Review and Monograph

Research Progress on Lifetime Reproductive Factors and Stroke Development in Women

SUN Weidi, SHAN Shiyi, ZHU Xuan, WU Jing, HOU Leying, SONG Peige*

School of Public Health, Zhejiang University, Hangzhou 310058, China

*Corresponding author: SONG Peige, Researcher/Doctoral supervisor; E-mail: peigesong@zju.edu.cn

Abstract
Stroke is one of the leading causes of morbidity and mortality worldwide and ranks as the foremost cause of death in China, representing a major public health threat to societal health and development. Previous studies have demonstrated significant sex differences in stroke risk, influencing factors, and prognostic outcomes. Due to sex-specific reproductive factors, women generally face higher lifetime stroke risk and poorer post-stroke functional recovery compared to men, with stroke-related disease burden increasingly intensifying in this population. Identifying key female-specific determinants of stroke incidence and establishing scientific early risk stratification systems are critical pathways for achieving precise primary prevention and optimizing healthcare resource allocation. This article provides a comprehensive review of research on women's lifetime reproductive factors and stroke occurrence and progression, aiming to summarize the current state of research on how reproductive factors influence women's stroke risk and to promote further in-depth research and clinical innovation in women's stroke.

Key words Stroke; Women; Reproductive factors; Life course; Risk prediction; Review

1 Epidemiology of Stroke in Women

Stroke refers to acute focal neurological dysfunction caused by sudden infarction or hemorrhage in the brain, retina, or related spinal cord regions, with symptoms persisting for more than 24 hours \cite{1}. According to the Global Burden of Diseases 2021 (GBD 2021) study, there were 93.8 million prevalent stroke cases and 11.9 million new cases globally in 2021, with stroke causing 72 million disability-adjusted life years (DALYs) and 7.3 million deaths, accounting for 10.7% of total deaths and making stroke the third leading cause of death worldwide \cite{2}. In China, the stroke burden is even higher than the global average. In 2021, China's age-standardized stroke prevalence was 1,301.42 per 100,000, with age-standardized prevalence and incidence of ischemic stroke ranking highest globally \cite{3}. As the leading cause of death among Chinese populations, stroke caused 2.19 million deaths in 2019—a 59.0% increase over the past 30 years—making it a non-negligible major public health problem \cite{4,5}. Stroke not only affects patients' physical and mental health and social functioning but also imposes severe economic burdens on families, healthcare systems, and society \cite{6}. Therefore, effectively identifying major risk factors for stroke occurrence and development and developing targeted early prevention interventions are crucial for reducing China's stroke-related disease burden.

Existing research indicates significant sex differences in stroke risk, influencing factors, and prognostic outcomes. The World Stroke Organization's World Stroke Fact Sheet 2022 showed that over half (56%) of stroke survivors globally are women \cite{12}. GBD 2021 epidemiological survey data revealed approximately 46 million (43.5–48.8 million) prevalent cases and 5.7 million (5.1–6.3 million) new cases among women, with stroke attributable DALYs reaching 72.2 million and attributable deaths 3.5 million \cite{2,13}. Stroke is the second leading cause of cardiovascular disease death in women globally, but the foremost cause in East Asia, Southeast Asia, high-income Asia-Pacific regions, and southern and eastern sub-Saharan Africa \cite{9}. Studies from the United States, Canada, and the Netherlands show that young women's stroke incidence is higher than or equal to men's, while middle-aged men have higher incidence than women—a difference that narrows after female menopause and reverses in those over 80 \cite{14}. Due to women's longer average lifespan, their lifetime cumulative stroke risk is higher. The Framingham Study estimated American middle-aged women's lifetime stroke risk at 20–21% compared to 14–17% for middle-aged men \cite{15}. Common stroke risk factors include hypertension, diabetes, atrial fibrillation, dyslipidemia, smoking, and obesity, with evidence from primary studies and meta-analyses showing that atrial fibrillation and diabetes have more pronounced effects on stroke in women than men \cite{15-21}.

Over recent decades, China has experienced rapid health transitions and socioeconomic development. Meanwhile, lifestyle changes and environmental factors have increased the prevalence of stroke risk factors like hypertension, smoking, and obesity, significantly exacerbating China's stroke burden \cite{22}. A national stroke epidemiological survey showed Chinese women's age-standardized stroke prevalence was 1,426.2 per 100,000, continuously increasing with age from 17.0 per 100,000 in the 20–29 age group to 4,805.4 per 100,000 in those ≥80 years \cite{23}. The age-standardized incidence was 226.9 per 100,000 person-years, and age-standardized mortality was 142.2 per 100,000 \cite{23}. From 1990–2019, China's age-standardized overall stroke incidence decreased by 10.1%, while ischemic stroke age-standardized incidence increased by 31.4% and DALYs grew by 21.5% \cite{23}.

2 Health Impact of Stroke on Women

Stroke is characterized by sudden onset, rapid progression, high disability rates, and poor prognosis, causing severe harm to patients' health \cite{24}. A meta-analysis covering 13 population-based stroke incidence surveys showed women's 1-year and 5-year crude mortality rates were higher than men's (mortality rate ratios [MRR] of 1.35 and 1.24, respectively), but this reversed after adjusting for age, pre-stroke functional limitations, stroke severity, atrial fibrillation history, and other factors (MRR of 0.81 and 0.76), suggesting women's higher post-stroke mortality may be attributed to older age, more severe post-stroke symptoms, and higher atrial fibrillation prevalence \cite{25}. Additionally, female stroke patients generally face worse prognostic outcomes and lower health-related quality of life \cite{26,27}. Women perform worse than men across multiple dimensions including pain, anxiety, depression, frailty, and functional activity, partially explained by older age, lack of social support, and greater emotional sensitivity to stressful events like widowhood \cite{28-30}. Female patients are also more prone to post-stroke depression. A systematic review covering 45 primary studies reported women's post-stroke depression risk was 78% higher than men's \cite{31}. Another 2018 systematic review indicated women tend to have higher post-stroke depression prevalence, incidence, or more severe depressive symptoms, remaining significant after adjusting for age, stroke severity, and other potential confounders \cite{32}. A prospective study of British stroke patients over 25 years of follow-up found female patients had more severe anxiety symptoms and worse activities of daily living prognosis \cite{33}.

Regarding post-stroke cognitive dysfunction, previous research conclusions remain controversial. A study among 1,227 first-time stroke patients in the United States explored sex differences in cognitive function 90 days post-stroke, finding women's cognitive function levels were significantly lower than men's. However, after adjusting for covariates including widowhood prevalence, education level, and pre-stroke cognitive function, the sex difference was no longer significant, suggesting these factors may be primary contributors to women's post-stroke cognitive impairment \cite{34}. Another cohort study of American community-dwelling adults found that after controlling for pre-stroke cognitive indicators, women's post-stroke cognitive impairment incidence remained higher than men's, with this difference particularly pronounced in the short term post-stroke \cite{35}.

3 Association Between Female Reproductive Factors Across the Lifespan and Stroke Risk

Beyond traditional cardiovascular risk factors like environmental exposures and lifestyle, female-specific reproductive factors as sex-specific risk determinants have unique and profound impacts on women's health across the lifespan. From menarche to menopause, women experience a series of physiological events throughout their reproductive cycle, with fluctuations in estrogen and progesterone levels and vascular endothelial changes potentially leading to vascular complications that may increase future cardiovascular and cerebrovascular disease risk \cite{11,36-39}. For example, WELTEN et al. \cite{40} found that among Dutch postmenopausal women, premature menopause was associated with increased ischemic stroke risk. A European study showed that higher parity and early menarche were both associated with elevated stroke risk in women \cite{41}. Evidence also links miscarriage and stillbirth with stroke occurrence \cite{42}. Therefore, scholars have suggested incorporating sex-specific risk factors into cardiovascular disease prediction models to avoid misclassifying women into low-risk groups \cite{10}.

3.1 Age at Menarche

Menarche marks the beginning of women's reproductive cycle and signifies reproductive system maturation and endocrine function activation \cite{43}. Previous studies have demonstrated that menarche age affects women's cardiometabolic health, though findings remain inconsistent. The Nurses' Health Study (NHS) found that compared to participants with menarche at age 13, those with menarche ≤10 years had higher cardiovascular disease risk (including coronary heart disease and stroke) \cite{44}. In a Chinese postmenopausal women cohort, a U-shaped association was observed between menarche age and fatal stroke risk, with both early menarche (≤12 and 13 years) and late menarche (17–18 years) associated with higher risk \cite{37}. A large UK female cohort study observed a similar U-shaped association, with menarche age ≤10 years and ≥17 years associated with 16% and 13% relative increase in stroke risk compared to menarche at age 13 \cite{45}. The association between menarche age and stroke and its underlying mechanisms remain insufficiently established. Potential mechanisms for early menarche's effect on stroke risk include mediating effects of hypertension, diabetes, and hyperlipidemia \cite{46}, as well as shared risk factor pathways between early menarche and late cardiovascular events, including low birth weight and childhood overweight/obesity \cite{37}. Another study suggested that later menarche age is associated with increased brachial artery diameter and impaired flow-mediated dilation, with this vascular endothelial dysfunction leading to systemic subclinical atherosclerosis that may partially explain the excess stroke risk associated with late menarche \cite{47}.

3.1.2 Adolescent Pregnancy

Adolescent pregnancy causes severe adverse health and social development impacts and has been designated a global public health priority intervention area by WHO and the UN Sustainable Development Goals agenda \cite{48}. Previous studies indicate that adolescent pregnancy significantly increases risks of preeclampsia, systemic infection, preterm birth, and puerperal endometritis, with these pathological events potentially linked to long-term cardiovascular and cerebrovascular disease development \cite{49}. Two Korean studies of postmenopausal women found that pregnancy before age 19 significantly increased hypertension and diabetes risks \cite{50,51}, both important stroke risk factors. Potential biological mechanisms may relate to abnormal early-life estrogen exposure, with the dramatic estrogen elevation during adolescent pregnancy overstimulating immature organ systems and disrupting physiological homeostasis \cite{50}. Additionally, adolescent mothers are concentrated in socioeconomically disadvantaged groups with lower health literacy, more likely to develop unhealthy lifestyles, and have poorer healthcare access—factors persisting throughout the reproductive cycle that may further exacerbate multiple stroke risk indicators including smoking, overweight/obesity, hypertension, and hyperglycemia \cite{52,53}.

3.2.1 Pregnancy and Childbirth

Pregnancy-related stroke refers to ischemic or hemorrhagic stroke occurring during pregnancy or the peripartum period. Previous evidence shows approximately 30 per 100,000 pregnant women experience pregnancy-related stroke, with incidence about three times higher than in non-pregnant women of the same age \cite{54}. By subtype, hemorrhagic stroke (including subarachnoid hemorrhage and intracerebral hemorrhage) and cerebral venous sinus thrombosis account for relatively high proportions of pregnancy-related stroke, with main pathogenic mechanisms including cardioembolism, carotid artery dissection, reversible cerebral vasoconstriction syndrome, and vascular malformations \cite{55,56}. Pregnancy-specific physiological remodeling imposes significant load on maternal vascular systems, including hemodynamic and vascular changes, increased coagulation factor activity, and upregulated immune system sensitivity \cite{54}. To meet increasing metabolic demands of mother and fetus, pregnant women's blood volume and cardiac output typically increase by approximately 45% compared to pre-pregnancy, which may worsen pre-existing heart disease and increase vascular embolic events like stroke \cite{57}. Additionally, pregnant women may experience systemic vasodilation and decreased resistance, causing venous stasis; combined with increased coagulation factor activity and decreased physiological anticoagulants, maternal blood enters a hypercoagulable state. These physiological changes increase thrombosis risk by 4–10 times, potentially triggering embolic events like stroke \cite{58}. Immune system regulation during pregnancy plays important roles in early placental implantation, peripartum induction, and delivery; however, dysregulated immune responses causing excessive inflammation may lead to endothelial dysfunction and increased stroke risk \cite{59}. Other pregnancy complications such as gestational hypertension, preeclampsia, and gestational diabetes are also stroke risk factors \cite{8}. Pregnancy and childbirth effects extend beyond the perinatal period, influencing future health trajectories. A Chinese study showed that compared to women with one delivery, women with multiple deliveries had higher future stroke risk, with a dose-response relationship between live birth number and risk \cite{60}. A US cohort study found that compared to women with 1–2 live births, those with ≥5 live births had higher stroke risk, though this association became non-significant after adjusting for baseline BMI \cite{61}. The association between childbearing age and future stroke risk has also attracted research attention. Some studies suggest early childbearing age leads to higher stroke risk, possibly related to low socioeconomic status and education; while others indicate later childbearing age also increases future stroke risk, potentially through mechanisms including reduced vascular elasticity and impaired regulatory function in older mothers \cite{62-64}.

3.2.2 Lactation

Breastfeeding is crucial not only for infant growth and development but also provides long-term health benefits for mothers \cite{65}. A US postmenopausal women cohort study found that women who had ever breastfed had 23% lower future stroke risk than those who never breastfed, with stroke risk further decreasing as lactation duration increased \cite{66}. A large Chinese postmenopausal women prospective cohort study found significant inverse associations between lifetime lactation duration and incident ischemic and hemorrhagic stroke. Specifically, compared to women who never breastfed, those with lifetime lactation duration exceeding 7 months had lower stroke incidence \cite{67}. The specific protective mechanisms of lactation against stroke remain unclear. Previous research suggests lactation may reset postpartum maternal metabolism, improving visceral fat accumulation and insulin resistance during pregnancy and maintaining maternal cardiovascular health \cite{11}. Additionally, lactation stimulates oxytocin secretion, triggering neuroendocrine stress responses that reduce maternal inflammatory responses, placing the cardiovascular system in a balanced stable environment and reducing atherosclerosis and stroke risk \cite{67}. Some scholars hypothesize lactation reduces cardiovascular disease risk by mobilizing excess fat reserves accumulated during pregnancy, though studies have found lactating women's cardiovascular disease risk remains lower even after BMI adjustment \cite{68}, suggesting protective effects extend beyond fat reduction through other unexplored mechanisms.

3.2.3 Pregnancy Loss

Pregnancy loss events, including miscarriage and stillbirth, may cause potential vascular damage. An NHS II cohort study found that women with spontaneous abortion history had 20% higher stroke incidence, with no significant mediating effects observed for hypertension, hyperlipidemia, or type 2 diabetes \cite{69}. A meta-analysis covering 18 primary studies showed that women experiencing miscarriage or stillbirth had higher stroke risk than those without such experiences, with risk increasing by 13% per additional miscarriage or 25% per additional stillbirth; recurrent miscarriage and stillbirth were associated with 42% and 14% excess stroke risk, respectively \cite{70}. One possible linking mechanism is vascular endothelial dysfunction, a common cause of miscarriage also associated with late stroke development. Additionally, immune and inflammatory responses play important roles in pregnancy loss, particularly recurrent miscarriage, with alloimmune and autoimmune responses not only causing hemolysis and miscarriage but also promoting arterial thrombosis, where elevated antiphospholipid antibodies are significantly associated with ischemic stroke development \cite{71}.

3.3 Perimenopause and Postmenopause: Menopause Age and Hormone Therapy

Menopause marks the end of female fertility and reproductive cycles. As women age, ovarian function gradually declines, decreasing endogenous estrogen secretion that provides cardiovascular protection, making menopause an important temporal factor affecting female cardiovascular disease incidence \cite{72}. Both the 2021 European Society of Cardiology (ESC) Clinical Practice Guidelines on Cardiovascular Disease Prevention and the 2019 American College of Cardiology (ACC)/American Heart Association (AHA) Joint Guidelines on Primary Prevention of Cardiovascular Disease identify premature menopause as a "risk enhancer" or "risk modifier" for atherosclerotic cardiovascular disease to guide patient risk assessment \cite{73,74}. Both premature natural and surgical menopause are associated with traditional cardiovascular risk factors (hypertension, hyperlipidemia, diabetes) as well as atrial fibrillation, venous thromboembolism, and stroke \cite{11}. A European postmenopausal women cohort study found that compared to menopause at age 50–54, menopause before age 40 increased stroke risk by 48%, with each additional year of menopause age reducing stroke risk by 2% \cite{40}. Some research suggests a bidirectional association between premature menopause and cardiovascular risk, where poorer pre-menopause cardiovascular health may lead to early menopause \cite{11}. The association between menopausal hormone therapy and cardiovascular disease has also received widespread attention, with clinical trial data showing increased stroke risk (particularly ischemic stroke) in women receiving estrogen alone or combined estrogen-progestin therapy \cite{75}, though other studies suggest low-dose estrogen preparations effectively alleviate menopausal symptoms without affecting late stroke risk \cite{13}.

3.4 Lifetime Cumulative Estrogen Exposure

As research on female reproductive factors deepens, scholars have proposed comprehensive reproductive indicators to measure the joint impact of life course events on women's health. Reproductive lifespan, defined as the interval from menarche to menopause, can serve as an indicator reflecting lifetime endogenous estrogen exposure. A large pooled study found that compared to women with reproductive lifespan of 36–38 years, those with <30 years had 75% higher stroke risk, with the association remaining significant after adjusting for menarche and menopause ages \cite{76}. Another study proposed a more complex comprehensive indicator of lifetime cumulative estrogen exposure, integrating reproductive lifespan, parity, pregnancy loss, lactation duration, oral contraceptive duration, and other factors through detailed formulas to represent endogenous and total estrogen exposure patterns, then assessing associations with late stroke \cite{77}. Research found that among Chinese postmenopausal women, the highest quartile of reproductive lifespan had lower risks of overall stroke, ischemic stroke, and intracerebral hemorrhage, with longer endogenous and total estrogen exposure duration associated with lower stroke risk \cite{77}. Additionally, life course epidemiology provides theoretical frameworks and multiple applicable models for assessing cumulative effects of chronic disease risk factor exposures, offering suitable methodological foundations for measuring combined impacts of multiple reproductive factors \cite{78}. A prospective study of Chinese postmenopausal women used life course cumulative risk models to calculate contributions of reproductive risk factor exposures to stroke burden, estimating that approximately 17.2% of incident stroke cases were attributable to combined multiple reproductive factor influences \cite{79}.

Currently, empirical research on lifetime estrogen exposure and stroke development remains insufficient, with few studies exploring overall effects and comprehensive evaluations of multiple reproductive factors. Existing composite indicators have limitations including incomplete coverage of reproductive factors and poor interpretability. Future women's stroke research should increase attention to female-specific reproductive factors, reveal sex differences in stroke pathophysiological mechanisms, and optimize female-specific stroke prevention and control decision-making programs to help reduce women's stroke-related health risks and safeguard female cardiovascular health.

Author Contributions: SUN Weidi was responsible for conceptualization, design, literature collection, figure design, and manuscript writing; SHAN Shiyi for manuscript revision and polishing; ZHU Xuan for manuscript revision, polishing, and submission; WU Jing for manuscript revision and polishing; HOU Leying for manuscript revision and polishing; SONG Peige for framework conceptualization and overall quality control and supervision.

Conflict of Interest: None declared.

ORCID IDs:
SUN Weidi https://orcid.org/0000-0002-8763-3569
SONG Peige https://orcid.org/0000-0002-0196-9759

References

\cite{1} HANKEY G J. Stroke \cite{J}. Lancet, 2017, 389(10069): 641-654. doi:10.1016/S0140-6736(16)30962-X.

\cite{2} GBD 2021 Stroke Risk Factor Collaborators. Global, regional, and national burden of stroke and its risk factors, 1990-2021: a systematic analysis for the Global Burden of Disease Study 2021\cite{J}. Lancet Neurol, 2024, 23(10): 973-1003. DOI:10.1016/S1474-4422(24)00369-7.

\cite{3} HE Q, WANG W J, ZHANG Y C, et al. Global, regional, and national burden of stroke, 1990-2021: a systematic analysis for the Global Burden of Disease 2021\cite{J}. Stroke, 2024, 55(12): 2815-2824. DOI:10.1161/STROKEAHA.124.048033.

\cite{4} MA Q F, LI R, WANG L J, et al. Temporal trend and attributable risk factors of stroke burden in China, 1990-2019: an analysis for the Global Burden of Disease Study 2019\cite{J}. Lancet Public Health, 2021, 6(12): e897-e906. DOI:10.1016/S2468-2667(21)00253-2.

\cite{5} WU S M, WU B, LIU M, et al. Stroke in China: advances and challenges in epidemiology, prevention, and management\cite{J}. Lancet Neurol, 2019, 18(4): 394-405. DOI:10.1016/S1474-4422(18)30500-3.

\cite{6} GERSTL J V E, BLITZ S E, QU Q R, et al. Global, regional, and national economic consequences of stroke\cite{J}. Stroke, 2023, 54(9): 2380-2389. DOI:10.1161/STROKEAHA.123.043131.

\cite{7} RYU W S, CHUNG J, SCHELLINGERHOUT D, et al. Biological mechanism of sex difference in stroke manifestation and outcomes\cite{J}. Neurology, 2023, 100(24): e2490-e2503. DOI:10.1212/WNL.0000000000207346.

\cite{8} KAPRAL M K, BUSHNELL C. Stroke in women\cite{J}. Stroke, 2021, 52(2): 726-728. DOI:10.1161/strokeaha.120.033233.

\cite{9} VOGEL B, ACEVEDO M, APPELMAN Y, et al. The lancet women and cardiovascular disease commission: reducing the global burden by 2030\cite{J}. Lancet, 2021, 397(10292): 2385-2438. DOI:10.1016/S0140-6736(21)00684-X.

\cite{10} OKOTH K, CHANDAN J S, MARSHALL T, et al. Association between the reproductive health of young women and cardiovascular disease in later life: umbrella review\cite{J}. BMJ, 2020, 371: m3502. DOI:10.1136/bmj.m3502.

\cite{11} O'KELLY A C, MICHOS E D, SHUFELT C L, et al. Pregnancy and reproductive risk factors for cardiovascular disease in women\cite{J}. Circ Res, 2022, 130(4): 652-672. DOI:10.1161/CIRCRESAHA.121.319895.

\cite{12} FEIGIN V L, BRAININ M, NORRVING B, et al. World stroke organization (WSO): global stroke fact sheet 2022\cite{J}. Int J Stroke, 2022, 17(1): 18-29. DOI:10.1177/17474930211065917.

\cite{13} REXRODE K M, MADSEN T E, YU A Y X, et al. The impact of sex and gender on stroke\cite{J}. Circ Res, 2022, 130(4): 512-528. DOI:10.1161/CIRCRESAHA.121.319915.

\cite{14} YOON C W, BUSHNELL C D. Stroke in women: a review focused on epidemiology, risk factors, and outcomes\cite{J}. J Stroke, 2023, 25(1): 2-15. DOI:10.5853/jos.2022.03468.

\cite{15} SESHADRI S, BEISER A, KELLY-HAYES M, et al. The lifetime risk of stroke: estimates from the Framingham study\cite{J}. JAMA, 2003, 289(20): 2673-2684. DOI:10.1001/jama.289.20.2673.

\cite{16} O'DONNELL M J, CHIN S L, RANGARAJAN S, et al. Global and regional effects of potentially modifiable risk factors associated with acute stroke in 32 countries (INTERSTROKE): a case-control study\cite{J}. Lancet, 2016, 388(10046): 761-775. DOI:10.1016/S0140-6736(16)30506-2.

\cite{17} Emerging Risk Factors Collaboration, SARWAR N, GAO P, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies\cite{J}. Lancet, 2010, 375(9733): 2215-2222. DOI:10.1016/S0140-6736(10)60484-9.

\cite{18} PETERS S A E, CARCEL C, MILLETT E R C, et al. Sex differences in the association between major risk factors and the risk of stroke in the UK Biobank cohort study\cite{J}. Neurology, 2020, 95(20): e2715-2726. DOI:10.1212/WNL.0000000000010982.

\cite{19} KURTH T, EVERETT B M, BURING J E, et al. Lipid levels and the risk of ischemic stroke in women\cite{J}. Neurology, 2007, 68(8): 556-562. DOI:10.1212/01.wnl.0000254472.41810.0d.

\cite{20} PAN B Q, JIN X, JUN L, et al. The relationship between smoking and stroke: a meta-analysis\cite{J}. Medicine, 2019, 98(12): e14872. DOI:10.1097/MD.0000000000014872.

\cite{21} WOODWARD M. Rationale and tutorial for analysing and reporting sex differences in cardiovascular associations\cite{J}. Heart, 2019, 105(22): 1701-1708. DOI:10.1136/heartjnl-2019-315299.

\cite{22} YANG G H, WANG Y, ZENG Y X, et al. Rapid health transition in China, 1990-2010: findings from the global burden of disease study 2010\cite{J}. Lancet, 2013, 381(9882): 1987-2015. DOI:10.1016/S0140-6736(13)61097-1.

\cite{23} WANG W Z, JIANG B, SUN H X, et al. Prevalence, incidence, and mortality of stroke in China: results from a nationwide population-based survey of 480,687 adults\cite{J}. Circulation, 2017, 135(8): 759-771. DOI:10.1161/CIRCULATIONAHA.116.025250.

\cite{24} GAO J J, CHEN Z Y. Clinical research progress on stroke\cite{J}. Modern Medical Imaging, 2017, 26(2): 337-339, 342.

\cite{25} PHAN H T, BLIZZARD C L, REEVES M J, et al. Sex differences in long-term mortality after stroke in the INSTRUCT (INternational STRoke oUtComes sTudy): a meta-analysis of individual participant data\cite{J}. Circ Cardiovasc Qual Outcomes, 2017, 10(2): e003436. DOI:10.1161/CIRCOUTCOMES.116.003436.

\cite{26} PHAN H T, BLIZZARD C L, REEVES M J, et al. Sex differences in long-term quality of life among survivors after stroke in the INSTRUCT\cite{J}. Stroke, 2019, 50(9): 2299-2306. DOI:10.1161/STROKEAHA.118.024437.

\cite{27} PHAN H T, GALL S L, BLIZZARD C L, et al. Sex differences in quality of life after stroke were explained by patient factors, not clinical care: evidence from the Australian Stroke Clinical Registry\cite{J}. Eur J Neurol, 2021, 28(2): 469-478. DOI:10.1111/ene.14531.

\cite{28} REEVES M J, BUSHNELL C D, HOWARD G, et al. Sex differences in stroke: epidemiology, clinical presentation, medical care, and outcomes\cite{J}. Lancet Neurol, 2008, 7(10): 915-926. DOI:10.1016/S1474-4422(08)70193-5.

\cite{29} BUSHNELL C, MCCULLOUGH L D, AWAD I A, et al. Guidelines for the prevention of stroke in women: a statement for healthcare professionals from the American heart association/american stroke association\cite{J}. Stroke, 2014, 45(5): 1545-1588. DOI:10.1161/01.str.0000442009.06663.48.

\cite{30} KATZAN I L, THOMPSON N R, UCHINO K, et al. The most affected health domains after ischemic stroke\cite{J}. Neurology, 2018, 90(16): e1364-1371. DOI:10.1212/WNL.0000000000005327.

\cite{31} POYNTER B, SHUMAN M, DIAZ-GRANADOS N, et al. Sex differences in the prevalence of post-stroke depression: a systematic review\cite{J}. Psychosomatics, 2009, 50(6): 563-569. DOI:10.1176/appi.psy.50.6.563.

\cite{32} GALL S, PHAN H, MADSEN T E, et al. Focused update of sex differences in patient reported outcome measures after stroke\cite{J}. Stroke, 2018, 49(3): 531-535. DOI:10.1161/STROKEAHA.117.018417.

\cite{33} XU M, AMARILLA VALLEJO A, CANTALAPIEDRA CALVETE C, et al. Stroke outcomes in women: a population-based cohort study\cite{J}. Stroke, 2022, 53(10): 3072-3081. DOI:10.1161/STROKEAHA.121.037829.

\cite{34} DONG L M, BRICENO E, MORGENSTERN L B, et al. Poststroke cognitive outcomes: sex differences and contributing factors\cite{J}. J Am Heart Assoc, 2020, 9(14): e016683. DOI:10.1161/JAHA.120.016683.

\cite{35} BAKO A T, POTTER T, TANNOUS J, et al. Sex differences in post-stroke cognitive decline: a population-based longitudinal study of nationally representative data\cite{J}. PLoS One, 2022, 17(5): e0268249. DOI:10.1371/journal.pone.0268249.

\cite{36} JACOBSEN B K, HEUCH I, KVÅLE G. Age at natural menopause and stroke mortality: cohort study with 3561 stroke deaths during 37-year follow-up\cite{J}. Stroke, 2004, 35(7): 1548-1551. DOI:10.1161/01.STR.0000131746.49082.5c.

\cite{37} HU Z B, LU Z X, ZHU F. Age at menarche, age at menopause, reproductive years and risk of fatal stroke occurrence among Chinese women: the Guangzhou Biobank Cohort Study\cite{J}. BMC Womens Health, 2021, 21(1): 433. DOI:10.1186/s12905-021-01505-1.

\cite{38} IORGA A, CUNNINGHAM C M, MOAZENI S, et al. The protective role of estrogen and estrogen receptors in cardiovascular disease and the controversial use of estrogen therapy\cite{J}. Biol Sex Differ, 2017, 8(1): 33. DOI:10.1186/s13293-017-0152-8.

\cite{39} HUMPHRIES K H, IZADNEGAHDAR M, SEDLAK T, et al. Sex differences in cardiovascular disease–Impact on care and outcomes\cite{J}. Front Neuroendocrinol, 2017, 46: 46-70. DOI:10.1016/j.yfrne.2017.04.001.

\cite{40} WELTEN S J G C, ONLAND-MORET N C, BOER J M A, et al. Age at menopause and risk of ischemic and hemorrhagic stroke\cite{J}. Stroke, 2021, 52(8): 2583-2591. DOI:10.1161/STROKEAHA.120.030558.

\cite{41} ARDISSINO M, SLOB E A W, CARTER P, et al. Sex-specific reproductive factors augment cardiovascular disease risk in women: a mendelian randomization study\cite{J}. J Am Heart Assoc, 2023, 12(5): e027933. DOI:10.1161/JAHA.122.027933.

\cite{42} MIKKELSEN A P, EGERUP P, KOLTE A M, et al. Pregnancy loss and the risk of myocardial infarction, stroke, and all-cause mortality: a nationwide partner comparison cohort study\cite{J}. J Am Heart Assoc, 2023, 12(15): e028620. DOI:10.1161/JAHA.122.028620.

\cite{43} DIVALL S A, RADOVICK S. Pubertal development and menarche\cite{J}. Ann N Y Acad Sci, 2008, 1135: 19-28. DOI:10.1196/annals.1429.026.

\cite{44} LEY S H, LI Y P, TOBIAS D K, et al. Duration of reproductive life span, age at menarche, and age at menopause are associated with risk of cardiovascular disease in women\cite{J}. J Am Heart Assoc, 2017, 6(11): e006713. DOI:10.1161/JAHA.117.006713.

\cite{45} CANOY D, BERAL V, BALKWILL A, et al. Age at menarche and risks of coronary heart and other vascular diseases in a large UK cohort\cite{J}. Circulation, 2015, 131(3): 237-244. DOI:10.1161/CIRCULATIONAHA.114.010070.

\cite{46} KIVIMÄKI M, LAWLOR D A, SMITH G D, et al. Association of age at menarche with cardiovascular risk factors, vascular structure, and function in adulthood: the Cardiovascular Risk in Young Finns study\cite{J}. Am J Clin Nutr, 2008, 87(6): 1876-1882. DOI:10.1093/ajcn/87.6.1876.

\cite{47} SCHNABEL R B, BIENER M P, WILDE S, et al. Sex differences in noninvasive vascular function in the community\cite{J}. J Hypertens, 2013, 31(7): 1437-1446; discussion 1446. DOI:10.1097/HJH.0b013e328360f755.

\cite{48} World Health Organization. Adolescent Pregnancy\cite{EB/OL}. [2024-12-20]. https://www.who.int/news-room/fact-sheets/detail/adolescent-pregnancy.

\cite{49} GANCHIMEG T, OTA E, MORISAKI N, et al. Pregnancy and childbirth outcomes among adolescent mothers: a World Health Organization multicountry study\cite{J}. BJOG, 2014, 121: 40-48. DOI:10.1111/1471-0528.12630.

\cite{50} PARK J S, JUNG I, YOUN J C, et al. Impact of adolescent pregnancy on hypertension in postmenopausal women\cite{J}. J Hypertens, 2020, 38(9): 1735-1741. DOI:10.1097/HJH.0000000000000747.

\cite{51} KIM J H, JUNG Y, KIM S Y, et al. Impact of age at first childbirth on glucose tolerance status in postmenopausal women: the 2008-2011 Korean National Health and Nutrition Examination Survey\cite{J}. Diabetes Care, 2014, 37(3): 671-677. DOI:10.2337/dc13-1784.

\cite{52} PETROVIC D, DE MESTRAL C, BOCHUD M, et al. The contribution of health behaviors to socioeconomic inequalities in health: a systematic review\cite{J}. Prev Med, 2018, 113: 15-31. DOI:10.1016/j.ypmed.2018.05.003.

\cite{53} STORMACQ C, VAN DEN BROUCKE S, WOSINSKI J. Does health literacy mediate the relationship between socioeconomic status and health disparities? Integrative review\cite{J}. Health Promot Int, 2019, 34(5): e1-17. DOI:10.1093/heapro/day062.

\cite{54} SWARTZ R H, CAYLEY M L, FOLEY N, et al. The incidence of pregnancy-related stroke: a systematic review and meta-analysis\cite{J}. Int J Stroke, 2017, 12(7): 687-697. DOI:10.1177/1747493017723271.

\cite{55} KATSAFANAS C, BUSHNELL C. Pregnancy and stroke risk in women\cite{J}. Neurobiol Dis, 2022, 169: 105735. DOI:10.1016/j.nbd.2022.105735.

\cite{56} LIU S L, CHAN W S, RAY J G, et al. Stroke and cerebrovascular disease in pregnancy\cite{J}. Stroke, 2019, 50(1): 13-20. DOI:10.1161/strokeaha.118.023118.

\cite{57} STERGIOPOULOS K, SHIANG E, BENCH T. Pregnancy in patients with pre-existing cardiomyopathies\cite{J}. J Am Coll Cardiol, 2011, 58(4): 337-350. DOI:10.1016/j.jacc.2011.04.014.

\cite{58} BRENNER B. Haemostatic changes in pregnancy\cite{J}. Thromb Res, 2004, 114(5/6): 409-414. DOI:10.1016/j.thromres.2004.08.004.

\cite{59} KELLY P J, LEMMENS R, TSIVGOULIS G. Inflammation and stroke risk: a new target for prevention\cite{J}. Stroke, 2021, 52(8): 2697-2706. DOI:10.1161/STROKEAHA.121.034388.

\cite{60} ZHANG Y M, SHEN L J, WU J, et al. Parity and risk of stroke among Chinese women: cross-sectional evidence from the Dongfeng-Tongji cohort study\cite{J}. Sci Rep, 2015, 5: 16992. DOI:10.1038/srep16992.

\cite{61} VLADUTIU C J, MEYER M L, MALEK A M, et al. Racial differences in the association between parity and incident stroke: results from the REasons for geographic and racial differences in stroke study\cite{J}. J Stroke Cerebrovasc Dis, 2017, 26(4): 749-755. DOI:10.1016/j.jstrokecerebrovasdis.2016.10.010.

\cite{62} ROSENDAAL N T A, PIRKLE C M. Age at first birth and risk of later-life cardiovascular disease: a systematic review of the literature, its limitation, and recommendations for future research\cite{J}. BMC Public Health, 2017, 17(1): 627. DOI:10.1186/s12889-017-4519-x.

\cite{63} SHEEN J J, WRIGHT J D, GOFFMAN D, et al. Maternal age and risk for adverse outcomes\cite{J}. Am J Obstet Gynecol, 2018, 219(4): 390.e1-390.e15. DOI:10.1016/j.ajog.2018.08.034.

\cite{64} SUN W D, SHAN S Y, HOU L Y, et al. Socioeconomic disparities in the association of age at first live birth with incident stroke among Chinese parous women: a prospective cohort study\cite{J}. J Glob Health, 2024, 14: 04091. DOI:10.7189/jogh.14.04091.

\cite{65} VICTORA C G, BAHL R, BARROS A J D, et al. Breastfeeding in the 21st century: epidemiology, mechanisms, and lifelong effect\cite{J}. Lancet, 2016, 387(10017): 475-490. DOI:10.1016/S0140-6736(15)01024-7.

\cite{66} JACOBSON L T, HADE E M, COLLINS T C, et al. Breastfeeding history and risk of stroke among parous postmenopausal women in the women's health initiative\cite{J}. J Am Heart Assoc, 2018, 7(17): e008739. DOI:10.1161/JAHA.118.008739.

\cite{67} REN Z Y, YI Q, HOU L Y, et al. Lactation duration and the risk of subtypes of stroke among parous postmenopausal women from the China kadoorie biobank\cite{J}. JAMA Netw Open, 2022, 5(2): e220437. DOI:10.1001/jamanetworkopen.2022.0437.

\cite{68} SCHWARZ E B, RAY R M, STUEBE A M, et al. Duration of lactation and risk factors for maternal cardiovascular disease\cite{J}. Obstet Gynecol, 2009, 113(5): 974-982. DOI:10.1097/01.AOG.0000346884.67796.ca.

\cite{69} WANG Y X, MÍNGUEZ-ALARCÓN L, GASKINS A J, et al. Pregnancy loss and risk of cardiovascular disease: the Nurses' Health Study II\cite{J}. Eur Heart J, 2022, 43(3): 190-199. DOI:10.1093/eurheartj/ehab737.

\cite{70} LIANG C, CHUNG H F, DOBSON A J, et al. Infertility, miscarriage, stillbirth, and the risk of stroke among women: a systematic review and meta-analysis\cite{J}. Stroke, 2022, 53(2): 328-337. DOI:10.1161/STROKEAHA.121.036271.

\cite{71} MATTHIESEN L, KALKUNTE S, SHARMA S. Multiple pregnancy failures: an immunological paradigm\cite{J}. Am J Reprod Immunol, 2012, 67(4): 334-340. DOI:10.1111/j.1600-0897.2012.01121.x.

\cite{72} RAJENDRAN A, MINHAS A S, KAZZI B, et al. Sex-specific differences in cardiovascular risk factors and implications for cardiovascular disease prevention in women\cite{J}. Atherosclerosis, 2023, 384: 117269. DOI:10.1016/j.atherosclerosis.2023.117269.

\cite{73} VISSEREN F L J, MACH F, SMULDERS Y M, et al. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice\cite{J}. Eur Heart J, 2021, 42(34): 3227-3337. DOI:10.1093/eurheartj/ehab484.

\cite{74} ARNETT D K, BLUMENTHAL R S, ALBERT M A, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American college of cardiology/American heart association task force on clinical practice guidelines\cite{J}. Circulation, 2019, 140(11): e596-e646. DOI:10.1161/CIR.0000000000000678.

\cite{75} WASSERTHEIL-SMOLLER S, HENDRIX S L, LIMACHER M, et al. Effect of estrogen plus progestin on stroke in postmenopausal women: the Women's Health Initiative: a randomized trial\cite{J}. JAMA, 2003, 289(20): 2673-2684. DOI:10.1001/jama.289.20.2673.

\cite{76} MISHRA S R, CHUNG H F, WALLER M, et al. Association between reproductive life span and incident nonfatal cardiovascular disease: a pooled analysis of individual patient data from 12 studies\cite{J}. JAMA Cardiol, 2020, 5(12): 1410-1418. DOI:10.1001/jamacardio.2020.4105.

\cite{77} HOU L Y, LI S T, ZHU S Y, et al. Lifetime cumulative effect of reproductive factors on stroke and its subtypes in postmenopausal Chinese women: a prospective cohort study\cite{J}. Neurology, 2023, 100(15): e1574-1586. DOI:10.1212/WNL.0000000000206863.

\cite{78} WAGNER C, CARMELI C, JACKISCH J, et al. Life course epidemiology and public health\cite{J}. Lancet Public Health, 2024, 9(4): e261-269. DOI:10.1016/S2468-2667(24)00009-0.

\cite{79} SUN W D, WU J, SHAN S Y, et al. Socioeconomic variations in the proportions of stroke attributable to reproductive profiles among postmenopausal women in China\cite{J}. BMC Med, 2025, 23(1): 149. DOI:10.1186/s12916-025-03976-5.

(Received: April 10, 2025; Revised: June 10, 2025)
(This article was edited by JIA Mengmeng)