Distribution and trends of the global burden of female infertility attributable to sexually transmitted infections from 1990 to 2021.

Given the potential collinearity between chronic disease burden indicators, we first examined the correlation between the ASPR and ASDR across global and SDI regions. At the global level, the two metrics showed an extremely high positive correlation (Pearson’s r  = 0.992, p  < 0.001). Similarly, strong and consistent positive correlations were observed across all SDI groupings (Supplementary Fig. 1 and Supplementary Table 1 ). Based on this finding, and to avoid redundancy and overestimation of temporal trends, subsequent analyses were based on ASPR to quantify the burden of STIs-related female infertility. After confirming the strong correlation between the two indicators, we proceeded to describe the global burden. To transition from correlation assessment to overall burden estimation. We then analyzed the global prevalence rates of primary and secondary STIs-related female infertility. In 1990, the ASPR of SRPI was 85.24 per 100,000 (95% UI:8.15 to 135.28), and the ASPR of SRSI was 347.86 per 100,000 (95% UI: 263.05 to 432.80). In 2021, the ASPR of SRPI was 90.08 per 100,000 (95% UI: 48.03 to 148.05), and the ASPR of SRSI was 365.04 per 100,000 (95% UI: 292.30 to 443.57) (Fig. 1 A and B and Supplementary Table 2 ). While both absolute rate changes and EAPC were calculated, their temporal patterns were nearly identical across all SDI regions, except for the global-level SRPI (e.g., rate change: +5.68% vs. EAPC: -0.18, 95% CI -0.28 to -0.08) (Fig. 1 C). Generally, the global burden of STIs-related infertility indicated a stable trend. The EAPC of the SRPI burden was − 0.18 (95% CI: -0.28 to -0.08), and the EAPC of the SRSI burden was 0.01 (95% CI: -0.04 to 0.07) (Fig. 1 D). To facilitate understanding of disparities across levels of socioeconomic development, we next compared the patterns of change across SDI strata. At the SDI regional level, the ASPR of SRPI and SRSI has consistently remained the lowest in high-middle SDI regions over the past 32 years. For SRPI, before 2005, the low SDI regions had the highest ASPR. However, after 2005, the ASPR in low-middle SDI regions surpassed that of the former. For SRSI, low SDI regions have persistently exhibited the highest burden in terms of the ASPR from 1990 to 2021. Over the 32-year period, the burden of STIs-related infertility in low SDI regions has shown a significant downward trend. The EAPCs of the burden for SRPI and SRSI were − 1.20 (95% CI: -1.38 to -1.01) and − 1.30 (95% CI: -1.48 to -1.11) respectively (Fig. 1 D). Notably, in high SDI regions and high-middle SDI regions, the burden of SRPI and SRSI has shown opposite trends of change. Fig. 1 Spatiotemporal trends and long-term changes in STIs-related primary infertility (SRPI) and STIs-related secondary infertility (SRSI). ( A ) Spatiotemporal distribution of age standardized prevalence rate for SRPI from 1990 to 2021; ( B ) ASPR distribution for SRSI in the same period; ( C ) Change of rate in SRPI and SRSI from 1990 to 2021; ( D ) Estimated annual percentage change (EAPC) for SRPI and SRSI over the past three decades Spatiotemporal trends and long-term changes in STIs-related primary infertility (SRPI) and STIs-related secondary infertility (SRSI). ( A ) Spatiotemporal distribution of age standardized prevalence rate for SRPI from 1990 to 2021; ( B ) ASPR distribution for SRSI in the same period; ( C ) Change of rate in SRPI and SRSI from 1990 to 2021; ( D ) Estimated annual percentage change (EAPC) for SRPI and SRSI over the past three decades We then extended the analysis to GBD regions to obtain more geographically refined insights beyond the SDI categories. At the GBD regional level, East Asia has consistently had the lowest ASPR for SRPI, while the regions with the highest ASPR have varied across different years. Regarding SRSI, the ASPR in Western Sub-Saharan Africa has been persistently the highest. The downward trend of the burden in Sub-Saharan Africa is the most remarkable. For the burden of SRPI in Southern Sub-Saharan Africa, Western Sub-Saharan Africa, and Eastern Sub-Saharan Africa, the EAPCs are − 1.98 (95% CI: -2.52 to -1.43), -1.75 (95% CI: -2.03 to -1.47), and − 1.54 (95% CI: -1.70 to -1.38), respectively. For the burden of SRSI, the EAPCs are − 1.52 (95% CI: -1.95 to -1.08), -1.69 (95% CI: -1.95 to -1.42), and − 1.33 (95% CI: -1.52 to -1.15), respectively. By contrast, the burden of STIs-related infertility in Tropical Latin America has shown a significant upward trend [SRPI EAPC 3.46 (95% CI: 2.35 to 4.58); SRSI EAPC 4.53 (95% CI: 3.25 to 5.84)] (Supplementary Table 2 ). Examining individual countries offered an even more detailed view of these regional patterns. We further conducted a country-level analysis of SRPI and SRSI trends across 204 countries and territories from 1990 to 2021. For ASPR, the country with the highest SRPI remained Cameroon throughout the period (1990: 305.34 per 100,000, 95%UI 195.06 to 425.35, 2021:197.60 per 100,000, 95%UI 93.47 to 349.58, respectively), while the highest ASPR for SRSI shifted from Mali (2016.96 per 100,000, 95%UI 1513.99 to 2417.97) in 1990 to Sierra Leone in 2021 (1127.16 per 100,000, 95%UI 975.44 to 1345.43). In contrast, the lowest ASPR for SRPI changed from China (21.38 per 100,000, 95%UI 9.37 to 40.35) in 1990 to Taiwan (Province of China) (20.71 per 100,000, 95%UI 9.22 to 39.72), as reported separately in the GBD dataset in 2021 (Fig. 2 A and B). While for SRSI, it decreased from Denmark (54.43 per 100,000, 95%UI 31.82 to 81.13) to Iceland (57.65 per 100,000, 95%UI 41.86 to 73.98) (Fig. 3 A and B). When comparing the absolute number of prevalent cases, Qatar had the largest increase in both SRPI (Change Cases = 656.28%) and SRSI (Change Cases = 766.66%), whereas Latvia (Change Cases = -43.50%) and the United States Virgin Islands (Change Cases = -37.61%) showed the lowest counts in 2021 (Figs. 2C and 3C). EAPC analysis revealed that Brazil exhibited the most significant increasing trends in both SRPI and SRSI [EAPC: 3.56 (95% CI: 2.43 to 4.69) and 4.64 (95% CI: 3.33 to 5.96), respectively], while Burkina Faso [EAPC of SRPI: -3.55 (95% CI: -4.25 to -2.84)] and Mali [EAPC of SRSI: -3.12 (95% CI: -3.40 to -2.84)] showed marked declines (Fig. 2 D and 3 D and Supplementary Tables 3 and 4 ). Fig. 2 Global distribution of STIs-related female infertility burden for primary infertility. ( A ) Age-standardised prevalence rate (ASPR) in 1990, ( B ) ASPR in 2021, ( C ) Percentage change in case number between 1990 and 2021, and ( D ) Estimated annual percentage change (EAPC) in ASPR from 1990 to 2021 Global distribution of STIs-related female infertility burden for primary infertility. ( A ) Age-standardised prevalence rate (ASPR) in 1990, ( B ) ASPR in 2021, ( C ) Percentage change in case number between 1990 and 2021, and ( D ) Estimated annual percentage change (EAPC) in ASPR from 1990 to 2021 Fig. 3 Global distribution of STIs-related female infertility burden for secondary infertility. ( A ) Age-standardised prevalence rate (ASPR) in 1990, ( B ) ASPR in 2021, ( C ) Percentage change in case number between 1990 and 2021, and ( D ) Estimated annual percentage change (EAPC) in ASPR from 1990 to 2021 Global distribution of STIs-related female infertility burden for secondary infertility. ( A ) Age-standardised prevalence rate (ASPR) in 1990, ( B ) ASPR in 2021, ( C ) Percentage change in case number between 1990 and 2021, and ( D ) Estimated annual percentage change (EAPC) in ASPR from 1990 to 2021 Globally, the burden of infertility caused by different types of STIs showed diverse trends. Consistent with the approach in section “ The global and regional burden of STIs-related female infertility ”, we focused on reporting EAPC. It is worth noting that the absolute rate of change exhibited conflicting directions compared to EAPC in other STI-related primary infertility (e.g., high SDI region, rate change: +1.55% vs. EAPC: -0.54, 95% CI -0.75 to -0.33) (Fig. 4 A). For primary infertility, the EAPC of ASPR for chlamydia - related infertility was − 0.15 (95% CI: -0.25 to -0.05). Gonorrhoea-related infertility showed a larger decline, with an EAPC of -0.95 (95% CI: -1.06 to -0.84), while other STI-related infertility had a smaller decrease (EAPC: -0.12, 95% CI: -0.22 to -0.02). Regarding secondary infertility, the EAPC for chlamydia-related infertility was 0.10 (95% CI: 0.04 to 0.17), for gonorrhoea-related infertility was − 0.61 (95% CI: -0.72 to -0.50), and for other STI was 0.03 (95% CI: -0.02 to 0.09) (Fig. 4 B and Supplementary Table 2 ). Fig. 4 Temporal trends in primary and secondary infertility rates associated with chlamydia, gonorrhoea, and other STI. ( A ) Rate of change for primary and secondary infertility caused by Chlamydia, Gonorrhoea, and other STI from 1990 to 2021; ( B ) Estimated annual percentage change (EAPC) for both primary and secondary infertility in chlamydia, gonorrhoea, and other STI over the past three decades Temporal trends in primary and secondary infertility rates associated with chlamydia, gonorrhoea, and other STI. ( A ) Rate of change for primary and secondary infertility caused by Chlamydia, Gonorrhoea, and other STI from 1990 to 2021; ( B ) Estimated annual percentage change (EAPC) for both primary and secondary infertility in chlamydia, gonorrhoea, and other STI over the past three decades Building on the global and SDI-level findings, the regions with the most remarkable changes varied according to the type of infection and infertility. For primary infertility, the largest reductions occurred in low SDI regions, with chlamydia-related infertility showing an EAPC of -1.23 (95% CI: -1.42 to -1.04). Gonorrhoea-related infertility in low SDI regions decreased with an EAPC of -1.70 (95% CI: -1.89 to -1.50), and other STI-related infertility declined with an EAPC of -1.13 (95% CI: -1.31 to -0.95) (Supplementary Table 2 ). In secondary infertility, low SDI regions again experienced the most pronounced declines. Chlamydia-related infertility had an EAPC of -1.24 (95% CI: -1.43 to -1.06), gonorrhoea-related infertility − 1.70 (95% CI: -1.91 to -1.49), and other STI-related infertility − 1.28 (95% CI: -1.46 to -1.09). Overall, the burden of STIs-related infertility in low SDI regions showed a distinct downward trend across various infection types, indicating significant reductions in both primary and secondary infertility (Supplementary Table 2 ). After characterizing regional heterogeneity, we next examined country-level patterns to assess whether these trends persisted at finer geographic resolution. We also conducted a national-level analysis and found that the temporal trends (1990–2021) in infertility burden caused by different STIs were largely consistent with the overall STIs-related infertility trends. Brazil exhibited the most substantial increases in both primary and secondary infertility across all three STI subtypes. For primary infertility, EAPCs were 3.73 (95% CI: 2.58 to 4.90) for chlamydia, 3.00 (95% CI: 2.04 to 3.98) for gonorrhoea, and 3.53 (95% CI: 2.41 to 4.67) for other STI. For secondary infertility, EAPCs were 4.78 (95% CI: 3.45 to 6.12) for chlamydia, 4.10 (95% CI: 2.95 to 5.26) for gonorrhoea, and 4.63 (95% CI: 3.32 to 5.96) for other STI. In contrast, countries such as Burkina Faso and Mali showed the steepest declines. In Burkina Faso, primary infertility reductions were strongest for chlamydia (EAPC: -3.48, 95% CI: -4.16 to -2.80), gonorrhoea (EAPC: -4.07, 95% CI: -4.82 to -3.31), and other STI (EAPC: -3.52, 95% CI: -4.22 to -2.81). In Mali, the largest decreases occurred in secondary infertility for chlamydia (EAPC: -3.11, 95% CI: -3.40 to -2.82), gonorrhoea (EAPC: -3.82, 95% CI: -4.17 to -3.47), and other STI (EAPC: -3.04, 95% CI: -3.31 to -2.77) (Supplementary Tables 3 and 4 ). To better capture turning points in temporal trends, we conducted Joinpoint regression analyses across multiple levels. At the global level, the ASPR of SRPI generally fluctuated with short periods of increase (1990–1992, APC = 3.56; 1992–1995, APC = 1.14; 2015–2021, APC = 0.64) and two longer periods of decline (1995–2006, APC = -0.42; 2006–2010, APC = -1.08), while changes during 2010–2015 were not statistically significant, highlighting a modest long-term downward tendency with recent mild increases (Fig. 5 A). For SRSI, the ASPR increased in 1990–1994 (APC = 0.56), 2008–2016 (APC = 0.15), 2016–2019 (APC = 1.19), and 2019–2021 (APC = 0.58), while declines were observed during 1994–2001 (APC = -0.12) and 2001–2008 (APC = -0.36) (Fig. 5 B and Supplementary Table 5 ). We also applied Joinpoint analysis to further delineate the temporal trends in Brazil from 1990 to 2021. For SRPI, significant decreases were observed during 1990–1995 (APC = -1.44) and 2004–2018 (APC = -1.85), while marked increases occurred during 1995–2000 (APC = 18.92) and 2000–2004 (APC = 9.34). In recent years (2018–2021), the trend has stabilized (Fig. 5 C). For SRSI, an upward trend was observed in 1990–1995 (APC = 5.32), followed by a substantial rise in 1995–2004 (APC = 16.40). Subsequently, the trend reversed, showing declines during 2004–2010 (APC = -3.02) and 2010–2021 (APC = -1.24) (Fig. 5 D and Supplementary Table 6 ). A Joinpoint analysis was also conducted for various regions and other countries, detailed results are provided in the relevant tables (Supplementary Tables 5 and 6 ). Fig. 5 Joinpoint regression analysis of age-standardized prevalence rate (ASPR) for STIs-related female primary and secondary infertility from 1990 to 2021. ( A ) Global primary infertility; ( B ) Global secondary infertility; ( C ) Primary infertility in Brazil; ( D ) Secondary infertility in Brazil Joinpoint regression analysis of age-standardized prevalence rate (ASPR) for STIs-related female primary and secondary infertility from 1990 to 2021. ( A ) Global primary infertility; ( B ) Global secondary infertility; ( C ) Primary infertility in Brazil; ( D ) Secondary infertility in Brazil Globally, the burden of primary infertility among the 15–19 age group has shown a significant downward trend (Supplementary Fig. 2 A and B). The EAPC for chlamydia-related primary infertility is -0.74(95% CI: -0.99 to -0.49), for gonorrhoea-related infertility, is -0.96 (95% CI: -1.18 to -0.74), and for other STI is -0.75 (95% CI: -1.02 to -0.48). Overall, these patterns indicate a consistent decline in early adolescence across all infection types. However, in the 40–44 and 45–49 age groups, the trend reverses, showing an increase in burden. For chlamydia-related primary infertility, the EAPC is 0.34 (95% CI: 0.16 to 0.54) in the 40–44 age group and 0.44 (95% CI: 0.19 to 0.69) in the 45–49 age group. Similarly, other STI-related infertility also shows an increasing trend, with EAPCs of 0.29 (95% CI: 0.13 to 0.45) in the 40–44 age group and 0.41 (95% CI: 0.20 to 0.61) in the 45–49 age group (Supplementary Table 7 ). For secondary infertility, the global burden among individuals aged 15–19 and 30–34 group has shown an upward trend for both Chlamydia-related and other STI-related infertility. In the 15–19 age group, the EAPC for chlamydia-related infertility is 0.86 (95% CI: 0.64 to 1.08), while that for other STI-related infertility is 0.65 (95% CI: 0.47 to 0.83). This shared upward pattern across infection types suggests a similar increase among younger adults. However, in the 40–44 and 45–49 age groups, the burden shifts to a declining trend. The EAPC for chlamydia-related infertility in the 40–44 age group is -0.10 (95% CI: -0.21 to 0.01) and − 0.32 (95% CI: -0.48 to -0.16) in the 45–49 age group. Similarly, the EAPC for other STI-related infertility is -0.12 (95% CI: -0.19 to -0.06) in the 40–44 age group and − 0.24 (95% CI: -0.38 to -0.11) in the 45–49 age group (Supplementary Table 7 ). Thus, as with primary infertility, the main contrast lies between rising burden at younger ages and declining burden in older adults. Additionally, the burden of gonorrhoea-related secondary infertility shows an increasing trend in the 15–19 and 20–24 age groups, with EAPC of 0.44 (95% CI: 0.25 to 0.63) and 0.32 (95% CI: 0.20 to 0.43), respectively. Unlike chlamydia and other STIs, however, gonorrhoea demonstrates the clearest turning point, as this upward trend reverses after 25–29 years of age, with a more pronounced decline in the 45–49 age group (EAPC = -1.05; 95% CI: -1.23 to -0.87) (Supplementary Table 7 ). We analyzed the association between STIs-related infertility burden estimates and SDI levels across 21 GBD regions from 1990 to 2021. Overall, the data indicates that different sexually transmitted infections have varying relationships with SDI levels in the context of infertility. For primary infertility, gonorrhoeae infection exhibited a significant positive correlation with SDI ( r  = 0.308, p  < 0.001) (Supplementary Fig. 3 and Supplementary Table 8 ), whereas chlamydial infection ( r  = 0.067, p  = 0.099) and other STI ( r =-0.063, p  = 0.120) showed no statistically significant associations. To better guide interpretation across SDI levels, the burden of SRSI remains stable at moderate SDI (0.4–0.7). At lower SDI levels ( 0.7), the correlation becomes positive. This can also be observed in infertility cases related to different infectious causes. Regions such as Southern Latin America, Australasia, and High-income North America exhibit a higher-than-expected SRSI burden, while areas including East Asia, Southeast Asia, and Western Europe show a lower-than-expected burden. For secondary infertility, both gonorrhoeae infection ( r  = 0.337, p  < 0.001) and chlamydial infection ( r  = 0.152, p  < 0.001) were positively correlated with SDI, while other STI had no significant association ( r =-0.058, p  = 0.152). A similar SDI-stratified pattern is observed for SRPI, when the SDI is less than 0.5, the burden of SRPI is negatively correlated with the SDI. When the SDI is greater than 0.7, the two show a positive correlation. However, when the SDI ranges from 0.5 to 0.7, the burden estimates remain stable (Fig. 6 A). The regional trends of SRSI burden are largely consistent with those of SRPI burden (Fig. 6 B). Fig. 6 Association between Sociodemographic Index (SDI) and age-specific prevalence rates (ASPR) of STIs-related infertility. ( A ) SDI and ASPR trends for STIs-related primary infertility; ( B ) SDI and ASPR trends for STIs-related secondary infertility Association between Sociodemographic Index (SDI) and age-specific prevalence rates (ASPR) of STIs-related infertility. ( A ) SDI and ASPR trends for STIs-related primary infertility; ( B ) SDI and ASPR trends for STIs-related secondary infertility We constructed an A-P-C model to disentangle the independent effects of age, period, and birth cohort on the temporal trends of STI-related infertility burden. For SRPI, globally, the age effect exhibited an approximately inverted V-shaped trend, with the peak observed in the 40–44 age group (Fig. 7 A and Supplementary Table 9 ). Notably, the age-specific impact of chlamydia and gonorrhoea was more pronounced in the 25–39 age group compared to other SRPI. The period effect demonstrated a V-shaped pattern, with the lowest point occurring between 2010 and 2014. However, for gonorrhoea, the period effect did not rebound after its initial decline. The cohort effect showed a gradual increase until the 1958–1962 birth cohort, followed by a continuous decline thereafter. For SRSI, globally, the trends were largely consistent with those observed for SRPI. The age effect also displayed an inverted V-shaped pattern, albeit more pronounced than that of SRPI, with the peak similarly occurring in the 40–45 age group (Fig. 7 B and Supplementary Table 9 ). The period effect resembled a U-shaped curve, with the lowest point observed between 2007 and 2012. However, the period effect for gonorrhoea peaked earlier, between 1995 and 1999, whereas the peak for other STI-related infertility occurred later, between 2020 and 2024. The cohort effect began to decline after the 1953–1957 birth cohort, with no subsequent recovery observed. Fig. 7 Age–period–cohort (A-P-C) effect of burden for age standardized prevalence rate(ASPR) of STIs-related infertility. ( A ) A-P-C model of STIs-related primary infertility; ( B ) A-P-C model of STIs-related secondary infertility. Age (red), period (blue), cohort (green) Age–period–cohort (A-P-C) effect of burden for age standardized prevalence rate(ASPR) of STIs-related infertility. ( A ) A-P-C model of STIs-related primary infertility; ( B ) A-P-C model of STIs-related secondary infertility. Age (red), period (blue), cohort (green) Following the description of global trends, we examined how these patterns varied across SDI levels. The results across SDI regions demonstrated trends in age factors and cohort factors that were generally consistent with global patterns (Supplementary Table 9 ). However, notable disparities emerged in period factor trends. For primary infertility, high and high-middle SDI regions exhibited gradually declining period effects, middle SDI regions showed progressive increases, while low and low-middle SDI regions displayed an initial decline followed by subsequent elevation. Regarding secondary infertility, chlamydia and other STI manifested an overall upward trend in high, high-middle, and middle SDI regions, whereas gonorrhoea prevalence generally decreased. Conversely, all STI categories in low and low-middle SDI regions demonstrated a characteristic V-shaped trajectory of initial decline followed by resurgence.

The GBD 2021 database ( https://ghdx.healthdata.org/gbd-2021 ) integrates global population health and demographic statistics, including census data, surveys, registry systems, modeled metrics, administrative health records, and health-related financial data [ 17 , 18 ]. We extracted STIs-related infertility data from 1990 to 2021, including age-standardized prevalence rates (ASPR) with 95% uncertainty intervals (UI) for women aged 15–49 years, stratified into 5-year age groups. According to the SDI, a multidimensional metric incorporating fertility patterns, educational attainment, and economic status, 204 countries and territories were stratified into five different groups (low, low-middle, middle, high-middle, and high SDI regions). The SDI is a composite indicator reflecting fertility rates, educational attainment, and economic development. Based on SDI levels, the 204 countries and territories included in the GBD 2021 were categorized into five groups: low, low-middle, middle, high-middle, and high SDI regions [ 11 ]. In this study, data on the burden of female infertility attributable to STIs were derived from the GBD 2021 database. GBD explicitly identifies CT and NG as the primary causative pathogens. Additionally, an “other STI” category is included to account for disease burden arising from other pathogens that are either insufficiently reported or not explicitly modeled. Pathogens such as Mycoplasma genitalium and Treponema pallidum [ 19 ], which have been associated with PID or infertility in the literature, may be subsumed within this residual category. However, GBD 2021 does not specify which pathogens are in the “other STI” category, and robust epidemiological data for these agents remain limited. The burden attributable to this category is typically estimated through post-modeling residual analysis and epidemiological inference, aiming to ensure comprehensive representation of STIs-related disease burden [ 16 ]. The study cohort comprised women aged 15–49 years with STIs-related infertility, including complete datasets for SRPI and SRSI. Additionally, an “other STI” category is included to account for the disease burden arising from pathogens that are not individually reported or explicitly modeled in the GBD framework. Data on prevalence and disability-adjusted life years (DALYs) were extracted to quantify the burden of STIs-related female infertility. Age-standardized prevalence rates (ASPR) and age-standardized DALYs (ASDR) were calculated. Pearson correlation coefficients were computed at the global level and across SDI regions to assess associations. Two-sided P-values < 0.05 were considered statistically significant, consistent with standard epidemiological practice for evaluating associations. To assess the disease burden and temporal trends of STIs-related female infertility from 1990 to 2021, we adopted the ASPR and the estimated annual percentage change (EAPC) as core metrics. ASPR was used to account for differences in age distribution, thereby facilitating standardized comparisons across different time periods and regions. The EAPC was calculated based on a log-linear regression model of the ASPR, specified as: \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\ln(\mathrm{ASPR})=\alpha+\beta\mathrm{x}+\varepsilon$$\end{document} where x represents the calendar year and β is the regression coefficient reflecting the annual change rate [ 20 ]. This model assumes that the logarithm of the ASPR changes linearly over time and that residuals follow the expected distribution for ordinary least squares regression, providing a transparent framework for estimating long-term temporal trends. Accordingly, EAPC was computed using the following formula: \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\mathrm{EAPC}=100\times(\exp(\beta)-1)$$\end{document} An EAPC with a 95% confidence interval (CI) entirely above zero indicates a significant upward trend, while a CI entirely below zero suggests a significant downward trend. If the CI includes zero, the trend is considered stable [ 21 ]. To ensure temporal comparability and consistency with the GBD study, all EAPC estimations were based on ASPR trends from 1990 to 2021. The EAPC values presented in the tables for different age groups, regions, or countries were all derived from trend analyses over this period. To examine changes in the ASPR of STIs-related female infertility from 1990 to 2021, we applied Joinpoint regression analysis. Developed by the U.S. National Cancer Institute, this method detects statistically significant shifts in temporal trends (“joinpoints”) and calculates the Annual Percentage Change (APC) with 95% confidence intervals. The Joinpoint Regression Program was used to fit log-linear models, allowing up to five joinpoints. Significance testing was performed using the Monte Carlo permutation method. The Average Annual Percent Change (AAPC) was also calculated to reflect the overall trend across the study period. A statistically significant P-value was less than 0.05 [ 22 ]. A Poisson regression-based Age-Period-Cohort (A-P-C) model was applied to disentangle the independent effects of age, period, and birth cohort on STIs-related infertility burden across global and SDI-stratified regions, with age effects reflecting biological susceptibility to tubal damage, period effects capturing changes in STI diagnosis and treatment over time, and cohort effects representing generational differences in STI exposure and reproductive health behaviors. The model was implemented in R (version 4.4.1) using the “mgcv” and “apc” packages, with age, period, and cohort intervals set at 5 years. Age factor refers to the cumulative impact of physiological aging on disease risk. Period effect refers to short-term burden fluctuations driven by public health interventions or environmental changes. The cohort effect refers to exposure disparities across birth generations. Longitudinal age curves quantified age-related risk variations, with a relative risk (RR) > 1 indicating higher risk than the reference group and RR < 1 indicating reduced risk. Pearson correlation coefficients were used to assess associations between SDI and ASPR. Wald tests evaluated the statistical significance of A-P-C model components. R software (version 4.4.1) served as the computational framework, with correlation analyses and A-P-C modeling conducted within R, figures generated using the ggplot2 package, and Joinpoint outputs integrated into the visualization workflow. Adobe Illustrator (version 2023) was used solely for graphical refinement without altering analytical results. All raw data were sourced from the public GBD 2021 platform.

In summary, STIs-related infertility remains a growing public health challenge requiring urgent global attention. Our analysis revealed divergent epidemiological trajectories: while low and low-middle SDI regions achieved significant reductions in burden, other regions exhibited rising trends. The substantial disparities between primary and secondary infertility burdens are coupled with pathogen-specific variations across SDI levels. These STI-related patterns add to existing research on non-infectious causes of infertility, including ovulatory disorders, non-infectious tubal disease, and environmental exposures, by underscoring the distinct and preventable contribution of infectious factors. Integrating our findings with these broader determinants underscores the need for comprehensive reproductive health policies that simultaneously strengthen STI control and address non-infectious causes. Therefore, governments and public health authorities must prioritize coordinated, data-driven measures to alleviate the proliferating global burden of STIs-related infertility.

Our study focuses on STIs-related infertility, providing a detailed analysis of both primary and secondary infertility. We first observed that although the burden of STIs-related infertility has significantly decreased in low and low-middle SDI regions, the global ASPR of both SRPI and SRSI has shown no substantial reduction, and an upward trend has emerged in recent years as reflected by their positive EAPCs. High SDI regions also display a positive correlation with prevalence rates. These patterns suggest that the global decline is uneven and that high-SDI settings may require prioritized attention. Based on these findings, differential management strategies should be implemented for the two infertility types caused by distinct etiologies, alongside age-stratified management measures for different age groups [ 23 , 24 ]. The results indicate a continued decline in the burden of gonorrhoea-related infertility, suggesting that control strategies for other infectious diseases could replicate this successful model. While existing studies under the GBD 2021 update have analyzed infertility as a whole [ 25 ], our research specifically focuses on conducting a longitudinal analysis of STIs-related infertility. Our findings reveal the dual burden of STIs-associated infertility, demonstrating distinct trend patterns between primary and secondary infertility. Notably, on a global scale, the ASPR of SRPI demonstrates a gradual decline, whereas SRSI exhibits a slightly upward trend. This inverse epidemiological pattern suggests that the pathogenic mechanisms underlying these two forms of infertility may be differentially influenced by multilevel social determinants, such as access to timely STI diagnosis and treatment, partner notification practices, contraceptive and condom use patterns, and the coverage of routine STI screening. Although our dataset cannot directly evaluate these determinants, their potential relevance is supported by previous evidence, Berga’s research also mentions this [ 26 ]. Of particular significance is the pronounced heterogeneity in epidemiological distribution across SDI regions, underscoring the pivotal role of healthcare resource allocation [ 27 ]. Low and lower-middle SDI regions, despite some improvements through medical technologies and healthcare infrastructure [ 28 ], still exhibit substantially elevated prevalence, with SRSI showing more than twice the burden of SRPI, as indicated by Supplementary Tables 2 and Fig. 4 B. Targeted interventions, such as community-based screening programs and mobile health units [ 29 ], remain necessary to bridge this gap. In contrast, middle and high SDI regions maintain relatively lower prevalence but show limited improvement over the past three decades, indicating persistent challenges in prevention and control despite lower baseline burdens [ 30 ], collectively indicate insufficient adaptive capacity within existing prevention frameworks. We further analyzed the distribution patterns of the disease burden associated with chlamydia, gonorrhoea, and other STI. The findings reveal that the trends of chlamydia and other STI align closely with the overall burden, whereas gonorrhoea exhibits a distinct global decline. This divergence may be attributed to multiple factors, Enhanced antibiotic stewardship programs targeting gonorrhoea may have contributed to improved early diagnosis and treatment adherence [ 31 ]. Emerging antimicrobial resistance surveillance networks may have indirectly reduced underreporting and promoted targeted interventions in high-risk populations [ 32 ]. Notably, the prevalence of gonorrhoea in high SDI regions remains relatively elevated, even surpassing that in low SDI regions in cases of primary infertility, though its incidence has shown a consistent downward trajectory over time. This pattern could be closely associated with effective prevention and control measures reported in high SDI regions, including robust diagnostic surveillance systems and standardized antibiotic use, according to previous literature [ 33 , 34 ]. Given the continued decline in the societal burden of gonorrhoea, the prevention and control of chlamydia and other STI currently hold greater significance and should be prioritized as key areas for intervention. To maximize impact, strategies should focus on scaling up asymptomatic screening programs for chlamydia in high-risk populations, such as sexually active youth, and leveraging existing surveillance infrastructure developed for gonorrhoea to monitor emerging resistance patterns in other STI [ 35 ]. At the national level, our analysis revealed that Brazil has consistently experienced a high and increasing burden of STIs-related infertility over the past three decades, highlighting it as a key region for future surveillance and intervention. Additionally, Cameroon exhibited the highest ASPR of primary infertility, yet no significant downward trend was observed during the study period, indicating an urgent need for targeted public health strategies. Notably, Mali had the highest ASPR of secondary infertility in 1990, but showed a substantial decline thereafter. This trend may reflect the impact of local STI control or reproductive health interventions, but in the absence of direct data on policy implementation or coverage, this interpretation should be regarded as a hypothesis requiring further empirical validation. Joinpoint analysis provided more detailed insights into the long-term trends over the past three decades. From 1995 to 2010, the ASPR of both primary and secondary infertility showed a sustained decline, which may be partially related to the broader implementation of sex education programs and increased condom use. However, in the past decade, this trend has reversed, with a noticeable resurgence in STIs-related infertility burden. An in-depth analysis of Brazil revealed that, despite a significant overall increase in ASPR from 1990 to 2021, there has been a steady decline in decades. This improvement may be partially linked to the publication of the 3rd edition of the STD Control Manual, as well as the enhanced implementation of the Brazilian National Program on Sexually Transmitted Diseases and AIDS (PN-DST/AIDS) [ 36 ]. From an age-specific perspective, SRPI and SRSI demonstrate significant disparities. Globally, the burden of SRPI in the 15–39 age group exhibits a gradual decline, while the burden in the 40–49 age group continues to rise. These patterns may reflect lower sexual health screening coverage, limited awareness of asymptomatic infections, and shifting sexual behaviors among middle-aged adults [ 35 ]. In contrast, the ASPR of SRSI exhibits an opposite age-distribution profile. Further analysis of STIs-related infertility shows that chlamydia and other STI follow the overall SRSI trend, while gonorrhoea-related SRSI displays a distinct pattern, with an increasing burden in the 15–24 age group but declines in most older groups. This finding suggests that intervention strategies for SRPI and SRSI should be differentiated across age groups rather than adhering to a uniform standardized approach. The U-shaped association between SDI and the burden of infertility underscores the necessity of establishing a dynamic monitoring system to track the evolution of risk factors during socioeconomic transitions. When SDI is below 0.4, a significant decline in both primary and secondary infertility is observed, which can largely be attributed to improved access to healthcare driven by socioeconomic development, including enhanced reproductive health services and the widespread availability of contraceptive measures [ 37 , 38 ]. As SDI exceeds 0.8, the infertility burden begins to rise; this pattern is not directly measured in our data but may be related to factors described in previous literature, such as lifestyle changes, delayed childbearing, or the spread of drug-resistant pathogens [ 39 ]. This nonlinear trend suggests that long-term surveillance mechanisms should be implemented to identify and address key factors affecting reproductive health during socioeconomic development. In high-SDI regions, such measures may include enhanced antimicrobial stewardship, regular screening for high-risk populations, and strengthened STIs prevention education, as recommended in prior studies [ 40 , 41 ]. We further examined the relative contributions of age, period, and birth cohort to prevalence trends of STIs-related infertility. The impacts of age and cohort effects were broadly consistent across both primary and secondary infertility associated with various STIs. Notably, period effects showed a more pronounced rebound pattern in SRSI, indicating that temporal changes may exert a stronger influence on secondary infertility. Additionally, gonorrhoea-related infertility exhibited the greatest overall reduction in period effects compared with chlamydia and other STIs, suggesting a relatively more favorable trend for this pathogen category. Significant geographic disparities in period effects were observed across SDI regions. Declining trends in high and high-middle SDI regions were generally aligned with literature describing improvements in diagnostic screening and standardized treatment protocols. The relatively stable period effects in middle SDI regions may reflect persistent challenges in healthcare resource distribution. Meanwhile, the V-shaped resurgence in low and low-middle SDI regions points to the limited durability of short-term intervention efforts and highlights underlying structural inequities in healthcare access. Recent research on STIs-related female infertility has made significant advances. Deeper molecular mechanisms have been uncovered, such as pyroptosis-mediated suppression of CT and the role of miRNAs in preserving female fertility [ 42 , 43 ]. Concurrently, rapid diagnostic methods for STIs have also advanced considerably [ 44 ]. In addition to advances in diagnosis and molecular understanding, public health strategies have also played a crucial role. Expanded asymptomatic screening has been shown to significantly reduce the prevalence of STIs and associated long-term complications such as infertility. For instance, the CDC recommends annual screening for CT among sexually active women under 25 and those at increased risk, which has proven effective in reducing PID and infertility. In contrast, although Mycoplasma genitalium—with a prevalence of 1.3% (95% CI: 1.0-1.8%) in the general population of high-development countries and 3.9% (95% CI: 2.2–6.7%) in lower-development countries [ 45 ]—is an emerging pathogen associated with PID and potential reproductive harm, routine screening for asymptomatic individuals is not currently recommended [ 46 ]. This is due to several factors, including limited clinical laboratory capacity, the need for additional molecular testing to detect resistance, and the pathogen’s high rates of antimicrobial resistance—especially to azithromycin. Broad screening could lead to overtreatment and further spread of resistance [ 47 ]. As a result, current guidelines recommend targeted testing only in symptomatic patients or those with high-risk profiles. Our study demonstrates the following strengths. Firstly, we synthesized the most recent data from multiple sources published in 2021. Then, we systematically dissected disparities in infertility burden attributable to socioeconomic gradients, and age strata. Finally, we conducted a comprehensive investigation into the epidemiological profiles of both primary and secondary female infertility associated with diverse STIs. However, our study still has several limitations. First, although we included country-level descriptive results in the main analysis, we did not perform a dedicated heterogeneity assessment across countries (e.g., formal cross-national modeling or policy-level comparative analysis). Thus, the statement refers not to the absence of country-specific results, but to the lack of in-depth evaluation of between-country variability, which may mask critical differences in health policy implementation. Future research should incorporate cross-national comparative frameworks to identify context-specific barriers. Second, regional disparities in diagnostic capabilities and case-reporting completeness may introduce systematic bias, potentially influencing both absolute ASPR estimates and temporal trends. In low-SDI regions, asymptomatic chlamydia infections often go undiagnosed due to limited access to nucleic acid amplification tests (NAATs) [ 48 ], whereas high-SDI regions may overreport cases through routine screening programs. Such differential misclassification may partially exaggerate regional contrasts or attenuate true temporal changes. Although we applied statistical corrections, residual bias likely persists, particularly in settings with fragmented health information systems [ 49 ]. Additionally, we have not thoroughly explored the underlying causes of the recent rise in STIs-related infertility prevalence. While we considered the potential impact of COVID-19 [ 50 , 51 ], the upward trend had already emerged before 2019. As the dataset only extends to 2021, the full effects of COVID-19 require further observation over time. Despite these shortcomings, this study elucidates global and region variations in STIs-related infertility patterns. While our analysis focuses on the infectious component of infertility, it is important to recognize that non-infectious causes—such as PCOS, endometriosis, and limited access to ART—also contribute substantially to the overall burden. Previous research has addressed these non-STI factors. For example, the study by T. Lin demonstrated a continuous increase in the prevalence of PCOS [ 52 ], while countries in lower SDI categories were found to bear a disproportionately higher burden of endometriosis [ 53 ]. Additionally, Chiware TM et al. highlighted the limited access to ART among lower-income populations in low- and middle-income countries [ 9 ]. By situating our findings alongside this literature, our study complements these non-infectious perspectives by clarifying how the infectious etiologies of infertility vary across sociodemographic contexts. Together, these strands of evidence suggest that a comprehensive infertility policy must integrate both infectious and non-infectious determinants, ensuring that STI prevention, reproductive healthcare access, and chronic gynecological conditions are addressed within a unified framework.

The World Health Organization (WHO) defines infertility as the inability of reproductive-aged couples to attain a clinically confirmed pregnancy following 12 consecutive months of frequent unprotected sexual activity (≥ 2 times per week) [ 1 ]. Primary infertility refers to the absence of a prior clinical pregnancy, while secondary infertility specifically describes couples who have previously achieved a successful pregnancy but fail to conceive again under the same conditions [ 2 , 3 ]. Global epidemiological data indicate that approximately 8%-12% of reproductive-aged individuals are affected by infertility, equating to 50–80 million couples worldwide facing fertility challenges, highlighting its substantial global health relevance [ 4 , 5 ]. Female factors are responsible for 40%-50% of etiologies, underscoring the importance of understanding female-specific contributors [ 6 ]. Female infertility exerts multifaceted negative impacts on individuals and societies [ 7 ]. Studies demonstrate that the prevalence of clinically significant depressive symptoms is markedly higher among infertile women compared to those with normal fertility [ 8 ]. In less developed countries (LDCs), assisted reproductive technologies (ART) are predominantly accessible to high-income populations, while low- and middle-income groups face significant barriers to accessing these treatments [ 9 ]. The causes of female infertility are diverse, including sexually transmitted infections (STIs), polycystic ovary syndrome (PCOS), Turner syndrome, and idiopathic cases [ 10 ]. STIs are an important and preventable cause among these, implicated in nearly 30% of female infertility cases [ 11 ], indicating their prominent role among preventable etiologies. STIs can lead to pelvic inflammatory disease (PID), which may damage the fallopian tubes and surrounding structures, ultimately causing tubal factor infertility (TFI) [ 12 ]. The high incidence of PID and TFI is strongly associated with STIs pathogens, most commonly Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) [ 13 – 15 ]. Despite extensive research on the pathological mechanisms of STIs-related female infertility, the global disease burden attributable to STIs remains systematically unquantified. This study draws on the Global Burden of Disease (GBD) database, an epidemiological repository encompassing health metrics from over 200 countries and territories over three decades (1990–2021) to evaluate the epidemiological trends, disease burden, and regional disparities of STIs-induced female infertility [ 16 ]. We will investigate STIs-related primary infertility (SRPI) and STIs-related secondary infertility (SRSI). And for each, we will examine subtypes including chlamydia, gonorrhoea, and other STIs. Analyses will be conducted across geographic regions, sociodemographic index (SDI) groups, age strata, and temporal dimensions. These findings will support policymakers in developing targeted interventions and improving global reproductive health outcomes.

Below is the link to the electronic supplementary material. Supplementary Material 1 Supplementary Material 1 Supplementary Material 2 Supplementary Material 2 Supplementary Material 3 Supplementary Material 3 Supplementary Material 4 Supplementary Material 4 Supplementary Material 5 Supplementary Material 5 Supplementary Material 6 Supplementary Material 6 Supplementary Material 7 Supplementary Material 7 Supplementary Material 8 Supplementary Material 8 Supplementary Material 9 Supplementary Material 9 Supplementary Material 10 Supplementary Material 10