Disease burden of infertility in five East Asian countries from 1990 to 2021 and prediction for 2050: An analysis of the Global Burden of Disease study 2021.

Clinical infertility is defined as the inability to conceive after 1 year of unprotected attempts and has emerged as a pressing public health priority. It is estimated that approximately 10–20% of couples worldwide suffer from infertility [ 1 ]. This condition not only affects the physical and mental health of individuals but also significantly diminishes their quality of life [ 2 ]. On a broader scale, infertility impacts society and the nation as a whole, contributing to population decline, increased pressure on social security systems, and constrained economic development [ 3 ]. Infertility can be categorized into female infertility (FI) and male infertility (MI), each with distinct causes and prevalence patterns. FI is often attributed to factors such as ovulation dysfunction, tubal blockage, endometriosis, uterine abnormalities, and cervical issues [ 4 ]. Several studies have leveraged the Global Burden of Disease (GBD) database to analyze the global prevalence and trends of infertility. FI tends to garner more attention due to prevailing social and traditional concepts. For instance, Shen et al. reported the trends of FI across global, regional, and national levels from 1990 to 2019 [ 5 ], while Liu et al. investigated the burden of endometriosis-related primary and secondary FI [ 6 ]. However, it is crucial to recognize that reproductive success depends on the combined contributions of both partners. MI is a significant contributor to infertility, accounting for 30%−50% of cases [ 7 ]. It is commonly associated with sexual dysfunction or poor semen quality [ 8 – 10 ]. Sun et al. described the global prevalence and disability-adjusted life-years (DALY) of MI using the GBD database from 2017 [ 11 ]. Previous studies have laid the foundation for a comprehensive global analysis of infertility. Infertility is not merely a medical issue concerning reproductive health; it also carries significant psychological, economic, and social implications. It can lead to trauma and stress, particularly in societies and cultures where fertility is highly emphasized [ 12 ]. In East Asia, for example, fertility is regarded as a vital social responsibility and family obligation. Consequently, infertility poses a substantial psychological burden, especially in the context of traditional beliefs and heightened societal expectations. Recent research indicates that the prevalence of female infertility is highest in East Asia [ 13 ]. In East Asian countries such as China, Japan, and the Republic of Korea, individuals over the age of 20 are considered adults. Therefore, this study focuses on the disease burden and trends of infertility among individuals aged 20–49 in East Asian countries, based on prevalence and DALY data. The objective of this study is to elucidate the trends and patterns of infertility burden, thereby providing critical insights for the effective management of infertility in East Asia.

The data for this study was sourced from the Global Burden of Disease (GBD) 2021, an extensive database that compiles comprehensive information on 371 diseases and 88 risk factors across the globe, encompassing 5 Socio-Demographic Index (SDI) regions and 204 countries and territories [ 14 ]. In order to capture the widest array of information, multiple data types were included. For non-fatal information, data sources were collected from scientific literature, household survey data, epidemiological surveillance data, disease registry data, clinical informatics data, and other sources. For fatal information, data sources were mainly collected from vital registration and verbal autopsy, as well as survey, census, surveillance, cancer registry, police records, open-source databases, and minimally invasive tissue sampling [ 15 ]. Analyzing the data from GBD 2021 yields insights crucial for policymakers, health practitioners, and other key stakeholders. It enables a comprehensive understanding of disease occurrence and epidemic trends, thereby informing the development of effective health strategies. The data on female and male infertility in China, the Democratic People’s Republic of Korea, Japan, Mongolia, and the Republic of Korea, including prevalence rates and disability-adjusted life years (DALY) estimates, can be accessed through the following link: https://vizhub.healthdata.org/gbd-results . This link is managed by the Institute for Health Metrics and Evaluation (IHME) at the University of Washington in the United States [ 14 , 15 ]. The cases of female infertility and male infertility were identified using the International Classification of Diseases, 10th revision (ICD-10) codes (N97-N98.9 for female infertility and N46-N46.02, N46.022-N46.12, N46.122-N46.9 for male infertility) and 9th revision (ICD-9) codes (628–628.9, V26-V26.49, V26.51, V26.8-V26.9, V59.7-V59.74 for female infertility and 606–606.9, V26.5, V26.52 for male infertility). The dataset employed in this investigation was sourced exclusively from the GBD 2021 database which was conducted in accordance with the ethical guidelines established by the Declaration of Helsinki and complies with relevant jurisdictional regulatory requirements. As this secondary analysis exclusively utilized publicly accessible aggregated data from an open-source epidemiological database, it was exempted from requiring ethics committee approval under applicable institutional guidelines. Joinpoint regression analysis was conducted to evaluate temporal trends in East Asia’s infertility burden (1990–2021), identifying significant trend changes (joinpoints) that divide the overall period into distinct phases. Annual percentage change (APC) quantified annual variations within each phase, while average APC (AAPC) characterized cumulative trends. Upward trends required both estimated AAPC and its 95% CI lower limit >0; downward trends necessitated AAPC and 95% CI upper limit <0. This segmentation enabled clearer interpretation of burden fluctuations across chronological intervals. The APC model was used to evaluate the effects of age, period and cohort in disease burden of infertility. Age effect analysis represented the impact of different age group on outcomes; period effect analysis evaluated disease risk across different years; cohort effect analysis examined risk changes between different groups with same birth years. In this study, we divided 20–49 years old into six age groups according to five years. Because 1990–1991 was less than 5 years, 1992–2021 was divided into six period groups according to five years to involve period effect analysis. The APC model was helpful to understand the disease burden of different groups of people, and was available on the National Cancer Institute (NCI) website ( https://analysistools.cancer.gov/apc/ ) [ 16 ]. In this study, we utilized prevalence and DALYs as metrics to assess the global burden of female and male infertility. DALYs are computed by combining years lived with disability (YLDs) and years of life lost (YLLs), reflecting the unhealthy lost survival time attributed to disease [ 17 ]. In order to make the data from different regions comparable, these indicators were qualified by using age-standardized rate (ASR). The ASR was computed per 100,000 persons utilizing the following formula: A S R = Σ i = 1 A a i w i Σ i = 1 A w i × 100 , 000 ( a i :the rate in i th age group; w i : the number of people in the same i th age group among the standard population; A: the number of age groups). We also adopted Bayesian age-period-cohort (BAPC) model comprising integrated nested Laplace approximations to predict the future trend of infertility burden. Compared with other prediction method, the BAPC method had better accuracy by previous studies [ 18 , 19 ]. All analytical procedures and visual representation were performed by using R software (version 4.3.1) with using R packages including “ggplot2”, “BAPC”, “dplyr”, “RcolorBrewer”, “patchwork”.

Between 1990 and 2021, the prevalence of FI and MI among individuals aged 20–49 years exhibited divergent trends across East Asian countries. Specifically, the prevalence cases of FI and MI increased in China, the Democratic People’s Republic of Korea, Mongolia and Republic of Korea, while it decreased in Japan ( Table 1 ). The trends in DALYs mirrored those of prevalence, suggesting that changes in prevalence were a dominant factor influencing DALYs ( Fig 1 ). For FI, the ASPR and age-standardized DALY rate followed a consistent ranking from highest to lowest: China, the Democratic People’s Republic of Korea, Mongolia, Japan, and the Republic of Korea ( Fig 1A ). In Mongolia, the ASPR of FI increased from 3,781.13 cases per 100,000 persons in 1990–4,164.18 cases per 100,000 persons in 2021, with an AAPC of 0.3 (95%UI: 0.24 to 0.35) ( Table 1 ). A similar upward trend was observed in China, with an AAPC of 0.12 (95% UI: 0.01 to 0.22). In contrast, the Democratic People’s Republic of Korea, Japan, and the Republic of Korea maintained stable infertility burdens, with AAPCs of 0.0 (95% UI: −0.16 to 0.17), 0.06 (95% UI: −0.3 to 0.41), and 0.07 (95% UI: −0.57 to 0.72), respectively ( Table 1 ). The trends for MI were comparable ( Table 1 , Fig 1B ). China had the highest ASPR for MI among the five countries, with an increasing trend (AAPC: 0.14, 95% UI: 0.02 to 0.27). The Republic of Korea had the lowest ASPR and maintained a stable trend (AAPC: −0.13, 95% UI: −0.29 to 0.03) from 1990 to 2021. The Democratic People’s Republic of Korea also exhibited a stable MI burden (AAPC: 0.07, 95% UI: −0.28 to 0.03). Notably, Japan’s ASPR for MI surpassed that of Mongolia before 2012, but this pattern reversed after that ( Fig 1B ). Japan’s MI trend remained stable (AAPC: −0.03, 95% UI: −0.16 to 0.1), while Mongolia experienced an increase (AAPC: 0.25, 95% UI: 0.21 to 0.28) ( Table 1 ). In the five East Asian countries—China, the Democratic People’s Republic of Korea, Japan, Mongolia, and the Republic of Korea—infertility exhibited distinct patterns in terms of prevalence and DALYs across different age groups and countries. In 2021, China, the Democratic People’s Republic of Korea, and Mongolia showed a similar disease burden, with the number of FI cases far exceeding MI cases in each age group, except for the 20–24 years age group (S1-S2 Figs in S1 File). Conversely, in Japan and the Republic of Korea, MI cases outnumbered FI cases in all age groups except the 40–44 years age group. From 1990 to 2021, the trends of FI and MI were consistent within each country ( Fig 2A , 2B ). The number and ASR of prevalence (A) and DALYs (B) by sex in five East Asian countries from 1990 to 2021. To better observe these trends, we divided the 20–49 years age range into six groups. In 2021, China had the highest ASR of FI across all age groups (S3A Fig in S1 File). For MI, individuals aged 25–44 years in China had the highest ASR, while Mongolia had the highest ASR in the 20–24 years age group, and Japan had the highest ASR in the 45–49 years age group (S3B Fig in S1 File). We further evaluated the trends in each age group from 1990 to 2021 across different countries (S4 Fig in S1 File). China consistently had the highest ASPR and age-standardized DALY rate for FI across all six age groups during this period (S4A Fig in S1 File). For MI, China had the highest ASR among individuals aged 25–44 years from 1990 to 2021 (S4B Fig in S1 File). However, in the 20–24 years age group, China had a higher ASPR from 1995 to 2012, while Mongolia had a higher ASPR from 2013 to 2021. Japan had the highest ASR for MI in the 45–49 years age group throughout the study period. We also assessed the trends of different age groups within each country (S5 Fig in S1 File). Compared to other age groups, individuals aged 35–39 years had the highest ASR of infertility in China, the Democratic People’s Republic of Korea, and Mongolia from 1990 to 2021 (S5A, S5B, S5D Fig in S1 File). In contrast, individuals aged 40–44 years had the highest ASR in Japan and the Republic of Korea (S5C, S5E Fig in S1 File). Notably, the 45–49 years age group had the lowest ASR across all five countries from 1990 to 2021. In the joinpoint analysis of infertility trends across the five East Asian countries, the prevalence rates exhibited complex and dynamic patterns from 1990 to 2021 ( Fig 3 , S1 Table ). In China, although the overall trends for both FI and MI were upward, the increases were concentrated in specific periods. For FI, the significant rise occurred from 1990 to 1995, with APC of 1.76 (95% CI: 0.89 to 2.64) from 1990 to 1992 and 0.8 (95% CI: −0.05 to 1.66) from 1992 to 1995. For MI, the most notable increase was from 1990 to 1996, with APC values of 1.86 (95% CI: 1.4 to 2.31) from 1990 to 1993 and 0.5 (95% CI: −0.35 to 1.40) from 1993 to 1996. Following these periods, both FI and MI showed a gradual decline ( Fig 3A ). In the Democratic People’s Republic of Korea, infertility burden increased and remained at a higher level throughout the 1990s, but has shown a downward trend in the past four years ( Fig 3B ). Japan and the Republic of Korea exhibited similar patterns of infertility burden, characterized by significant fluctuations from 1990 to 2021 ( Fig 3C , 3E ). Initially, both FI and MI prevalence decreased, followed by periods of both increases and decreases in the middle years. However, since 2016, there has been a notable upward trend in the prevalence of both FI and MI in both countries. In Mongolia, the overall trends for FI and MI were significantly upward. The most substantial growth in FI occurred from 2005 to 2010, with an APC of 1.41 (95% CI: 1.21 to 1.60), while the most significant increase in MI was from 2010 to 2015, with an APC of 1.63 (95% CI: 1.51 to 1.75) ( Fig 3D , S1 Table ). Joinpoint regression analysis of the APC in the prevalence of female and male infertility diseases from 1990 to 2021 across five East Asian countries including China (A) , Democratic People’s Republic of Korea (B) , Japan (C) , Mongolia (D) , and Republic of Korea (E) . These findings highlight that the prevalence of infertility in different countries has undergone dynamic and complex changes over various time periods. This underscores the necessity for developing targeted public health strategies to effectively address these burdens. The prevalence of infertility significantly increases with age and then decreases across five East Asian countries ( Fig 4 , S6 Fig in S1 File). Differently, the highest risk of FI occurring in the 35–39 age group across three developing countries including China, Democratic People’s Republic of Korea and Mongolia, while 40–44 age group was observed in developed countries including Japan and Republic of Korea. In MI, the longitudinal age curves of MI were similar to FI. Age-period–cohort effects model depicting the burden of female infertility across five East Asian countries including China (A) , Democratic People’s Republic of Korea (B) , Japan (C) , Mongolia (D) , and Republic of Korea (E) . The analysis of the period effect revealed that the relative risk of infertility disease varied among the five East Asian countries at different times from 1992 to 2021 ( Fig 4 , S6 Fig in S1 File). In Mongolia, a continuous upward trend was observed in FI and MI. China experienced growth in the early stages, but gradually declined afterwards. It was seen as a growth trend at recent period in Democratic People’s Republic of Korea, Japan and the Republic of Korea. Cohort effect analyses showed substantial differences in the risk of developing infertility diseases across different birth years in five East Asian countries ( Fig 4 , S6 Fig in S1 File). In Mongolia, disease risk continued to increase as birth year increased. In the other four countries, the risk of infertility was lower in late birth cohorts, which indicated that lower disease risk was seen among younger generations. Based on the GBD 2021 data, we projected the future disease burden of infertility in five East Asian countries through to 2050 (S7 Fig in S1 File). Our analysis indicates that China and the Democratic People’s Republic of Korea will experience a declining trend in the ASPR of infertility for both females and males by 2050 (S7A, S7B Fig in S1 File). Conversely, Japan, Mongolia, and the Republic of Korea are projected to see a more pronounced increase in ASPR by 2050 (S7C, S7D, S7E Fig in S1 File). Specifically, for females, the ASPR in Japan is projected to rise to 2,726.68 cases per 100,000 by 2050. In Mongolia, the rate is expected to reach 5,055.3 cases per 100,000, while the Republic of Korea will see an increase to 1,239.31 cases per 100,000. For males, the ASPR in Japan will climb to 3,420.29 cases per 100,000 by 2050. Mongolia is projected to reach 2,681.3 cases per 100,000, and the Republic of Korea will see an increase to 2,120.3 cases per 100,000. Governments in Japan, Mongolia, and the Republic of Korea should consider implementing measures to address the anticipated rise in infertility cases, thereby mitigating the potential impact on individuals and society.

The results of this study show that the infertility burden of the five East Asian countries aged 20–49 years is different among different countries from 1990 to 2021, which is still a public threat. The burden of infertility in developing countries is significantly higher than that in developed countries. In developed countries, the burden of MI is significantly higher than that of FI, and the highest age of onset is 40–44 years old. In developing countries, the burden of FI is heavier, mostly at the age of 35–39. The burden of infertility may have a significant impact on social and economic development. Each country should formulate effective public health intervention measures according to the actual situation to alleviate the current situation.

ASPR of infertility diseases in five East Asian countries in 2021, broken down by age group and sex. S2 Fig. Age and sexual distribution of aged-standardized DALY rate in 2021. Aged-standardized DALY rate of infertility diseases in five East Asian countries in 2021, broken down by age group and sex. S3 Fig. Age and national burden in 2021. The ASR of prevalence and DALYs grouped by age group among five East Asian countries in 2021 between female (A) and male (B) infertility burden. S4 Fig. National trend among different age group. Trends of female (A) and male (B) infertility burden of ASPR and aged-standardized DALY rate among five East Asian countries from 1990 to 2021, grouped by 20-24 year group, 25-29 year group, 30-34 year group, 35-39 year group, 40-44 year group, 45-49 year group. S5 Fig. Trend of age burden among five countries. Trends of female and male infertility burden of ASPR and aged-standardized DALY rate grouped by age group from 1990 to 2021 among China (A), Democratic People's Republic of Korea (B), Japan (C), Mongolia (D), and Republic of Korea (E). S6 Fig. Age-period-cohort analysis in male. Age-period–cohort effects model depicting the burden of male infertility across five East Asian countries including China (A), Democratic People's Republic of Korea (B), Japan (C), Mongolia (D), and Republic of Korea (E). S7 Fig. The future forecasts to 2050. The forecast of infertility to 2050 in ASPR among China (A), Democratic People's Republic of Korea (B), Japan (C), Mongolia (D), and Republic of Korea (E). (ZIP) (DOCX)