As summarized in the Central Illustration (Supplementary Fig. 1), this systematic review highlights the persistent underrepresentation of females in CV clinical trials, with particularly limited inclusion of pregnant and lactating individuals, despite the substantial and growing burden of CVD among women. From 2017 to 2023, no significant increase was observed in either the number of all-female trials or the total number of female participants enrolled in cardiovascular studies. These findings are consistent with previous literature indicating that women have historically comprised only 20–35% of participants in major CV trials, even in studies targeting conditions that predominantly affect them4,5. This underrepresentation hinders the development of sex-specific evidence, limits the external validity of clinical trial findings, and perpetuates disparities in cardiovascular care.
The continued lack of progress is concerning, given global efforts to improve female representation in research. In 1993, the U.S. FDA issued guidelines encouraging the inclusion of women in clinical trials, and more recently, policies from the NIH and European Medicines Agency have called for sex-specific analysis and transparency in enrollment6,7,8. Despite these initiatives, our findings suggest that implementation remains inconsistent, especially for vulnerable populations such as pregnant and postpartum women. Regulatory hesitancy, legal liability concerns, and perceived ethical dilemmas continue to deter trial sponsors from enrolling these groups9,10. Furthermore, the lack of harmonized international guidance for trial conduct involving these populations discourages inclusion.
Our analysis also revealed that a disproportionate number of trials focused on obesity (58%) and hypertension (26%), with drug-based (50%) and lifestyle intervention (30%) studies being the most common designs. These trends likely reflect the global emphasis on modifiable risk factors for CVD, particularly in primary prevention. Obesity and hypertension are highly prevalent among women of reproductive age and are major contributors to maternal morbidity and mortality, making them appealing and justifiable targets for intervention11,12. However, the narrow concentration on these risk factors may neglect other equally critical conditions such as ischemic heart disease, heart failure with preserved ejection fraction (HFpEF), spontaneous coronary artery dissection (SCAD), and arrhythmias, all of which exhibit sex-specific patterns in presentation and response to treatment13,14. Notably, conditions like SCAD disproportionately affect younger women and are among the leading causes of myocardial infarction in pregnancy, yet remain poorly studied in clinical trials15.
Another key finding is the age distribution of participants. Although older men are also underrepresented in CV trials due to strict age cutoffs and comorbidity exclusions, the disparity is even greater for older women. Women develop CVD later in life and constitute a larger proportion of the elderly population, making age-based exclusions disproportionately impactful. Across all-female and pregnancy/postpartum trials, 78–88% of participants were in the 19–55 year range, while a few studies included women over 60. This age range reflects eligibility for reproductive-age studies focused on obesity and hypertension, but overlooks postmenopausal women, a group at significantly elevated CV risk16. Older women are more likely to present with atypical symptoms, experience adverse drug reactions, and respond differently to therapies, yet they are often excluded due to polypharmacy, frailty, or cognitive impairment, and a historical emphasis on younger, healthier cohorts to reduce study complexity and attrition rates17,18. These overlapping barriers exacerbate evidence gaps and underscore the need for more inclusive trial designs that account for aging female populations.
The predominance of university-sponsored trials (54%) also warrants attention. Academic institutions may be more motivated to address sex- and gender-based research gaps, often driven by public health mandates or funding tied to equity metrics. In contrast, industry-sponsored trials may prioritize regulatory approval and marketability, potentially avoiding “higher-risk” populations such as pregnant women due to the complexity and liability associated with this demographic19. Addressing this imbalance requires not only greater accountability but also policy-driven incentives for industry to engage in inclusive and ethically responsible research.
Importantly, our findings show that the number of trials exclusively enrolling pregnant and postpartum women has not increased meaningfully over the study period (nptrend z = −0.13, p = 0.895), despite mounting evidence of the cardiovascular risks associated with pregnancy. The focus of these trials remained largely limited to obesity (50%) and hypertension (44%), echoing similar findings from prior reviews and meta-analyses20. While these are important contributors to adverse maternal outcomes, they do not fully capture the diversity of cardiovascular complications encountered during pregnancy, including peripartum cardiomyopathy, preeclampsia-related endothelial dysfunction, and postpartum thromboembolic events21,22. The scarcity of trials investigating these conditions contributes to therapeutic uncertainty and a reliance on anecdotal guidance in clinical decision-making. The lack of representation severely limits our ability to provide evidence-based care during this high-risk period, often leading to treatment decisions based on expert consensus rather than robust clinical evidence.
Geographically, most trials were conducted in or sponsored by institutions in the United States (89.5% for all-female trials; 94% for pregnancy/postpartum trials). As ClinicalTrials.gov is a U.S.-based registry, this predominance is expected but limits geographic generalizability. While the U.S. leads in clinical research infrastructure, this concentration raises questions about the applicability of findings to populations in other regions. Cultural, genetic, socioeconomic, and healthcare system differences across regions can significantly impact disease manifestation and treatment efficacy23. The limited global participation also reflects disparities in research funding and capacity, and highlights the need for expanded international collaboration, particularly with low- and middle-income countries where maternal cardiovascular morbidity and mortality are disproportionately high.
Collectively, these findings emphasize the critical need for a multifaceted approach to address the persistent gaps in female representation in cardiovascular trials. Regulatory bodies must strengthen policies that require sex-specific enrollment targets and transparency in reporting. Funding agencies should prioritize and support trials that explicitly address the cardiovascular needs of underrepresented groups, including older women and those who are pregnant or lactating. Additionally, clinical trial protocols must be redesigned to account for the physiological nuances and ethical considerations specific to these populations, rather than excluding them altogether.
Equally important is the need for cross-sector collaboration. Partnerships between academia, industry, government, and patient advocacy groups can facilitate inclusive trial designs, support culturally competent recruitment strategies, and ensure that women are not only enrolled but retained and studied meaningfully. Research networks focused on maternal health and cardiovascular outcomes could also serve as platforms for generating real-world data and informing evidence-based guidelines.
Persistent underrepresentation of women in CV trials stems from well-established structural, regulatory, and design-related barriers. Moving forward, the next step is implementing actionable solutions—broadening inclusion criteria, supporting pregnancy- and age-inclusive protocols, and mandating transparent, sex-disaggregated reporting. Coordinated efforts across regulatory bodies, funders, and research institutions are essential to ensure that cardiovascular evidence becomes more inclusive, clinically relevant, and equitable across the female lifespan.
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