Reproductive-associated risk factors and incident coronary heart disease in women: an umbrella review.

Khadeeja Alnefaie: Conceptualization, Methodology, Formal analysis, Investigation, Data curation, Visualization, Writing – original draft preparation. Jennifer R. Dungan: Conceptualization, Validation, Supervision, Writing – review & editing.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

An umbrella review examined systematic reviews and meta-analyses of the association between female reproductive factors and CHD development in women. This review followed PRISMA guidelines [ 9 ] and was registered with INPLASY 2024120118. A comprehensive search was performed in PubMed and CINAHL from January 2013 to December 2024, using keywords and MeSH terms to identify relevant studies. Appendix 1 presents the search strategy. Filters limited results to English, and reference lists were manually screened for additional studies. Two reviewers independently screened articles for inclusion. Inclusion and exclusion criteria are summarized in Table 1 . Study quality was assessed using the AMSTAR 2 tool [ 10 ]. Potential bias and methodological limitations were documented. Data extraction was guided by the Joanna Briggs Institute Assessment Form [ 11 ]. The lead author and co-author conducted regular audits and consensus meetings after extraction to ensure accuracy and reliability. Table 1 Inclusion & exclusion criteria. Table 1 Inclusion criteria Exclusion criteria • Study Design: Systematic reviews and meta-analysis. • Outcome Measures: Studies reporting RR or HR. • Studies reporting incidence or first-time diagnosis of the specified outcomes. • Exposure: (Hypertensive Disorders of Pregnancy (HPD), Pre-eclampsia, Preterm Delivery, Gestational Diabetes Mellitus (GDM), Stillbirth, Miscarriage, Placental Abruption, Polycystic Ovary Syndrome (PCOS), Menopause, Endometriosis, Vasomotor Symptoms (VMS), Parity, Fertility Treatment and Breastfeeding). The detailed identification and diagnostic criteria for each risk factor are provided in Appendix 1. • Outcomes: Coronary Heart Disease (CHD), ischemic heart disease (IHD). CHD encompasses both atherosclerotic (e.g., obstructive CAD) and non-atherosclerotic (e.g., microvascular dysfunction, vasospasm) conditions, while IHD focuses on reduced blood flow to the heart muscle due to CAD or other causes. Detailed definitions, conditions, and ICD codes are provided in Appendix 1. • Language: English-language publications. • Publication Date: Studies published within the last 10 years. • Exclude studies reporting prevalence rather than incidence or first-time diagnosis. • Exclude studies focusing on recurrent cardiovascular events or secondary events. Recurrence is more relevant to disease progression and prevalence, whereas our analysis aims to assess how reproductive factors contribute to the initial development of CHD. • Exclude studies focusing on cardiovascular events occurring during pregnancy or the peripartum period, including pregnancy-associated myocardial infarction and peripartum cardiomyopathy, as we examine CVD as a long-term health consequence of reproductive risk factors—such as hypertensive disorders of pregnancy, gestational diabetes, and preterm birth—rather than as an immediate maternal outcome during pregnancy. • As well as studies focused on fetal cardiovascular outcomes were excluded. • Exclude studies that report cardiometabolic outcomes unless they provide a separate risk measure for IHD or CHD. • Exclude studies focusing on inherited cardiomyopathies as primary outcomes. • Conditions not directly related to CHD and IHD such as cerebrovascular diseases (e.g., stroke) heart failure, peripheral artery disease, and non-ischemic cardiomyopathies. • Exclude studies published in languages other than English. • Exclude studies published >10 years prior to the current date. Note: CHD, CAD, and IHD are often used interchangeably in literature. For consistency, this review used CHD and IHD as primary terms, with CAD as a subset of atherosclerotic CHD. Some studies reported CVD as a composite outcome, including conditions beyond CHD and IHD. We extracted and analyzed data related to CHD and IHD. If CHD/IHD-specific data were unavailable, we assessed if primary cardiovascular outcomes were driven by coronary pathology. Studies where non-coronary conditions (e.g., cerebrovascular disease and heart failure) were primary outcomes were excluded. Inclusion & exclusion criteria. Study Design: Systematic reviews and meta-analysis. Outcome Measures: Studies reporting RR or HR. Studies reporting incidence or first-time diagnosis of the specified outcomes. Exposure: (Hypertensive Disorders of Pregnancy (HPD), Pre-eclampsia, Preterm Delivery, Gestational Diabetes Mellitus (GDM), Stillbirth, Miscarriage, Placental Abruption, Polycystic Ovary Syndrome (PCOS), Menopause, Endometriosis, Vasomotor Symptoms (VMS), Parity, Fertility Treatment and Breastfeeding). The detailed identification and diagnostic criteria for each risk factor are provided in Appendix 1. Outcomes: Coronary Heart Disease (CHD), ischemic heart disease (IHD). CHD encompasses both atherosclerotic (e.g., obstructive CAD) and non-atherosclerotic (e.g., microvascular dysfunction, vasospasm) conditions, while IHD focuses on reduced blood flow to the heart muscle due to CAD or other causes. Detailed definitions, conditions, and ICD codes are provided in Appendix 1. Language: English-language publications. Publication Date: Studies published within the last 10 years. Exclude studies reporting prevalence rather than incidence or first-time diagnosis. Exclude studies focusing on recurrent cardiovascular events or secondary events. Recurrence is more relevant to disease progression and prevalence, whereas our analysis aims to assess how reproductive factors contribute to the initial development of CHD. Exclude studies focusing on cardiovascular events occurring during pregnancy or the peripartum period, including pregnancy-associated myocardial infarction and peripartum cardiomyopathy, as we examine CVD as a long-term health consequence of reproductive risk factors—such as hypertensive disorders of pregnancy, gestational diabetes, and preterm birth—rather than as an immediate maternal outcome during pregnancy. As well as studies focused on fetal cardiovascular outcomes were excluded. Exclude studies that report cardiometabolic outcomes unless they provide a separate risk measure for IHD or CHD. Exclude studies focusing on inherited cardiomyopathies as primary outcomes. Conditions not directly related to CHD and IHD such as cerebrovascular diseases (e.g., stroke) heart failure, peripheral artery disease, and non-ischemic cardiomyopathies. Exclude studies published in languages other than English. Exclude studies published >10 years prior to the current date. Note: CHD, CAD, and IHD are often used interchangeably in literature. For consistency, this review used CHD and IHD as primary terms, with CAD as a subset of atherosclerotic CHD. Some studies reported CVD as a composite outcome, including conditions beyond CHD and IHD. We extracted and analyzed data related to CHD and IHD. If CHD/IHD-specific data were unavailable, we assessed if primary cardiovascular outcomes were driven by coronary pathology. Studies where non-coronary conditions (e.g., cerebrovascular disease and heart failure) were primary outcomes were excluded.

Include hypertensive disorders of pregnancy (e.g., gestational hypertension, pre-eclampsia), preterm delivery, gestational diabetes mellitus (GDM), stillbirth, miscarriage and placental abruption. HDP includes gestational hypertension, pre-eclampsia, eclampsia, and chronic hypertension with superimposed pre-eclampsia. Six meta-analyses reviewed 22–83 studies involving up to 29 million women with HDP. With three assessing preeclampsia and the others focusing on HDP either individual subtypes or composite outcomes [ 12 , [14] , [15] , [16] , [17] , [18] ]. Table 2 and Fig. 2 present the risk estimates for each factor. Pooled risk estimates revealed that HDP increased CHD risk, ranging from an RR 1.66 of 3.13. Preeclampsia is linked to increased CHD risk, with a pooled RR of 2.5, which increases after adjusting for age, BMI, and diabetes mellitus [ 12 ]. In three studies of 10,522 women with recurrent pre-eclampsia and 58,490 with single pre-eclampsia, the pooled IHD risk was 2.4 [ 13 ]. Patients with prior pre-eclampsia and severe features had an increased risk of IHD RR 2.11. Despite low evidence, preeclampsia with severe features significantly increased the risk of IHD RR, 6.67. Severe features were not defined in the meta-analysis. Sensitivity analyses assessed whether the effects of HDP on IHD varied with the time since onset. CVD risk post-HDP is highest in the first 10 years postpartum compared to >10 years. A meta-analysis showed that CVD risk linked to HDP was higher with shorter follow-up and gradually declined as follow-up increased [ 14 ]. This risk reduction over longer periods may be influenced by baseline risk differences. Fewer cardiovascular events and smaller sample sizes in the >10-year follow-up group may have contributed to less precise long-term risk estimates. Future CVD risk was highest for women with a history of HDP during the first five years after delivery RR 2.06, but evidence certainty was low due to study limitations and inconsistency. The influence of preeclampsia severity and onset on long-term outcomes remains inconclusive. These findings emphasize the increased CVD risk after HDP, especially in women with severe preeclampsia, highlighting the need for proper screening and early detection of subclinical CVDs, particularly during the first five years postpartum [ 15 ]. Further analysis reported CVD risk in preeclampsia OR 2.7 [ 16 ]. A recent meta-analysis of 22 studies involving over 13 million women found that preeclampsia increases CAD risk (ES 2.04) with risk evident within 1–3 years post-diagnosis and remained elevated throughout the long-term follow-up [ 17 ]. Table 2 Summary of studies assessing reproductive risk factors and coronary disease. Table 2 Study Effect / sample sizes 1. Update on long-term cardiovascular risk after pre-eclampsia: a systematic review and meta-analysis, (Inversetti et al., 2023). PE was associated with a higher risk of coronary artery diseases (ES 2.04, 95 % CI 1.76–2.38, I2 87%, P  < 0.00001). The total sample size is 13,162,030 women including 598,733 women with PE and 12,563,297 without. 2. Hypertensive Disorders of Pregnancy and Risk of Cardiovascular Disease-Related Morbidity and Mortality: A Systematic Review and Meta-Analysis, (R. Wu et al., 2020). The overall combined relative risks (RRs) for women with a history of HDP compared with the reference group were: 1.80 (95 % confidence interval [CI] 1.67–1.94) for any CVD, 1.66 (1.49–1.84) for coronary artery heart disease. The sample size involving >13 million women. 3. Preeclampsia and Future Cardiovascular Health a Systematic Review and Meta- Analysis (P. Wu et al., 2017). Preeclampsia was independently associated with coronary heart disease (RR, 2.50; 95 % CI, 1.43–4.37). Sensitivity analyses showed that preeclampsia continued to be associated with an increased risk of future coronary heart disease, heart failure, and stroke after adjusting for age (RR, 3.89; 95 % CI, 1.83–8.26), body mass index (RR, 3.16; 95 % CI, 1.41–7.07), and diabetes mellitus (RR, 4.19; 95 % CI, 2.09–8.38). The sample size is >6.4 million women, which includes >258,000 women with preeclampsia. 4. Recurrence of pre-eclampsia and the risk of future hypertension and cardiovascular disease: a systematic review and meta-analysis (Brouwers et al., 2018). Recurrent pre-eclampsia was consistently associated with an increased pooled risk ratio of IHD (RR 2.40; 95 % CI 2.15–2.68). The sample sizes, varying from 28 to 1,108,581 participants. 5. Risk of future cardiovascular diseases in different years postpartum after hypertensive disorders of pregnancy A systematic review and meta-analysis, (Sukmanee & Liabsuetrakul, 2022). Women with prior HDP had increased risks of ischemic heart disease (RR 2.06, 95 % CI: 1.38–3.08). This study included a total of 15,973,780 women, including 1,262,726 women with a history of HDP and 14,711,054 controls. 6. Cardiovascular Disease-Related Morbidity and Mortality in Women with a History of Pregnancy Complications. (Grandi et al. (2019). The risk of CVD was highest in women with gestational hypertension (OR 1.7; 95 % ICI, 1.3–2.2), preeclampsia (OR 2.7; 95 % ICI, 2.5–3.0), placental abruption (OR 1.8; 95 % ICI, 1.4–2.3), preterm birth (OR 1.6; 95 % ICI, 1.4–1.9), gestational diabetes mellitus (OR 1.7; 95 % ICI, 1.1–2.5), and stillbirth (OR 1.5; 95 % ICI, 1.1–2.1). This review included 83 studies with a total of 28,993,438 patients. Sample sizes ranged from 250 to 2,000,000. 7. Cardiovascular disease risk in women with a history of spontaneous preterm delivery: A systematic review and meta-analysis, (Heida et al., 2016). Spontaneous preterm delivery was related to an increased risk of developing or dying from IHD (HR 1.38, 95 %(CI) 1.22–1.57) and overall CVD (relative risk (HR) 2.01, 95 % CI 1.52–2.65). This study sample sizes ranged from 3706 to 923,686 women. 8. History of preterm birth and subsequent cardiovascular disease: a systematic review, (Robbins et al., 2014). Women with any history of PTB had an increased risk of CVD morbidity (adjusted hazard ratio [aHR] ranged from 1.2 to 2.9; 2 studies), ischemic heart disease (aHR, 1.3–2.1; 3 studies), and atherosclerosis (aHR, 4.1; 1 study). The sample sizes of the individual studies ranged from 446 to 923,686 participants. 9. Gestational diabetes mellitus and development of intergenerational overall and subtypes of cardiovascular diseases: a systematic review and meta-analysis, (Chen et al., 2024). The results showed a 46 % increased risk (RR 1.46, 95 % CI 1.34–1.59) for mothers of developing overall CVDs after delivery, following a GDM-complicated pregnancy. The subgroup analysis revealed that mothers with a history of GDM faced various risks (20 % to 2-fold) of developing different subtypes of CVDs, including coronary artery disease. The sample sizes in these studies ranged from 391 to 2,201,352. 10. Gestational diabetes and the risk of cardiovascular disease in women: a systematic review and meta-analysis, (Kramer et al., 2019). Women with GDM had a twofold higher risk of future cardiovascular events (RR 1.98 [95 % CI 1.57, 2.50]). Moreover, when restricted to women who did not develop type 2 diabetes, GDM remained associated with a 56 % higher risk of future cardiovascular events (RR 1.56 [95 % CI 1.04, 2.32]). GDM conferred a 2.3-fold increased risk of cardiovascular events in the first decade postpartum (RR 2.31 [95 % CI 1.57, 3.39]). The total sample size across the included studies was 5,390,591 women, with 101,424 cardiovascular events reported. 11. Increased risk of cardiovascular disease in women with prior gestational diabetes: A systematic review and meta-analysis, (Li et al., 2018). In the pooled analysis, women with previous GDM had a higher risk of CVD (RR: 1.74, 95%CI: 1.28–2.35, I 2  = 95.7 %). The overall RR for CAD was 2.09 (95%CI: 1.56–2.80, I 2  = 91.2 %) In view of the high level of heterogeneity, adjustments were made for this, with the resulting adjusted OR for CVD and CAD being 1.95 (95%CI: 1.83–2.08) and 1.59 (95%CI: 1.30–1.94). The analysis included 3,417,020 women and 14,146 CVD events. 12. Association of gestational diabetes mellitus with overall and type-specific cardiovascular and cerebrovascular diseases: systematic review and meta-analysis, (Xie et al., 2022). (Risk of overall cardiovascular and cerebrovascular diseases (risk ratio 1.45, 95 % confidence interval 1.36 to 1.53), for cardiovascular diseases (1.72, 1.40 to 2.11), Women with gestational diabetes mellitus showed increased risks of incident coronary artery diseases (1.40, 1.18 to 1.65). The study included 513,324 women with gestational diabetes mellitus, of whom 9507 had cardiovascular and cerebrovascular disease. 13. The risk of cardiovascular diseases after miscarriage, stillbirth, and induced abortion: a systematic review and meta-analysis, (Kyriacou et al., 2022). Recurrent miscarriage was associated with a higher CHD risk (RR = 1.37, 95 % CI: 1.12–1.66). One or more stillbirths were associated with a higher CVD (RR = 1.41, 95 % CI: 1.09–1.82), CHD (RR = 1.51, 95 % CI: 1.04–1.29), Recurrent stillbirth was associated with a higher CHD risk (RR = 1.28, 95 % CI: 1.18–1.39). One or more abortions were associated with a higher CVD (RR = 1.04, 95 % CI: 1.02–1.07), as was recurrent abortion (RR = 1.09, 95 % CI: 1.05–1.13). This study included a total of 4,337,683 women. 14. Miscarriage and future maternal cardiovascular disease: a systematic review and meta-analysis, (Oliver-Williams et al., 2013). History of miscarriage was associated with a greater odd of developing coronary heart disease, OR (95 % CI) =1.45 (1.18 to 1.78), There was a strong association between recurrent miscarriage and coronary heart disease OR = 1.99 (1.13 to 3.50). The meta-analysis included 517,504 individuals for coronary heart disease and 134,461 individuals for cerebrovascular disease. 15. Fetal loss and long-term maternal morbidity and mortality: A systematic review and meta-analysis (Vlachou et al., 2024). Women with a history of stillbirth had a greater risk of ischemic heart disease (IHD) RR 1.56, 95 % CI [1.30, 1.88]; p  < 0.001, 95 % PI [0.49 to 5.15]) and any circulatory/cardiovascular disease (RR 1.86, 95 % CI [1.01, 3.45], p  = 0.05, 95 % PI [0.74, 4.10]). There was no evidence of increased risk of cardiovascular disease (IHD: RR 1.11, 95 % CI [0.98, 1.27], 95 % PI [0.46, 2.76] or cerebrovascular: RR 1.01, 95 % CI [0.85, 1.21]) in women experiencing a miscarriage. Only women with a previous stillbirth were more likely to develop type 2 diabetes mellitus (T2DM) (RR: 1.16, 95 % CI [1.07 to 2.26]; p  < 0.001, 95 % PI [1.05, 1.35]). The study included 1,119,815 women with pregnancy loss (951,258 with miscarriage and 168,557 with stillbirth) and 11,965,574 women without previous loss. 16. Miscarriage and stillbirth in relation to risk of cardiovascular diseases: A systematic review and meta-analysis, (Wang et al., 2024). Women with a history of miscarriage, the pooled RRs for the risk of total CVDs, and coronary heart disease (CHD) was1.16 (95 % CI 1.10–1.22), and 1.26 (1.12–1.41) respectively. For women with a history of stillbirth, the pooled RRs for the risk of total CVDs, and CHD, were 1.60 (1.34–1.89), 1.30 (1.12–1.50) respectively. With each additional miscarriage, the risk increased for total CVDs (1.08, 1.04–1.13), and CHD (1.08, 1.04–1.13). With each additional stillbirth, the risk increased for total CVDs (1.11, 1.03–1.21) and CHD (1.13, 1.07–1.19). The sample sizes of studies that qualified varied from 3637 to 1,293,640, while total number of participants was 7,847,648. 17. Maternal Cardiovascular and Cerebrovascular Health After Placental Abruption: A Systematic Review and Meta-Analysis (CHAP-SR) (Ananth et al., 2021). Risks of combined CVD morbidity-mortality among abruption and no abruption groups were 16.7 and 9.3 per 1000 births, respectively (RR = 1.76, 95 % CI: 1.24, 2.50; I2 = 94 %; τ2 = 0.22). The study comprised 6,325,152 pregnancies, including 69,759 cases of placental abruption and 49,265 cases of coronary heart disease (CHD) and stroke. 18. Risk and incidence of cardiovascular disease associated with polycystic ovary syndrome (Wan et al., 2024). The risk of CVD was significantly increased in women with PCOS for an all-age group (pooled RR 1.51, 95 % confidence interval 1.36–1.69) and 10- to 54-year-olds (1.37, 1.17–1.59). The data extracted from 17 articles that contributed to the analysis. 19. Polycystic ovary syndrome (PCOS) and the risk of coronary heart disease (CHD): a meta-analysis, (Zhao et al., 2016). PCOS was significantly associated with the increased risk of CVD (OR = 1.30; 95 % CI 1.09–1.56; P  = 0.004). In stratified analysis by type of CVD, a significant association was found between PCOS and coronary heart disease (CHD) (OR = 1.44; 95 % CI 1.13–1.84, P  = 0.004). The study sample size involving a total of 104,392 subjects. 20. Risk of Cardiovascular and Cerebrovascular Events in Polycystic Ovarian Syndrome Women: A Meta-Analysis of Cohort Studies (Zhang et al., 2020). The pooled risk of CVD events in PCOS women of CVD (OR: 1.66, 95 % CI: 1.32–2.08, P  < 0.00001; I2 = 66 %, P  < 0.0001) in a random-effects model, ischemic heart disease (OR: 2.77, 95 % CI: 2.12–3.61). The study sample size comprising 166,682 subjects. 21. Association of Age at Onset of Menopause and Time Since Onset of Menopause with Cardiovascular Outcomes, Intermediate Vascular Traits, and All-Cause Mortality: A Systematic Review and Meta-analysis. (Muka et al., 2016). Women who experienced menopause younger than 45 years and women 45 years or older at onset; the relative risks (95 % CIs) were 1.50 (1.28–1.76) for overall CHD, 1.11 (1.03–1.20) for fatal CHD, 1.23 (0.98–1.53). The total of 342,284 women were included in this review. 22. Cardiovascular disease risk in women with premature ovarian insufficiency: A systematic review and meta-analysis, (Roeters Van Lennep et al., 2016). POI was related to an increased risk of developing or dying from IHD (hazard ratio (HR) 1.69, 95 % CI 1.29–2.21, p  = 0.0001) and total CVD (HR 1.61, 95 % CI 1.22–2.12, p  = 0.0007). This review comprising 190,588 women with 9440 events. 23. The risk of long-term cardiometabolic disease in women with premature or early menopause: A systematic review and meta-analysis (Liu et al., 2023). Women with menopause at age > 45 years, women with premature menopause (PM) or early menopause (EM) had a higher risks of coronary heart disease (RR: 1.52, 95 % CI: 1.22–1.91; RR: 1.19, 95 % CI: 1.07–1.32, respectively), and total cardiovascular event (RR: 1.36, 95 % CI: 1.16–1.60; RR: 1.14, 95 % CI: 0.97–1.35, respectively). This study included 921,517 participants in their analysis. 24. Endometriosis and cardiovascular disease: A systematic review and meta-analysis (Poeta do Couto et al., 2023). Endometriosis was associated with a significantly increased risk of ischemic heart disease (HR 1.50, 95%CI 1.37–1.65; I 2  = 0 %). This review included a total of 254,929 participants. 25. Vasomotor symptoms and risk of cardiovascular disease in peri- and postmenopausal women: A systematic review and meta-analysis (Armeni et al., 2023). Women with VSM younger than 60 years at baseline had a higher risk of an incident CVD event than women without VSM of the same age (RR 1.12, 95 % CI 1.05–1.19, I 2 0%). Conversely, the incidence of CVD events was not different between women with and without VMS in the age group >60 years (RR 0.96, 95 % CI 0.92–1.01, I 2 55%). This analysis yielding a total of 51,133 women with and 93,892 without VMS. 26. Association of Vasomotor and Other Menopausal Symptoms with Risk of Cardiovascular Disease: A Systematic Review and Meta-Analysis (Muka et al., 2016). The age and non-established cardiovascular risk factors adjusted RRs) [95 %] for development of CHD, Stroke, and CVD comparing women with and without any menopausal symptoms were 1.34 [1.13–1.58], 1.30 [0.99–1.70], 1.48 [1.21–1.80] respectively, and the corresponding RRs adjusted for cardiovascular risk factors and potential mediators were 1.18 [1.03–1.35], 1.08 [0.89–1.32], 1.29 [0.98–1.71]. This review including 213,976 women with a total of 10,037 cardiovascular disease outcomes. 27. Parity and risk of maternal cardiovascular disease: A dose-response meta-analysis of Cohort studies (Li et al., 2018). A significant association between parity and cardiovascular disease risk was observed while comparing parity with nulliparity, with a summarized relative risk of 1.14 (95 % (CI) 1.09 1.18; I 2  = 62.0 %, P  = 0.002). The sample size is 3,089,929 participants involving 150,512 incident cases of cardiovascular disease. 28. Cardiovascular risk following fertility therapy (Dayan et al., 2017). There was no increased risk of a cardiac event (pooled HR: 0.91; 95 % CI: 0.67 to 1.25; I 2  = 36.6 %). The study including 41,910 women who received fertility therapy and 1,400,202 women who did not. 29. Breastfeeding is associated with a reduced maternal cardiovascular risk: Systematic Review and meta-analysis involving data from 8 studies and 1,192,700 parous women (Tschiderer et al., 2022). The pooled multivariable-adjusted hazard ratios were 0.89 for CVD (95 % CI, 0.83–0.95; I 2  = 79.4 %), 0.86 for coronary heart disease (95 % CI, 0.78–0.95; I 2  = 79., and 0.83 for fatal CVD (95 % CI, 0.76–0.92; I 2  = 47.7 %). This review involving 1,192,700 parous women. Fig. 2 Forest plot showing results of meta-analyses from the included studies investigating the association between various reproductive factors and risk of specific heart disease (CVD/CHD/CAD/IHD). Fig. 2 Summary of studies assessing reproductive risk factors and coronary disease. Forest plot showing results of meta-analyses from the included studies investigating the association between various reproductive factors and risk of specific heart disease (CVD/CHD/CAD/IHD). Delivering a baby before the 37th week is associated with an increased risk of CVD [ 18 ]. A review of three cohort studies with nearly 923,686 women revealed RRs ranging from 1.2 to 4.1 for CVD. In two studies, the adjusted HR for developing CVD, ranged from 1.2 to 2.9, with elevated risks for IHD between 1.3–2.1 and 4.1 for atherosclerosis when compared to women who had term deliveries after adjusting for hypertension/preeclampsia, birth weight, and socioeconomic status [ 19 ]. In a post-hoc analysis of 5 NW European women followed for 35 years, PTB was associated with an increased risk of IHD HR 1.38 and increased CVD risk HR 2.01 [ 20 ]. Findings align with a comprehensive review in which preterm birth women were 63 % more likely to experience cardiovascular events, including CAD [ 16 ]. Despite this, detailed information on preterm delivery timing was not indicated. Interpretation of results should account for variability in hazard ratios, small sample sizes, and potential publication biases. GDM has been evaluated in several meta-analyses, demonstrating an increased risk of cardiovascular outcomes. A meta-analysis of 15 studies with over 9500 women with GDM showed an RR 1.72 risk of CVD and 1.4 risk of developing CAD [ 21 ]. Cardiovascular outcomes varied by region, study design, and adjustment for confounding variables. When restricted to women who did not develop overt diabetes later, the risk remained high but attenuated with an RR of 1.09. An analysis of over 5 million women from observational studies, with follow-up periods up to 25.7 years, revealed that women with GDM had an RR of 1.98 for future cardiovascular events, including IHD. When excluding women who later developed type 2 diabetes, GDM remained associated with a 56 % increased risk of cardiovascular events [ 22 ]. Pronounced risk occurred within the first decade postpartum, with a risk of cardiovascular events (RR 2.31). This risk persists regardless of subsequent type 2 diabetes development, indicating long-term cardiovascular implications of mild glucose intolerance during pregnancy. A study of approximately 3.4 million women from seven cohorts, with a median follow-up of 7 years, demonstrated an increased risk of CAD, with an RR of 2.09, with adjusted OR for CVD at 1.95 and CAD at 1.59 [ 23 ]. A recent meta-analysis reported a 46 % increased risk of developing overall CVDs RR 1.46 among women with a history of GDM. Subgroup analyses showed a 2-fold higher risk for different CVD subtypes, including CAD [ 24 ]. Pregnancy loss, including stillbirth and miscarriage, is linked to increased CVD risk. Meta-analyses report relative risks (RRs) of 1.02 to 1.29 for miscarriage and 1.41 to 1.57 for stillbirths [ [25] , [26] , [27] , [28] ]. The relationship is complex, with factors like obesity and smoking contributing. A meta-analysis of over 4 million women found no significant CVD risk with one miscarriage (RR 1.02), but recurrent miscarriages had a slightly higher risk RR (1.29). Stillbirth was linked to higher CVD risk (RR 1.41) and increased recurrent stillbirth risk (RR 1.57) [ 25 ]. For CHD, one miscarriage showed a non-significant risk increase (RR 1.17), while recurrent miscarriages had higher risk RR (1.37) [ 25 ]. Another analysis of 518,000 women found miscarriage linked to CHD OR (1.45), with stronger effect for recurrent miscarriage (OR 1.99) [ 26 ]. Analysis of over 1.1 million women showed stillbirth associated with IHD (RR1.56), but no significant miscarriage increase (RR1.11), though recurrent loss showed modest IHD risk increase [ 27 ]. Recent evidence supports these findings. A pooled analysis of 23 studies found RRs of 1.16 for total CVD and 1.26 for CHD in women with miscarriage history. For stillbirths, pooled RRs were 1.60 for total CVD and 1.30 for CHD. Risk increased with each additional loss: for miscarriage, RRs for total CVD and CHD were 1.08, and for stillbirth, 1.11 for total CVD and 1.13 for CHD [ 28 ]. However, underreporting, residual confounding, and inconsistent miscarriage definitions affect reliability of these findings. Placental abruption, occurring in approximately 1 % of pregnancies, is linked with an increased future CVD risk and a 10-fold higher recurrence rate [ 29 ]. Two meta-analyses examined CVD risk. The first, with around 70,000 placental abruption cases and nearly 49,000 CHD cases, found combined CVD morbidity and mortality risks were 16.7 per 1000 births in the abruption group (RR 1.76). Increased risks were noted for IHD, with an HR of 1.6. Sensitivity analysis showed that recurrent abruption linked to higher CHD risk, with increased CHD-related deaths in women with multiple abruption episodes [ 30 ]. An analysis of seven studies found an OR of 1.8 for the link between abruption and CVD risk [ 16 ]. Differences in risk estimates may arise from varying exposure and outcome definitions, and cardiovascular subtypes. Whether the CHD risk from abruption is independent of HDP remains unclear. However, both analyses highlighted the link between abruption and future CVD, suggesting monitoring women with this history [ 16 , 30 ]. PCOS is characterized by hyperandrogenism, ovarian cysts, and irregular menstrual cycles. A meta-analysis of ten studies with 104,392 mainly Caucasian women found PCOS associated with increased CVD risk (OR 1.30). Analysis by CVD type showed a significant association between PCOS and CHD (OR 1.44) [ 31 ]. However, unclear covariate adjustment raises questions about result robustness. The absence of follow-up data may underestimate the true PCOS-associated risk. Another analysis of cohort studies, comparing 166,682 PCOS participants to non-PCOS women with 5–22 years follow-up, showed increased CVD risk (OR1.66) and IHD (OR 2.77) [ 32 ]. A recent meta-analysis confirmed a higher CVD risk in women with PCOS, including those aged <55 years (pooled RR 1.51; RR 1.37 for women aged 10–54) [ 33 ]. These results highlight early CVD onset in PCOS patients. However, heterogeneity of symptoms and metabolic profiles across PCOS phenotypes may influence cardiovascular risk, with elevated blood pressure and atherogenic lipid profile contributing to increased susceptibility. Accurate CVD risk assessment in PCOS requires addressing these complexities. Menopause, defined as the cessation of menstruation for 12 consecutive months, typically occurs between ages 49 and 52. About 5 % experience menopause between ages 40 and 45, and approximately 1 % before age 40, termed “early” and “premature menopause” (or premature ovarian insufficiency, [POI] if spontaneous) [ 34 ]. Women undergoing menopause earlier face higher cardiovascular risks, particularly CHD. A meta-analysis of over 342,000 women with 51-year follow-ups found those experiencing menopause before 45 had a 50 % higher CHD risk than those at 45 or older. Menopause between 45 and 49 years modestly elevates CHD risk [ 35 ]. The analysis adjusted for confounders like age and hormone therapy, despite inconsistencies in hormone therapy descriptions. In a POI meta-analysis, data from 10 studies with nearly 190,600 women showed a 69 % increase in IHD risk, higher in Western populations but insignificant among Asians [ 36 ]. Many studies lack thorough POI subgroup analysis, indicating more research is needed. A review of 20 cohort studies with nearly one million participants examined premature and early menopause. Premature menopause increases CHD risk by 52 %, and early menopause by 19 % [ 37 ]. Both are linked to higher CHD risk. Premature menopause was associated with a 36 % increased total CVD risk, and early menopause with a 16 % increase. This review, with follow-up periods from 4 to 67 years, highlights long-term cardiovascular impacts of early menopause. However, variability in self-reported menopause ages and inconsistent cardiovascular risk factor documentation introduced inconsistencies. EM is an inflammatory condition characterized by endometrial-like tissues outside the uterus. A systematic review examined the association between EM and CVD. Over 250,000 EM patients from six cohort studies were followed up from 9.2 to 28 years. After adjusting for age, findings showed EM was associated with increased risk of IHD (HR 1.50) [ 38 ]. As studies used different methodologies, results must be interpreted cautiously. Using only surgically confirmed EM cases can introduce selection bias. Clinically diagnosed cases increase inclusivity, but risk misdiagnosis due to symptom overlap with other conditions. Hormonal and pharmacological factors may contribute to the EM-CVD association. Future studies controlling for associated covariates are required to establish a rigorous association. The association between severe menopausal symptoms (i.e., hot flashes and night sweats) and increased CVD risk highlights the interplay between hormonal changes and cardiovascular health. Two studies noted a potential association between severe VMS and CVD risk, with a range of 1.12–1.48. An analysis of over 144,000 women showed those under 60 had a higher CVD risk, and women with VMS had increased CVD risk (RR1.12) versus those without VMS. For women over 60, CVD risk differences with or without VMS were not significant (RR 0.96) [ 35 ]. Adjusted analyses indicated that VMS and other menopausal symptoms (e.g., depression, panic attacks) were linked to higher CHD and CVD risk, with RR 1.34 and 1.48, respectively [ 39 ]. Thus, menopausal symptoms may predict cardiovascular risk. Despite high-quality prospective studies enhancing the meta-analysis, results are limited by heterogeneity, confounding factors, limited subgroup analyses, and insufficient data on symptom timing and severe VAS detection. The number of live births has been associated with CVD risk. One meta-analysis of 10 high-quality cohort studies conducted across five countries, had 900 to 1.3 million participants, followed for 6 to 52 years, found a (RR) of 1.14 for CVD associated with parity compared to nulliparity, indicating a relative increase in risk. Furthermore, a dose-response relationship was established with incremental increases in CVD risk with each additional live birth contributing to a 4 % increase in CVD risk RR (1.04). Subgroup analyses highlighted heterogeneity in CHD outcomes, particularly in European studies, suggesting the importance of regions and disease types when assessing the generalizability of research findings. Additionally, the reported the J-shaped association between parity and CVD risk may be attributable to infertility and PCOS at low parity and cumulative physiological, hormonal, and lifestyle changes at high parity. Although the studies controlled for many confounders, such as age, adjustments for lifestyle factors and age at first birth were not made [ 40 ]. Future research should control for confounding variables to ensure the validity of the findings. Fertility therapy includes medical and surgical interventions to assist conception, such as ovulation-enhancing treatments and fertility-restoring surgery. Six observational studies followed 41,190 women to assess the long-term cardiovascular safety of fertility therapy. The median follow-up was 9.7 years, with no increased risk of ischemia or CHD events (pooled HR 0.91) [ 41 ]. However, exposure classification varies, with many studies using broad codes without specifying treatment type, frequency, or dosage, potentially leading to misclassification bias. Additionally, short follow-up periods may have underestimated long-term cardiovascular risk in young women. Future research should address these limitations and explore fertility therapy's impact on cardiovascular outcomes. Lactation has been associated with decreased risk of CVD. A meta-analysis of over 1 million women with a mean breastfeeding duration of 15.6 months and a median follow-up of 10.3 years reported adjusted HRs were 0.89 for CVD, 0.86 for CHD, and 0.83 for fatal CVD in women who breastfed compared to those who never breastfed [ 42 ]. Adjustments for demographic, cardiovascular, and reproductive factors did not alter these associations, regardless of age at study initiation, follow-up duration, number of children, study quality, or region. The dose-response analysis showed a gradual risk reduction with breastfeeding for up to 12 months, although the effects beyond this duration remain uncertain. Additionally, each additional six months of breastfeeding per child was associated with a 4 % lower risk of CHD, suggesting the protective benefits of extended breastfeeding.

This umbrella review involved the analysis of previously published systematic reviews and meta-analyses. As no primary data was collected, and all included studies adhered to ethical standards outlined by their respective institutional review boards, this review does not require new ethical approval. The authors declare no conflicts of interest, and the study adheres to the ethical guidelines for publishing in peer-reviewed journals. All references were properly cited, and data were synthesized transparently and accurately without any manipulation.

This review highlights the influence of reproductive factors on the risk of CVD in women. These findings demonstrate that reproductive-associated risk factors are closely associated with a high risk of CVD. For instance, preeclampsia increases CHD risk by 2.5-fold, with the greatest risk observed within the first five years postpartum. Preterm birth and GDM are associated with 1.2-to 4.1-fold and 1.72-fold higher CVD risk, respectively. Recurrent pregnancy loss, such as miscarriage and stillbirth, also elevates the CVD risk, with recurrent stillbirth showing a 1.57-fold increase. Additionally, increased risks were noted for IHD, with an HR of 1.6 in placental abruption. Reproductive-associated factors, such as PCOS and early menopause, further contribute to CVD risk, with PCOS linked to a 1.3-to 2.77-fold higher risk and early menopause tied to a 50 % greater CHD risk. Emerging factors, including endometriosis and severe vasomotor symptoms, add to this risk, while breastfeeding offers protective benefits, reducing CHD risk by 4 % for every additional six months of breastfeeding per child. These findings emphasize the need to incorporate reproductive history into cardiovascular risk assessment, enabling the earlier identification of at-risk women and the implementation of targeted prevention strategies. This review advocates a paradigm shift in CVD prevention, moving beyond traditional risk models to include reproductive health as a central component of women's cardiovascular care. Enhancing awareness, improving risk prediction tools, and implementing tailored interventions are critical steps toward improving cardiovascular outcomes in women.

This This umbrella review evaluated the association between reproductive factors, including HPD, pre-eclampsia, preterm delivery, gestational diabetes, stillbirth, miscarriage, placental abruption, PCOS, menopause, endometriosis, VAS, parity, fertility treatment, breastfeeding, and the risk of CVD in women. These findings align with the European and American guidelines that recognize preeclampsia, gestational diabetes, and preterm birth as risk factors for CVD and raise the potential for clinical guideline consideration for the other reproductive risk factors identified in this umbrella review [ 43 ]. History of premature menopause and APO, including preeclampsia, gestational diabetes, and preterm birth, are now recognized as risk-enhancing factors that refine atherosclerotic cardiovascular disease (ASCVD) risk assessment and inform statin prescriptions for women aged 40–75 years with borderline or intermediate 10-year ASCVD risk [ 45 , 46 ]. Consistent with our findings, women with a history of preeclampsia or gestational diabetes had the highest risk of CVD within the first decade postpartum. Consensus statements further emphasize the importance of monitoring CVD risk factors during the first year postpartum in women with APO [ 47 ] highlighting the need for early intervention during this critical period. Similarly, early or premature menopause is associated with an increased risk of CHD and IHD in the years after menopause. Recognizing this increased risk, the AHA has recommended a prevention-focused approach for women during the menopause transition to reduce future CVD events [ 48 , 49 ]. Age and lifespan considerations for the timing of reproductive factors and subsequent periods of elevated risk have important implications for risk-mitigation strategies. These findings are also consistent with the conclusions of a previous umbrella review, further reinforcing the association between reproductive risk factors and number of cardiovascular outcomes [ 44 ]. Overall, these findings highlight the importance of incorporating reproductive history into cardiovascular risk assessments and prevention strategies. Pregnancy-related and other reproductive risk factors present a valuable opportunity for both primordial and primary prevention, allowing healthcare providers to identify at-risk women earlier and to implement targeted interventions to improve long-term cardiovascular outcomes. The review's strength lies in its comprehensive synthesis that demonstrates how reproductive health intersects with CHD risk. Adherence to PRISMA guidelines ensured methodological rigor. The AMSTAR 2 quality appraisal revealed some studies of low quality partly due to heterogeneity in definitions of reproductive risk factors and CVD subtypes. There was a lack of or limited number of studies meeting our criteria for specific reproductive risk factors such as age at menarche and delivering a small-for-gestational-age infant. Excluding non-English studies may also limit generalizability. These findings highlight the importance of incorporating reproductive history into cardiovascular risk assessment. While robust evidence supports the inclusion of risk factors such as preeclampsia, gestational diabetes, and early menopause, other reproductive factors, such as age at menarche and delivery of a small-for-gestational-age infant, remain underexplored in systematic reviews despite emerging evidence linking them to CVD risk. Future research should explore the additive effects of multiple reproductive risk factors on cardiovascular risk to refine the prediction models and prevention strategies. Expanding current risk models to integrate these reproductive factors could enhance early detection and targeted prevention strategies.

Cardiovascular diseases (CVDs) are a major global health threat to women, causing one-third of female deaths in the U.S [ 1 ]. While heart disease mortality has generally declined, ischemic heart disease (IHD) rates in women <55 years remain constant [ 2 ]. This trend is due to sex-specific risk factors, symptom differences, diagnostic delays, and varied treatment responses [ 3 ]. Common cardiovascular risk factors like hypertension and smoking affect men and women differently [ 4 ]. Reproductive risk factors, such as preeclampsia, gestational hypertension, gestational diabetes, and preterm birth, uniquely elevate IHD risk, highlighting the need to integrate reproductive history into women's cardiovascular risk assessments [ 5 ]. Current heart disease prevention and treatment guidelines are still male-centric [ 3 ]. The American College of Obstetricians and Gynecologists (ACOG) and the American Heart Association (AHA) recommend long-term cardiovascular monitoring for women with preeclampsia, gestational hypertension, or gestational diabetes [ 6 ], but specific follow-up protocols are lacking. Women with IHD and left ventricular dysfunction often miss out on essential guideline-directed medical therapy (GDMT), such as statins and antiplatelet agents, despite similar adherence to treatment recommendations. These pharmacotherapy disparities may affect long-term outcomes, emphasizing the need for targeted cardiovascular risk management in women [ 7 ]. Identifying sex-specific factors that increase IHD risk is crucial for improving health outcomes and reducing mortality. Focusing on reproductive risk factors, we considered biological sex differences. Following the Sex and Gender Equity in Research (SAGER) guidelines [ 8 ], we use “female” for individuals assigned female at birth, acknowledging that sex refers to biological attributes. This study aimed to evaluate incident CHD risk from reproductive history factors and provide follow-up and risk screening recommendations.

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.