Cirrhosis and chronic liver disease (CLD) can result from various etiologies, with the most prominent being hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection, excessive alcohol consumption, and non-alcoholic fatty liver disease (NAFLD) (1). CLD is among the top ten leading causes of global mortality (2). Although the incidence of HBV has declined due to vaccination programs (3), the prevalence of NAFLD and alcoholic liver disease (ALD) continues to rise, contributing to an anticipated increase in the overall prevalence of CLD in the near future (4). The etiology of CLD exhibits remarkable variations across different sociodemographic index regions (SDIRs) (5). In high SDIR, lifestyle factors, such as obesity and excessive alcohol consumption, have emerged as the primary drivers of the rising incidence of CLD. Conversely, in low SDIR, viral infections, particularly HBV and HCV, remain the leading causes of CLD (3, 5). The impact of these regional disparities in etiology is reflected in the global burden of CLD, with each country undergoing distinct epidemiological shifts that align with evolving public health priorities, healthcare access, and economic development (6). Gaining a deeper understanding of these etiological variations across SDIRs and key countries is crucial for the development of targeted prevention, diagnosis, and treatment strategies for CLD at a global level.

The World Health Organization (WHO) characterizes women of childbearing age (WCBA) as women aged 15–49 years, a demographic that constitutes approximately one-quarter of the global population. With a global fertility rate of 2.4 children per woman, the health status of women within this age group is closely tied to the well-being of newborns (5). As the incidence of liver disease continues to rise among WCBA, a concomitant increase in pregnancies in this demographic is noteworthy. Previous research indicated that the delivery rate among women with cirrhosis has nearly doubled over the past two decades (6). CLD significantly and adversely impacts maternal morbidity and mortality (7). Women with CLD are at an increased risk of giving birth to infants with low birth weight or preterm birth, with up to two-thirds of pregnant women with CLD experiencing preterm birth. Notably, one-fifth of these pregnancies result in deliveries before 30 weeks (8). Pregnant women diagnosed with NAFLD are at elevated risk of developing gestational diabetes and preeclampsia (9).

While numerous studies have examined the prevalence of CLD in specific age groups, there is a notable gap in understanding the trends in CLD prevalence among WCBA, particularly with regard to age, period, and birth cohort effects. While the global burden of CLD is noteworthy, it is essential to acknowledge the growing importance of understanding the specific etiologies driving these trends. Remarkably, NAFLD has emerged as the leading cause of CLD, surpassing HBV and HCV in several regions, reflecting the global shift towards metabolic liver diseases. However, the complexities in the temporal evolution of CLD necessitate a more granular examination of etiology-specific trends, especially by age and period. For instance, the rise in NAFLD prevalence has been more remarkable in older age groups, particularly those over 30, where lifestyle factors, such as obesity, diabetes, and poor dietary habits have exacerbated the condition's prevalence. On the other hand, the decline in HBV prevalence, influenced by vaccination programs, is more apparent in younger cohorts, with notable reductions in incidence rates across successive generations. To address this gap, the present study also explored etiology-specific temporal trends by stratifying the data by age groups and examining period and birth cohort effects. By analyzing the evolving patterns of HBV, HCV, NAFLD, and ALD across different periods and age groups, this research aimed to provide a more comprehensive understanding of the shifting landscape of liver diseases. The study extracted data related to CLD among WCBA from the Global Burden of Disease (GBD) 2021 database, and an APC model was applied to analyze the temporal trends in CLD prevalence from 1992 to 2021, both globally and across regional and national levels. Specifically, the APC model allows for an in-depth assessment of how each etiology has contributed to the overall rise in CLD prevalence, concentrating on the differential impacts of age and period factors.

Notably, CLD can lead to severe complications and death, significantly impacting quality of life and imposing a substantial economic burden (17). Despite various conditions leading to CLD, HBV, HCV, NAFLD, and ALD are the most common culprits (18). In 2015, the United Nations established defined objectives under Sustainable Development Goal 3, with a target to decrease the global maternal mortality ratio to less than 70 per 100,000 live births by 2030 (19). These include gestational hypertension, gestational diabetes, preeclampsia, preterm birth, and low birth weight (6, 7). Such severe complications not only pose significant challenges to maternal survival but also impede progress towards achieving the United Nations' Sustainable Development Goals. This study explored the relative influence of age, period, and birth cohort on the prevalence trends of CLD among WCBA. The increasing global prevalence of CLD, particularly driven by NAFLD, underscores the need for public health initiatives focusing on metabolic health. Given the strong association between NAFLD and obesity, type 2 diabetes, and poor dietary habits, it is critical that preventive strategies target lifestyle factors, particularly in high-middle and high SDI countries where the trends are more pronounced. Furthermore, the rising prevalence of CLD in younger populations, coupled with the slow decline in HBV cases, suggests that while vaccine programs have been successful in curbing viral infections, the focus must now shift to managing the growing burden of metabolic liver diseases.

Globally, we observed adverse period effects and favorable birth cohort effects. CLD period effects have been rising over the past decade. Period effects reflect changes in incidence or mortality rates due to societal, economic, cultural, or environmental changes (20). Over time, with improvements in socio-economic conditions, education, and living standards, the overall incidence of CLD has increased. Recent studies indicated that the rising prevalence of CLD is mainly driven by the increasing prevalence of NAFLD (21). Over the past decade, the incidence of CLD has continued to increase, attributable primarily to the growth of metabolic-related risk factors driven by societal, economic, and environmental changes, rather than population expansion alone (22). These trends, intertwined with factors such as reduced physical activity and altered gut microbiota, underscore the pivotal role of metabolic and lifestyle factors in liver disease risk (23). The shift towards more sedentary lifestyles, accompanied by the proliferation of calorie-dense, nutrient-poor foods, has exhibited a remarkable impact on health outcomes. The increase in the period effect, particularly in the later years of the study, cannot solely be attributed to general social development. Instead, more specific factors may be influential, such as the increase in the consumption of ultra-processed foods. These dietary changes may significantly contribute to the rise in conditions, such as obesity and type 2 diabetes, which are key drivers of diseases like NAFLD (21). Given the escalating global prevalence of NAFLD, particularly in low-middle and high-middle SDI countries, public health strategies require adaptation. It is recommended to enhance promotion of healthy lifestyles, emphasize dietary and physical activity interventions, and implement early screening for metabolic risk factors in individuals over 30 years of age. Furthermore, air pollution deserves attention as a potential risk factor for liver disease (24). Moving forward, targeted health education should be advanced to address the continued rise in the burden of CLD (4).

With improved access to HBV vaccines globally, implementation of mother-to-child transmission prevention programs, and approval of antiviral medications for children and adolescents, the incidence of chronic viral hepatitis has significantly reduced (25, 26). This is consistent with our findings, although the decline was slower in low SDIR. In low SDIR, limited access to antiviral medications (27), challenges in standardizing screening and diagnosis, and low HBV vaccine coverage exacerbate the prevention and treatment burden of liver diseases among WCBA (28). As of 2016, nearly half of children aged 1 to 6 in India had not been administered the hepatitis B vaccine (29). Expanding screening for HBV, increasing vaccine coverage, and improving access to antiviral drugs are crucial in these regions. In the present study, the improvements in birth cohort effects, particularly for those born after 1980–1989, can be attributed to the widespread introduction of HBV vaccines, which have successfully reduced the risk of chronic viral hepatitis in subsequent generations (30). The WHO has recommended routine HBV immunization for newborns worldwide and has been advocating for the inclusion of HBV vaccines in national immunization programs since 1992. Surveys indicated that between 1990 and 2019, the prevalence of HBV surface antigen among infants and children under the age of five decreased by 77% (3). Additionally, significant improvements in healthcare services for newborns have occurred alongside social progress. However, this positive trend contrasts with the growing burden of metabolic CLD, especially NAFLD, which has increasingly affected younger populations. The growing prevalence of NAFLD highlights the need for concentration on preventive strategies, including promoting healthier dietary habits and lifestyles, especially in the younger population.

This study has several limitations. Firstly, while this study outlined the prevalence trends of CLD among WCBA, remarkable socio-economic and clinical changes over the past three decades might influence the impact of different types of CLD, a factor that was not explored in this study. Secondly, in certain underdeveloped countries with limited healthcare infrastructure, misdiagnosis and underdiagnosis might contribute to an underestimation of CLD prevalence. The extensive statistical modeling employed by the GBD collaborators might also influence the precision of the age, period, and birth cohort effect estimates. Thirdly, the delayed nature of the GBD data should be considered. In conclusion, nearly half of the countries globally are experiencing an upward trend in CLD, with concurrent increases in associated risks, highlighting a critical shortage of resources allocated to CLD healthcare for WCBA. Notably, while HBV is declining, NAFLD is rapidly increasing. The consistent pattern of increasing CLD risk with age is not surprising, as the development of CLD is closely linked to cumulative exposure to risk factors. However, the divergent trends found across SDIRs, with high SDI countries experiencing more rapid increases in prevalence, demonstrate that socio-economic factors, including lifestyle and access to healthcare, play a pivotal role in shaping these patterns. While the APC model presents valuable insights into the trends of CLD prevalence, it is important to recognize its limitations. One known limitation is the recognition problem, where the model may not always accurately capture complex relationships between age, period, and cohort effects, especially in regions with incomplete or inconsistent data. Additionally, boundary effects may arise, particularly when the model does not adequately handle data at the extremes of age or time periods, potentially skewing results. The sensitivity of the model to input data quality is another critical factor, as inaccuracies in the underlying data can significantly influence the model's output. Critically, the model did not incorporate several important covariates that could significantly influence these trends. Factors, such as obesity rates, dietary patterns, alcohol consumption, and HBV vaccine coverage are well-established drivers of CLD and could provide a more detailed understanding of the observed prevalence trends. For example, the rise in NAFLD has been closely linked to increasing obesity and poor dietary habits, while the decline in HBV prevalence could highly be attributed to successful vaccination programs, varying in coverage across regions and time periods. Furthermore, the APC model did not account for pregnancy status, parity, or gestational age, which are critical factors in understanding the impact of CLD on maternal and fetal health. Given the significant effect of these factors on the prevalence and outcomes of CLD in women, future studies may benefit from incorporating them into more detailed models to better capture the unique dynamics of liver disease among pregnant women and in different reproductive stages. The absence of these covariates in the current model represents a limitation, as it may overlook important contributors to CLD trends, especially in the context of rapidly changing socio-economic and health conditions. Future research incorporating these factors will provide deeper insights into the interaction among lifestyle, public health interventions, and disease progression, potentially informing more targeted prevention and intervention strategies for WCBA globally.