLR, we can look forward to a future where research is more inclusive, collaborative, and aligned with patient needs and perspectives.

Ethics statements

Patient consent for publication.

Not applicable.

Ethics approval

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Supplementary materials

Supplementary data.

This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

• Data supplement 1
• Data supplement 2

Handling editor Kimme L Hyrich

X @krystelaouad, @Stiddyo, @LGossec

Contributors All authors have contributed to this work and approved the final version. KA, MDW and LG accept full responsibility for the work and/or the conduct of thestudy, had access to the data and controlled the decision to publish.

Funding Funded by EULAR grant RES005.

Competing interests KA—research grant (EULAR grant RES005); over the last 3 years, research grants from UCB; consulting fees from Novartis. MdW—over the last 3 years, Stichting Tools has received fees for lectures or consultancy provided by MdW from UCB. ME—congress travel support from Janssen and AstraZeneca outside of the submitted work. DB—research grants from Novartis; speakers bureau from AbbVie, BMS, Galapagos, Janssen and Lilly; consulting fees from Pfizer, Sandoz and UCB. PS—speakers bureau from AstraZeneca; consulting fees from AbbVie; travel support from Janssen and Galapagos. LG—research grants from AbbVie, Biogen, Lilly, Novartis and UCB; consulting fees from AbbVie, Amgen, BMS, Celltrion, Galapagos, Janssen, Lilly, MSD, Novartis, Pfizer, Sandoz and UCB.

Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.

Provenance and peer review Not commissioned; externally peer reviewed.

Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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Systematic review article, association between low birth weight and impaired glucose tolerance in children: a systematic review and meta-analysis.

• 1 Department of Pediatrics, Heping Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, China
• 2 Department of Gastroenterology, Guangzhou Red Cross Hospital, Guangzhou, Guangdong, China
• 3 Department of Otolaryngology, Heping Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, China
• 4 Department of Nursing, Heping Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, China

Background: A potential association between the onset of diabetes and normal birth weight (NBW) has been discovered. Diverse conclusions and study methodologies exist regarding the connection between low birth weight (LBW) and impaired glucose tolerance in children, underscoring the need for further robust research. Our institution is embarking on this study to thoroughly examine the association between LBW and impaired glucose tolerance in children.

Methods: We conducted searches on Cochrane Library, ScienceDirect, EMBASE, PubMed, China National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature data (CBM) online database, VIP full-text Database, and Wanfang Database to identify correlation analyses or case-control studies investigating the relationship between LBW and abnormal glucose tolerance in children. The search spanned from January 2010 to September 2023. The quality of observational studies was evaluated using the Newcastle–Ottawa Scale (NOS) tool. Data synthesis was performed using the statistical software RevMan 5.3 for meta-analysis.

Results: Based on the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines, we finally included 10 clinical control studies consisting of a total of 2971 cases. There wasn’t considerably change in blood sugar levels among LBW, NBW and high birth weight (HBW) infants ( P  > 0.05). There was no significant difference in insulin levels between LBW infants and NBW infants ( P  > 0.05). The HOMA-IR of LBW infants was considerably higher than that of NBW infants ( P  < 0.05). The risk of abnormal glucose tolerance in LBW infants was 0.42 times higher than that in NBW and HBW infants [Fisher's Z  = 0.42, 95% CI = (0.09, 0.75), P  = 0.01].

Conclusion: LBW is associated with an increased risk of abnormal glucose tolerance, as indicated by elevated HOMA-IR level in LBW infants compared to NBW and HBW pediatric population. Further research is needed to confirm and expand upon these findings to better understand the complex relationship between LBW and impaired glucose tolerance in children.

1 Introduction

In China, the prevalence of diabetes has surged, with over 30 million individuals affected, marking a substantial rise from 0.8% in 1980 to 3.5% in 2000 ( 1 , 2 ). A study conducted from 2015 to 2017 revealed that in China, the overall prevalence of diabetes among adults is 12.8%, including a newly diagnosed diabetes prevalence of 6.8% and a self-reported diabetes prevalence of 6.0% ( 3 – 6 ). The rising incidence of diabetes has led to an increased prevalence of the condition among young adults, and reports indicate that diabetes can manifest in individuals as young as 13 years old ( 7 , 8 ). The presence of concurrent complications such as hyperlipidemia, hypertension, and other conditions alongside diabetes has garnered increasing attention in terms of the onset, progression, outcomes, and management of diabetes. Diabetic complications are more common in macrovascular and microvascular diseases, and abnormal blood lipid metabolism is involved in the whole process of this disease. A randomized controlled trial study has demonstrated the intricate interplay between blood glucose and blood lipids in individuals with diabetes ( 9 – 11 ).

Given the rising incidence and prevalence of type 2 diabetes among children and adolescents, this issue may emerge as a significant public health concern impacting both developed and developing nations. Consequently, from a population standpoint, it is imperative to identify potential risk factors and identify susceptible groups that could benefit from screening and preventive measures ( 12 – 14 ). So far, scholars have explored the etiology of diabetes from various perspectives and directions, including pathology, genetics, genomics, social factors, and other fields. The formation of diabetes corresponds to abnormal birth weight ( 15 , 16 ). The occurrence of high birth weight infants, often stemming from fetal overnutrition, maternal diabetes, and other maternal health conditions, can significantly predispose individuals to obesity and diabetes in adulthood, typically around the age of 18. This association may be attributed to genetic polymorphisms and the onset of insulin resistance ( 17 ). Additionally, abnormal insulin secretion during the fetal period, impacting fetal growth and development, may contribute to the prevalence of infants with low birth weight (LBW) and heighten the risk of diabetes in adulthood ( 18 , 19 ).

At present, numerous investigations have explored the link between LBW and impaired glucose tolerance in children. However, these studies yield varying conclusions and employ designs, leading to poor applicability. The findings of a single study regarding the correlation between LBW and impaired glucose tolerance in children may lack conviction without robust scientific support. Therefore, additional research is warranted, necessitating reputable scientific studies to comprehensively evaluate this relationship. Consequently, a thorough, quantitative, and systematic meta-analysis of independent studies with similar objectives was conducted to investigate the association between LBW and impaired glucose tolerance in children. This analysis aims to provide valuable insights to inform further exploration of the underlying causes of type 2 diabetes and to enhance eugenic strategies.

2.1 Database and literature search

A computer-based search was carried out across multiple databases, including CochraneLibrary, ScienceDirect, EMBASE, Wanfang Database, the Chinese Biomedical Literature Data (CBM), VIP Full-text Database, China National Knowledge Infrastructure (CNKI). This extensive search strategy encompassed a wide range of sources, including both degree papers, conference papers, Chinese and foreign periodicals, news articles, and manual searches, among others.

The main aim was to collect pertinent data regarding the association between LBW and impaired glucose tolerance in children. The literature retrieval process utilized a combination of free-text and subject-specific keywords. Key search terms such as “newborn,” “low birth weight,” and “impaired glucose tolerance” were employed, with the search period spanning from January 2010 onwards. This comprehensive strategy aimed to encompass the latest and most relevant research findings in the field.

2.2 Inclusion criteria and exclusion criteria

2.2.1 criteria for include literature.

(1) Observational studies that were published in full-text format.

(2) Inclusion of newborns with birth weight of less than 1,500 g.

(3) Assessment of the correlation between LBW and impaired glucose tolerance in children.

(4) Adjustment or control for the potential confounding factors, with the reporting of relative risk factors or the comparison of blood glucose, insulin, and Model Assessment for Insulin Resistance (HOMA-IR) indices with those of normal newborns and high-birth-weight newborns. Based on a previous literature ( 20 ), children were classified into LBW (<2,500 g), normal birth weight (NBW; 2,500–3,999 g), and high birth weight (HBW; ≥4,000 g). Impaired glucose tolerance was defined as having 2-h plasma glucose concentration (2hPG) 140–199 mg/dl ( 21 ).

2.2.2 The literature exclusion criteria

(1) Studies with incomplete and unusable data.

(2) Duplicate research content, with preference given to the most recent study.

(3) Reviews, editorials, preclinical studies, and literature that did not directly relate to the special purpose of the current meta-analysis.

(4) Clinical cases, which were not considered in this particular meta-analysis.

2.3 Study selection and data extraction

The process of extracting data and screening books followed a rigorous and systematic approach.

2.3.1 Independent screening

Two researchers conducted separate reviews of the selected literature and extracted relevant information.

2.3.2 Quality evaluation

These researchers also assessed the quality of the included studies.

2.3.3 Cross-check

To ensure accuracy and consistency, the results of the independent screenings and data extractions were cross-checked. Any discrepancies were addressed through discussion and consensus. In instances of unresolved discrepancies, a third researcher was consulted to provide adjudication.

2.3.4 Software utilization

NoteExpress document management software and Excel office software were employed for data management and extraction, facilitating efficient organization and analysis of the research data.

2.3.5 Data completeness

In cases where the literature lacked necessary information, the authors of the respective articles were contacted to request Supplementary Data .

The information retrieved from the data comprised: (1) the authors’ names, the publishing year and the country of the institute; (2) the characteristics of the study design; (3) the characteristics of participants, including health status, sample size and average age; (4) the number of normal weight, overweight and LBW newborns; and (5) confounding factors adjusted or controlled when reporting correlations.

2.4 Qualitative assessment

For assessing the quality of observational studies in this meta-analysis, the Newcastle-Ottawa Scale (NOS) tool was utilized. Studies with a NOS score of ≥6 were categorized as medium to high quality, whereas those with an NOS score <6 were classified as low quality.

2.5 Statistical analysis

RevMan 5.3 software, derived from the Cochrane Collaboration, was used for conducting meta-analyses. The mean values, and standard deviations for Blood glucose levels, insulin levels, HOMA-IR in each group were input into RevMan 5.3 for analysis. The weighted mean difference (WMD) was used as the effect size, and 95% confidence intervals (CI) were calculated. Heterogeneity was evaluated using the χ 2 test and the I 2 statistic, which quantifies the total variation across studies attributed to heterogeneity. P -value below 0.05 was deemed statistically significant ( 22 , 23 ).

3 Results and analysis

3.1 the outcomes of literature retrieval and the fundamental circumstances behind literature inclusion.

In adherence to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines, the study initiated with a computer-based database search, resulting in the retrieval of 742 studies. After eliminating duplicate studies, 561 unique studies remained. These papers were then subject to preliminary screening, during which 308 studies were reviewed.

After the initial screening, 142 studies met the inclusion criteria for further assessment, while irrelevant studies, reviews, case reports, and uncontrolled documents were excluded. Subsequently, the full texts of the selected literature underwent thorough examination, with papers containing incomplete data or lacking key outcome indicators being excluded. Ultimately, the study integrated data from 10 clinical control studies, comprising a total of 2,971 samples. This meticulous selection process ensured that the included studies were pertinent, met the required criteria, and enhanced the robustness of the meta-analysis. Figure 1 illustrates the flow chart detailing the literature screening process, while Table 1 presents the fundamental characteristics identified in the literature.

Figure 1 . Illustration of literature screening.

Table 1 . Basic characteristics of literature.

3.2 An assessment of the study’s methodology’s quality

All the literatures described the detailed intervention methods and observation indicators, and all the literatures did not describe the quantity and causes of blind procedures, as well as missed follow-up or withdrawal, in detail. The NOS scale study indicated that low-quality literature had a score of <6, while high-quality literature had a score of ≥6 ( Table 2 ).

Table 2 . Literature quality.

3.3 Meta analysis result

3.3.1 blood glucose level.

The blood glucose levels of each group were examined using meta, and the heterogeneity test results revealed that LBW vs. NBW: Chi 2  = 25.86, I 2  = 85%, P  < 0.0001, df = 4; LBW vs. HBW: Chi 2  = 0.31, I 2  = 0%, P  = 0.58, df = 1. From the analysis shown as Figures 2 , 3 , there was no statistical difference in blood sugar levels between LBW infants and normal weight and overweight infants ( P  > 0.05).

Figure 2 . Comparison of blood glucose levels between normal weight and low birth weight children forest analysis chart F.

Figure 3 . Comparison of blood glucose levels between overweight and low birth weight children forest analysis map.

3.3.2 Insulin level

A meta-analysis of the comparative results of insulin levels was performed in each group. In the comparison between LBW and NBW, with four degrees of freedom, the Chi 2 statistic yielded a value of 6.85, resulting in a p -value of 0.14 and an I 2 of 42%. These findings indicate moderate heterogeneity among the studies for this comparison. In the comparison between LBW and HBW, the Chi-squared value was 11.78 with one degree of freedom, resulting in a p -value of 0.0006, and I 2 was determined to be 92%. These results indicate a high level of heterogeneity among the studies for this comparison. According to the analysis of the random-effect model ( Figure 4 ), there wasn't considerably difference in insulin level between LBW infants and normal weight children ( P  > 0.05).

Figure 4 . Comparison of insulin levels between normal weight and low birth weight children forest analysis map.

3.3.3 HOMA-IR

In the comparison between LBW and normal birth weight (NBW) children ( Figure 5 ), with four degrees of freedom, the Chi-squared statistic was 6.85, yielding a p -value of 0.14 and an I 2 of 42%, indicating a moderate level of heterogeneity among the studies.

Figure 5 . Forest analysis map of HOMA-IR comparison between normal weight and low birth weight children.

In the comparison of LBW with HBW children ( Figure 6 ), with one degree of freedom, the Chi-squared statistic was 11.78, yielding a p -value of 0.0006, and I 2 was determined to be 92%, suggesting a high level of heterogeneity among the studies for this comparison. The meta-analysis findings reveal that LBW infants have significantly higher HOMA-IR values when compared to NBW children ( P  < 0.05). Nonetheless, in comparing LBW to HBW children, the observed high level of heterogeneity underscores the need for caution in interpreting the results. This heterogeneity indicates significant variability among the included studies in this comparison, potentially influencing the overall findings.

Figure 6 . Forest analysis map of HOMA-IR comparison between overweight and low birth weight children.

3.3.4 Analysis of correlation between low birth weight and HOMA-IR

This study encompassed data from 10 clinical controlled studies, comprising a total of 2,971 samples, and conducted a meta-analysis on the association between LBW and HOMA-IR. The heterogeneity test results indicated significant heterogeneity, with Chi 2  = 912.67, df = 7, P  < 0.00001, and I 2  = 99%. These findings suggest a substantial level of variation among the included studies’ meta-analyses, assessed using a random effects model ( Figure 7 ), the risk of abnormal glucose tolerance in LBW newborns was 0.42 times higher than that in normal and overweight children [Fisher's Z  = 0.42,95% CI:0.09–0.75, P  = 0.01].

Figure 7 . Forest analysis map of the correlation between low birth weight and HOMA-IR.

3.3.5 Publication bias analysis

The funnel diagram was created using the blood glucose, insulin level, HOMA-IR value and correlation analysis results of each group, and an examination of publication bias was conducted ( Supplementary Figures S1–S4 ). The results revealed that while a small proportion of the included studies exhibited asymmetry, the majority of funnel plots appeared symmetrical, suggesting potential publication bias in the included literature. This bias could be linked to the heterogeneity observed in the study.

4 Analysis and discussion

Previous research has shown a link between diabetes and LBW ( 33 ). The “Fetal Origin hypothesis,” proposed in the 1990s, suggests that the conditions experienced during fetal intrauterine development significantly influence the risk of developing diseases in adulthood. According to this hypothesis, individuals born with LBW are at a considerably higher risk of developing type 2 diabetes later in life ( 34 ). Preterm delivery or intrauterine growth restriction is the most common cause of LBW ( 35 ). 63% of LBW infants are born prematurely, while the remaining cases are attributed to intrauterine dysplasia. It is noteworthy that nearly all very low birth weight infants are born prematurely, with some being extremely premature, with gestational ages of less than 25 weeks. In utero stunting of development in LBW infants impairs the development and function of the pancreas, leading to problems with lipid and glucose metabolism and hypertension in adulthood ( 36 , 37 ). Genetic research indicates that variations in susceptibility genes associated with type 2 diabetes may also be linked to LBW. This suggests a potential genetic predisposition for both lower birth weight and an increased risk of type 2 diabetes later in life. These findings underscore the intricate interplay between genetic factors and health outcomes across the lifespan ( 38 ). If an individual has a low birth weight or childhood weight, there is a tendency for rapid weight gain in adulthood (after 18 years of age) due to dietary changes, which significantly increases the risk of developing diabetes and other related metabolic disorders. Reduced birth weight has been associated with the upregulation of certain genes, commonly known as “thrift genes.” These genes might be involved in metabolic adaptations to prenatal undernutrition. Furthermore, there is evidence connecting LBW to a higher risk of developing several disorders, including diabetes, in adulthood, suggesting that early life factors, including birth weight, can influence gene expression and can aid in the later-life development of chronic illnesses.

Recently, LBW infants are prone to developing obesity, insulin resistance, hypertension, and vascular diseases in adulthood. Additionally, the incidence and mortality rates of other conditions such as enterocolitis, late-onset septicemia, and intraventricular hemorrhage are elevated in this population ( 39 ). The prevalence of diabetes and hypertension in LBW infants heightened significantly in adulthood. A survey has shown that the incidence of type 2 diabetes and birth weight are correlated in a U-shaped manner, and the quantity of diabetes cases complicated with hypertension in LBW is significantly increased. Diabetes is also associated with high birth weight, while hypertension is notably more prevalent among high birth weight infants. It is hypothesized that hypertension in high birth weight infants and LBW infants may arise from distinct metabolic phenotypes or similar environmental factors. Moreover, LBW infants exhibit a significantly higher prevalence of hyperlipidemia compared to those with normal birth weight ( 40 ). Previous study has found that 300 cases of high birth weight infants, and the results show the detection rates of overweight and obesity in the macrosomia group (13.10% vs. 2.86%) are higher than those in the control group (9.69% vs. 1.61%) ( 41 ), which suggested that the risk of insulin resistance and abnormal lipid metabolism in abnormal birth weight infants is greater than that in normal birth weight infants. China's Chinese multi-provincial Study on Risk Factors of Cardiovascular Diseases (CMCS) has suggested that the proportion of diabetic patients with abnormal blood lipid metabolism is considerably higher, and the proportion of diabetic patients with atherosclerosis risk factors such as coronary heart disease, cerebral infarction and venous thrombosis is also significantly higher than that of non-diabetic patients.

More and more evidence shows that the LBW of newborns is directly related to the abnormal glucose tolerance of children. The blood sugar and insulin levels of LBW newborns, normal newborns and overweight newborns were analyzed by meta-analysis. The findings indicated that there was not a significant variation between the blood sugar levels of LBW newborns and overweight and normal newborns. Meta-analysis of the comparison results of HOMA-RI values in each group showed that the HOMA-IR values of LBW infants were considerably higher. It is suggested that there is a certain correlation between LBW of newborns and HOMA-IR. Meta-analysis was made on the correlation between LBW and HOMA-IR, and random effect model analysis showed the risk of abnormal glucose tolerance in LBW newborns was 0.42 times higher than that in normal and overweight children [Fisher's SZ = 0.42, P  = 0.01, 95%CI = (0.09, 0.75)]. Through an analysis of existing research in this domain, it is evident that there exists a connection between abnormal glucose tolerance and atypical birth weight in LBW infants. This association cannot be solely attributed to factors related to the fetus itself, prenatal malnutrition, or the intrauterine environment; rather, it encompasses various other contributing factors. These factors encompass aspects related to the pregnant woman's health, as well as lifestyle choices and dietary habits during adulthood. Additionally, genetic modifications resulting from certain factors in adulthood may also influence this intricate relationship. Understanding these multifaceted connections is crucial for comprehensively addressing and managing health risks associated with abnormal glucose tolerance and birth weight.

However, the study has certain limitations that warrant consideration:

(1) Stringent Criteria for Inclusion and Exclusion: The study employed rigorous criteria for inclusion and exclusion, leading to a relatively small number of included studies. Furthermore, detailed subgroup analysis was not conducted on studies displaying heterogeneity. This limited the diversity of the included literature and may affect the generalizability of the findings.

(2) Inconsistent Treatment Protocols and Outcome Measures: Variability in the treatment protocols and outcome indicators across the included studies may introduce heterogeneity and impact the reliability of the outcomes.For example, insulin level is influenced by age and gender ( 42 ). Therefore, these factors may influence the results in this study. To bolster the robustness of the findings, it is imperative to conduct further research, encompassing high-quality correlation studies and case-control trials. These endeavors will provide a deeper understanding of the relationship between abnormal glucose tolerance and birth weight, thus advancing our knowledge in this critical area of study.

5 Conclusion

It has been shown that LBW in babies is associated with poor glucose tolerance in pediatric population and a higher chance of type 2 diabetes in adults. This underscores the significance of preventive measures to manage birth weight abnormalities.Highlighting the significance of dietary and exercise management during the perinatal and developmental stages is crucial for mitigating the risk of diabetes. These insights underscore the necessity of early interventions and a comprehensive healthcare approach to mitigate the enduring adverse impacts of low birth weight on health outcomes.

Data availability statement

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

Author contributions

JM: Data curation, Formal Analysis, Writing – original draft. YW: Conceptualization, Writing – review & editing. MM: Data curation, Methodology, Writing – original draft. ZL: Conceptualization, Formal Analysis, Methodology, Writing – original draft.

The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.

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

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Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fped.2024.1362076/full#supplementary-material

Supplementary Figure S1 Funnel chart based on blood glucose level. Note: ( A ) Comparison between LBW and DBW; ( B ) LBW compared with HBW.

Supplementary Figure S2 Funnel chart based on insulin level.

Supplementary Figure S3 Funnel diagram based on HOMA-IR. Note: ( C ) LBW compared with DBW; ( D ) LBW compared with HBW.

Supplementary Figure S4 Funnel chart based on the results of correlation analysis.

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Keywords: newborn, low birth weight, abnormal glucose tolerance, diabetes, meta-analysis

Citation: Ma J, Wang Y, Mo M and Lian Z (2024) Association between low birth weight and impaired glucose tolerance in children: a systematic review and meta-analysis. Front. Pediatr. 12:1362076. doi: 10.3389/fped.2024.1362076

Received: 27 December 2023; Accepted: 23 April 2024; Published: 9 May 2024.

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© 2024 Ma, Wang, Mo and Lian. 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: Zerong Lian [email protected]