Introduction

Sickle cell disease (SCD) is a group of heritable hematologic conditions stemming from mutations in the hemoglobin subunit beta gene (HBB). Hemoglobin comprised of mutant beta-globin polymerizes the cells which induces red blood cell (RBC) stiffness and less deformability, contributing to vessel occlusion and tissue ischemia [1, 2]. These RBCs then adhere to the endothelium and blood components, adding to vessel occlusion and repeated cycles of inflammation [3]. Polymerization also causes hemolysis through fragility of the RBCs and oxidative stress [4, 5]. These processes contribute to significant morbidity in patients with SCD, including pain crises, acute chest syndrome, stroke or silent infarction, pulmonary hypertension, kidney disease, avascular necrosis, and functional asplenia with risk for infection [6, 7]. Approximately 100,000 people live with SCD in the United States (US), a small fraction of the estimated 7.74 million affected globally [8, 9]. Despite being considered a rare disease in the US, the adverse health outcomes attributed to SCD lead to frequent utilization of healthcare services. A previous study found that individuals with SCD in the US average 2.59 care encounters per year, with an average of 1.52 of these encounters resulting in hospitalization [10]. Of the hospital admissions in this study, the rehospitalization rates within 14 and 30 days were 28.4% and 41.1%, respectively [10]. Insufficient disease management, whether through inconsistent medication, lack of a primary care physician (PCP), or missed outpatient appointments, raises the risk of vaso-occlusive events, hospitalization, and rehospitalization [11–15]. This greater need for healthcare involves increased costs. In addition to the high morbidity faced by those with SCD, which includes a 20-year reduction in lifespan on average, the total mortality burden was estimated to be 376,000 people globally [8]. Speller and colleagues [9], despite limiting their sample to SCD patients with Medicaid insurance, noted these patients, despite having a rare disease, accounted for double the average annual spending relative to others with public insurance in the US. In an earlier study by Brousseau and colleagues [10], researchers found significant differences in acute hospitalization rates between public and privately insured individuals. Most notably, adults with public insurance experienced twice as many acute care encounters [10]. To alleviate widespread morbidity, mortality, and costs from SCD, healthcare services must be effective and accessible.

With the disproportionate burden of SCD, improved disease management strategies and health system interventions are needed to enhance health outcomes in patients with SCD. One aspect of healthcare delivery that hinders disease management is medical mistrust (MM). MM is a multifaceted concept that has been broadly defined as a “lack of confidence in healthcare providers (HCPs), institutions, and systems” [16], and is not synonymous with distrust, which is an attitude based on the belief that one’s trust has been diminished or violated [16]. MM is rooted in historical events, cultural identity, and lived experiences; it encompasses the social dynamics of how patients interact with healthcare entities [16, 17]. Marginalized patients, such as people of color, LGBTQ populations, and older adults, often develop heightened levels of MM due to their encounters with healthcare discrimination and systemic inequities [18–22]. The cognitive and behavioral attributes of MM include suspicion toward the motives and practices of healthcare professionals. These attributes contribute to concerns about receiving substandard or harmful treatment and lead to underutilization of medical services [16–23]. To assess levels of MM, researchers have developed reliable and validated tools. The two most used tools are the MM Index (MMI) [23] and the Group-Based MM Scale (GBMMS) [24]. These tools quantify patients’ perceptions of the healthcare system. Decades of research using these tools [23, 24] have found that MM influences health behaviors, engagement with medical services, and interactions with providers. Previous studies have shown that those with higher levels of MM were less likely to complete health-maintenance behaviors, i.e., participating in primary screenings and adhering to treatment regimens [24–31]. Avoidance of healthcare services results in adverse health outcomes [29]. Despite the obvious overlap between patients with SCD and marginalized populations, research evaluating MM in this context is underdeveloped and represents a long-standing gap in knowledge.

The goal of this systematic review was to assess the extent and nature of the MM research available within the realm of SCD studies in order to summarize the findings and identify gaps in the literature. SCD positions most patients at the intersection of race and chronic illness, where MM is often encountered [24]. Therefore, this review will consider studies that examine patients’ perceptions of the influence of race/ethnicity on the medical care they receive. Studies that either qualitatively or quantitatively describe potential predictors of MM in patients with SCD will be considered. Based on this context, the following research questions were formulated to guide this systematic review:

R1: How has MM been measured and/or described in patients with SCD?

R2: What factors have been described in the literature that predispose patients with SCD to develop MM?

R3: What consequences or outcomes have been described as a result of patients with SCD developing MM?

Materials and methods

This systematic review is based on the methodological framework of Arksey and O’Malley [32]. The approach was selected because MM in patients with SCD is an under-researched topic, and Arksey and O’Malley’s framework allows for maintenance of a broad scope for research questions. This allows researchers to be able to summarize the extent, range, and nature of activities related to the research question [32]. This review will include primary, quantitative, qualitative, and mixed methods peer-reviewed studies that meet the inclusion criteria. Studies had to focus on the patient with SCD and not on a HCP, caregiver, or family member. The studies were limited to only English language, data-based empirical research articles. Studies had to describe concepts found in the group-based MM instrument [24] [e.g., suspicion of the health care system (items 3, 4, 5, 6, 7, 9); group disparities in health care (items 8, 10, 11) and lack of support from health care (items 1, 2, 12)] [24]. Literature reviews, opinion texts, editorials, conference proceedings, dissertations, and studies about mistrust of research and genetic testing in SCD were excluded.

Article search strategies were developed in coordination with a research librarian specializing in systematic reviews. Using search terms “sickle cell anemia,” “sickle cell disease,” “trust,” “mistrust,” “distrust,” “stigma,” “racism,” “disparity,” “healthcare inequality,” “health disparities,” “physician-patient relations,” “nurse-patient relations,” “physician-patient communications,” and “discrimination” across six electronic databases (CINAHL, EMBASE, Scopus, PubMed, Psycinfo, and Web of Science) yielded 527 articles from 1994 to 2025. After removing duplicates, 402 articles remained. These titles and abstracts were then independently screened by three members of the systematic review team for relevance (MS, MF, NS), resulting in 321 remaining articles for full-text screening. During the full-test screening stage, two team members (MS, MF) independently conducted full-text screening of studies for fulfillment of the inclusion criteria.

Amongst the data-based articles that were ultimately selected for inclusion, two team members (MF, NS) screened their reference lists for potentially relevant articles based on titles, resulting in 38 new articles, added to the 321 full-text articles which needed full screening. Full-text screening of these 359 articles was conducted independently by two team members (MS, MF). Two reviewers (MS, MF) extracted relevant data using an Excel template designed for this review. The following information was collected: study settings, participant characteristics, objectives, any framework used, methodology, study design, recruitment, data collection methods, and findings specific to MM. The data extraction template was pre-tested on five eligible studies and refined. Themes, interpretations, and quotations were extracted from qualitative studies, while numbers and interpretations were extracted from quantitative findings. Both reviewers extracted relevant data, which was then double checked by the other reviewer (MS, MF). Any disagreement was resolved through discussion, and when required, by involving a third reviewer (RB). An iterative narrative synthesis approach to analysis was then conducted. The authors developed a synthesis of findings from included studies, explored relationships in the data, and discussed the emerging themes and concepts. These detailed findings from each article, including excerpts of patient statements, are listed in the in-text tables and in Table S1.

A final body of 42 original peer-reviewed articles was included in this systematic review. Figure 1 illustrates the flow of study screening and inclusion/exclusion. This systematic review was registered on Open Science Framework, maintained by the Center for Open Science (https://osf.io/).

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Figure 1. Literature search Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram and database search indicators. Adapted from “PRISMA” (http://www.prisma-statement.org/). Accessed July 1, 2025. © 2024–2026 the PRISMA Executive. Distributed under a Creative Commons CC BY 4.0 license.

Results

Based on the systematic review framework [32], this review compiled study characteristics and findings on the topic of MM in patients with SCD. Table S1 provides a comprehensive presentation of the 42 included studies. Thirty-nine studies used cross-sectional designs, with only three studies utilizing a longitudinal design [33–35]. Five studies used strictly quantitative methodology, 26 studies were strictly qualitative, and eleven studies used mixed methods analyses. Table S1 also provides information on recruitment sites, a description of participants, frameworks, and tools utilized in each study, and a description of each study’s findings relevant to MM.

Overlap in recruitment strategies and settings was noted across studies. Four studies recruited from inpatient settings [36–39], 25 studies recruited from outpatient hematology clinics, and two studies recruited participants from the emergency department (ED) [40, 41]. Three studies recruited participants from market research company participant panels [42–44]. Ten studies recruited participants from community centers or national/local SCD advocacy foundations or groups, and two studies recruited participants from national SCD conferences [45, 46].

Seven of the 42 studies had higher male participant ratios than female participants [37, 44, 47–51]. Over half (n = 21) of the studies included older adult participants (above age 50 years old) with SCD, and only 13 studies examined pediatric patients (< 18 years of age) with SCD [34, 35, 38, 39, 42, 48, 49, 51–56]. Twenty-one (50%) studies specified the sickle cell genotype of participants, with the predominant form of sickle cell across these studies being hemoglobin SS. Notably, none of these studies differentiated their study findings or outcomes based on participant genotype.

Three studies included participants as dyads [42, 51, 52]. Nelson and Hackman [52] collected data on “patient and family” dyads with no further specification given as to the type of family member. Durgam and associates [42] collected data on adolescent patients and caregiver dyads, with no further specification about the caregiver. Lastly, Hauser and colleagues [51] provided specifics about dyads. All the dyads were adolescent and primary caretaker (17 parents, 4 grandparents, and 1 aunt) [51]. The only commonality discussed across the three articles was a description of the caregivers as being predominantly black and female [42, 51, 52].

Seventeen studies included participants with self-reported ethnicities that were non-Black or African American, with five of these studies reporting Hispanic participants [39, 48, 57–59], one study reporting an Asian participant [43], and three studies reporting White participants [43, 54, 59]. The remainder of the study participants self-identified as “other race” [39, 46–48, 51, 54, 58–60]. The majority of studies were conducted in the US, with eight studies conducted in England [34–37, 56, 61–63]. One study was conducted in Canada [42] and one in Brazil [47].

Research question 1: How has MM been measured and/or described in patients with SCD?

Only six articles used quantitative methodologies (Table 1). Sample sizes in these studies ranged from 20 to 556 participants [33, 39, 43, 52, 60, 64]. Only two quantitative studies [39, 52] included adolescents with SCD. None of these studies with quantitative methodology utilized a theoretical framework. No study utilized a psychometrically validated measure of MM, such as the GBMMS or the MMI or examined MM as either a discrete study variable or as a primary study aim. The instruments that were utilized included the Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-ME) [65], the discrimination subscale of the interpersonal processes of care (IPC) survey [66], Perceptions of Racism in Children and Youth (PRaCY) Tool [67], the national Behavioral Risk Factor Surveillance System (BRFSS) dataset, and the Sickle Cell Transfer Questionnaire [68]. Table 1 summarizes the findings of studies that used quantitative methodologies. With the GBMMS [24] as a guide, most of these studies focused on the GBMMS sub-concept of group disparities in health care, i.e., discrimination based on race or drug seeking.

Thirty-six articles employed qualitative methodologies (eleven of which utilized mixed methods). Sample sizes in these qualitative studies ranged from seven to 95 participants. Fourteen studies explicitly described the use of a qualitative framework, theory or design. The qualitative frameworks/theories utilized included hermeneutics [69], phenomenonology [55, 56, 59, 61], van Manen’s Thematic analysis [69], ethnography [70], The Sociological Theory of Stigma [47], grounded theory [34, 35, 71], Ecological Framework for Palliative Care of SCD [72], Leininger Culture Care Theory [72], critical race theory [59], Theory of Self Care Management for SCD [40], and a new paradigm research design from Reason & Rowan 1981 and Webb’s 1991 feminist methodology [36]. Table 2 summarizes the findings of the qualitative studies.

Most studies utilizing qualitative methodologies employed a semi-structured interview guide that was administered individually, with eight studies administering focus groups [44, 49, 51, 56, 59, 63, 70, 73]. One study utilized an open-ended, fill-in-the-blank written section for qualitative data collection [57], and one study had participants use digital technology, specifically the Photovoice program to provide qualitative data [44]. Further description of these studies can be found in Table S1.

Research question 2: What factors have been described in the literature that predispose patients with SCD to develop MM?

To answer research question 2, themes were extracted from the 42 studies that met inclusion criteria to predict the development of MM in patients with SCD by two authors (MS, MF). The aggregated themes included HCP/staff behaviors and characteristics, inadequate pain control, poor transition of care from pediatric to adult medical care, lack of HCP transparency about medical treatments, and adolescents’ specific predictors of MM. Table 2 summarizes the predictors of MM with illustrative quotes.

Maladaptive coping strategies

Across studies, a common finding was the discussion of the development of maladaptive coping strategies to seek a sense of control due to being left in uncontrolled pain. Participants described illicit substance use (e.g., marijuana) as a way of managing pain in a “non-opioid” manner. In contrast, others described the use of non-prescribed opioids in both inpatient and outpatient settings to manage the pain. Commonly, participants expressed a desire to learn about alternative pain medication strategies so pain could be managed on their own, in their own home, and to avoid hospital utilization [45, 62, 63]. Another form of maladaptive coping in order to maintain a sense of control was the practice of nondisclosure to medical providers [72]; this strategy was common after being made to feel helpless or like a “drug addict” during medical care. Another maladaptive coping mechanism was the recurring discussion of self-discharging from inpatient settings when care was perceived to be poor quality, racist, or harmful [58]. Figure 2 conceptualizes the findings of this review, and depicts the predictors and outcomes of MM development in patients with SCD.

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Figure 2. Conceptualization of medical mistrust development in patients with sickle cell disease (SCD). HCP: healthcare provider.

Discussion

This systematic review surveyed the extant literature on MM in patients with SCD. Study characteristics and findings were compiled to present the overall results of the review and the types of research conducted to date. The predictors of MM centered around HCP characteristics, HCP specific behaviors, and institutional factors. The outcomes of the development of MM in patients with SCD included patient behaviors negative psychological conditions, negative impacts on treatment plan adherence, development of medical trauma, and the development of maladaptive coping mechanisms. Overall, the review summarized the linkage of the predictors and the resultant outcomes of MM.

Most surprisingly, with a genetic disease found almost exclusively in populations of persons of color, this review found significant deficits in the measurement and evaluation of race-based MM. There were no studies that explicitly examined (quantitatively or qualitatively) MM as a primary study aim, predictor, or outcome. In addition, despite the availability of two psychometrically validated and widely used MM scales (e.g., GBMMS or the MMI) [23, 24], none of the quantitative studies measured MM utilizing either of these scales in their analyses. Furthermore, there were no quantitative associations measured between MM and SCD-specific health outcomes despite the multitude of chronic illness studies reporting an association between MM and health outcomes [24, 79–83]. These findings represent opportunities for future research using valid and reliable MM measures to capture quantifiable data specific to sickle cell health outcomes of interest.

Even though the racial and ethnic makeup of people with SCD in the US is primarily African American [52], only 17 of the 42 studies reported the ethnicities of patients with SCD as either non-Black or non-African American. Similarly, the location of most studies in the review was limited to US, with only a few from non-US countries, Europe, Canada, and South America. As the paradigm of race has a very unique history and a myriad of sociopolitical implications in US [84–86], it can be assumed that race may not play the same role in the development of MM in other countries, especially in ethnically homogenous nations where patient-provider racial discordance does not occur. Future studies that examine MM with a non-racial lens in patients with SCD of other ethnicities and in other countries may provide a more comprehensive picture of this phenomenon. Additionally, future studies conducted in US should also take into consideration the nuances of group-based MM across different geographical regions of US, as perspectives about racial/ethnic minorities vary widely.

All but one quantitative study [33] and two qualitative studies [34, 35] employed cross-sectional study designs. Given that individuals with SCD have frequent interaction with the health care system, it is imperative that future studies examine the longitudinal and dynamic nature of MM across the SCD continuum. The importance of examining how the developmental stages of adolescence and emerging adulthood impact the development of MM requires significant attention. Although few studies have examined MM in this population [87–89], early research suggests that MM can be intergenerationally transmitted [90]; therefore, its development likely begins much before adulthood [16, 17]. Future studies should include an assessment of the impact of intergenerational MM among sickle cell patients and their caregivers/family members. While patient-caregiver dyads were studied across three studies in this review [42, 51, 52], this potential contributor to MM development was not explicitly studied as a predictor in these studies. Also, as disease self-management increases with chronological age and as these adolescents with SCD approach the transition to care from pediatric hematology to adult hematology, it is critical to understand how MM in adolescents with SCD impacts the transition process.

Another key aspect to examine is the influence of gender on the phenomenon of MM in patients with SCD. Most studies had predominantly female participants; it is imperative to examine the male perspective since the literature on MM has found differences by gender [91]. Furthermore, only a handful of studies recruited patients while they were inpatients. The contribution of inpatient admission, while the patient is acutely in a sickling crisis, to the development of MM deserves targeted attention. A comparison of inpatient versus outpatient predictors of MM may provide insight into tailored interventions by care setting.

Qualitative studies examining MM in patients with SCD should provide a more nuanced investigation across the lifespan and across the genotypes of SCD. Studies should explicitly investigate patient-identified suggestions to mitigate MM in this population. While qualitative studies are more likely (than quantitative studies) to use a theoretical framework [92], future qualitative studies examining MM in patients with SCD would benefit basing their studies on theories, utilizing structured study designs, and creative use of data collection processes. The use of technology, such as Photovoice [93], should be explored to enhance day-to-day narratives and a more comprehensive understanding of MM in this population.

Future quantitative studies need larger sample sizes, operationalized empirical predictors of MM in this population, and need to examine MM as a mediator using more advanced statistical methodologies. Benkert and colleagues [17] argue that MM is not solely a psychological outcome of the healthcare system, but also behaves as a mediator between the system and patient health outcomes, such as medication adherence and healthcare utilization patterns. Future studies should also stratify results related to MM by age, gender, and type of SCD. Specifically, future quantitative studies should examine the relationship between MM and healthcare utilization, HU medication adherence, or mistrust toward blood transfusions, which are frequent and lifelong components of sickle cell medical care.

Strengths of this systematic review include a thorough review of the perspectives of MM in patients with SCD as informed by an extensive literature search. The searches were conducted with the support of an experienced librarian. To avoid selection bias, there were three researchers involved in the article selection process. The review also identified specific HCP behaviors that contribute to the development of MM. One unique aspect was the HCPs’ outward display of mistrust towards patients, which then led to development of mistrust within patients. Similar to Benkert and colleagues’ findings [17], this review found that anxiety and depression were described as psychological outcomes of MM. A new finding of this review is the identification of medical trauma and medical fatalism as outcomes of MM in patients with SCD. These outcomes need to be rigorously investigated and measured in future SCD studies.

This review had limitations as well. First, by design, the review excluded studies that focused on the perspectives of caregivers, family members, and friends of patients with SCD. However, caregivers and family are an important aspect of MM development, particularly the intergenerational component of MM [16, 17]. The development of MM in patients with SCD could be influenced by family members who also have SCD and/or negative health care experiences. This review also excluded studies that examined mistrust of medical research and/or blood transfusions in patients with SCD. As important aspects of a sickle cell medical plan of care, these two foci need further study.

Another limitation was the lack of availability of descriptors among studies of “preventive management techniques” used by patients to prevent a sickling crisis and subsequent healthcare utilization. Although avoidance was a result identified in several studies, clear descriptions by patients were not provided regarding exact management strategies utilized to avoid hospitalization or emergency room (ER) visits. This remains an area that requires further probing in future studies to elicit as a potential healthcare behavior whose onset is induced by MM in patients with SCD. Another limitation of the review was that most of the included studies recruited patients who were already affiliated with regular clinical care. Consequently, the results of this review may not represent the views of those patients with SCD who have low healthcare utilization. The results may not represent the views of those with other genotypes of SCD (such as thalassemic variants) that have fewer crises, have less intensive medical plans of care, and thus have fewer encounters with the health care system.

Despite these limitations, the review highlights the precursors of MM as well as the medical and psychological outcomes in patients with SCD. The paucity of extant literature on this topic emphasizes the need for more rigorous and larger-scale studies in the sickle cell population to establish more conclusive linkages between MM and health outcomes. Furthermore, HCPs such as emergency physicians and nurses, PCPs, and adult hematology providers can utilize these findings to identify modifiable characteristics and behaviors that contribute to the development of MM in their patients with SCD. By doing so, MM onset can be prevented, delayed, or even reversed in this population, and can ultimately cease to be a barrier to medical care.

In conclusion, this systematic review provides a solid basis for further detailed investigation into the concept of MM in patients with SCD. More studies are needed using various methodologies, frameworks, and theories to further elucidate this concept. The qualitative predictors of race-based MM presented in this systematic review may help inform clinicians to improve care delivery. A foundation for comprehensive interventions can be developed from the findings to decrease MM and improve health behaviors in patients with SCD. The authors urge other researchers to use the findings to develop more in-depth studies focused on the predictors, development and consequences of MM in patients with SCD.