Pregnancy, menarche, and menopause are all key events of female reproductive life and are heavily influenced by hormones. The reproductive lifespan spans from the first to the last menstrual cycle of women (1), while pregnancy loss is known as the discrepancy between the tally of confirmed pregnancies and live newborns, which primarily involves adverse pregnancy events, such as miscarriages, stillbirths, and genetic terminations (2). Since hormone levels and cardiovascular health (CVH) have a complicated relationship, exposure to multiple factors that impair CVH during critical windows could alter the reproductive lifespan and pregnancy outcome. Growing evidence shows that cardiovascular diseases (CVDs) interfere with female reproductive factors, including fertility. On one hand, women with cardiovascular risk factors may heighten the risk of adverse perinatal outcomes during pregnancy (3, 4), and pregnant individuals with preexisting CVDs have elevated incidence rates of preeclampsia, placental abruption, and postpartum hemorrhage (5, 6). On the other hand, CVDs can cause endocrine issues and then alter ovulation and the menstrual cycle (7, 8), ultimately affecting fertility. Hence, the impact of CVH on reproductive health could be substantial.

More recently, the American Heart Association (AHA) introduced an emerging CVH indicator, termed as Life’s Essential 8 (LE8) score (9), which consists of diet, physical activity, smoking, sleep health, body mass index (BMI), untreated total cholesterol, fasting blood glucose, and untreated blood pressure (BP). LE8 was a redefined and recalculated indicator based on Life’s Simple 7, which integrates the above metrics without the sleep domain. It has been demonstrated that sleep quality is associated with female reproductive factors (10). LE8 underpins our study since it reflects up-to-date clinical guidelines and more appropriate responses to interindividual differences and changes. Higher CVH scores indicate better health and lower risk for multiple subsequent cardiovascular and non-cardiovascular events.

Inflammation responses are implicated in the physiological and pathological mechanisms of female reproductive events (11). Alkaline phosphatase (ALP) is an enzyme with multifaceted anti-inflammatory action, which mainly presents in the bone and liver, as well as the placenta, intestine, kidney, and leukocytes (12, 13). Increased serum ALP activity demonstrates significant covariation with inflammation (14, 15) and CVDs (16). In addition, detecting markedly high levels of ALP during the pregnancy might indicate additional risk for adverse obstetrics and perinatal outcome such as preterm labor, gestational diabetes, and hypertensive disorders (17, 18). Of note, it remains to be elucidated as to whether the immune response modulated through the ALP pathway could play important roles in the relationship between CVH and female reproductive health, which could promote a deeper understanding of the mechanistic role orchestrated by ALP in immune metabolism.

The National Health and Nutrition Examination Survey (NHANES) is an ethically approved, cross-sectional, nationwide survey that tracks Americans’ health and nutritional status over the past few decades. Drawing on diverse NHANES cycles, the associations of CVH with life expectancy, metabolic dysfunction, female infertility, cancer mortality, and liver, lung, renal, psychiatry diseases have been highlighted (19–23). However, the association of CVH with reproductive lifespan and pregnancy loss remains poorly understood in the general population. Herein, we comprehensively evaluated the above associations in a nationally representative sample of U.S. women from the 2005–2018 NHANES and sought to identify the mediating effects of immune response involving the ALP pathway.

In a representative sample of U.S. postmenopausal women from NHANES 2005–2018, adherence to the LE8 metrics for CVH was associated with a shorter reproductive lifespan. Notably, the inverse association between CVH and reproductive lifespan was stronger among never-married women. Mediation analyses revealed that inflammation biomarker ALP may mediate the association between CVH and reproductive lifespan. There was compelling evidence indicating that the likelihood of reporting an elevated frequency of pregnancy loss was also lower as CVH levels improve. Further analyses using RCS models revealed a linear relationship between higher CVH levels and shorter reproductive lifespan, while the number of pregnancy losses decreases as CVH levels increase within a specific range and roughly presented an L-shaped relationship.

Reproductive lifespan holds significance of health status and physical aging in women. Since the timing of both onset and cessation of menstruation are known to be independent and vary among individuals, there may be distinct determinants, from hereditary and developmental factors to the combined effects of complex hormonal, environmental, and lifestyle exposures, influencing the reproductive timing (25–28). Thus far, no previous studies have considered the association of CVH estimated from LE8 score with reproductive lifespan, although better CVH was reported to be associated with lower occurrence of female infertility (22, 29). In our large population made of postmenopausal women, higher CVH levels were associated with shorter reproductive lifespan, exactly, delayed menarche and early menopause. It is known that significant overlap existed between female reproductive disorders like infertility, polycystic ovary syndrome, and the risk factors of CVDs as well as metabolic dysfunction (30). Previous pieces of evidence showed that female infertility was related to increased risk of early menopause (31), and the predicted reproductive lifespan of polycystic ovary syndrome cases was extended by an average of two years compared with normo-ovulatory females (32). Rather, in a Mendelian randomization analysis, biomarkers of CVD risk factors as measured by several types of lipids and blood pressure showed no impact on the risk of female infertility; of note, circulating levels of cardiometabolic risk determinants were not available in this investigation (33). The direct comparison of the above studies may be difficult due to different categories of CVH assessments. Notably, we employed LE8 as a novel CVH measurement which considers a broader range of health components. Numerous studies have emphasized the advantages of LE8 as a predictor of cardiovascular-related events. For example, LE8 surpassed LS7 in the prediction of coronary artery stenosis (34), and LE8 showed superior predictive ability for the risk of subsequent CVD mortality in individuals diagnosed with chronic kidney disease (35). Moreover, it is well recognized that sleep quality and pattern are frequently interrelated with reproductive events. Accordingly, the present results which has been disclosed under this newly developed scoring method were likely to be more fully and accurate.

Currently, there is an expanding body of data demonstrating that worse maternal CVH is associated with the incidence of adverse pregnancy outcomes, such as fetal death, preterm birth, preeclampsia, and small-for-gestational age birth (36, 37). Our findings are in agreement with the above evidence, showing that lower degree of CVH was suggestively related to increased number of pregnancy losses, which occur in 12%–15% of pregnancies. Several individual CVH metrics potentially correlated with pregnancy loss have been proven in previous research studies; for example, healthy dietary pattern and moderate occupational physical activity could reduce the chance of pregnancy loss (38, 39), while sedentary behavior, smoking, sleep–wake disorders, overweight or obesity, low-density lipoprotein cholesterol, blood glucose abnormality, and hypertensive disorders are highly associated with pregnancy loss (40–45). Results from the above observational studies may be distorted owing to residual confounding. Herein, LE8 score, which explores the overall effects of numerous health-related factors on CVH, was utilized, thus providing more solid evidence for understanding the diverse determinants affecting pregnancy loss before formulating effective intervention strategies.

While a priori, a shorter reproductive lifespan will reduce the chances of initiating pregnancy, there is substantial evidence supporting that extending the length of reproductive lifespan does not necessarily mean better pregnancy outcomes; for example, diabetes, hypertension, and other age-related diseases can negatively impact reproductive endpoints (46–48). Moreover, both premature and delayed timing of menarche and menopause have been correlated with non-reproductive detrimental health outcomes. It should be noted that women experiencing premature menarche or delayed menopause are at higher risk of steroid hormone-driven cancers, like breast, endometrial, and ovarian cancer (49–51). In addition, premature menarche also has been related with premature death, depression, CVDs, obesity, and type 2 diabetes mellitus (52–54), while diminished bone mineral density and a rising incidence of depressive disorders have been linked to delayed menarche (55, 56). Meanwhile, early menopause may increase the likelihood of long-term health issues, including reduced overall survival and increased risk of CVDs, osteoporosis, and mortality (57–59). Our results in the current research align with the above hypothesis that a prolonged reproductive lifespan does not seem to be related to optimal pregnancy outcome, but higher frequency of pregnancy loss. Potential mechanisms of the capacity damage of pregnancy maintenance could be through an increase in maternal age, which may lead to an increase in the rate of aneuploidy in embryos or a higher risk of neuroendocrine disorder, both in the reproductive organs and the entire body system. Given the adverse health effects of extended reproductive lifespan, public health interventions and effective and safe individualized plans could be urgently warranted.

Recent studies have elucidated novel insights into the mechanistic function of ALP in immunometabolic regulations. The potential anti-inflammatory ALP pathways may include the anti-inflammatory adenosine production, lipopolysaccharide detoxification, autophagy-dependent cellular degradation, mitochondrial biogenesis, and caveolin-dependent endocytosis (60–62). In this study, we found that ALP functioned as a critical modifier in the stable negative association between CVH and the duration of reproductive lifespan, accounting for 9.4% of the proportion using mediation analysis. Thus, we speculated that exposure to CVH metrics can balance inflammation states in the organ systems, at least partially, and then potentially lead to the alteration of reproductive events. The well-established mechanisms of immune response induced by the CVH metrics have yet to be determined, but in theory, it can be inferred from the aforementioned mechanism. Apart from the most prominent clinical diagnostic values on hepatobiliary system and musculoskeletal diseases, ALP also experiences noteworthy changes in various types of pathological pregnancy. Current studies have demonstrated that women with habitual abortion exhibit significantly elevated ALP levels compared to control groups (63), and ALP heightens the risk of spontaneous pregnancy loss in pregnant women (64). However, the pathology linking ALP to pregnancy loss is not well established in our cohort. To our knowledge, ALP is present in many tissues in the body while it was only measured in the serum in NHANES; thus, we were unable to confirm the origin of the enzyme, which means that this viewpoint remains speculative, and future researches should focus on specific ALP isozymes for further characterization.

The strength of our study lies in the statistically rigorous sampling design and weighted analysis of the large-scale NHANES data, which enable our findings to be extended to the U.S. general population, although it may not be directly generalized to other study settings or populations. More importantly, previous research has also reported the adverse effect of CVDs on female reproduction, but this is the first effort to focus on the association of CVH with reproductive lifespan and pregnancy loss. The employment of LE8, a currently updated measure of CVH with superior predictive ability, strengthened the credibility and accuracy of the results. The extensive adjustments for confounding factors, including age, race/ethnicity, education level, PIR, and marital status, ensured the validity and stability of the conclusion. There are also some limitations to note. Firstly, our conclusions must be interpreted cautiously in light of the cross-sectional design, which means it is not possible to infer causality. Although they have not always been consistent, few studies reported that reproductive factors such as the number of pregnancies may have influence on the risk of CVDs, supporting a likely possibility of a mutual influence between CVH and reproductive events. Secondly, despite considerably adjusting potential confounders and conducting sensitivity analyses, we were unable to assess the impact of residual confounding factors such as menstrual regularity, which was not available in NHANES. To clarify the underlying mediation effect, more unmeasured confounders need to be accurately identified and deeply evaluated by further prospective studies. Finally, we had difficulties in discarding some misclassified data due to the age information on menstruation. In addition, the calculated number of pregnancy losses was based on self-reports and may be prone to reporting bias.

Our study based on the NHANES data involving 3964 female adults suggested that higher CVH levels were associated with a shorter reproductive lifespan and a higher proportion of never-married women. ALP appeared to mediate the relationship between CVH and reproductive lifespan duration. Additionally, higher CVH levels were linked to lower odds of pregnancy loss prevalence. Promoting the convenience of data collection and calculation of LE8 score may allow the general public to get earlier practitioner-directed guidance for achieving optimal cardiovascular and reproductive health in women. Further prospective studies and mechanistic research are needed to clarify the underlying causal relationships and biological mechanisms.