Rheumatic heart disease (RHD) disproportionately affects developing countries and remains the predominant acquired heart disease among the young in these regions (1). According to the most recent Global Burden of Disease estimates, RHD prevalence has decreased in high-income countries (2); however, it has increased in low-to-middle-income countries, affecting nowadays over 40 million patients worldwide (2). RHD also accounts for more than 300,000 annual deaths and nine million disability-adjusted life years lost (3).

RHD development involves complex interactions among host susceptibility factors, with sex predisposition playing a crucial role (4, 5). The prevalence ratio of acute rheumatic fever (ARF) between males and females is unclear, but most evidence supports equal prevalence (4, 6, 7). Despite that, the risk of heart valve damage from RHD significantly rises in adult females, especially between the ages of 25 and 45 (8, 9). Chronic RHD has a clear female predominance, with ratios ranging from 2:1 to 4:1 in different studies (9, 10). Nonetheless, the precise age when these sex differences become evident is still a gap in the literature. This epidemiological data is crucial to stimulate further research in sex predisposition in RHD, increasing our understanding of RHD pathophysiology and potentially improving disease management through new therapeutic targets.

Early identification of RHD, prior to established valvular dysfunction, and the prompt initiation of penicillin prophylaxis may prevent disease progression and reduce RHD burden worldwide (1). Moreover, a double-blind placebo-controlled trial indicated that regular use of penicillin G benzathine every four weeks can significantly reduce the risk of progression of echocardiographically detected RHD (11). RHD burden tends to be highest in resource-limited countries owing to social disparities and lack of access to adequate diagnostic tools and therapies. Echocardiographic screening for RHD allows early detection, supporting timely decision-making for initiating antibiotic prophylaxis. (12, 13).

Our study aims to provide current insights into the prevalence of RHD across continents, ages, and risk factors, with a particular focus on sex disparities. Aligned with research priorities set by both the American Heart Association and World Heart Federation (WHF), we conducted a systematic review and updated meta-analysis of the prevalence, severity, and variations of RHD across clinical and socioeconomic subgroups (1, 14). This is a summary of the literature prior to the application of 2023 WHF diagnostic criteria for RHD screening (15).

This systematic review and meta-analysis were conducted in line with Cochrane recommendations and Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement guidelines (16, 17). Accordingly, it was prospectively registered with the International Prospective Register of Systematic Reviews (PROSPERO number CRD42023491941).

We conducted a comprehensive systematic review and meta-analysis to determine the prevalence of RHD, analyzing data from 58 studies encompassing a total of 215,552 children and adolescents. The overarching prevalence of RHD was found to be 24 per 1,000 individuals, and we identified a consistent prevalence in all endemic areas. This meta-analysis differs from prior work by focusing exclusively on echocardiographic screening studies, examining RHD severity and morphological features, and addressing sex disparities in latent RHD. By directly comparing prevalence across subgroups, we confirmed previous knowledge and highlighted vulnerable populations—(i) females, (ii) individuals in rural areas, (iii) students in public schools, and (iv) low-income households. Additionally, latent RHD prevalence exceeded twice in patients aged 10 years or older compared to younger individuals.

Chronic RHD exhibits a higher prevalence among females, with at least a 2:1 ratio (5, 9, 10). Previous studies including patients with rheumatic mitral stenosis, a late stage of RHD, reveal an even higher female predominance, exceeding 80% (10, 79). However, ARF, the primary precursor to RHD, has not been reported as more prevalent in female children and adolescents; most studies suggest a 1:1 ratio (4). Our study extends the findings of a prior meta-analysis, which, via univariate meta-regression, revealed an association between female sex and latent RHD diagnosis (80). In our investigation, this finding was confirmed through a first direct comparison of latent RHD prevalence across sexes, with a ratio female/male of 1·4:1. In summary, current literature supports that (i) ARF has approximately a 1:1 female/male ratio, our meta-analysis showed that it is (ii) 1·4:1 in latent RHD and is well-known that (iii) chronic it is at least 2:1. These findings suggest a tendency towards a higher prevalence of RHD progression in females.

Environmental factors may contribute to the increased risk in females, given the more frequent role of women in caring for children and younger siblings outside their household, which may expose them to a greater risk of group A streptococcus infections (4, 81). In addition, females typically are also more susceptible to autoimmune conditions, which may contribute to these outcomes (82). A recent study conducted proteomic analysis on 30 cardiac valves from patients without RHD and compared them to valves affected by RHD (5). This investigation revealed a higher presence of prothymosin-alpha in RHD-related valve pathologies (5). Notably, this protein, which plays an important pathogenetic role in streptococcal antigen presentation by HLA molecules and CD8 lymphocyte activation, is linked to estrogen receptor alpha activity, suggesting its potential role as a regulator of the female predisposition to developing RHD (5).

RHD exerts a greater burden on low-to-middle-income nations (14). This may be secondary to superior healthcare in middle-to-high-income nations, including prompt treatment for streptococcal sore throats more widespread implementation of secondary prophylaxis with penicillin, and better living conditions that avoid overcrowding (81). Disparities in healthcare support can also be observed within regions of the same country. Our study revealed, by direct comparison, a heightened prevalence of latent RHD among children from rural areas, those attending public schools, and those from low-income families, all of whom exhibit increased health vulnerability. The study with the highest latent RHD prevalence included African refugees residing in Italy and unveiled a prevalence of 21%, which is tenfold greater than the overall prevalence in our analysis (69). This can indicate the environmental vulnerability associated with the disease and immigrant population.

The WHO first proposed echocardiographic screening criteria for RHD in 2005, introducing the concepts of definite, probable, and possible disease based on echocardiographic findings and epidemiological factors such as residence in endemic areas or a history of ARF. In 2012, the WHF released updated criteria (19), defining only borderline and definite RHD, based solely on echocardiographic parameters (see Supplementary Appendix). In our analysis, the prevalence by WHO criteria (eight studies) was 24 per 1,000 (95% CI 13–40; I² = 97%), and by WHF criteria (46 studies) 25 per 1,000 (95% CI 19–32; I² = 98%), with no significant difference. However, rates varied among studies, and Spitzer et al. (66) did a direct comparison in a Peruvian cohort and found prevalence rates of 19.7/1,000 (WHO) vs. 3.9/1,000 (2012 WHF). Most recently, the 2023 WHF classification introduced four stages (A–D) reflecting valve morphology and regurgitation severity (15). This staging recognizes RHD as a spectrum, enhancing the understanding of disease progression. Nevertheless, none of the included studies were performed after the adoption of the new WHF criteria.

Latent RHD was categorized into two groups according to 2012 WHF criteria: definite and borderline (19). Within the definite category, there are further subdivisions, namely mild, moderate, and severe, each associated with distinct disease progression patterns and outcomes. Moderate and severe RHD exhibit a higher propensity for disease progression and are linked to increased mortality (83). One study followed latent RHD patients for over one year, revealing that, during the follow-up, 40% of those with moderate to severe definite RHD experienced disease progression, and 10% succumbed to the condition (83). A meta-analysis on disease progression reported a 7.5% progression rate in definite RHD, with 60% remaining stable; however, one limitation was the variability in follow-up durations across studies (80). Therefore, a large amount of latent RHD patients improve without any treatment. In our pooled analysis, 41% of individuals with definite RHD had moderate-severe disease. The overall prevalence of definite RHD by WHF among screened children is 9 cases per 1,000, and with moderate-severe definite RHD at 41%, it is plausible that more than 3 children out of every 1,000 in endemic regions may have a more severe form of the disease.

Definite RHD could benefit from a screening program: (i) it typically manifests later in life, stemming mainly from childhood ARF (4); (ii) there is a disease progression, advancing from borderline latent RHD to definite latent RHD and ultimately clinical RHD (80); (iii) Current evidence supports that secondary prophylaxis can prevent disease progression (11), and (iv) sensitive diagnostic examinations as echocardiogram are available for detection (12). Efforts to combat RHD could greatly benefit from the identification of a biomarker. The Leducq Foundation is currently funding multi-center research groups aimed at discovering a biomarker for ARF that could be utilized for effective screening. Nonetheless, some challenges persist, such as the need for specialized echocardiogram interpretation, more studies on secondary prophylaxis, and the necessity for further data to determine the optimal age for screening initiation, as the timing of maximum treatment effectiveness remains uncertain. Our meta-analysis unveiled a higher prevalence of latent RHD in children aged 10 years and older when compared with those younger than 10 years (Supplementary Figure S6). This outcome aligns with expectations, given that the disease exhibits progressive development over time, with a significant proportion of ARF cases occurring between the ages of 5 and 15 years.

Our study contributes to the discussion on public health strategies for RHD prevention, such as echocardiographic screening and subsequent penicillin prophylaxis. Before these approaches can be implemented as public policy, further studies are needed to assess cost-effectiveness and to compare screened and treated groups with unscreened populations. Based on our findings, initial screening efforts could focus on high-risk settings, such as rural areas, low-income families, and children attending public schools, who are likely to benefit the most. Additionally, a promising strategy to provide region specific data and further understand disease burden is the development of high-quality RHD databases, such as the ARGI from Egypt (84).

Two previous meta-analyses (2014 and 2019) examined the global prevalence of latent RHD (80, 85). However, the current meta-analysis provides a more focused and comprehensive approach by narrowing the scope to echocardiogram-based screening studies in endemic regions. This strategy allowed us to delve deeper into at-risk groups, identifying higher susceptibility among females, public school children, rural residents, and individuals from low-income families. Additionally, we assessed prevalence patterns based on echocardiogram criteria, mitral lesion types, and the prevalence of moderate and severe cases. Importantly, our systematic search incorporated 24 new studies, screening over 85,000 individuals, significantly expanding the evidence base since the last global meta-analysis. This updated and detailed perspective highlights emerging trends and provides critical insights to guide targeted interventions and policy development in high-burden regions.

Our study has limitations. As a worldwide systematic review, we utilized data with varying inclusion criteria, ethnicities, baseline characteristics, and risk factors. While these factors contributed to a broader result, they also increased heterogeneity. To mitigate this, we only included studies that used echocardiogram as a screening tool due to its high sensitivity compared to other methods. Nevertheless, the consistency of overall prevalence across the endemic areas despite different clinical and geographic settings suggests that the current results are reproducible. Furthermore, we scrutinized the findings by constructing a meta-regression with several potential confounding or modifier variables. Ultimately, the heterogeneity may simply be secondary to different regional prevalences between studies.

The present study reveals a higher prevalence of RHD in females, consistent with patterns observed in chronic RHD. By highlighting the early-stage female predominance in latent RHD, our study provides support for the concept that gender disparity in RHD emerges at an early stage, preceding the onset of heart valve damage. Moreover, there is a higher prevalence in children from rural areas, public schools, and low-income families, emphasizing the need for targeted interventions in these vulnerable populations.