Infertility is defined as the inability to conceive after at least 12 months of unprotected intercourse. Approximately 8%-12% of couples of reproductive age worldwide suffer from infertility (1). Although male infertility accounts for more than half of these cases, the burden of infertility is still predominantly borne by women (2). Infertility is a condition characterized by reproductive dysfunction resulting from various etiologies and is a significant reproductive health issue for couples of childbearing age. The causes of infertility can be attributed to organic factors (such as pelvic diseases) or iatrogenic factors (such as postoperative adhesions), but lifestyle and psychological stress may also play a role (3). The risk factors and mechanisms of infertility remain subjects of ongoing research. Several studies have indicated that infertility is associated with sleep (3), diet (4), appropriate exercise (5), diabetes (6), obesity (7), dyslipidemia (8), cardiovascular diseases (9), and smoking (10).

In 2010, the American Heart Association (AHA) defined cardiovascular health (CVH) and quantified it using seven metrics known as Life’s Simple 7, which includes diet, physical activity, smoking status, BMI, total cholesterol, blood pressure, and blood glucose. In 2022, the AHA added sleep as a new component of CVH, introducing Life’s Essential 8 (LE8) to further encourage personal and community health and to provide a more comprehensive reflection of cardiovascular health (11). On February 27, 2024, an article published in Circulation highlighted that individual mental health is a crucial component of enhancing cardiovascular health (12). Therefore, it is proposed to expand Life’s Essential 8 (LE8) by adding a mental health metric, creating what can be termed Life’s Crucial 9 (LC9). LC9 encompasses four health behaviors (diet, physical activity, smoking cessation, sleep) and five health factors (healthy weight, normal cholesterol levels, blood glucose, blood pressure, and mental health). Compared to LE8, LC9 redefines cardiovascular health by incorporating the new mental health metric, making it more aligned with clinical practice. Consequently, LC9 can better represent an individual’s cardiovascular health status and more accurately reflect the underlying pathophysiological changes within the body.

To date, numerous studies have explored the impact of the four health above behaviors and five health factors of CVH on infertility. However, the relationship between LC9 (the composite metric) and infertility has not yet been investigated. Previous research has indicated that infertility is associated with lower CVH scores in middle-aged women, focusing solely on diet, sleep, physical activity, smoking, BMI, total cholesterol, blood pressure, and blood glucose (13), without considering the impact of mental health on infertility. Nevertheless, mental health is very prevalent in the occurrence and development of infertility (14–19), and various psychological interventions are currently employed to address infertility (20).

With the ongoing changes in global lifestyles and environmental factors, the incidence of infertility has shown a marked upward trend. Given its complex etiology and uncertain treatment options, identifying modifiable factors associated with infertility has become a critical focus of current research, aiming to intervene and prevent its occurrence. Therefore, this study utilized data from the 2013-2018 cycles of the National Health and Nutrition Examination Survey (NHANES) in the United States. This database, with its comprehensive individual health indicators and lifestyle data, provides a broad population sample and a solid foundation for investigating infertility-related factors and their impact on cardiovascular health. For the first time, this study systematically analyzed the relationship between various independent LC9 factors and infertility, evaluating their potential roles in preventing infertility. This research not only aims to uncover further details about the complex causes of infertility but also provides important evidence-based support for clinical practice, advancing the development and implementation of public health strategies.

In this study, we found a significant negative correlation between CVH (quantified by LC9 scores) and the risk of infertility. Subgroup analysis further revealed a more pronounced interaction between LC9 scores and age in women younger than 35 years. This underscores the potential impact of cardiovascular health on the occurrence of infertility and highlights the importance of early monitoring and control of CVH, as quantified by LC9 scores, to reduce the incidence of infertility. In addition, the WQS regression results showed that sleep health (weight = 0.244) was considered the most important factor influencing the occurrence of infertility, followed by mental health and body mass index score (weights = 0.178 and 0.148).

To our knowledge, this is the first study to investigate the association between the new CVH metric (LC9) and the prevalence of infertility. Previous research has indicated that women with infertility have an increased risk of poorer CVH in middle age (quantified by LE8 scores) compared to women without infertility (13). This suggests a link between infertility and cardiovascular health, providing valuable insights for exploring CVH metrics and their relationship with infertility.

However, merely indicating the association between LE8 and infertility is insufficient. Infertility is a multifactorial condition closely related to various cardiovascular risk factors. For instance, a cross-sectional study involving 1,820 participants highlighted a strong association between sleep disorders and female infertility, potentially linked to the activation of the HPA axis (hypothalamic-pituitary-adrenal axis), which reduces endometrial receptivity (27). Additionally, a prospective study involving 385,292 participants demonstrated that healthy sleep patterns are associated with a reduced risk of cardiovascular diseases, coronary heart disease, and stroke (28). Another case-control study of 180 infertile women and 540 fertile women indicated that the psychological health of infertile women might be adversely affected (29). These shared risk factors may underlie both infertility and cardiovascular disease, with women experiencing infertility having a higher prevalence of cardiovascular risk factors even before conception (30). These pieces of evidence suggest that the CVH score assessed by LC9 could serve as an indicator of both cardiovascular health status and infertility incidence. Our study results demonstrate a negative linear relationship between CVH and infertility from various perspectives. For example, WQS results indicate that sleep health, mental health, BMI, and tobacco exposure are more closely associated with infertility after adjusting for other confounding factors.

The mechanisms underlying the relationship between cardiovascular health and infertility are multifaceted and complex. Possible mechanisms include:(1) Insulin Resistance (IR): Insulin resistance is a pathogenic mechanism in various diseases. Research suggests that IR may affect oocyte quality by reducing mitochondrial function and exacerbating oxidative stress in follicles, thereby further impairing mitochondrial function and inducing the release of inflammatory factors (31). (2) Lipid Metabolism Disorders: Dyslipidemia, a major contributor to cardiovascular disease, is typically characterized by elevated circulating levels of low-density lipoprotein cholesterol (LDL-C) and/or triglycerides (TG), along with reduced levels of high-density lipoprotein cholesterol (HDL-C). Women with lipid metabolism disorders tend to exhibit deteriorated cumulus-oocyte complex (COC) morphology and a decreased number of cleavage-stage embryos. Elevated TC concentrations may adversely affect endometrial receptivity, leading to infertility (8). (3) Endothelial Dysfunction: It is well-known that the incidence of cardiovascular diseases is significantly lower in premenopausal women compared to men, largely due to the protective role of estrogen on cardiovascular health. Estrogen regulates lipoproteins and possesses anti-apoptotic properties by increasing the activation of the protective PI3K/Akt pathway and reducing inflammation and cytokine production. Endothelial cell damage is closely related to cardiovascular diseases, and estrogen also plays a role in vascular function regulation. Studies suggest that the decline in regulatory function is due to estrogen loss rather than aging (32). Endocrine abnormalities causing female infertility, such as polycystic ovary syndrome (PCOS), are associated with endocrine disorders like hyperandrogenism.

Studies have shown that sleep disorders, including disturbances in sleep duration and continuity, can interfere with reproductive capabilities or lead to the activation of the hypothalamic-pituitary-adrenal (HPA) axis, further disrupting reproductive functions. Sleep disorders may also affect reproductive hormones such as thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), and prolactin (PRL) (3). Age is negatively correlated with oocyte quality, potentially due to the accumulation of DNA damage in oocytes from environmental stress factors over time or the first-in-first-out principle, where higher-quality oocytes are ovulated earlier in life. Additionally, the shortening of oocyte telomeres with age contributes to the decline in oocyte and embryo viability (33). A meta-analysis indicated that psychological interventions could improve pregnancy rates (20). For example, a study by Rong Zhou and colleagues (34) demonstrated that cognitive behavioral therapy (CBT) and the integrative body–mind–spirit (BMS) approach play important roles in improving pregnancy rates, with BMS being associated with reduced anxiety. Additionally, a prospective, controlled, single-blind, randomized study by Alice D. Domar et al. (35), which included 184 women who had been attempting to conceive for 1 to 2 years, demonstrated that group psychological interventions appeared to increase pregnancy rates in women with infertility. Moreover, factors such as obesity, diet, smoking (33), and lipid abnormalities—components of LC9—affect these pathophysiological processes. Therefore, these studies collectively emphasize the importance of LC9 in infertility and provide further theoretical support for this research.

The results of this study provide important guidance for the management and prevention of infertility. This is the first time LC9 has been used to predict the risk of infertility, demonstrating its potential clinical value. By adjusting for other confounding factors, the results are more reliable, and the representative sample obtained through national sampling allows for extrapolation to a larger population. However, there are limitations: (1) This study is cross-sectional, which prevents establishing a causal relationship between LC9 and infertility (36). Large-scale cohort studies are needed to further validate the current findings. (2) Data collection primarily relied on questionnaires, which may introduce measurement errors. (3) Despite adjusting for many confounding factors, the limitations of the NHANES database prevented us from including certain potential confounders of infertility, such as male-only causes, uterine structural abnormalities, and other anatomical factors, which may have a weaker association with CVH. (4) This study did not take into account participants’ job status or their exposure to other chemical and physical pollutants. For example, global warming and working in hot and humid environments may impact reproductive health in both men and women, potentially leading to infertility, which could affect the study’s findings. Therefore, caution should be exercised when interpreting the results due to this limitation. In future studies, we plan to include these factors as confounding variables in the model to improve the accuracy of infertility research.

In conclusion, the findings of this study reveal a significant protective association between Life’s Crucial 9 (LC9) and the incidence of infertility. This discovery not only provides scientific support for the application of LC9 in infertility risk assessment but also underscores its potential clinical significance in promoting reproductive health. By integrating LC9 into routine health management, healthcare professionals can more effectively identify and manage high-risk populations for infertility, thereby enhancing overall reproductive health. Furthermore, this study lays the groundwork for future research to validate the efficacy and mechanisms of LC9 in larger populations, advancing the development of infertility prevention strategies.