A scoping review of health-related stigma outcomes for high-burden diseases in low- and middle-income countries

Background Stigma is associated with health conditions that drive disease burden in low- and middle-income countries (LMICs), including HIV, tuberculosis, mental health problems, epilepsy, and substance use disorders. However, the literature discussing the relationship between stigma and health outcomes is largely fragmented within disease-specific siloes, thus limiting the identification of common moderators or mechanisms through which stigma potentiates adverse health outcomes as well as the development of broadly relevant stigma mitigation interventions. Methods We conducted a scoping review to provide a critical overview of the breadth of research on stigma for each of the five aforementioned conditions in LMICs, including their methodological strengths and limitations. Results Across the range of diseases and disorders studied, stigma is associated with poor health outcomes, including help- and treatment-seeking behaviors. Common methodological limitations include a lack of prospective studies, non-representative samples resulting in limited generalizability, and a dearth of data on mediators and moderators of the relationship between stigma and health outcomes. Conclusions Implementing effective stigma mitigation interventions at scale necessitates transdisciplinary longitudinal studies that examine how stigma potentiates the risk for adverse outcomes for high-burden health conditions in community-based samples in LMICs. Electronic supplementary material The online version of this article (10.1186/s12916-019-1250-8) contains supplementary material, which is available to authorized users.


Background
Stigma is a major social determinant of health that drives morbidity, mortality, and health disparities [1], and has been described by the World Health Organization as a 'hidden' burden of disease [2]. Stigma is characterized by cognitive, emotional, and behavioral components and can be reflected both in the attitudes, often conceptualized as perceived, anticipated, or internalized stigmas, and experiences, including enacted or experienced stigmas affecting a particular trait, among individuals [3][4][5]. Perceived stigma refers to a person's understanding of how others may act towards, and think or feel about, an individual with a certain trait or identity [6]. Anticipated stigma refers to expectations of stigma experiences happening in the future [7]. Internalized stigma refers to the individual level process of awareness, acceptance, and application of stigma (to oneself ) [8][9][10]. Finally, experienced or enacted stigma refers to discriminatory acts or behaviors [11].
Stigma adversely impacts individual health outcomes as well as related 'life chances' , including educational opportunities, employment, housing, and social relationships [1]. It has also been shown to negatively affect help-and treatment-seeking behaviors, hindering the ability of public health agencies to treat and prevent stigmatized health conditions [12]. HIV-related stigma, in particular, has been cited as one of the most enduring barriers to ending the HIV pandemic [13,14]. Yet, while HIV-related stigma has received greater attention, tuberculosis (TB), mental, neurological, and substance use disorders are also highly stigmatized drivers of the global burden of disease, with significant unmet treatment needs in low-and middle-income countries (LMICs) [15][16][17][18][19][20].
Hatzenbuehler et al. [1] argued that research on stigma and health outcomes is inappropriately siloed within specific disease/disorder domains. Across health disciplines, this separation has limited the ability to understand the overall impact of stigma on individual wellbeing and on global disease burden [1]. Research siloes have also restricted our ability to develop interventions addressing stigma, particularly in LMICs and among at-risk populations (e.g., lesbian, gay, bisexual, transgender, queer populations (LGBTQ); racial/ethnic minorities; refugees) for whom effective interventions are needed. Despite considerable progress in stigma research over the past decade, a critical review of the literature on the consequences of stigma across health conditions has not been undertaken.
This paper presents a scoping review of the literature on the health consequences of stigma at both the individual and healthcare system levels in LMICs. The review focuses on the main drivers of disease burden in LMICs, namely HIV, TB, mental health, epilepsy, and substance use. The purpose is to summarize recent research on the association between stigma and these conditions, including the direct impact of stigma on affected individuals and its indirect impact on health systems according to help-seeking behavior or service utilization. In so doing, this review highlights commonalities across conditions as well as the key mediators and moderators of the relationship between stigma and health, and identifies at-risk and vulnerable groups. Finally, the strengths and limitations of the current state-of-the-science are highlighted, and recommendations are made for future studies measuring the health-related outcomes of stigma, their pathways, and approaches for evidence-based interventions in LMICs.

Methods
Search strategy, data charting, and data summary We conducted a scoping literature review [21] to summarize current research on stigma and health in relation to five high-burden conditions in LMICs, highlighting the gaps and informing future directions [22]. Five searches of peer-reviewed manuscripts published between 2008 and 2017 were conducted between November 2017 and February 2018 using the PubMed (MEDLINE), PsychINFO, and EMBASE databases. Searches included terms related to (1) 'stigma' or other associated terms such as 'discrimination'; (2) 'LMICs' , including all countries with this classification according to the World Bank; and (3) specific diseases or disorders.
Epilepsy was selected to represent neurologic disorders due to the lack of stigma data related to other neurologic conditions. Additional file 1 includes the full list of search terms for each database searched.
Each review and synthesis was conducted by a single study author with condition-specific expertise. An initial title and abstract review was performed, followed by full-text review of any article included during the first phase. For charting, data were extracted according to study authors and year of publication, study design, sample size and sampling characteristics, type of stigma measured (i.e., perceived, anticipated, internalized, experienced/enacted), strength and significance, if applicable, of the stigma and health outcome association, and mediators or moderators.
In reviewing stigma related to the five diseases/disorders assessed, our team identified three populations most adversely affected by stigma, namely LGBTQ individuals, racial and ethnic minorities, and refugees. Boxes 1, 2 and 3 present further details on the relationship between stigma and health for these populations, focusing on commonalities across disorders.

Box 1. Population of concern:
LGBTQ A study done among transgender female sex workers in China reveals limited access to services due to amplified stigma because of their gender identity and their profession [230]. Thus, many decide to engage in self-medication, especially for the transitioning phase, including self-administering hormone use. A case study exploring the economic costs of stigma in India indicates different reasons; if discussing LGBTQ, it is the fear of family deprecation, professional discrimination, and overall societal rejection, yet healthcare providers confidentiality can also lead to discrimination, ultimately leading to breach of human rights [231]. All of them could potentially lead to adverse sexual health outcomes, suicide, and depression. A study performed in Vietnam [232], as a part of a case study series on researching LGBTQ in Asia, found that due to the stigma around the transgender society, transgender people end up doing their own research on gender-confirmation surgery or self-inject cheap and impure chemicals such as silicone and other petroleum products, which in some cases lead to serious harm and even fatalities. The same case study series, with findings from Nepal [233], reported that LGBTQ encounter stigma on daily basis from an early age, shaping how they perceive and interact with all aspects of society, including healthcare. The vast number of institutions, including those in Nepal, stigmatize gender and sexual minorities, with important implications for the ability of healthcare providers and institutions to address their health needs [233]. .

Characteristics of included studies
The database search identified a total of 186 articles discussing one or more of the defined diseases and their relationship with stigma, including 59 articles on HIV (32%), 29 on TB (16%), 27 on mental health (14%), 25 on epilepsy (13%), and 46 on substance use (25%) (Fig. 1). Across studies, 52 LMICs were represented, with 79 studies (43%) focusing on Asia, 70 (38%) on Africa, 21 (11%) on South and Central America, 10 (5%) on Eastern Europe and Russia, and 6 (3%) that included more than one region. The most frequently included countries were China (n = 30), India (n = 21), and South Africa (n = 19). Over half of all included studies were published in 2015 or later, with more publications in 2017 than in any other year, suggesting that research attention to stigma is growing (Fig. 2).
Internalized stigma was the most common stigma type measured (44% of studies), whereas fewer studies focused on experienced (enacted), anticipated, or perceived stigma. Children and adolescents were underrepresented in the included studies, with less than 5% of the included studies involving youth populations. Cross-sectional (68%) and qualitative (15%) study designs were most common, and only 9% of studies used longitudinal data.
Herein, a summary of the reviews for each disease/ disorder is provided (Tables 1, 2, 3, 4 and 5), followed by a discussion on the overlap and intersection of these stigmas.

HIV
Among people with HIV, both internalized and experienced stigma have been associated with increased prevalence of HIV-related symptoms and poorer self-reported health [23][24][25][26] (Table 1). Internalized and experienced HIV-related stigma have been associated with increased prevalence of mental health disorders [27][28][29], particularly depression [30][31][32][33][34][35][36][37][38][39][40] and anxiety [41,42]. For example, among Nigerians with HIV [43], stigma was associated with a diagnosis of severe depression, although it was not associated with mild or moderately severe depression. Among Tanzanian youth [28] and South African adults [28,36], post-traumatic stress Box 2. Population of concern: Racial and ethnic minorities Qualitative studies with refugee, asylum seeking, and immigrant new mothers [234] with depressive symptoms seeking mental health services, including a study with Korean American immigrant women [235], showed a challenging path to recovery due to social isolation and perceived stigma. A study that explored depression and care among Asian Indians in the USA collected data from interviews of 23 multidisciplinary mental health professionals and retrospective review of 20 medical records of patients [236]. Findings revealed that that social stigma contributed to the prolonged denial of a condition, difficulty in communicating the problem, and delayed professional intervention in those suffering from depression.
People living with HIV are stigmatized and looked at negatively, with the fear of discrimination preventing patients from accessing care and the stigma remains a barrier to effectively addressing the disease [237]. Immigrant HIV-positive Latina women in the Midwest USA experienced feelings of stigma, leading to depression, rejection, or suicidal attempts; few had received any type of mental health care intervention [238]. Few cases of self-imposed stigma or 'self-stigma' as a result of minority status has led to reduced health-seeking behavior from health professionals due to fear that disclosing the minority status might be an obstacle from receiving care [239]. Similar findings were presented as part of a qualitative study in mental health among Asian communities in Australia and the unwillingness to access help from healthcare services due to stigma and shame [240]. Immigration and transmission of tuberculosis were reinforcing each other's stigma [241].
Box 3. Population of concern: Refugees Tibetan refugees in Nepal faced different layers of barriers, behavioral norms, and institutional structures that impair the diffusion of relevant information, creating a challenge to develop a comprehensive understanding of HIV/AIDS [242]. The stigma in both host and their own societies was hindering the individual's willingness to discuss the issue with their peers and with medical professionals [242]. A case study based on a literature review and semi-structured interviews of urban refugees in Egypt at high risk for HIV/AIDS [243] revealed that intense stigma and discrimination, vulnerability, and social stability resulted in a lack of adequate health resources and a chain of causation that marginalized refugees in Egyptian society. These social processes result in unequal access to health resources, thereby increasing their potential exposure to HIV transmission.
The sexual violence being used as a weapon of war during conflicts (conflict-related sexual violence) has caused significant trauma in both women and men survivors. The experience of refugees in Ethiopia shows that the stigma associated with conflict-related sexual violence makes it challenging for the survivors to mitigate the potential long-term physical, mental, reproductive health, and social consequences [244]. disorder was also more common among those with high levels of internalized stigma. All forms of stigma have been associated with decreased resilience and self-esteem among Chinese adults [32].
HIV-related stigma has been linked to poor health behaviors. Anticipated, experienced, and internalized stigma have been repeatedly associated with decreased voluntary HIV testing and disclosure of infection [24,[44][45][46][47][48][49]. For example, among Tanzanian adults obtaining HIV services [50], internalized stigma has been linked to increased denial of HIV infection. HIV-positive individuals who report experienced (enacted) stigma are more likely to delay initiation or continuation of HIV care [25,51,52]. Those who experience stigma in a healthcare setting are also less likely to initiate antiretroviral therapy [25]. Available cohort data suggests that perceived stigma is associated with poor medication adherence according to participant reports and chart reviews [53][54][55]. A longitudinal cohort study of adults living with HIV in South Africa revealed that internalized stigma was associated with a greater incidence of condomless sex with both HIV-negative/unknown and HIV-positive partners [5]. Finally, stigma has been associated with increases in smoking, alcohol, and drug use [32], as well as with suicidal ideation and attempted suicide [56,57].
Significant mediators of the relationships between HIV-related stigma and health outcomes included individual resilience [23], depression, negative condom use attitudes [5], and self-efficacy [58]. While most data demonstrated an inverse relationship between quality of life and HIV-related stigma [59][60][61], this relationship may be mediated by depression [33,38] and self-efficacy [58]. The association between HIV stigma and depression has been shown to be moderated by individual affect, social support, socioeconomic status, employment status, rural versus urban residence, and disclosure avoidance [32,35,62].
Tuberculosis TB-related stigma negatively impacts health outcomes by impeding healthcare seeking behavior, care delivery, and recovery (Table 2). Qualitative and quantitative studies have generally shown that stigma delays healthcare seeking, although a recent quantitative study did not find a strong deterrent effect of TB-related stigma when major drivers of healthcare seeking were included in a model [63]. Additionally, TB-related stigma can temporarily diminish social capital during treatment [64], and damage to family reputation can impact                    NSP needle and syringe programs, PMTCT prevention of mother-to-child transmission, PWID persons with injection drug use, RCT randomized controlled trial, SES socioeconomic status employment, education, and the marriage prospects of its members [65,66]. Secondary stigma may manifest as a reluctance to expedite emergency care for acutely ill family members due to fear of disease disclosure to the broader community [66]. In communities where social capital functions as the safety net, loss of social status can imperil family survival [66,67]. TB-related stigma was shown to damage the support networks and quality of services given to those who have a stigmatized condition [66]. Mistreatment of TB patients can contribute to mental health sequelae, poor coping behaviors, and other comorbidities [68,69]. TB-related stigma may also erode patients' resilience to disease and household-level wellbeing [70]. Finally, healthcare workers who perceive TB stigma defer TB screening and prophylaxis [71].
Studies have suggested that the impact of stigma on TB treatment adherence varies [72][73][74], with some suggesting a decrease [75] and others an increase [76,77] in adherence. The predominance of cross-sectional data limits the ability to tease apart this relationship. Much of this variance can also likely be attributable to the diversity across studies with regards to measurement metrics and statistical power [78].
It is likely that drug-resistant TB (DRTB) has a different impact on the association of TB-related stigma with outcomes compared to drug-susceptible TB [79,80]. DRTB disease may be more susceptible to blame, shame, and self-stigma because healthcare workers often assume it is caused by non-adherence. Further, DRTB treatment side effects can expose DRTB patients to mental health, disability, and poverty stigmas [81]. Stigma fed by perceived dangerousness and isolation policies that erode social capital and resilience may disproportionately affect people with DRTB. DRTB-related stigma may also be considered more of a barrier to adherence than HIV stigma among co-morbid persons [79,82].
TB-related stigma can be exacerbated or attenuated by other forms of prejudice, including misogyny [83,84]. Studies of TB-related stigma have also drawn attention to the moderating role of gender. Two studies found women were more adherent to TB treatment when they perceived high levels of stigma, while men were less so, particularly if they found TB treatment humiliating [65,77]. There is also evident variation in the health impacts of TB-related stigma among sub-populations (e.g., people who inject drugs, alcohol dependent, pastoralists) [85][86][87].

Mental health
Studies have indicated that mental health-related stigma is negatively associated with quality of life, functioning, and other positive health outcomes ( Table 3). Quality of life was associated with either internalized or perceived stigma [89] and general functioning was inversely associated with internalized and perceived stigma [88,89]. Greater stigma was also associated with fatigue [90] and poorer diabetes-related outcomes [91] among those with depression, and with HIV-risk behaviors among those with a severe mental illness [92].
Treatment outcomes were a major area of focus within the mental health articles identified. For example, studies on treatment adherence found internalized stigma to be associated with poorer medication adherence both among those with schizophrenia [93] and among those with any diagnosis of a mental disorder [94]. Perceived discrimination was also associated with higher odds of discontinuing medication among individuals diagnosed with schizophrenia [95]. Data on treatment-seeking behaviors for mental health problems were mixed. For example, one study found that individuals identified as having depression yet rejected treatment were more likely to have higher internalized stigma relative to those who accepted treatment [91]. In a community-based study from Ukraine [96], only 8% of individuals who were identified as having a mental health problem but not having sought help from any medical source cited stigma as a reason. However, nearly 75% of individuals living with severe mental illness in India reported delaying seeking care in part due to fear of stigma [97].
Symptom severity was the most common health-related outcome tested for associations with stigma; however, findings on the impacts of mental health-related stigma on mental disorder symptom severity are mixed. For example, two studies found that, among those diagnosed with schizophrenia, those with higher levels of internalized stigma had greater general psychiatric symptoms [88,98]. In contrast, two studies found no relationship between general symptoms of psychopathology and most forms of internalized stigma assessed [89,99], and one study found fewer experiences of stigma among those with more severe general psychiatric symptoms who were living with a severe mental illness [92]. Findings related to symptoms specific to schizophrenia were similarly mixed. Negative schizophrenia symptoms were not significantly associated with most forms of internalized stigma [35,89,99,100]. Of three studies examining positive symptoms of schizophrenia [99][100][101], two found significant associations with stigma operating in opposite directions [99,101]. For individuals with depression, greater symptom severity was associated with greater perceived stigma [90,[102][103][104][105], though one study found less stigma among those with higher levels of symptoms [99].
Moderators were assessed in only two studies on mental health-related stigma and health outcomes and no studies assessed mediators. In Jordan [106], depression was a moderator of the relationship between stigma and treatment seeking. Adolescents with mild depression who reported high levels of stigma were more likely to seek care from a variety of sources (counselor, general practitioner, religious leader, or family member) and express willingness to take medication or receive therapy than adolescents with mild depression who reported low levels of stigma. While moderate to severe depression was associated with lower likelihood of seeking care overall, there was no association between stigma and care-seeking for adolescents with moderate to severe depression. In Egypt [107], insight did not significantly modify the relationship between stigma and suicide risk among persons with schizophrenia.

Epilepsy
Epilepsy-related stigma has been repeatedly linked to poor quality of life and associated with increased epilepsy-related concerns [108,109], poor self-esteem [110], and increased self-reported burden of disease [111], including increased psychiatric burden such as that attributed to anxiety and depression [111][112][113] ( Table 4). Qualitative and quantitative data suggest that epilepsy-related stigma leads to poor overall function, particularly regarding social engagement and employment [111,114,115]. Further, increased stigma has been associated with decreased disclosure and discussion about epilepsy [116,117]. For example, 34% of married Pakistani women with epilepsy actively concealed their epilepsy diagnosis during marriage negotiations in response to misconceptions regarding their diagnosis, pressure from family members, and to avoid rejection and further stigmatization [118].
Epilepsy-associated stigma has also been shown to affect family members of people with epilepsy. Among mothers of children younger than 8 years with epilepsy, stigma has been associated with increased maternal psychopathology [119]. Mothers were also more likely to actively limit their child's activities based on their own and perceived interpretation of their child's internalized stigma [119].
Epilepsy-related stigma has been associated with social withdrawal and adverse health behaviors such as poor medication adherence [120]. This relationship may be mediated by increased medication side-effects reported among adults with epilepsy [121] as these side-effects have previously been associated with increased stigma [122,123], though this relationship has yet to be formally examined as none of the epilepsy studies included in the review evaluated mediators or moderators.

Substance use
Stigma is often prevalent among persons who use alcohol or other substances in both the community and in healthcare settings, with possible adverse consequences (Table 5). Among persons using alcohol or other substances, substance-related stigma was identified as a barrier to accessing drug treatment services [124,125], general healthcare services [124,126], HIV testing [127,128], reduced antiretroviral therapy or treatment adherence [129][130][131], needle exchange programs [132], and to recovery generally [133]. Stigma among persons who use substances was also associated with less education and not being employed full-time [134], as well as lower quality of life across several domains, including the social, physical, psychological, and environmental domains [135], higher risk of relapse [136], social isolation, anxiety, and depression [137]. Healthcare professionals and trainees, including pharmacists and pharmacy students [138], medical students and recent medical graduates [139], and primary healthcare workers [140], expressed stigmatizing beliefs and attitudes towards persons who use drugs.
In addition to stigma occurring as a result of substance use, stigma related to HIV and other health conditions can also be associated with an increased risk for alcohol and other substance misuse. HIV stigma was associated with hazardous/harmful alcohol use among persons co-infected with HIV and TB [141]. Further, among persons with HIV and alcohol use, high levels of HIV-related stigma were associated with increased odds of experiencing physical and sexual violence [142]. Higher levels of HIV stigma were also associated with other (non-alcohol) substance use [143]. Stigma not attached to a health condition can also increase the risk of alcohol and other substance use; indeed, recent discrimination (e.g., based on race, age) was associated with increased odds of both alcohol and drug use [144][145][146].
Two studies investigated moderators. Years of study at university [145], income, and place of residence were found to be significant moderators of stigma-substance use relationships. One study investigated mediators and found that, among men who have sex with men, alcohol and substance use mediated the relationship between stigma and risky sexual behaviors [147].

Intersectional stigmas
Stigmatized medical co-morbidities were common across the five conditions. In many LMICs, the prevalence of HIV and TB can be high and the burden of chronic non-infectious disorders like epilepsy, mental illness, and substance use is growing. HIV-related stigma has been associated with harmful alcohol use among individuals with comorbid HIV and TB infection [87] as well as increased (non-alcohol) substance use among individuals with HIV (alone) compared to those without HIV [143]. Stigma due to other marginalized characteristics (sex, race, gender, country of origin, etc.) also increases the risk of substance use and physical and sexual violence [142,[144][145][146]. This interaction has culminated in a syndemic, with an increased burden of stigma [148].
HIV-related stigma has been shown to attenuate the impact of TB-related stigma in some settings [77,149], while potentiating it in others [150]. Comorbid stigmas do not always result in worse health outcomes. For example, while Zambian adults with HIV and epilepsy endorsed greater stigma, this did not translate into an increased prevalence of depression [151]. However, stigma due to one medical condition, such as substance use, has also been shown to hinder preventative care, including HIV testing [127,128] and, among individuals with comorbid HIV infection, medication adherence [129][130][131].

Discussion
Across disease types included in this scoping review, stigma was associated with poor individual health outcomes and health utilization patterns. Stigmas related to HIV, TB, epilepsy, and substance use were associated with increased psychiatric morbidity, particularly depression and anxiety. Stigma has repeatedly been associated with decreased quality of life and poorer functioning across conditions. Highly stigmatized individuals are more likely to conceal their condition and, as a result, are less likely to seek care or more likely to delay care. This is consistent with the literature from high-income countries on stigma related to mental health conditions. In a systematic review of 144 studies (the vast majority of which were from high income countries) [152], the median effect size of stigma on help-seeking for mental health disorder was -0.27, though there was some evidence that this relationship was stronger among ethnic minority groups within these countries; qualitative studies suggested that this is both a direct relationship and may be mediated through decreasing disclosure.
Among those obtaining treatment for all five conditions examined in this review, stigma was associated with decreased medication adherence and, among patients with substance use, relapse. In high-income countries, the relationships between treatment adherence and stigma related to mental health problems is varied. Perceived stigma has been found to predict poorer treatment outcomes for individuals with depression [153,154]; though this evidence is mixed, internalized stigma has also been found to be related to poorer treatment adherence for individuals living with multiple mental health conditions [155]. Conversely, anticipated and experienced discrimination has been found to not be significantly associated with antipsychotic medication adherence for people living with schizophrenia [156].
Studies examining individuals with multiple stigmatized conditions suggest that the effects of health-related stigma can be felt across all domains. Just as stigma among individuals with mental health problems or injection drug use decreases their use of mental health and substance disorder services, it also decreases HIV testing and medication adherence. Unfortunately, the effects of stigma across conditions are complex and, similar to studies describing stigma in high-income countries [1], our review found that studies of stigma and health outcomes in LMICs are largely focused on one stigmatizing condition (often only internalized stigma) and one health outcome. Few studies described the complex interactions between different types of stigma and the co-occurring health conditions likely to be present.
As highlighted in Boxes 1, 2 and 3, the review results showed that marginalized members of society are increasingly vulnerable to health-related stigma.
LGBTQ individuals, racial and ethnic minorities, and refugees suffer from increased stigma due to lack of social and economic stability, fear of encountering stigma, and increased self-stigmatization. Unequal access to treatment and, among refugee communities, decreased access to information, result in reduced healthcare-seeking behaviors. These associations can be amplified by perceived stigma from the healthcare community, which further delays care and reduces healthcare-seeking behavior. The effects of trauma, particularly among LGBTQ individuals and refugees, are often under-recognized, which also affects care. Unfortunately, as most studies recruit participants from healthcare settings, these individuals may have been overlooked within the available stigma data, and particularly in that related to HIV, mental health, and epilepsy. Similarly, difficulty in recruiting these populations presents a research challenge and affects data availability. Therefore, the effect of stigma on the health and health outcomes of vulnerable populations may be underestimated. While the substance use literature featured a wider range of populations, including representation of sexual and gender minorities, as well as geographies, the generalizability of this data is limited by its focus on alcohol and injection drug use; other substance types (e.g., inhalants, cocaine, prescription drugs) that may have associations with stigma have been largely neglected. Further, the effect of stigma on child and adolescent populations is poorly understood as only one study examining epilepsy-associated stigma focused on this vulnerable population [107]. Given that risk factors, symptom presentation, and trajectories of mental health and substance use problems may vary across the life course, increased research on stigma among children and adolescents is essential.
Comprehensive, multidisciplinary stigma-focused prevention and treatment approaches are warranted in LMICs. However, the design and implementation of these interventions is limited by the data available. This review highlights the paucity of longitudinal stigma studies on health-related stigma in LMICs, particularly among community-based samples, which limits our understanding of the mechanisms by which stigma impacts health outcomes. Appropriately designed quantitative cohort studies are vital to addressing these issues. Further, most of the studies included in this review were limited by small sample size and, as a result, data regarding mediators of the association between stigma and health outcomes is scant. Future research should include larger sample sizes that would enable more complex path modelling, including effect modification analysis. Available data suggests that gender is a moderator of both TB-related and substance use stigma. Understanding the effects of moderators and mediators on the relationship of stigma with individual health outcomes will improve the effectiveness of stigma reduction interventions.

Limitations of the review
The purpose of the review was to inform both potential future research studies and possible research questions that could be addressed by systematic reviews. Formal study inclusion and exclusion criteria were not used as the review was not systematic; however, similar search terms and databases were used across the five disease reviews. Although the types of study designs described in the literature were often noted, individual study quality was not assessed, as is typical in scoping reviews. Finally, we focused on five disease/disorders that significantly drive the disease burden in LMICs. Future reviews should focus on other stigmatized conditions affecting individuals in this setting, including abortion, cancer, leprosy, albinism, gender identity, sex work, sexual violence, and sexually transmitted infections.

Conclusion
A rapidly growing body of literature, mostly qualitative and cross-sectional in design, suggests that stigma is associated with poor health outcomes, including less help-seeking, among persons with HIV, TB, mental health, neurologic disorders, and substance use. This review highlights consistencies in the relationship of stigma with health outcomes, but also common methodological limitations. Future studies can address these limitations by (1) recognizing that comorbidity is the rule and not the exception and that the complex interconnected relationships between stigma and multiple health outcomes must be accounted for in the study design phase; (2) measuring multiple types of stigma at multiple health outcome levels; and (3) featuring longitudinal designs, investigation into mediators and moderators, and community-based study samples to improve generalizability. Removing the siloes from health-related stigma research in LMICs and addressing these limitations will improve the epidemiological literature on evidence-based stigma interventions, ultimately improving outcomes associated with high-burden diseases.