literature review on women's health

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• Published: 17 June 2024

Women’s health and rights in the twenty-first century

• Samuel Akombeng Ojong   ORCID: orcid.org/0000-0002-3983-9642 1 ,
• Marleen Temmerman   ORCID: orcid.org/0000-0003-2069-8752 2 , 3 ,
• Rajat Khosla   ORCID: orcid.org/0000-0002-4960-4994 4 &
• Flavia Bustreo 3 , 5  

Nature Medicine volume  30 ,  pages 1547–1555 ( 2024 ) Cite this article

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In the twenty-first century, the complex relationship between women’s health and rights has been influenced by a range of interconnected challenges, including gender inequity, reproductive health disparities, maternal mortality and morbidity, and women’s inability to access life-saving, high-quality healthcare services including family planning. Going forward, the world needs to find ways to implement the unfinished agenda of the International Conference on Population and Development (ICPD) 1994 and the Sustainable Development Goals (SDGs), thus prioritizing health and rights for women and girls as essential not only to their survival but also to their progress, agency and empowerment. It is also important to consider the interconnection between women’s health and rights and climate change, with its disproportionate impact on the well-being of girls and women, and to address the impact and opportunities afforded by digital technologies. By embracing a holistic approach, societies might be able to advance the cause of women’s health and rights in a more inclusive and sustainable manner.

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Sexual and reproductive health lies at the core of women’s health. This amply reveals why, at the heart of the contemporary global discourse on women’s health and rights, lies the unfinished agenda of the ICPD 1994 and the ambitious blueprint of the SDGs 1 , 2 , 3 . The 1994 ICPD conference in Cairo, with its groundbreaking approach to population and development, followed by the Program of Action (Beijing, 1995) emphasized reproductive health and rights, gender equality and women’s empowerment as key to ensuring comprehensive health and rights for women and girls worldwide 2 , 4 , 5 , 6 , 7 . Likewise, the SDGs, particularly goals 3 (good health and well-being) and 5 (gender equality), authoritatively enshrined the rights to health and gender equity for all worldwide 8 .

Hosted by the United Nations in Cairo, the ICPD marked a paradigm shift by affirming the integral link between human rights, reproductive health and gender equality. It called for universal access to reproductive health services, including maternal and child healthcare, family planning, cancer prevention, fertility care and safe, legal abortion options, integrating these services into primary healthcare and addressing critical issues like maternal mortality and gender-based violence. The conference also spotlighted the importance of sexual and reproductive health and rights (SRHR) for adolescents, advocating for equitable access to education, employment and economic resources for women, alongside promoting women’s empowerment across all life stages 1 , 9 , 10 , 11 .

Our focus on the intersectionality between women’s SRHR is both a reflection of and a response to the mandates set forth by the ICPD and the SDGs 3 , 12 , 13 , 14 as well as a call to implement their respective agendas. The urgency of this endeavor is compounded by the current global polycrisis marked by the disproportionate impact of climate change on the world’s women and children, demographic pressures underlined by increased population migration, emerging disease outbreaks and the politicization of women’s sexual and reproductive health 15 , 16 , 17 , 18 , 19 , 20 .

Furthermore, the twenty-first century is characterized by an unprecedented digital advancement, which offers both transformative opportunities and formidable challenges for the realization of women’s health and rights. These technological advancements, particularly the increase in telemedicine, could provide new opportunities to enhance access to healthcare, information and education 21 , 22 . These advances also have the potential to connect women and girls across borders, amplify their voices and advocate for their rights on a global scale 23 , 24 . Nevertheless, more than three decades after the inception of the ICPD 1994 and coming ever closer to the SDG 2030 endpoint, the full realization of their respective person-centered goals in favor of women and girls remains elusive 1 , 3 .

In this Review, we aim to succinctly explore the intersectionality between women’s health and rights against the backdrop of global progress and crises, emphasizing the importance of the ICPD 1994 as a guiding framework. We discuss how current global realities, including digital advancements, affect women’s health and rights, highlighting opportunities for innovation alongside risks that could worsen inequalities. In line with this, we propose evidence-based strategies and policy recommendations to ensure that no woman or girl is left behind, while advocating for progress in women’s health and rights well into the future.

The 1994 ICPD unfinished agenda

Figure 1 illustrates the historical progression toward recognizing the inseparable bond between women’s health and rights, tracing back to the nineteenth century and culminating in the landmark 1994 ICPD event as well as key milestones achieved since then toward ensuring better health and improved rights for women. Nevertheless, nearly 30 years since the landmark Cairo conference, the progress in people-focused development is under threat from global polycrises, diminished rights for women and girls in many settings worldwide, consequences of the coronavirus disease 2019 (COVID-19) pandemic and divisive opinions on reproductive health and rights 3 , 13 , 25 .

Key events relating to women’s rights are shown on top (blue boxes), and those relating to women’s health are shown at the bottom (pink boxes), from the suffragette movements through the second and third waves of feminism, highlighting shifts toward social change, cultural inclusion and intersectionality 15 , 131 , 132 , 133 . The timeline highlights the critical links between women’s rights and health, spurred by reproductive rights activism and supported by key United Nations agencies, notably WHO, UNICEF and UNFPA, alongside initiatives like ‘Every Woman Every Child’, ‘Ending Preventable Maternal Mortality’ and the ‘Every Newborn Action Plan’, which emphasize the crucial interconnection between women’s well-being and their rights 63 , 64 , 101 , 103 , 134 , 135 , 136 , 137 . Additionally, grassroots movements, nongovernmental organizations and organizations such as the International Planned Parenthood Federation, Marie Stopes International, the Guttmacher Institute and national entities like Sonke Gender Justice and Sahayog have had a crucial role in advancing reproductive healthcare, sexual education and addressing women’s health needs across diverse cultural contexts 41 , 123 , 138 , 139 , 140 , 141 ( https://sahayogindia.org/ , https://genderjustice.org.za/ ) (FDA, US Food and Drug Administration; MDG, Millennium Development Goals; v., versus).

Despite the momentum of movements pushing for justice, climate action and equality, efforts to safeguard prior achievements and move toward the targets of the complementary ICPD agenda and SDGs are severely strained. Considering the disparities and competing priorities of health systems worldwide, we reflect on some of the most urgent issues that, if adequately prioritized, could have a transformative impact on women’s and girls’ ability to survive and thrive. This includes tackling preventable maternal and perinatal mortality, enhancing access to high-quality, respectful family planning and safe abortion care services, investing in adolescent-friendly sexual and reproductive health services and protecting women from gender-based violence 26 , 27 .

The pursuit of maternal and newborn health, a cornerstone of the rights-based frameworks established by the ICPD and the SDGs, remains fraught with substantial challenges. According to the World Health Organization (WHO), childbirth complications cause roughly 287,000 maternal deaths per year, disproportionately impacting sub-Saharan Africa, where certain regions report mortality ratios surpassing 1,000 per 100,000 live births. It is appalling to note that, in 2020, three countries in sub-Saharan Africa had maternal mortality ratios above 1,000, while six other countries in the region have reported maternal mortality ratios between 500 and 999 during the last decade 28 , 29 , 30 . Moreover, the issues of severe maternal morbidity and newborn mortality, including stillbirths, reveal deep-seated disparities in access to dignified, rights-based care, adversely affecting marginalized groups such as women of color, the economically disadvantaged, migrants, adolescent girls and those with limited educational opportunities 31 , 32 .

Progress toward global maternal mortality reduction has been stalled by drastic funding cuts, deprioritization of maternal health and religious, cultural or politically driven agendas that curtail the socioeconomic rights of women. In sub-Saharan Africa, where 70% of maternal deaths occur, risks are exacerbated by insufficient healthcare access, a dearth of skilled healthcare workers, the inadequacy of emergency obstetric services and economic dependency issues 30 , 32 . Likewise, middle- and high-income nations grapple with healthcare system challenges like fragmentation and the excessive medicalization of childbirth. This has precipitated a surge in interventions, such as labor inductions and cesarean sections, particularly driven by litigation fears and financial motives, contributing to what is known as the ‘cesarean section epidemic’ in regions of North and South America. The overuse of such interventions carries distinct risks, underscoring the necessity for strategies that transcend mortality rates to emphasize overall health and well-being, ensuring that women and newborns worldwide receive quality, respectful care 33 , 34 , 35 , 36 , 37 , 38 , 39 .

Globally, a key element of the unfinished SDG agenda continues to be the absence of person-centered, respectful sexual and reproductive health services, in particular, the failure to meet the family planning needs of women and girls, and the lack of safe abortion care 35 , 40 , 41 , 42 . Although some progress has been made, women in low-income regions such as sub-Saharan Africa and South Asia still bear the burden of sexual and reproductive health-related mortality and morbidity. Consequently, in 2019, 163 million women had an unmet need for family planning, with over half of these living in Africa and Asia 43 , 44 , 45 , 46 , and this despite repeated calls to reposition family planning on the international agenda through the global Family Planning 2030 movement 47 , 48 . This neglect is astonishing, as meeting the need for family planning has beneficial impacts on health but also fosters economic growth by reducing healthcare costs and enabling more women to enter the workforce. Additionally, it has a crucial role in promoting environmental sustainability by helping to stabilize population growth, which can alleviate pressure on natural resources and support more sustainable land and resource management practices 41 , 46 , 49 , 50 .

Interestingly, despite the widespread availability of essential health services, high-income countries (HICs) also present substantial gaps in SRHR, including unequal access to services for women of color, migrant women and both young and elderly women 51 , 52 , 53 , 54 , 55 . Moreover, the inadequacy of comprehensive sexual education limits young people’s understanding of their SRHR, while the politicization of this ecosystem restricts access to life-saving safe abortion services, family planning and care for survivors of gender-based violence 12 , 20 , 42 , 56 , 57 . These gaps undermine the ICPD and SDG’s emphasis on universality and reproductive autonomy.

Adolescent sexual and reproductive health is another area of concern reflecting intersections of age and gender. This underscores the importance of fostering a supportive and informed environment for the young person navigating this transformative physical, emotional and social journey. The key components of adolescent sexual and reproductive health include puberty and its inherent physical and hormonal occurrences, age-sensitive sexual and reproductive health education and information and the upholding of adolescent reproductive rights and autonomy. To do this, it is crucial to identify and encourage support systems in families and across different community settings and to identify the impact of novel technologies on adolescent health and well-being 42 , 58 , 59 .

Sadly, as for women of all ages, adolescents experience huge global disparities in terms of experiences, challenges and access to sexual and reproductive healthcare and education across cultures and regions. The main drivers of these disparities include stigma surrounding discussions on sexual health and barriers to accessing healthcare services, including systemic barriers such as unfriendly policies and health worker skill gaps, that lead to a dearth of adolescent-friendly health services. Adolescents are especially prone to gender-based disparities and discrimination, including gender-based violence 42 , 59 , 60 , 61 . Similar to women’s health, addressing adolescent sexual and reproductive health requires a multifaceted approach that recognizes the complex interplay of economic, cultural and social factors. This includes policy reforms to ensure equitable access to healthcare, comprehensive sexual education programs and initiatives that sustainably empower adolescent girls economically and socially 26 , 62 , 63 , 64 .

The pervasive nature of physical, sexual and psychological gender-based violence remains a harsh reality for over a billion women and girls worldwide, impeding their fundamental right to live free from harm. This is driven by deeply rooted cultural norms, inadequate legal frameworks and societal attitudes that trivialize violence against women and undermine women’s rights and autonomy 60 , 65 , 66 , 67 , 68 , 69 . Sadly, the pandemic of gender-based violence has huge economic consequences and has been linked to annual losses in the trillions of dollars. These losses are linked to care-related costs, lack of productivity owing to survivor invalidity and the disorientation of key resources that could serve other essential sectors such as education 70 , 71 .

In low- and middle-income countries (LMICs), gender-based violence remains prevalent, with some population-based studies reporting intimate partner violence in 10–60% of ever-partnered women, while characterizing sexual coercion and abuse as frequent female experiences 72 , 73 . Similarly, despite reporting lower lifetime and lower past-year prevalence than LMICs, the persistence of gender-based violence in HICs and the disproportionate affliction of young persons highlights a collective failure to align with gender equality and women’s empowerment objectives globally 66 , 71 , 74 . Ultimately, gender-based violence not only violates women’s right to equal opportunity and dignified living, it exposes them and their children to life-long physical, sexual and reproductive and mental health complications as a consequence of that violence 60 , 66 , 69 , 71 , 75 , 76 .

It is worth mentioning that a critical, but often overlooked, aspect of the alignment between the ICPD and SDG agendas is the mental health of women and girls, which is integral to their overall health and empowerment. The WHO’s 2022 World Mental Health Report revealed that women and girls represent 52.4% of the 970 million people living with mental disorders globally. Additionally, pregnancy and the post-partum period constitute a supplementary risk for women and girls, as more than 10% experience depression, while perinatal mood and anxiety disorders are known to directly influence immediate and long-term maternal, fetal and newborn health and well-being, contributing to as much as 20% of maternal mortality in HICs 77 . Additionally, adolescent girls and survivors of intimate partner violence have a higher risk of depression, anxiety and suicidal ideation 78 , 79 , 80 , 81 , 82 .

Despite the clear link between women’s and girls’ mental health and their overall well-being and rights, funding for women’s and girls’ mental health and especially pregnancy-related mental health is grossly inadequate. Also, poor quality or lack of mental health services, largely due to stigma and cultural norms, and a lack of integration with SRHR service have been reported in LMICs as well as a lack of clear policies and laws targeting women’s and girls’ mental health. Likewise, HICs face challenges including unequal mental healthcare access for women of color, migrants and those in rural areas. Despite greater resources, these nations struggle to fully address mental health issues related to SRHR, such as post-partum depression, which affects as many as one in seven women, and the psychological outcomes of abortion and infertility treatments 35 , 40 , 80 , 81 , 82 .

The importance of intersectionality

The concept of women’s health and rights is deeply influenced by the intersectionality of legal, societal, policy and health advancements (Fig. 2 ). Intersectionality, a framework introduced by Kimberlé Crenshaw, recognizes that individuals face multiple, overlapping forms of oppression or privilege based on gender, race, socioeconomic status, age, geographical location, sexual orientation or disability status 83 , 84 , 85 . Women’s and girls’ health and rights cannot be fully addressed without considering these intersecting identities, which cumulatively impact their access to healthcare and human rights 61 , 86 , 87 , 88 , 89 .

Applying an intersectionality approach requires understanding multiple and intersecting drivers that work together to determine women’s and girls’ ability to realize their health and human rights. CEDAW, Convention on the Elimination of All Forms of Discrimination against Women; GBV, gender-based violence; SRH, sexual and reproductive health.

Reproductive justice, a term rooted in this intersectional framework, expands beyond reproductive rights to include the physical, social and economic conditions necessary for making autonomous decisions about one’s reproductive health. It encompasses not just the right to have children and to parent children in safe and sustainable communities but also the right to not have children. This broader perspective acknowledges that individual choice is substantially influenced by intersecting social determinants of health and systemic inequalities 19 , 20 , 49 , 90 , 91 , 92 , 93 . Intersectional issues between women’s and girls’ rights and health manifest in various ways. Women and girls in vulnerable and marginalized communities often face enhanced barriers in accessing quality women-centered healthcare, including reproductive services, due to discrimination and socioeconomic constraints. Reproductive justice highlights the need to address these barriers by ensuring equitable access to comprehensive sexual education, contraception, safe abortion services and respectful maternity care but also the underlying requirement to preserve the overall health and well-being of women (encompassing cancer screening and care, and care for noncommunicable diseases), recognizing that such access is inextricably linked to broader health outcomes and women’s autonomy 35 , 94 , 95 ( https://www.icpd25commitments.org/ ).

Intersectionality and reproductive justice together draw attention to the pervasive issue of gender-based violence, including practices like genital mutilation, child marriage, harassment at work and sexual exploitation, which disproportionately affect the world’s most vulnerable women and girls and reflect deep-seated power imbalances 60 , 68 , 96 , 97 , 98 . Addressing these issues requires multifaceted strategies that include legal reforms, support systems for survivors and initiatives to change harmful societal norms. By embracing an intersectional approach and the principles of reproductive justice, efforts to advance women’s and girls’ health and rights can more effectively tackle the complex, layered challenges they face. This necessitates comprehensive policies and programs that are responsive to the diverse experiences and needs of women and girls across different communities and contexts 26 , 56 , 66 , 68 , 75 , 96 , 97 .

The way forward in advancing women’s health and rights

The quest for gender equality and the promotion of women’s health and rights are intrinsic components of global development. Acknowledging the multifaceted challenges that women face is key to crafting a comprehensive strategy addressing diverse aspects of women’s well-being 42 , 63 , 64 , 99 . While it is almost impossible to exhaustively discuss the issues that are sure to impact women’s health and rights, in this section, we outline five essential, actionable priorities for advancing this cause. In particular, we advocate for the need to pursue the unfinished ICPD agenda, alleviate the impacts of climate change, empower women and girls, harness technology to benefit women and girls and promote gender equality in global health leadership.

Implementing the unfinished ICPD agenda

The 1994 ICPD established a forward-looking agenda for women’s and girls’ health and rights including SRHR, while underpinning their importance in achieving sustainable development 1 , 2 , 9 , 10 , 26 , 100 . Delivering this agenda will entail a multi-stakeholder approach focused on policy advocacy, funding allocation and community mobilization targeting key issues like gender equality, enhanced sex education, respectful maternity care, universal family planning access, upholding women’s and girls’ bodily autonomy and the eradication of harmful practices 13 , 14 , 64 , 100 , 101 .

Thus, governments worldwide and especially in the most burdened countries must be supported to reinforce their commitment, aligning national laws and policy frameworks with ICPD principles. This requires bolstering international cooperation and partnerships and advocating for substantial investments in high-impact comprehensive sexual and reproductive health services, which remain underfunded, but would provide a substantial return on investment. For example, the Guttmacher Institute highlights that meeting the need for modern contraception in developing regions could prevent 76,000 maternal deaths each year, underscoring the potential of targeted interventions 13 , 63 , 102 .

Advocacy groups, civil society and nongovernmental organizations also have pivotal roles in mobilizing support and pushing for policy reforms, while international bodies like the United Nations Population Fund and WHO can leverage their influence to ensure that nations adhere to their ICPD commitments. Simultaneously, researchers and healthcare professionals must contribute by generating strong evidence on barriers to access and best practices in women’s sexual and reproductive healthcare and should specifically make the case for its integration into primary health services to ensure widespread accessibility, affordability, acceptability and safety of services 39 , 45 , 49 , 81 , 103 . By prioritizing SRHR within the global development agenda and ensuring adequate resource allocation, the vision of the ICPD can move closer to realization.

Mitigating the impact of climate change on SRHR

Extreme weather events, changing ecosystems and resource scarcity impact women’s access to healthcare, exacerbating maternal and reproductive health risks 17 , 104 . Furthermore, women often have pivotal roles in agriculture and resource management, making them vulnerable to climate-induced disruptions 16 .

Addressing these issues requires recognizing women’s rights as integral to sustainable development, empowering women in climate adaptation efforts and ensuring equitable healthcare access 17 , 105 , 106 . Addressing the gender-specific impacts of climate change on women’s health requires a comprehensive and intersectional approach 88 , 104 . Policymakers and healthcare providers must recognize the unique vulnerabilities of women in the face of climate-related challenges and work toward developing adaptive strategies.

A key actionable priority should be to integrate climate change considerations into the design and implementation of policies and services relating to women’s SRHR 16 , 107 . Health infrastructure needs to be able to ensure continuous access to essential reproductive health services during emergencies. More specifically, infrastructure and policies must address the increased vulnerability of pregnant women during extreme weather events and must ensure the availability of contraceptives and maternal healthcare in the aftermath of disasters, for example, by preventing commodity shortages and promoting self-care where applicable 16 , 104 , 106 . Also, it is important to invest in education and awareness campaigns, as these are essential to inform communities about the intersection of climate change and health, fostering resilience and preparedness 16 , 104 , 106 , 107 . Ultimately, by integrating climate change adaptation measures into SRHR programs, we can ensure that women are not only protected from the immediate impacts but are also equipped to navigate the long-term challenges posed by environmental changes.

Empowering women and girls

Empowerment lies at the core of advancing women’s health and rights and encompasses a range of strategies and approaches aimed at fostering autonomy, education, economic independence and dismantling discriminatory norms and practices. Thus, it is utterly vital today to empower women and girls to make informed choices about their bodies toward fostering gender equality, while simultaneously addressing social and economic inequalities that bar women from achieving optimal levels of well-being 18 , 26 , 64 , 99 . This includes empowering women and girls to make decisions about the size of their families, providing them with the information and resources to make such decisions and enabling them to exercise their reproductive rights. This would not only result in better maternal, newborn and child health outcomes but would ultimately lead to more empowered and resilient communities in the face of environmental challenges 3 , 35 , 42 , 64 , 108 .

Quality education is a powerful catalyst for empowerment of women and girls and will be fundamental to break the cycle of poverty and empower future generations 84 , 94 , 109 . Comprehensive sexual education is also crucial in equipping women and girls with the knowledge and skills to make informed decisions about their bodies and health 91 , 92 , 110 . Furthermore, economic empowerment programs must have a pivotal role in enhancing women’s agency via initiatives such as microfinance programs, vocational training and support for female entrepreneurship. Economic vulnerability amplifies existing inequalities for women and girls and contributes enormously to the challenges women face in accessing healthcare and exercising their rights 37 , 40 , 88 , 90 . By creating economic opportunities, women are more likely to gain financial independence, enabling them to access healthcare services, including reproductive health services, on their own terms 7 , 95 , 111 , 112 .

Above all, efforts to eliminate discriminatory practices and norms must be intensified. This includes addressing gender-based violence, child marriage and harmful traditional practices, while legal frameworks that protect women’s rights and awareness campaigns need to be enforced toward changing societal attitudes and perceptions that perpetuate discrimination 60 , 66 , 68 , 76 . Also, increasing the involvement of men and boys in gender equality initiatives is crucial. By challenging and transforming traditional gender roles and fostering an environment of mutual respect, we can create a society where women and girls are empowered to make choices that positively impact their health and rights 68 , 76 , 96 , 111 .

Technology for women’s health and rights

Sadly, access to information and education remains a substantial hurdle for many girls and women, particularly in regions with entrenched gender biases 28 , 37 , 113 . In an increasingly digital world, however, technology (when leveraged effectively) can be a powerful tool for informing, educating and empowering women. The digital gender divide, which manifests via disparities in digital literacy and access to technology, still persists, thereby limiting women’s ability to participate fully in the digital economy, access online health information and engage sustainably in advocacy efforts 21 , 24 , 99 , 114 . Digital literacy programs, online platforms for education and employment, and initiatives that bridge the digital gender divide will enhance women’s participation in not only their healthcare but also in the rapidly evolving global landscape 21 , 22 , 23 , 24 , and such interventions should therefore be a priority.

Telemedicine stands out as a particularly transformative tool in providing rights-based and respectful reproductive health services, especially in remote or underserved areas 22 , 89 , 113 , 115 , 116 . Virtual consultations enable women to access healthcare professionals without the associated geographical constraints, thereby addressing mobility- and infrastructure-related health system gaps 117 , 118 . Mobile applications can also have a vital role in delivering high-quality health information and education materials on key issues like menstrual health, family planning, maternal care and gender-based violence 21 , 23 , 67 , 89 , 119 . Thus, innovative technologies can enhance the accessibility and acceptability of key health interventions for women and girls, while tailoring these to their diverse needs and preferences.

Ensuring digital literacy among women is critical in harnessing the full potential of technology. It is important that, going forward, countries and organizations should invest in the implementation of training programs aimed at empowering women to navigate digital platforms, access information and use technological tools for their health and rights, thereby preventing technology from becoming a source of further inequality 23 , 24 , 113 , 115 , 119 . Innovative research and development in digital health should be encouraged, with a focus on creating solutions that are girl and woman friendly, gender and culturally sensitive, available and affordable 115 , 116 , 117 , 118 .

Thus, by leveraging telemedicine and mobile health services, key health information, health access and referral gaps can be addressed, ensuring continuity of care for women and girls living in remote or affected communities or displaced by climate events 22 , 23 , 89 , 115 , 116 . Moreover, digitalization is key to creating low carbon-emitting healthcare systems and thus addressing the health sector’s 5% share of global greenhouse gas emissions 120 , 121 , 122 . Going forward, it is therefore important to invest in implementation research as well as digital solutions seeking to address the intersection between climate and women’s health and rights. Navigating this intersection requires adapting legal frameworks and societal norms to the evolving digital landscape and ensuring that women can harness the benefits of technology while safeguarding their rights and well-being.

Gender equality in global health leadership

Discrimination, stereotypes and systemic barriers still hinder women’s participation in decision-making processes, and, globally, women remain under-represented in decision-making spheres, even on issues relating to women’s well-being 4 , 7 , 95 , 123 . In the twenty-first century, the pursuit of gender equality within global health leadership is not just essential to global development but also critical to creating environments where women and girls thrive 124 . Today, gender equality should not just be seen as a matter of fairness but rather an unconditional strategic imperative for promoting women’s health and ensuring that their rights are upheld worldwide. Gender equity in health leadership will be crucial for addressing the pervasive disparities in health outcomes 61 , 65 , 75 , 125 .

Women leaders in global health bring perspectives that are often overlooked in an exceedingly male-driven ecosystem, leading to more inclusive and effective policies and interventions 65 , 111 , 126 , 127 . These informed perspectives are very much needed today and essential for fostering an environment where women can contribute not only to their own health and well-being but ultimately to positive societal transformation. Women and girls can therefore lead the process of dismantling systemic barriers that continue to hinder women’s advancement, such as discriminatory hiring practices, unequal pay and limited opportunities for career progression 124 .

Empowering women in leadership positions sets a precedent for inclusivity and creates role models for the next generation of women in healthcare worldwide. Efforts to promote gender equality in global health leadership must also consider intersectionality 33 , 89 , 128 , 129 , 130 to facilitate comprehensive health policies that address the diverse needs of women from different backgrounds, toward creating an inclusive and equitable healthcare system.

The future of women’s health and rights demands a multifaceted and dynamic approach, ultimately aimed at promoting the health, autonomy and economic empowerment of women. International collaborations are indispensable in the pursuit of this goal, by fostering knowledge exchange, supporting advocacy efforts, addressing cross-border challenges and facilitating resource allocation. As the world becomes ever more interconnected, collaboration and inclusive digital advancement will help to shape a future in which every woman can exercise her rights and enjoy optimal health. As we advance, adopting a global perspective that broadens the scope of women’s health beyond maternal or reproductive health to encompass comprehensive well-being including emerging challenges like noncommunicable diseases is essential for aligning with the ICPD and SDG agendas 100 . Through concerted efforts, we can shape a world where women’s health and rights are not just aspirations but lived realities.

The Lancet. ICPD at 25 years: time to expand the agenda. Lancet 394 , 1685 (2019).

CAS   PubMed   Google Scholar  

UN Population Commission. Cairo + 25: the UN Population Commission on Population Change since the 1994 ICPD. Popul. Dev. Rev. 45 , 445–448 (2019).

Google Scholar  

Zuccala, E. & Horton, R. Addressing the unfinished agenda on sexual and reproductive health and rights in the SDG era. Lancet 391 , 2581–2583 (2018).

PubMed   Google Scholar  

Rosenfield, A. G. After Cairo: women’s reproductive and sexual health, rights, and empowerment. Am. J. Public Health 90 , 1838–1840 (2000).

CAS   PubMed   PubMed Central   Google Scholar  

UN Women. Beijing Declaration and Platform for Action Beijing+5 Political Declaration and Outcome corsidilaurea.uniroma1.it/sites/default/files/report_conferenza_pechino_1995.pdf (1995).

UN Women. Fourth World Conference on Women, Beijing 1995 www.un.org/womenwatch/daw/beijing/platform/ (2024).

UN Women. The Beijing Platform for Action: Inspiration Then and Now. UN Women – Beijing+20 beijing20.unwomen.org/en/about (2015).

United Nations Sustainable Development. SDG. Sustainable Development Goals Report www.un.org/sustainabledevelopment/progress-report/ (2022).

Sippel, S. ICPD beyond 2014: moving beyond missed opportunities and compromises in the fulfilment of sexual and reproductive health and rights. Glob. Public Health 9 , 620–630 (2014).

Girard, F. Taking ICPD beyond 2015: negotiating sexual and reproductive rights in the next development agenda. Glob. Public Health 9 , 607–619 (2014).

Population Council. Program of action of the 1994 International Conference on Population and Development (chapters IX–XVI). Popul. Dev. Rev. 21 , 437–461 (1995).

Starrs, A., Ezeh, A., Sedgh, G. & Singh, S. To achieve development goals, advance sexual and reproductive health and rights. Lancet 403 , 787–789 (2024).

Starrs, A. M. et al. Accelerate progress—sexual and reproductive health and rights for all: report of the Guttmacher–Lancet Commission. Lancet 391 , 2642–2692 (2018).

Starrs, A. A Lancet Commission on sexual and reproductive health and rights: going beyond the Sustainable Development Goals. Lancet 386 , 1111–1112 (2015).

Bastia, T., Piper, N. & Carrón, M. P. Geographies of migration, geographies of justice? Feminism, intersectionality, and rights. Environ. Plan. Econ. Space 43 , 1492–1498 (2011).

McOmber, C. Women and climate change in the Sahel. West African Papers https://doi.org/10.1787/e31c77ad-en (2020).

Romanello, M. et al. The 2023 report of the Lancet Countdown on health and climate change: the imperative for a health-centred response in a world facing irreversible harms. Lancet 402 , 2346–2394 (2023).

Fisseha, S. et al. COVID-19: the turning point for gender equality. Lancet 398 , 471–474 (2021).

Schaaf, M. & Khosla, R. Necessary but not sufficient: a scoping review of legal accountability for sexual and reproductive health in low-income and middle-income countries. BMJ Glob. Health 6 , e006033 (2021).

PubMed   PubMed Central   Google Scholar  

Msetfi, R. et al. Restricted reproductive rights and risky sexual behaviour: how political disenfranchisement relates to women’s sense of control, well-being and sexual health. J. Health Psychol. 23 , 252–262 (2018).

Lupton, D. & Maslen, S. How women use digital technologies for health: qualitative interview and focus group study. J. Med. Internet Res. 21 , e11481 (2019).

Lupton, D. Young people’s use of digital health technologies in the Global North: narrative review. J. Med. Internet Res. 23 , e18286 (2021).

The Lancet Digital Health. Empowering women in health technology. Lancet Digit. Health 4 , e149 (2022).

Rajput, K. Women empowerment through digital technology. Int. J. Sci. Res. Publ. 11 , 447–448 (2021).

United Nations Population Fund. ICPD30 www.unfpa.org/icpd/icpd30 (2024).

Lusti-Narasimhan, M., Khosla, R., Temmerman, M. & Young Holt, B. Advancing the sexual and reproductive health and human rights of women beyond 2015. BJOG 121 , 1–2 (2014).

Ghebreyesus, T. A. & Kanem, N. Defining sexual and reproductive health and rights for all. Lancet 391 , 2583–2585 (2018).

Beattie, R. M., Brown, N. J. & Cass, H. Millennium Development Goals progress report. Arch. Dis. Child 100 , S1 (2015).

Say, L. et al. Global causes of maternal death: a WHO systematic analysis. Lancet Glob. Health 2 , e323–e333 (2014).

Zarocostas, J. Global maternal mortality rates stagnating. Lancet 401 , 632 (2023).

Bustreo, F., Khosla, R., Coll-Seck, A. M. & Temmerman, M. Why global health continues to deny gender equity. Global Policy www.globalpolicyjournal.com/blog/15/08/2023/why-global-health-continues-deny-gender-equity (2023).

World Health Organization. Trends in Maternal Mortality 2000 to 2020: Estimates by WHO, UNICEF, UNFPA, World Bank Group and UNDESA/Population Division www.who.int/publications-detail-redirect/9789240068759 (2023).

Betrán, A. P. et al. Interventions to reduce unnecessary caesarean sections in healthy women and babies. Lancet 392 , 1358–1368 (2018).

Boerma, T. et al. Global epidemiology of use of and disparities in caesarean sections. Lancet 392 , 1341–1348 (2018).

Ojong, S. A., Wamakima, B., Moyer, C. A. & Temmerman, M. Maternal health and well-being. Oxford Research Encyclopedia of Global Public Health https://doi.org/10.1093/acrefore/9780190632366.013.214 (2023).

Oladapo, O. et al. WHO model of intrapartum care for a positive childbirth experience: transforming care of women and babies for improved health and wellbeing. BJOG 125 , 918–922 (2018).

Rahman, M. M., Haque, S. E. & Zahan, M. S. Factors affecting the utilisation of postpartum care among young mothers in Bangladesh. Health Soc. Care Community 19 , 138–147 (2011).

Sandall, J. et al. Short-term and long-term effects of caesarean section on the health of women and children. Lancet 392 , 1349–1357 (2018).

Tunçalp, Ӧ et al. WHO recommendations on antenatal care for a positive pregnancy experience—going beyond survival. BJOG 124 , 860–862 (2017).

Dahab, R. & Sakellariou, D. Barriers to accessing maternal care in low income countries in Africa: a systematic review. Int. J. Environ. Res. Public Health 17 , 4292 (2020).

Gold, J. et al. Increasing access to family planning choices through public-sector social franchising: the experience of Marie Stopes International in Mali. Glob. Health Sci. Pract. 5 , 286–298 (2017).

Prata, N. & Weidert, K. Adolescent sexual and reproductive health. Oxford Research Encyclopedia of Global Public Health https://doi.org/10.1093/acrefore/9780190632366.013.206 (2020).

Assefa, A. A. et al. Unmet need for family planning and associated factors among currently married women in Hawella Tulla subcity, Hawassa, southern Ethiopia: community-based study. Contracept. Reprod. Med. 8 , 14 (2023).

Coulson, J., Sharma, V. & Wen, H. Understanding the global dynamics of continuing unmet need for family planning and unintended pregnancy. China Popul. Dev. Stud. 7 , 1–14 (2023).

Pillai, V. K. & Nagoshi, J. L. Unmet family planning need globally: a clarion call for sharpening current research frame works. Open Access J. Contracept. 14 , 139–147 (2023).

Starbird, E., Norton, M. & Marcus, R. Investing in family planning: key to achieving the sustainable development goals. Glob. Health Sci. Pract. 4 , 191–210 (2016).

FP2030. FP2030 Progress Report 2023. FP2030 Measurement Overview progress.fp2030.org/measurement/ (2023).

Marston, C. & Tabot, M. How can we put rights at the core of global family planning? Lancet 401 , 2096–2098 (2023).

Ngwena, C. G., Brookman-Amissah, E. & Skuster, P. Human rights advances in women’s reproductive health in Africa. Int. J. Gynecol. Obstet. 129 , 184–187 (2015).

Rodríguez, M. I., Say, L. & Temmerman, M. Family planning versus contraception: what’s in a name? Lancet Glob. Health 2 , e131–e132 (2014).

Koblinsky, M. et al. Quality maternity care for every woman, everywhere: a call to action. Lancet 388 , 2307–2320 (2016).

Kinney, M. V., Boldosser-Boesch, A. & McCallon, B. Quality, equity, and dignity for women and babies. Lancet 388 , 2066–2068 (2016).

Carniato, G. Access to maternal health care for indigenous Australians under international law. J. Law Med. 28 , 1018–1034 (2021).

Leonard, S. A., Main, E. K., Scott, K. A., Profit, J. & Carmichael, S. L. Racial and ethnic disparities in severe maternal morbidity prevalence and trends. Ann. Epidemiol. 33 , 30–36 (2019).

Flenady, V. et al. Stillbirths: recall to action in high-income countries. Lancet 387 , 691–702 (2016).

Thompson, J. et al. Harmonizing national abortion and pregnancy prevention laws and policies for sexual violence survivors with the Maputo Protocol: proceedings of a 2016 regional technical meeting in sub-Saharan Africa. BMC Proc. 12 , 5 (2018).

Granberg, D. The United States Senate votes to uphold Roe versus Wade. Popul. Res. Policy Rev. 4 , 115–131 (1985).

Manguro, G. & Temmerman, M. A critical review of adolescent sexual and reproductive health and rights in Kenya. Med 3 , 364–368 (2022).

WHO. Coming of Age: Adolescent Health www.who.int/news-room/spotlight/coming-of-age-adolescent-health (2023).

Heise, L., Ellsberg, M. & Gottmoeller, M. A global overview of gender-based violence. Int. J. Gynecol. Obstet. 78 , S5–S14 (2002).

Mazon, C., Jimenez-Maldonado, J. & Walters, F. P. Intersectionality and adolescent medicine: an overview. Curr. Opin. Pediatr. 35 , 401–407 (2023).

Khosla, R., Say, L. & Temmerman, M. Sexual health, human rights, and law. Lancet 386 , 725–726 (2015).

Kuruvilla, S. et al. The Global strategy for women’s, children’s and adolescents’ health (2016–2030): a roadmap based on evidence and country experience. Bull. World Health Organ. 94 , 398–400 (2016).

Temmerman, M., Khosla, R., Bhutta, Z. A. & Bustreo, F. Towards a new global strategy for women’s, children’s and adolescents’ health. BMJ 351 , h4414 (2015).

Crockett, C. & Cooper, B. Gender norms as health harms: reclaiming a life course perspective on sexual and reproductive health and rights. Reprod. Health Matters 24 , 6–13 (2016).

Decker, M. R., Miller, E., Illangasekare, S. & Silverman, J. G. Understanding gender-based violence perpetration to create a safer future for women and girls. Lancet Glob. Health 1 , e170–e171 (2013).

Faith, B. Tackling online gender-based violence; understanding gender, development, and the power relations of digital spaces. Gend. Technol. Dev. 26 , 325–340 (2022).

Lancet, T. Opening the door on gender-based violence. Lancet 380 , 703 (2012).

Spencer, C. N. et al. Health effects associated with exposure to intimate partner violence against women and childhood sexual abuse: a burden of proof study. Nat. Med. 29 , 3243–3258 (2023).

UN Women. The Economic Costs of Violence Against Women www.unwomen.org/en/news/stories/2016/9/speech-by-lakshmi-puri-on-economic-costs-of-violence-against-women (2016).

Knaul, F. M., Bustreo, F. & Horton, R. Countering the pandemic of gender-based violence and maltreatment of young people: the Lancet Commission. Lancet 395 , 98–99 (2020).

Decker, M. R. et al. Gender-based violence against adolescent and young adult women in low- and middle-income countries. J. Adolesc. Health 56 , 188–196 (2015).

Kawuki, J., Sserwanja, Q., Mukunya, D., Sepenu, A. S. & Musaba, M. W. Prevalence and factors associated with sexual violence among women aged 15–49 years in rural Uganda: evidence from the Uganda Demographic and Health Survey 2016. Public Health 196 , 35–42 (2021).

Sardinha, L., Maheu-Giroux, M., Stöckl, H., Meyer, S. R. & García-Moreno, C. Global, regional, and national prevalence estimates of physical or sexual, or both, intimate partner violence against women in 2018. Lancet 399 , 803–813 (2022).

Sahay, M. R. et al. Health-related challenges and coping strategies among women during pandemics: a systematic review of qualitative studies. Front. Health Serv. 2 , 847753 (2022).

García-Moreno, C. Dilemmas and opportunities for an appropriate health-service response to violence against women. Lancet 359 , 1509–1514 (2002).

Howard, L. M. & Khalifeh, H. Perinatal mental health: a review of progress and challenges. World Psychiatry 19 , 313–327 (2020).

Alderdice, F. & Newham, J. Global maternal mental health: where you live matters. J. Reprod. Infant Psychol. 34 , 1–2 (2016).

Camacho, E. M. & Shields, G. E. Cost-effectiveness of interventions for perinatal anxiety and/or depression: a systematic review. BMJ Open 8 , e022022 (2018).

Moore Simas, T. A. et al. The humanistic burden of postpartum depression: a systematic literature review. Curr. Med. Res. Opin. 35 , 383–393 (2019).

World Health Organization. World Mental Health Report www.who.int/teams/mental-health-and-substance-use/world-mental-health-report (2022).

Woody, C. A., Ferrari, A. J., Siskind, D. J., Whiteford, H. A. & Harris, M. G. A systematic review and meta-regression of the prevalence and incidence of perinatal depression. J. Affect. Disord. 219 , 86–92 (2017).

Crenshaw, K. Mapping the margins: intersectionality, identity politics, and violence against women of color. Stan. Law Rev. 43 , 1241–1299 (1991).

Santovec, M. L. The necessity of intersectionality: a profile of Dr. Kimberlé Crenshaw. Women High. Educ. 26 , 8–9 (2017).

Cho, S., Crenshaw, K. W. & McCall, L. Toward a field of intersectionality studies: theory, applications, and praxis. Signs J. Women Cult. Soc. 38 , 785–810 (2013).

Fridman, S. E. & Prakash, N. Intimate partner violence (IPV) as a public health crisis: a discussion of intersectionality and its role in better health outcomes for immigrant women in the United States (US). Cureus 14 , e25257 (2022).

Hoang, T. M. H. & Wong, A. Exploring the application of intersectionality as a path toward equity in perinatal health: a scoping review. Int. J. Environ. Res. Public Health 20 , 685 (2022).

Philibert, L., Simon, D. J. & Lapierre, J. [Intersectionality to better understand women’s health issues]. Soins 67 , 18–21 (2022).

Figueroa, C. A., Luo, T., Aguilera, A. & Lyles, C. R. The need for feminist intersectionality in digital health. Lancet Digit. Health 3 , e526–e533 (2021).

Nieuwenhuijze, M. & Leahy-Warren, P. Women’s empowerment in pregnancy and childbirth: a concept analysis. Midwifery 78 , 1–7 (2019).

Osamor, P. E. & Grady, C. Women’s autonomy in health care decision-making in developing countries: a synthesis of the literature. Int. J. Womens Health 8 , 191–202 (2016).

Stotland, N. L. Reproductive rights and women’s mental health. Psychiatr. Clin. North Am. 46 , 607–619 (2023).

Stotland, N. L. Update on reproductive rights and women’s mental health. Med. Clin. North Am. 103 , 751–766 (2019).

Noghanibehambari, H. & Noghani, F. Long-run intergenerational health benefits of women empowerment: evidence from suffrage movements in the US. Health Econ. 32 , 2583–2631 (2023).

Pratley, P. Associations between quantitative measures of women’s empowerment and access to care and health status for mothers and their children: a systematic review of evidence from the developing world. Soc. Sci. Med. 169 , 119–131 (2016).

Sandis, E. E. United Nations measures to stop violence against women. Ann. N. Y. Acad. Sci. 1087 , 370–383 (2006).

Vives-Cases, C. et al. Coping with intimate partner violence and the COVID-19 lockdown: the perspectives of service professionals in Spain. PLoS ONE 16 , e0258865 (2021).

World Health Organization. Violence against Women Prevalence Estimates, 2018 www.who.int/publications-detail-redirect/9789240022256 (2021).

Khosla, R., Mishra, V. & Singh, S. Sexual and reproductive health and rights and bodily autonomy in a digital world. Sex. Reprod. Health Matters 31 , 2269003 (2023).

Bustreo, F., Knaul, F. M., Bhadelia, A., Beard, J. & Araujo de Carvalho, I. Women’s health beyond reproduction: meeting the challenges. Bull. World Health Organ. 90 , 478–478A (2012).

Zeid, S., Bustreo, F., Barakat, M. T., Maurer, P. & Gilmore, K. For every woman, every child, everywhere: a universal agenda for the health of women, children, and adolescents. Lancet 385 , 1919–1920 (2015).

Guttmacher Institute. Adding It Up: Investing in Contraception and Maternal and Newborn Health, 2017 www.guttmacher.org/fact-sheet/adding-it-up-contraception-mnh-2017 (2017).

Kennedy, H. P. et al. Asking different questions: a call to action for research to improve the quality of care for every woman, every child. Birth 45 , 222–231 (2018).

Jolly, M. in How Gender Can Transform the Social Sciences: Innovation and Impact (eds Sawer, M. et al.) 187–197 (Springer International, 2020).

McKune, S. M. C. Is gender being considered within climate services? ccafs.cgiar.org/news/gender-being-considered-within-climate-services (2013).

Romanello, M., Whitmee, S., Mulcahy, E. & Costello, A. Further delays in tackling greenhouse gas emissions at COP28 will be an act of negligence. Lancet 402 , 2055–2057 (2023).

The Lancet Planetary Health. Empower women to grow. Lancet Planet. Health 7 , e537 (2023).

Allotey, P. & Denton, F. Challenges and priorities for delivering on the Beijing Declaration and Platform for Action 25 years on. Lancet 396 , 1053–1055 (2020).

Malhotra, A., Pande, R. & Grown, C. Impact of investments in female education on gender equality. In XXV IUSSP International Population Conference 1–40 www.demoscope.ru/weekly/knigi/tours_2005/papers/iussp2005s51014.pdf (IUSSP, 2005).

Abreha, S. K. & Zereyesus, Y. A. Women’s empowerment and infant and child health status in sub-saharan Africa: a systematic review. Matern. Child Health J. 25 , 95–106 (2021).

Grown, C., Gupta, G. R. & Pande, R. Taking action to improve women’s health through gender equality and women’s empowerment. Lancet 365 , 541–543 (2005).

Poku, O. B. et al. ‘Mothers moving towards empowerment’ intervention to reduce stigma and improve treatment adherence in pregnant women living with HIV in Botswana: study protocol for a pragmatic clinical trial. Trials 21 , 832 (2020).

Richardson, B., Goldberg, L., Aston, M. & Campbell-Yeo, M. eHealth versus equity: using a feminist poststructural framework to explore the influence of perinatal eHealth resources on health equity. J. Clin. Nurs. 27 , 4224–4233 (2018).

Somali, C., Lew, R., Mingeirou, K. & Osman, Y. Accelerating Efforts to Tackle Online and Technology Facilitated Violence Against Women and Girls (VAWG) www.unwomen.org/en/digital-library/publications/2022/10/accelerating-efforts-to-tackle-online-and-technology-facilitated-violence-against-women-and-girls (2022).

Crawford, A. & Serhal, E. Digital health equity and COVID-19: the innovation curve cannot reinforce the social gradient of health. J. Med. Internet Res. 22 , e19361 (2020).

Dorsey, E. R. & Topol, E. J. Telemedicine 2020 and the next decade. Lancet 395 , 859 (2020).

Reynolds, R. M. Telehealth in pregnancy. Lancet Diabetes Endocrinol. 8 , 459–461 (2020).

Romanis, E. C., Parsons, J. A., Salter, I. & Hampton, T. Safeguarding and teleconsultation for abortion. Lancet 398 , 555–558 (2021).

Mackey, A. & Petrucka, P. Technology as the key to women’s empowerment: a scoping review. BMC Women’s Health 21 , 78 (2021).

Lokmic-Tomkins, Z., Borda, A. & Humphrey, K. Designing digital health applications for climate change mitigation and adaptation. Med. J. Aust. 218 , 106–110 (2023).

Lapao, V. Digital health and the climate change: introductory key concepts and research topics. Eur. J. Public Health 31 , ckab164.190 (2021).

Rahimi-Ardabili, H., Magrabi, F. & Coiera, E. Digital health for climate change mitigation and response: a scoping review. J. Am. Med. Inform. Assoc. 29 , 2140–2152 (2022).

Brueggemann, I. The road from Beijing. IPPF. 306 , 3 JOICFP News (1999).

World Health Organization. Closing the Leadership Gap: Gender Equity and Leadership in the Global Health and Care Workforce www.who.int/publications-detail-redirect/9789240025905 (2021).

Amuchástegui, A., Cruz, G., Aldaz, E. & Mejía, M. C. Politics, religion and gender equality in contemporary Mexico: women’s sexuality and reproductive rights in a contested secular state. Third World Q 31 , 989–1005 (2010).

Prasad, A. Roopa Dhatt: advancing gender equality in global health leadership. Lancet 396 , 1480 (2020).

Hawkes, S., Allotey, P., Elhadj, A. S., Clark, J. & Horton, R. The Lancet Commission on Gender and Global Health. Lancet 396 , 521–522 (2020).

Barry, M. et al. A new vision for global health leadership. Lancet 390 , 2536–2537 (2017).

Yount, K. M. et al. Gender equality in global health leadership: cross-sectional survey of global health graduates. Glob. Public Health 15 , 852–864 (2020).

Ludwig, S., Dhatt, R. & Kickbusch, I. Women leaders in global health — the importance of gender equality in global health. Eur. J. Public Health 28 , cky218.020 (2018).

Edelstein, J. Why second-wave feminism has gone soft. Public Policy Res. 14 , 164–167 (2007).

Grundy, M. P. The road to Seneca Falls: Elizabeth Cady Stanton and the first woman’s rights convention (review). Quaker Hist. 94 , 61–62 (2005).

Parker, A. M. The Seneca Falls Convention of 1848: a pivotal moment in nineteenth-century America. Rev. Am. Hist. 36 , 341–348 (2008).

Chou, D., Daelmans, B., Jolivet, R. R., Kinney, M. & Say, L. Ending preventable maternal and newborn mortality and stillbirths. BMJ 351 , h4255 (2015)

Jolivet, R. R. et al. Ending preventable maternal mortality: phase II of a multi-step process to develop a monitoring framework, 2016–2030. BMC Pregnancy Childbirth 18 , 258 (2018).

Guo, S., Rafique, N., You, D. & Noble, D. J. Progress in south Asia after the launch of the Global Every Newborn Action Plan. Lancet Glob. Health 4 , e682–e683 (2016).

Kinney, M. V. et al. Implementation of the Every Newborn Action Plan: progress and lessons learned. Semin. Perinatol. 39 , 326–337 (2015).

Bass, H. Guttmacher Institute. BMJ 344 , e623 (2012).

Claeys, V. Brave and angry — the creation and development of the International Planned Parenthood Federation (IPPF). Eur. J. Contracept. Reprod. Health Care 15 , S67–S76 (2010).

Newman, K. & Helzner, J. F. IPPF Charter on Sexual and Reproductive Rights. International Planned Parenthood Federation. J. Womens Health Gend. Based Med. 8 , 459–463 (1999).

Stewart, R. & Perera, G. D. Keeping up with the medical abortion revolution: the Marie Stopes International abortifacient quality assurance system. Int. J. Gynecol. Obstet. 152 , 288–290 (2021).

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BETTER LIFE- guidelines for chronic disease preventive care for people aged 18–39 years: a literature review

• Nasheed Moqueet 1 ,
• Sylvie D. Cornacchi 2 ,
• Jesmin Antony 3 ,
• Ielaf Khalil 4 ,
• Donna Manca 5 ,
• Carolina Fernandes 5 ,
• Lawrence Paszat 6 ,
• Kris Aubrey-Bassler 7 ,
• Eva Grunfeld 8 , 13 ,
• Nicolette Sopcak 5 ,
• Andrew Pinto 9 ,
• Jill Konkin 5 ,
• Candace Nykiforuk 10 ,
• Linda Rabeneck 11 ,
• Peter Selby 12 , 13 ,
• Becky Wall 14 ,
• Mary Ann O’Brien 13   na1 &
• Aisha Lofters 3 , 13   na1  

BMC Primary Care volume  25 , Article number:  224 ( 2024 ) Cite this article

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The original ‘BETTER’ (Building on Existing Tools To Improve Chronic Disease Prevention and Screening in Primary Care) approach consisted of a prevention-focused visit between participants aged 40–65 years and a “Prevention Practitioner” (PP), who empowered the participant to set achievable prevention and screening goals for cancers and chronic diseases. BETTER was successfully adapted for economically deprived communities (BETTER HEALTH) in Canada. Our objective was to conduct a review of guidelines in preparation for adapting the ‘BETTER HEALTH’ approach for younger adults aged 18–39 years living with lower income, a group known to have earlier mortality due to a higher prevalence of preventable chronic diseases than their peers with higher income.

We searched multiple electronic databases and grey literature for clinical practice guidelines on prevention/screening and included those that met the following criteria: published in English from 2008–2020 in Canada or any of the following countries (Australia, Ireland, New Zealand, Scotland, United States and England); and addressed prevention or screening. We assessed quality using the Appraisal of Guidelines for Research and Evaluation (AGREE) II tool and extracted data (publication details, recommendations, and Quality/Level of evidence as reported by authors) from sources with overall scores of 5 or higher. Final recommendations were compiled after harmonization with input from diverse stakeholders (co-investigators, PPs, and the Community Advisory Committee).

We included a total of 85 guidelines, and developed a final list of 42 recommendations for 18–39 year-olds across 21 topics. Specific recommendations fell under the following topics: cancers, cardiovascular disease, diabetes, obesity, lifestyle (alcohol; healthy nutrition/physical activity); healthy relationships and healthy sexuality, immunization, oral health, social determinants of health, and substance use .

We identified evidence-based guidelines on individual-level prevention/screening actions for adults 18–39 years old and relevant for those living with lower income which will directly inform development and implementation of the BETTER LIFE intervention.

Peer Review reports

Introduction

Despite the existence of strong evidence for lifestyle modifications and for screening and preventive actions to improve health outcomes, an implementation gap exists due to limited physician time [ 1 ], conflicting/unclear guidelines, and difficulties inherent to sustained behaviour change [ 2 ]. The original BETTER (Building on Existing Tools To Improve Chronic Disease Prevention and Screening in Primary Care) intervention was designed to address this gap by providing an integrated approach to increasing uptake of chronic disease prevention and screening (CDPS) actions using a framework of shared decision-making between patient and practitioner. In a pragmatic cluster randomised control trial (RCT), the BETTER approach improved the uptake of CDPS actions against heart disease, diabetes and several cancers (colorectal, breast and cervical cancers) by 32.5% in urban primary care settings in Alberta and Ontario, Canada [ 2 , 3 ]. The intervention consisted of an individual prevention-focussed visit between participants aged 40–65 years and a “Prevention Practitioner” (PP), who used principles of motivational interviewing to empower the participant to set achievable prevention and screening goals, based on the harmonization of evidence, which were then recorded in a goals sheet and a personalized ‘prevention prescription’.

There have been subsequent modifications of the BETTER approach with similar positive results. ‘BETTER 2’ targeted the same age group as the original BETTER but modified the approach for different populations due to equity concerns, including individuals from rural, lower income, or historically marginalized backgrounds in Newfoundland and Labrador and the Northwest Territories, Canada [ 4 ]. Subsequently, BETTER WISE (Building on Existing Tools to Improve Cancer and Chronic Disease Prevention and Screening in Primary Care for Wellness of Cancer Survivors and Patients) tailored the BETTER approach for cancer survivors (breast, colorectal, prostate) aged 40–65 and also included screening for poverty, as well as an updated literature review to recommend specific prevention and screening actions [ 5 ]. Another modified version, BETTER HEALTH: Durham used a public health-led model with public health nurses serving as PPs for 40–64 year-olds living with lower income in Durham, Ontario, and found a 53% increase in completed health actions (immediate intervention, n = 60 vs. wait-listed arm, n = 66) [ 6 , 7 ]. Although there were positive results for this age group, the community advisory group for BETTER HEALTH: Durham suggested that starting the intervention at 40 years of age was too late for people living with low income, where evidence shows an earlier onset of chronic diseases [ 8 ]. We aimed to adapt the BETTER HEALTH: Durham intervention to a new population of adults aged 18–39 years living with low income, a group known to have earlier mortality due to, and higher prevalence of, preventable chronic diseases than their peers with higher income.

To support the adaptation, we conducted a review of guidelines to identify and assess prevention and screening actions for health issues and risk factors amenable to individual change for the 18–39 year age group. This paper describes the methods and results of the literature review.

Overview of search strategy

First, we assessed the data sources (clinical practice guidelines) from the most recent BETTER WISE study [ 9 ], which had entailed a rigorous evidence review process to recommend specific prevention and screening actions, for applicability to adults aged 18–39 years.Then, we used a structured grey literature search of specific repositories and websites to find relevant clinical practice guidelines for new topics suggested by the research team. If guidelines were unavailable for these topics, we performed a systematic literature search in the databases Ovid Medline, CINAHL (Cumulated Index to Nursing and Allied Health Literature), and the Cochrane Database of Systematic Reviews to identify systematic reviews/meta-analyses. Thus, our search and eligibility criteria for new sources was restricted to clinical practice guidelines (i.e. excluding systematic reviews, meta-analyses, and review of reviews when guidelines were found) and expanded to allow systematic reviews and meta-analyses when guidelines were not available (See Fig.  1 ).

Search strategy for guidelines for BETTER LIFE

Search strategy for topics of interest

To create the overall search strategy, we consulted an experienced information specialist (CZ). We used different combinations of key words such as ‘guidelines’, ‘chronic disease prevention’, ‘prevention’, ‘clinical practice guidelines’, and ‘screening’ with terms from topics of interest from previous versions of BETTER ( cardiovascular disease, diabetes, cancer, obesity, diet and nutrition, physical activity, smoking/tobacco and alcohol use) and new topics suggested by the wider research team (co-investigators, PPs, Community Advisory Committee (CAC)) due to their importance for our target population (See Supp Table  1 ).

Search sources

We conducted a structured search in repositories of guidelines at the provincial level (Ontario, Alberta, Newfoundland & Labrador): Cancer Care Ontario; Cancer Control Alberta; Eastern Health Cancer Care Program; and national level: Health Canada; Public Health Agency of Canada (PHAC); and the Canadian Task Force on Preventive Health Care (CTFPHC). (Details in Fig.  1 ).

We did not find guidelines for four topics recommended by our study team for our target population ( speeding, texting & driving, seat belts, bullying & cyberbullying). Therefore, we then conducted a systematic search on select databases (Ovid Medline, CINAHL, Cochrane Database of Systematic Reviews) for systematic reviews and meta-analyses published from 2008-August 2020 on these topics.

Inclusion & exclusion criteria

When screening abstracts obtained from our searches, we included articles for full-text review if they met the following criteria: clinical practice guidelines in English only; published from 2008–2020; country of publication was Australia, Canada, England, Ireland, New Zealand, Scotland, or US; included at least one of the identified topics in title or abstract; and addressed prevention or screening.

At full-text screening, we excluded articles if they met any of the following: exclusively focused on management or treatment; exclusively targeted ages not 18–39 years old (i.e., under 18, 40 or older); lacked individual-level recommendations (i.e. contained only macro-level data (e.g. legal, policy)); or lacked evidence of synthesis. With the exception of the four topics covered during the systematic search, we also excluded full-texts if they were systematic reviews, review of reviews, or meta-analyses.

During full-text screening, if multiple eligible sources existed, we used a hierarchical approach to determine inclusion: preference for most recent Canadian guideline/ review and if not available, relevant guidelines from any of 6 aforementioned primarily English-speaking countries of interest. If there were discrepancies or disagreements among guidelines, we searched for and extracted information from primary or common references.

All abstracts and full-texts were uploaded and screened using Covidence [ 10 ].

Quality assessment

We chose AGREE-II for quality assessment since it was developed specifically for assessing quality of existing practice guidelines, unlike GRADE (Grading of Recommendations, Assessment, Development, and Evaluations), which is most suited for developing guidelines de novo and for rating primary sources of evidence for specific outcomes, which was outside the scope of our study. We used a two-step process to assess guideline quality. For the first step, two trained reviewers (NM and SC) independently used a shorter 2-item AGREE-II [ 11 ] rating system to assess the “Rigour of development” (items 7 and 12—‘ Systematic methods were used to search for evidence’ and ‘There is an explicit link between the recommendations and the supporting evidence’ , respectively) on all references. If methodological details were missing from guidelines, we emailed authors or guideline developers to request more information. Both reviewers had to assign a score of 4 or higher (out of 7) on both AGREE-II items for the article to move to full quality assessment with the 23-item AGREE-II tool.

Specifically, the reviewers examined the ‘ Methods ’ section of each guideline to assess the details of systematic methods (Item #7) that were used and consulted any methods papers that governed the overall initiative when available [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. If the guideline developer did not report any evidence of an independent synthesis as per the first step in the AGREE–II screening process, the guideline was not assessed further. If no Canadian reference met the criteria for the 2-item AGREE-II screening tool on a given topic, the reviewers then assessed the quality of the non-Canadian documents. Disagreement over scores was discussed and a final decision was determined by consensus.

For step 2, two reviewers independently applied the full AGREE-II instrument on all guidelines that passed the 2-item screening. Overall scores of 5 and above (out of 7) by both reviewers were used to move to full data extraction phase. To ensure consistent interpretation of data quality, we pilot tested the full AGREE-II tool on 5 articles that had previously been included in BETTER WISE and that also met the eligibility criteria for BETTER LIFE.

Data extraction

Two reviewers also pilot tested the data extraction form on 5 articles and resolved differences by consensus. Each reviewer independently extracted data from half the included articles and then checked a subset from the other reviewer for consistency, resolving differences by discussion. Extracted data included publication details (issuing body/author, year and country of publication), participant characteristics (target population, age, ethnicity, socioeconomic metrics, identified risk factors, clinical context) and guideline details (individual-level recommendations, quality of supporting evidence, and whether conflict of interest was declared or not).

Harmonization and synthesis of extracted data

The extracted data were grouped by topics. Each article was assigned to two reviewers who independently either categorized recommendations for inclusion in BETTER LIFE or excluded them if they were duplicative, out of scope, or not actionable (See Fig.  2 ).

Harmonization process for BETTER LIFE

The reviewers met to discuss and assign a final primary categorization to each recommendation with the overall team meeting to resolve differences if there was no agreement between reviewers. The senior co-authors (AL and MAO) reviewed the categorizations, clarified unclear recommendations and identified specific recommendations for further review from content experts/co-investigators in the BETTER team.

Harmonization and synthesis

We followed a similar harmonization process to Campbell-Sherer et al [ 9 ] within an overarching ADAPT-ITT framework [ 21 ].

All the co-investigators and PPs in the BETTER team were invited to provide input on topics in which they had expertise and asked to rank the newly included recommendations in an online survey (Qualtrics, Provo, UT), with the goal of reaching consensus on the top ranked (most relevant) recommendations. Recommendations ranked with a mean of 90% or above were included, while those that were that consistently ranked low (mean of less than 75%) were removed. For topics with multiple individual recommendations with mean scores of 80–89%, we combined, summarized and simplified the multiple recommendations where it seemed appropriate to do so and included them.

After the harmonization process, we compiled the final list of recommendations and topics into a table and also grouped all related included topics into existing or new ‘domains’ for data visualization.

There were 864 abstracts, of which 762 were unique. Of these, 435 were moved to the full-text phase and assessed for inclusion. One hundred and eighty-five guidelines met the inclusion criteria for quality assessment (Fig.  3 a).

a  Summary flow from literature search to full-text review for quality assessment. b  Quality assessment of guidelines using the AGREE-II instrument to the data extraction stage

From the 150 guidelines included in BETTER WISE that were published in 2008 or later, 40 guidelines were applicable to the 18–39 year age group, of which 14 had been updated since inclusion in BETTER WISE. Newer versions were available for the following 8 topics: cancers (breast, cervical, colorectal), CVD, diabetes, obesity, lifestyle (alcohol; healthy nutrition/physical activity) .

From the search for topics for which there were no identified guidelines (speeding, texting and driving, seat belts, bullying and cyberbullying) , 213 papers were uploaded into Covidence after removing duplicates. However, all the papers on these topics were excluded at various stages.

One hundred and eighty-five guidelines were eligible for quality screening (Fig.  3 b). After exclusion at various stages, 93 guidelines were rated with the 2-item AGREE-II. Of these, 75 were rated with the full AGREE-II tool and 58 papers (77%, 58/75) were scored 5 or higher by both reviewers.

We extracted data from 85 guidelines (58 were new guidelines and 27 were from previous versions of BETTER). Of the 38 new topics (Supp Table  1 ), 22 were relevant to the 18–39 year age group (Supp Table 2).

Of the 19 colleagues invited, 9 responded, reporting expertise on atleast one of the topics on the list (between 1–8 respondents provided ranking on each of the various new recommendations). At the harmonization stage, the team removed the topic ‘ falls/injury prevention’ as the recommendation was deemed not in scope for the 18–39 age group.

Due to low ranking scores from Co-investigators, we removed 6 topics from inclusion in the final BETTER LIFE recommendations ( intimate partner violence, sexual health, skin cancer, sleep, violence, vitamins ). We also excluded hepatitis C as only one co-investigator provided a ranking for this recommendation, and the recommendation was to not screen for hepatitis C. On the advice of the research team, we also included screening for Adverse Childhood Experiences (ACE) [ 22 , 23 ].

Based on the results of the data extraction and harmonization, the final list of topics contained 42 recommendations for 18–39 year-olds across 21 total topics (Table  1 ). We grouped the final list of topics into existing or new domains (See Supp Fig.  1 ).

The CDPS recommendations for heart disease and colorectal and breast cancers were only targeted to those deemed ‘high-risk’ (based on various clinical criteria such as family history) in the 18–39 age group. For most of the new topics, we also identified specific maneuvers or screening questions/tools that could be incorporated into the BETTER visits or into BETTER tools.

We used a structured search of published and grey literature, and a systematic search of specific databases to compile recent evidence from clinical practice guidelines on risk factors and individual prevention and screening actions relevant to adults aged 18–39 years, particularly those living with low income, in Canada. We also obtained input from our co-investigators, a team of experts in primary care, public health, the social determinants of health, and the BETTER program. Through this process, we were able to identify 42 recommendations within 21 total topics that will be applied in the BETTER LIFE approach for younger adults living with low income.

Some topics and health recommendations from previous BETTER versions were updated or included, such as those addressing diabetes, cardiovascular disease, cancer, smoking, alcohol, nutrition, and exercise . Risk assessments for diabetes, cardiovascular disease and most cancers were similar for those aged 18–39 years old as with previous versions of BETTER, though routine screening was only recommended for those deemed high risk (with the exception of cervical cancer screening). We found evidence-based guidelines addressing new topics relevant specifically to 18–39 year olds grouped into the following new domains: healthy relationships and healthy sexuality, immunization, oral health, social determinants of health, and substance use . Some recommendations in BETTER LIFE were similar to those published by others [ 97 , 98 , 99 ], though the recency, diversity, and sources of our search; our harmonization and implementation process, as well as the definition of our target population were different. For example, Persaud et. al. developed 15 preventive care recommendations and 1 policy recommendation that promote health equity in Canada. Although their work and ours both prioritize health equity in primary care, Persaud et al. did not have any age restrictions on their target population nor a primary focus on uptake of individual-level preventive actions. They also utilized systematic reviews, primary research articles and randomized controlled trials to develop recommendations using a GRADE approach. Because we prioritized recommendations that were individually actionable, supported by evidence that met our criteria, and ranked highly by content experts, topics like vitamins and skin cancer prevention were eventually omitted. Although we ultimately excluded skin cancer , this topic is an important one in many countries such as Australia [ 100 ].

Taking specific contexts into account is important when determining how best to implement and support uptake of the recommendations. For some new topics, we found stronger evidence for resources and screening tools for PPs than for specific recommendations (e.g. the National Institute on Drug Abuse (NIDA) Quick Screen or the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) for substance use ). PPs identified local community resources for some new health topics ( parenting; substance use; oral health ) which could help to support participants achieve recommended actions. They also suggested considering social contexts as opportunities for engagement, e.g. by focusing conversations in BETTER LIFE visits on the concepts of health promotion or meaningful overall health and social well-being rather than explicit chronic disease prevention; by using different media for sharing health information (e.g. mobile apps, social media or online resources); by considering social contexts as barriers or enablers of behaviour change, especially regarding physical activity, alcohol, substance use ; or by taking life stage into account (single adult vs. parenting).

Our study had several strengths and limitations. Our strengths include a rigorous critical appraisal of the literature with a two-step quality assessment process and independent review that ensured that only guidelines that met high methodological rigour and transparency were included for data extraction and harmonization; focus on actionable recommendations (e.g. goal-setting, access/referral to community resources); and meaningful collaborations with diverse community, public health, and clinical experts. However, all the guidelines were published prior to the COVID-19 pandemic, so did not take pandemic-related disruptions and health impact into account. COVID-19 has exacerbated health and economic inequities and disproportionately affected racialized and low income groups with a higher risk of exposure due to living and working conditions; higher prevalence of co-morbidities; inequitable access to testing and treatment; and disruption of health services [ 101 , 102 ]. We also relied on consensus to resolve disagreements during the screening process and to formulate the final recommendations as well as on voluntary responses during harmonization which led to varied numbers of reviewers for each recommendation, and which may be subject to bias. However, we used AGREE-II to ensure transparency and careful documentation, and also consulted a wide and diverse range of experts (in primary care, public health, the social determinants of health, Prevention Practitioners, and the Community Advisory Committee) at many stages of the project. Finally, we may have missed guidelines because we targeted our search to specific criteria, repositories, and databases.

Adults living with low income are at increased risk of chronic disease. Through critical literature review and guideline harmonization, we have curated a list of individual-level actionable recommendations relevant to prevention and screening for people aged 18–39 living with low income in English-speaking countries.

Availability of data and materials

Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.

Abbreviations

Adverse Childhood Experiences

Assessment, Decision, Adaptation, Production, Topical Experts, Integration, Training, Testing

Appraisal of Guidelines for Research & Evaluation II

Alcohol, Smoking and Substance Involvement Screening Test

Alcohol Use Disorders Identification Test

Building on Existing Tools To Improve Chronic Disease Prevention and Screening in Primary Care

Building on Existing Tools to Improve Cancer and Chronic Disease Prevention and Screening in Primary Care for Wellness of Cancer Survivors and Patients

Body mass index

Blood pressure

Community Advisory Committee

Chronic disease prevention and screening

Cumulated Index to Nursing and Allied Health Literature

Canadian Task Force on Preventive Health Care

Coronavirus disease 2019

Cardiovascular disease

Estimated glomerular filtration rate

Electronic nicotine delivery systems

Generalized Anxiety Disorder 2-item

Human papillomavirus

Manual office blood pressure device

National Institute on Drug Abuse

Public Health Agency of Canada

Primary care provider

Prevention Practitioner

Randomised control trial

Sexually transmitted infection

United States

Yarnall KSH, Pollak KI, Østbye T, Krause KM, Michener JL. Primary Care: Is There Enough Time for Prevention? Am J Public Health. 2003;93(4):635–41. https://doi.org/10.2105/AJPH.93.4.635 .

Article   PubMed   PubMed Central   Google Scholar  

Grunfeld E, Manca D, Moineddin R, et al. Improving chronic disease prevention and screening in primary care: results of the BETTER pragmatic cluster randomized controlled trial. BMC Fam Pract. 2013;14(1):175. https://doi.org/10.1186/1471-2296-14-175 .

BETTER. BETTER website. http://better-program.ca/evidence/ . Accessed Jan 23, 2022.

Aubrey-Bassler K, Fernandes C, Penney C, et al. The effectiveness of a proven chronic disease prevention and screening intervention in diverse and remote primary care settings: an implementation study on the BETTER 2 Program. BJGP Open. 2019;3(3):bjgpopen19X101656 https://doi.org/10.3399/bjgpopen19X101656 .

Manca DP, Fernandes C, Grunfeld E, et al. The BETTER WISE protocol: building on existing tools to improve cancer and chronic disease prevention and screening in primary care for wellness of cancer survivors and patients – a cluster randomized controlled trial embedded in a mixed methods design. BMC Cancer. 2018;18(1):927. https://doi.org/10.1186/s12885-018-4839-y .

Paszat L, Sutradhar R, O’Brien MA, et al. BETTER HEALTH: Durham – protocol for a cluster randomized trial of BETTER in community and public health settings. BMC Public Health. 2017;17(1):754. https://doi.org/10.1186/s12889-017-4797-3 .

Lofters AK, O’Brien MA, Sutradhar R, et al. Building on existing tools to improve chronic disease prevention and screening in public health: a cluster randomized trial. BMC Public Health. 2021;21(1):1496. https://doi.org/10.1186/s12889-021-11452-x .

Article   CAS   PubMed   PubMed Central   Google Scholar  

Roberts KC, Rao DP, Bennett TL, Loukine L, Jayaraman GC. Prevalence and patterns of chronic disease multimorbidity and associated determinants in Canada. Health Promot Chronic Dis Prev Can. 2015;35(6):87–94. https://doi.org/10.24095/hpcdp.35.6.01 .

Campbell-Scherer D, Rogers J, Manca D, et al. Guideline harmonization and implementation plan for the BETTER trial: Building on Existing Tools to Improve Chronic Disease Prevention and Screening in Family Practice. CMAJ Open. 2014;2(1):E1–10. https://doi.org/10.9778/cmajo.20130040 .

Covidence systematic review software. https://www.covidence.org . Melbourne, Australia. Computer program

Brouwers MC, Kho ME, Browman GP, et al. AGREE II: advancing guideline development, reporting and evaluation in health care. Can Med Assoc J. 2010;182(18):E839–42. https://doi.org/10.1503/cmaj.090449 .

Article   Google Scholar  

BC Guidelines. Guidelines and Protocols Advisory Committee Handbook: How our “Made in BC” Clinical Practice Guidelines and Protocols are Developed . Vancouver: British Columbia Ministry of Health;2017. gpachandbook2017.pdf (gov.bc.ca); Accessed Mar 20, 2024.

Alberta Health Services CancerControl Alberta. Guideline Methodology Handbook – Version 5 . 2020. GURU Handbook (albertahealthservices.ca) Accessed Mar 20, 2024.

Canadian Task Force on Preventive Health Care (CTFPHC). Canadian Task Force on Preventive Health Care Procedure Manual . Public Health Agency of Canada (PHAC);2014. https://canadiantaskforce.ca/methods/ Accessed Jan 23, 2022.

Davino-Ramaya C, Krause LK, Robbins CW, et al. Transparency Matters: Kaiser Permanente’s National Guideline Program Methodological Processes. Perm J. 2012;16(1):55–62. https://doi.org/10.7812/TPP/11-134 .

Michigan Quality Improvement Consortium (MQIC). MQIC Guideline Development Criteria . 2013. Clinical Care Guidelines | University of Michigan Health (uofmhealth.org) Accessed Jan 23, 2022.

National Institute for Health and Care Excellence (NICE). Developing NICE guidelines: the manual. Manchester: National Institute for Health and Care Excellence; 2014.

Toward Optimized Practice (TOP). Toward Optimized Practice Clinical Practice Guideline Development Methodology. 2016. https://actt.albertadoctors.org/cpgs Accessed May 25, 2020.

University of Michigan. Michigan Medicine Quality Department Clinical Care Guidelines: Purpose and Methods. 2019. https://www.uofmhealth.org/provider/clinical-care-guidelines . Accessed May 25 2020. Accessed Mar 20, 2024. 

World Health Organization (WHO). WHO handbook for guideline development, 2nd Edition. Geneva: World Health Organization, WHO Library Cataloguing-in-Publication Data; 2014.

Wingood GM, DiClemente RJ. The ADAPT-ITT Model. JAIDS J Acqu Immune Deficiency Syndromes. 2008;47(Supplement 1):S40–6. https://doi.org/10.1097/QAI.0b013e3181605df1 .

Article   PubMed   Google Scholar  

Watson P. How to screen for ACEs in an efficient, sensitive, and effective manner. Paediatr Child Health. 2019;24(1):37–8. https://doi.org/10.1093/pch/pxy146 .

California Surgeon General’s Clinical Advisory Committee. Adverse Childhood Experience Questionnaire for Adults. California: Office of the Surgeon General/California Department of Health Care Services; 2020.

BC Guidelines. Problem Drinking. 2013. https://www2.gov.bc.ca/gov/content/health/practitioner-professional-resources/bc-guidelines/problem-drinking . Accessed May 29, 2020.

Curry SJ, Krist AH, Owens DK, et al. Screening and Behavioral Counseling Interventions to Reduce Unhealthy Alcohol Use in Adolescents and Adults. JAMA. 2018;320(18):1899. https://doi.org/10.1001/jama.2018.16789 .

National Institute for Health and Care Excellence (NICE). [CG115] Alcohol-use disorders: diagnosis, assessment and management of harmful drinking (high-risk drinking) and alcohol dependence 2011. Overview | Alcohol-use disorders: diagnosis, assessment and management of harmful drinking (high-risk drinking) and alcohol dependence | Guidance | NICE, Accessed Mar 20, 2024.

Canadian Centre on Substance Abuse and Addiction (CCSA). Guidelines for Healthcare Providers to Promote Low-Risk Drinking Among Patients . 2013. www.ccsa.ca/Resource Library/2012-Canada-Low-Risk-AlcoholDrinking-Guidelines-Poster-en.pdf . Accessed May 25, 2020.

UK Chief Medical Officers (CMO). UK Chief Medical Officers’ Low Risk Drinking Guidelines 2016. https://www.gov.uk/government/consultations/health-risks-from-alcohol-new-guidelines . Accessed May 28, 2020

Katzman MA, Bleau P, Blier P, Chokka P, Kjernisted K, Van Ameringen M. Canadian clinical practice guidelines for the management of anxiety, posttraumatic stress and obsessive-compulsive disorders. BMC Psychiatry. 2014;14(Suppl 1):S1. https://doi.org/10.1186/1471-244X-14-S1-S1 .

Gregory KD, Chelmow D, Nelson HD, et al. Screening for Anxiety in Adolescent and Adult Women: A Recommendation From the Women’s Preventive Services Initiative. Ann Intern Med. 2020;173(1):48–56. https://doi.org/10.7326/M20-0580 .

Cancer Care Ontario. Magnetic Resonance Imaging Screening of Women at High Risk for Breast Cancer. 2018. https://www.cancercareontario.ca/en/guidelines-advice/cancer-continuum/screening/breast-cancer-high-risk-women/faqs-for-healthcare-providers . 2018. Accessed May 25, 2020.

Towards Optimized Practice. Breast Cancer Screening Clinical Practice Guideline. 2013. https://actt.albertadoctors.org/CPGs/Lists/CPGDocumentList/Breast-Cancer-Screening-CPG.pdf . Accesses May 29, 2020

Eastern Health. Breast Magnetic Resonance Imaging (MRI) and High Risk Hereditary Breast Cancer. 2017 https://www.easternhealth.ca/wp-content/uploads/sites/2/2018/06/Breast-Magnetic-Resonance-MRI-and-High-Risk-Guideline_2017.pdf Accessed May 25, 2020.

Eastern Health. Indications for Use of Breast Magnetic Resonance Imaging (MRI). 2018. https://www.easternhealth.ca/wp-content/uploads/sites/2/2018/06/Indications_for_Use_of_Breast_Magnetic_Imaging_MRI_Jan_2018.pdf Accessed May 25, 2020.

Fischer B, Russell C, Sabioni P, et al. Lower-Risk Cannabis Use Guidelines: A Comprehensive Update of Evidence and Recommendations. Am J Public Health. 2017;107(8):e1–12. https://doi.org/10.2105/AJPH.2017.303818 .

Toward Optimized P. Cervical Cancer Screening Clinical Practice Guideline. 2016. cervical-cancer-screening-cpg.pdf (albertadoctors.org) Accessed May 25, 2020.

Dickinson J, Tsakonas E, Conner Gorber S, et al. Recommendations on screening for cervical cancer. CMAJ. 2013;185(1):35–45. https://doi.org/10.1503/cmaj.121505 .

Cancer Care Ontario. Ontario Cervical Screening Guidelines Summary. Toronto: Cancer Care Ontario; 2016.

Toward Optimized Practice (TOP) Working Group for Colorectal Cancer Screening. Colorectal Cancer Screening Clinical Practice Practice Guideline. Edmonton: Accelerating Change Transformation Team (ACCT) Alberta Medical Association; 2013.

Provenzale D, Ness RM, Llor X, et al. NCCN Guidelines Insights: Colorectal Cancer Screening, Version 2.2020. J Nat Comprehen Cancer Net. 2020;18(10):1312–1320. https://doi.org/10.6004/jnccn.2020.0048 .

Scottish Intercollegiate Guidelines Network (SIGN). SIGN 126 Diagnosis and management of colorectal cancer. 2016. https://www.sign.ac.uk/media/1064/sign126.pdf Accessed Mar 20, 2024.

Leddin D, Lieberman DA, Tse F, et al. Clinical Practice Guideline on Screening for Colorectal Cancer in Individuals With a Family History of Nonhereditary Colorectal Cancer or Adenoma: The Canadian Association of Gastroenterology Banff Consensus. Gastroenterology. 2018;155(5):1325-1347.e3. https://doi.org/10.1053/j.gastro.2018.08.017 .

Canadian Task Force on Preventive Health Care. Recommendations on screening for colorectal cancer in primary care. CMAJ. 2016;188(5):340–8. https://doi.org/10.1503/cmaj.151125 .

Article   PubMed Central   Google Scholar  

Cancer Care Ontario. Colorectal Cancer. 2019 https://www.cancercareontario.ca/en/guidelines-advice/cancer-continuum/screening/resources-healthcare-providers Accessed Mar 20, 2024

U. S. Preventive Services Task Force. Screening for Colorectal Cancer: US Preventive Services Task Force Recommendation Statement. JAMA : the journal of the American Medical Association. 2016;315(23):2564–2575. Recommendation: Colorectal Cancer: Screening | United States Preventive Services Taskforce ( uspreventiveservicestaskforce.org ). Accessed 20 Mar 2024.

Black A, Guilbert E, Costescu D, et al. Canadian Contraception Consensus. J Obstet Gynaecol Can. 2015;37(11):1033–5. https://doi.org/10.1016/s1701-2163(16)30054-8 .

BC Guidelines. Hypertension – Diagnosis and Management. 2020. https://www2.gov.bc.ca/gov/content/health/practitioner-professional-resources/bc-guidelines/hypertension . Accessed Mar 20, 2024.

Lindsay P, Connor Gorber S, Joffres M, et al. Recommendations on screening for high blood pressure in Canadian adults. Can Fam Physician . 2013;59(9):927–933, e393–400.

Siu AL, U.S. Preventive Services Task Force. Screening for high blood pressure in adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2015;163(10):778–86 https://doi.org/10.7326/M15-2223 .

Rabi DM, McBrien KA, Sapir-Pichhadze R, et al. Hypertension Canada’s 2020 Comprehensive Guidelines for the Prevention, Diagnosis, Risk Assessment, and Treatment of Hypertension in Adults and Children. Can J Cardiol. 2020;36(5):596–624. https://doi.org/10.1016/j.cjca.2020.02.086 .

National Institute for Health and Care Excellence (NICE). Depression in adults: recognition and management : guidance (CG90). National Institute for Health and Care Excellence - NICE; 2009/10/28 2009. https://www.nice.org.uk/guidance/ng222 . Accessed May 25, 2020.

Siu AL, Bibbins-Domingo K, Grossman DC, et al. Screening for Depression in Adults: US Preventive Services Task Force Recommendation Statement. JAMA. 2016;315(4):380–7. https://doi.org/10.1001/jama.2015.18392 .

Article   CAS   PubMed   Google Scholar  

Joffres M, Jaramillo A, Dickinson J et al. Canadian Task Force for Preventive Health Care (CTFPHC). Recommendations on screeming for depression in adults . CMAJ 2013; 185(9):775–782. https://doi.oorg/ https://doi.org/10.1503/cmaj . 130403

Institute for Clinical Systems Improvement (ICSI). A dult Depression in Primary Care. 2016. https://www.icsi.org/wp-content/uploads/2021/11/Depr.pdf Accessed Mar 20, 2024.

Diabetes Canada Clinical Prractice Guidelines Expert Committee. Diabetes Canada 2018 Clinical Prractice Guidelines for the Prevention and Management of Diabates in Canada. Can J Diabetes. 2018;42(Suppl1):S1–325.

Google Scholar  

Pottie K, Jaramillo A, Lewin G, et al. Recommendations on screening for type 2 diabetes in adults. CMAJ. 2012;184(15):1687–96. https://doi.org/10.1503/cmaj.120732 .

Siu AL, U S Preventive Services Task Force. Screening for Abnormal Blood Glucose and Type 2 Diabetes Mellitus: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2015;163(11):861–8 https://doi.org/10.7326/M15-2345 .

ACOG Practice Bulletin No. 190: Gestational Diabetes Mellitus. Obstet Gynecol. 2018;131(2):e49–64. https://doi.org/10.1097/AOG.0000000000002501 .

American Diabetes Association. 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2020. Diabetes Care. 2020;43(Suppl 1):S14–31 https://doi.org/10.2337/dc20-S002 .

Wilson RD, Genetics Committee, Wilson RD, et al. Pre-conception Folic Acid and Multivitamin Supplementation for the Primary and Secondary Prevention of Neural Tube Defects and Other Folic Acid-Sensitive Congenital Anomalies. J Obstet Gynaecol Can. 2015;37(6):534–52 https://doi.org/10.1016/s1701-2163(15)30230-9 .

US Preventive Services Task Force, Bibbins-Domingo K, Grossman DC, et al. Folic Acid Supplementation for the Prevention of Neural Tube Defects: US Preventive Services Task Force Recommendation Statement. JAMA. 2017;317(2):183–9 https://doi.org/10.1001/jama.2016.19438 .

Health Canada. Canada’s Dietary Guidelines. 2018. CDG-EN-2018.pdf (canada.ca) Accessed Mar 20, 2024.

Nutrition Working Group, O’Connor DL, Blake J, et al. Canadian Consensus on Female Nutrition: Adolescence, Reproduction, Menopause, and Beyond. J Obstet Gynaecol Can. 2016;38(6):508-554.e18 https://doi.org/10.1016/j.jogc.2016.01.001 .

Anderson TJ, Grégoire J, Pearson GJ, et al. 2016 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in the Adult. Can J Cardiol. 2016;32(11):1263–82. https://doi.org/10.1016/j.cjca.2016.07.510 .

Toward Optimized Practice. Prevention and Risk Management of Cardiovascular Disease Risk in Primary Care Clinical Practice Guideline . 2015. https://actt.albertadoctors.org/media/b21chzfk/cvd-risk-cpg.pdf . Accessed Man 20, 2024.

U.S. Preventive Services Task Force (USPSTF). Behavioral Counseling to Promote a Healthful Diet and Physical Activity for Cardiovascular Disease Prevention in Adults Without Cardiovascular Risk Factors: US Preventive Services Task Force Recommendation Statement. JAMA :J Am Med Assoc. 2017;318(2):167–74 https://doi.org/10.1001/jama.2017.7171 .

Ross R, Chaput JP, Giangregorio LM, et al. Canadian 24-Hour Movement Guidelines for Adults aged 18–64 years and Adults aged 65 years or older: an integration of physical activity, sedentary behaviour, and sleep. Appl Physiol Nutr Metab. 2020;45(10 (Suppl. 2)):S57-S102. https://doi.org/10.1139/apnm-2020-0467

Piepoli MF, Hoes AW, Agewall S, et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts)Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J. 2016;37(29):2315–81. https://doi.org/10.1093/eurheartj/ehw106 .

National Institute for Health and Care Excellence (NICE). Cardiovascular disease: risk assessment and reduction, including lipid modification – NICE guideline . Royal College of Physicians of London - RCP; 2014/07/01 2016. https://www.nice.org.uk/guidance/ng238 . Accessed May 25, 2020.

Allan GM, Lindblad AJ, Comeau A, et al. Simplified lipid guidelines: Prevention and management of cardiovascular disease in primary care. Can Fam Phys. 2015;61(10):857–67 e439–50.

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Breast Cancer Risk Reduction version 1.2020. https://www.nccn.org/guidelines/category 1. Accessed May 25, 2020.

Public Health Agency of Canada. Rubella vaccine: Canadian Immunization Guide. 2016; https://www.canada.ca/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-20-rubella-vaccine.html . Accessed June 4, 2020.

Public Health Agency of Canada. Amendment to the 2015 “Update on the recommended Human Papillomavirus (HPV) vaccine immunization schedule.” Ottawa, Ontario: Public Health Agency of Canada; 2015.

Public Health Agency of Canada. Canadian immunization guide. Part 3. Vaccination of specific populations. 2016. https://www.canada.ca/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations.html . Accessed 4 June 2020.

Wharton S, Lau DCW, Vallis M, et al. Obesity in adults: a clinical practice guideline. Can Med Assoc J. 2020;192(31):E875–91. https://doi.org/10.1503/cmaj.191707 .

Brauer P, Gorber SC, Shaw E, et al. Recommendations for prevention of weight gain and use of behavioural and pharmacologic interventions to manage overweight and obesity in adults in primary care. CMAJ. 2015;187(3):184–95. https://doi.org/10.1503/cmaj.140887 .

US Preventive Services Task Force, Curry SJ, Krist AH, et al. Behavioral Weight Loss Interventions to Prevent Obesity-Related Morbidity and Mortality in Adults: US Preventive Services Task Force Recommendation Statement. JAMA. 2018;320(11):1163–71 https://doi.org/10.1001/jama.2018.13022 .

Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. Circulation. 2014;129(25 Suppl 2):S102–38. https://doi.org/10.1161/01.cir.0000437739.71477.ee .

Fitch A, Everling L, Fox C, et al. Institute for Clinical Systems Improvement. Prevention and Management of Obesity for Adults . . Updated May 2013. https://1library.net/document/y69pmp7y-prevention-and-management-of-obesity-for-adults.html . Accessed 20 Mar 2024.

LeFevre ML. U.S. Preventive Services Task Force. Behavioral counseling to promote a healthful diet and physical activity for cardiovascular disease prevention in adults with cardiovascular risk factors: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2014;161(8):587–93 https://doi.org/10.7326/M14-1796 .

Public Health England (PHE). Delivering better oral health: an evidence-based toolkit for prevention. 2017. Delivering better oral health: an evidence-based toolkit for prevention - GOV.UK (www.gov.uk ) Accessed Mar 20, 2024.

Kavan MG, Saxena SK, Rafiq N. General Parenting Strategies: Practical Suggestions for Common Child Behavior Issues. Am Fam Physician. 2018;97(10):642–8.

PubMed   Google Scholar  

Alberta Health Services. Nutrition Guideline Household Food Insecurity . 2013. https://www.albertahealthservices.ca/assets/info/nutrition/if-nfs-ng-household-food-insecurity.pdf Accessed Mar 20, 2024.

Pottie K, Kendall CE, Aubry T, et al. Clinical guideline for homeless and vulnerably housed people, and people with lived homelessness experience. CMAJ. 2020;192(10):E240–54. https://doi.org/10.1503/cmaj.190777 .

Moser A, Stuck AE, Silliman RA, Ganz PA, Clough-Gorr KM. The eight-item modified Medical Outcomes Study Social Support Survey: psychometric evaluation showed excellent performance. J Clin Epidemiol. 2012;65(10):1107–16. https://doi.org/10.1016/j.jclinepi.2012.04.007 .

Public Health Agency of Canada (PHAC). Sexually transmitted and blood-borne infections: guides for health professionals. Canadian Guidelines on Sexually Transmitted Infections. Ottawa: Public Health Agency of Canada; 2020.

LeFevre ML, U.S. Preventive Services Task Force. Screening for Chlamydia and gonorrhea: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2014;161(12):902–910. https://doi.org/10.7326/M14-1981

Workowski KA, Bolan GA. Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines. MMWR Recomm Rep. 2015;64(RR-03):1–137.

Kaiser P. Sexually Transmitted Infection: Screening, Testing and Treatment Guideline . 2019. https://wa-provider.kaiserpermanente.org/provider-manual/patient-care/clinical-guidelines Accessed May 25, 2020.

Siu AL. U.S. Preventive Services Task Force. Behavioral and Pharmacotherapy Interventions for Tobacco Smoking Cessation in Adults, Including Pregnant Women: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2015;163(8):622–34 https://doi.org/10.7326/M15-2023 .

Thombs BD, Jaramillo Garcia A, Reid D, et al. Recommendations on behavioural interventions for the prevention and treatment of cigarette smoking among school-aged children and youth. CMAJ. 2017;189(8):E310–6. https://doi.org/10.1503/cmaj.161242 .

CAN-ADAPTT. Canadian Smoking Cessation Clinical Practice Guideline . Toronto, Canada: Canadian Action Network for the Advancement, Dissemination and Adoption of Practice-informed Tabacco Treatment, Centre for Addiction and Mental Health. 2011. The first Canadian Guidelines for Tobacco Control was developed in 2010 (utoronto.ca) Accessed Mar 20, 2024.

Registered Nurses’ Association of Ontario. Engaging Clients Who Use Substances . 2015. https://rnao.ca/sites/rnao-ca/files/Engaging_Clients_Who_Use_Substances_WEB.pdf Accessed Mar 20, 2024.

US Preventive Services Task Force, Krist AH, Davidson KW, et al. Screening for Unhealthy Drug Use: US Preventive Services Task Force Recommendation Statement. JAMA. 2020;323(22):2301–9 https://doi.org/10.1001/jama.2020.8020 .

Ontario Health Cancer Care Ontario. Vaping products including e-cigarettes: Evidence summary . Ontario, Canada: Ontario Health (Cancer Care Ontario); 2020. https://www.cancercareontario.ca/en/content/vaping-products-including-e-cigarettes . Accessed Mar 20, 2024.

Livingston CJ, Freeman RJ, Costales VC, et al. Electronic Nicotine Delivery Systems or E-cigarettes: American College of Preventive Medicine’s Practice Statement. Am J Prev Med. 2019;56(1):167–78. https://doi.org/10.1016/j.amepre.2018.09.010 .

Shimizu T, Bouchard M, Mavriplis C. Update on age-appropriate preventive measures and screening for Canadian primary care providers. Can Fam Physician. 2016;62(2):131–8.

PubMed   PubMed Central   Google Scholar  

Ridley J, Ischayek A, Dubey V, Iglar K. Adult health checkup: Update on the Preventive Care Checklist Form©. Can Fam Physician. 2016;62(4):307–13.

Persaud N, Sabir A, Woods H, et al. Preventive care recommendations to promote health equity. Can Med Assoc J. 2023;195(37):E1250–73. https://doi.org/10.1503/cmaj.230237 .

Royal Australian College of General Practitioners. Guidelines for preventive activities in general practice (Red Book). Melbourne: Royal Australian College of General Practitioners; 2021. http://Guidelinesfor-preventive-activities-in-general-practice.pdf ( http://racgp.org.au ). Accessed 20 Mar 2024.

Sundaram ME, Calzavara A, Mishra S, et al. Individual and social determinants of SARS-CoV-2 testing and positivity in Ontario, Canada: a population-wide study. Can Med Assoc J. 2021;193(20):E723–34. https://doi.org/10.1503/cmaj.202608 .

Article   CAS   Google Scholar  

Toronto Public Health. COVID-19 and the Social Determinants of Health: What do we know? 2020. 96e0-SDOHandCOVID19_Summary_2020May14.pdf (toronto.ca). Accessed 20 Mar 2024.

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Acknowledgements

Carolyn Ziegler for the systematic search. Jane Ebreo for all administrative support. Kimberly Devotta for project management support. Tutsirai Makuwaza for feedback on the qualitative work on BETTER LIFE. Mary-Anne Pietrusiak for subject matter expertise. Ranya Mistry for Qualtrics survey development support.

This study was funded by a Canadian Institutes of Health Research Catalyst Grant: Disease Prevention and Risk Factor Modification – Non-Communicable Diseases (#428589).

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Mary Ann O’Brien and Aisha Lofters are co-senior authors.

Authors and Affiliations

Public Health Agency of Canada, Ottawa, ON, Canada

Nasheed Moqueet

McMaster University, Hamilton, ON, Canada

Sylvie D. Cornacchi

Women’s College Hospital, 76 Grenville St, Toronto, ON, M5S 1B2, Canada

Jesmin Antony & Aisha Lofters

Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada

Ielaf Khalil

Department of Family Medicine, University of Alberta, Edmonton, AB, Canada

Donna Manca, Carolina Fernandes, Nicolette Sopcak & Jill Konkin

Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, Canada

Lawrence Paszat

Primary Healthcare Research Unit, Memorial University of Newfoundland, St. John’s, NL, Canada

Kris Aubrey-Bassler

Ontario Institute for Cancer Research, Toronto, ON, Canada

Eva Grunfeld

Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, ON, Canada

Andrew Pinto

School of Public Health, University of Alberta, Edmonton, AB, Canada

Candace Nykiforuk

Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada

Linda Rabeneck

Centre for Addiction and Mental Health, Toronto, ON, Canada

Peter Selby

Department of Family and Community Medicine, University of Toronto, Toronto, ON, Canada

Eva Grunfeld, Peter Selby, Mary Ann O’Brien & Aisha Lofters

Durham Region Health Department, Whitby, ON, Canada

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NM, SDC, JA, IK, MAO, AL provided substantial contributions to the conception and design of the work (review, data synthesis, data extraction, quality assessment, harmonization); NM, SDC, JA, IK, DM, CF, LP, PS, MAO, AL acquired, analyzed, and interpreted data; NM, SDC, IK, MAO, AL wrote the manuscript;NM, SDC, JA, IK, DM,  CF, LP, KAB, EG, NS, AP, JK, CN, LR, PS, BW, MAO, AL (i.e. all authors) reviewed the manuscript critically for important intellectual content; NM, SDC, JA, IK, DM,  CF, LP, KAB, EG, NS, AP, JK, CN, LR, PS, BW, MAO, AL (i.e. all authors) read and approved the final manuscript.

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Correspondence to Aisha Lofters .

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Moqueet, N., Cornacchi, S.D., Antony, J. et al. BETTER LIFE- guidelines for chronic disease preventive care for people aged 18–39 years: a literature review. BMC Prim. Care 25 , 224 (2024). https://doi.org/10.1186/s12875-024-02471-9

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The 2017 Women’s Health Initiative study and use of hormone therapy: an emulated repeated cross-sectional study

• Chen-Han Chueh   ORCID: orcid.org/0000-0002-3337-2586 1   na1 ,
• Pei-Kuan Ho   ORCID: orcid.org/0009-0003-5525-5449 1   na1 ,
• Wai-Hou Li   ORCID: orcid.org/0009-0008-1151-9357 1 , 2 ,
• Ming-Neng Shiu   ORCID: orcid.org/0000-0003-1009-3696 1 , 3   na1 ,
• I.-Ting Wang   ORCID: orcid.org/0000-0001-9367-5442 1 ,
• Yu-Wen Wen   ORCID: orcid.org/0000-0002-7979-3845 4 &
• Yi-Wen Tsai   ORCID: orcid.org/0000-0003-1422-7217 1  

BMC Public Health volume  24 , Article number:  1674 ( 2024 ) Cite this article

Metrics details

Hormone therapy (HT) use among menopausal women declined after negative information from the 2002 Women’s Health Initiative (WHI) HT study. The 2017 post-intervention follow-up WHI study revealed that HT did not increase long-term mortality. However, studies on the effects of the updated WHI findings are lacking. Thus, we assessed the impact of the 2017 WHI findings on HT use in Taiwan.

We identified 1,869,050 women aged 50–60 years, between June and December 2017, from health insurance claims data to compare HT use in the 3 months preceding and following September 2017. To address the limitations associated with interval-censored data, we employed an emulated repeated cross-sectional design. Using logistic regression analysis, we evaluated the impact of the 2017 WHI study on menopausal symptom-related outpatient visits and HT use. In a scenario analysis, we examined the impact of the 2002 trial on HT use to validate our study design.

Study participants’ baseline characteristics before and after the 2017 WHI study were not significantly different. Logistic regressions demonstrated that the 2017 study had no significant effect on outpatient visits for menopause-related symptoms or HT use among women with outpatient visits. The scenario analysis confirmed the negative impact of the 2002 WHI trial on HT use.

Conclusions

The 2017 WHI study did not demonstrate any impact on either menopause-related outpatient visits or HT use among middle-aged women in Taiwan. Our emulated cross-sectional study design may be employed in similar population-based policy intervention studies using interval-censored data.

Peer Review reports

Menopausal women may experience discomfort owing to menopausal symptoms caused by changes in hormone levels. These symptoms affect various aspects of women's health, including physiological, psychological, and social aspects. From a physiological perspective, common symptoms include vasomotor symptoms [ 1 , 2 , 3 ], migraines [ 4 ], genitourinary symptoms with menopause [ 5 ], and osteoporosis [ 6 ]. From a psychological perspective, menopausal women may experience sleep problems [ 7 , 8 ], depression [ 2 ], and anxiety [ 3 ]. At the social level, an existing study showed that approximately 40% of women experience menopausal symptoms-associated impaired work performance [ 9 ]. Menopausal women may consider seeking clinical assistance to alleviate the discomfort associated with this life stage.

Hormone therapy (HT) involves hormone supplementation to maintain the necessary hormonal balance in the body to alleviate the physiological discomfort caused by menopausal symptoms [ 10 ]. The HT regimen choice depends on hysterectomy history [ 11 ]. For patients with a history of hysterectomy, estrogen alone is recommended, whereas combined estrogen and progesterone is recommended for those without such a history [ 11 ]. In the 1990s, observational studies suggested the potential of HT in preventing chronic diseases such as cardiovascular diseases [ 12 ]. In response, the U.S. Food and Drug Administration mandated randomized controlled trials (RCTs) to confirm these potential cardiovascular benefits [ 12 ].

The Women's Health Initiative (WHI) HT trials, which commenced in 1993, comprised two parallel RCTs (one for women with an intact uterus and the other for women with hysterectomy) designed to evaluate the benefits and risks of HT in the prevention of chronic diseases among predominantly healthy postmenopausal women aged 50–79 years [ 13 , 14 , 15 ]. In 2002, after 5.2 years of follow-up, the estrogen plus progesterone trial was terminated early because of an increased risk of several diseases, including breast cancer, coronary heart disease, non-fatal stroke, venous thromboembolism, and overall cardiovascular disease [ 14 ]. HT-associated health risks outweigh the benefits of HT use in the prevention of fractures and colorectal cancer [ 14 ]. Therefore, there has been a substantial decline in the use of HT among women following the release of the 2002 WHI HT trial findings [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. Moreover, Wu et al. documented a decrease in HT prescription rates among Taiwanese women aged 45–69, dropping from 21.6% in 2001 to 9.7% in 2004 [ 19 ].

While the estrogen plus progesterone trial was prematurely terminated, the postintervention follow-up for the two WHI HT trials continued. In 2017, Manson et al. presented the results of the 18-year follow-up study, revealing that HT use was not significantly associated with long-term risks of all-cause, cancer-related, or cardiovascular-related mortalities [ 24 ]. These findings contrast the perceived health disadvantages of HT stemming from the 2002 WHI HT trial findings, which garnered significant attention and affected the use of HT worldwide. Although descriptive studies conducted in the UK and Switzerland have shown an increasing trend in HT utilization after 2017 [ 25 , 26 ], they did not quantify the effect of the 2017 WHI information on HT use.

However, to the best of our knowledge, there is no existing evidence regarding the information impact of the results of the 2017 postintervention follow-up on menopause-related visits and HT utilization. Therefore, this study aimed to evaluate the short-term effects of the 2017 WHI findings on outpatient visits and use of HT for menopause-related symptoms among women aged 50–60 years and HT in Taiwan. We employed an emulated cross-sectional study design to address methodological challenges of interval-censored data in this study.

In the present study, we compared outpatient visits for menopause symptoms and HT use three months before and after the 2017 WHI study release. Conventional cross-sectional analysis cannot capture behavior changes. Ideally, a cohort study should be conducted to evaluate the 2017 WHI study's influence on HT discontinuation among women with menopause symptoms. Due to limitations in National Health Insurance claims data, we could not accurately track the onset and cessation of symptoms in individual women. This interval-censored data feature prevented us from identifying the menopause study population and distinguishing the reasons for stopping HT use. Consequently, conducting a cohort study to compare changes in HT use before and after the 2017 WHI study was not feasible.

To overcome these challenges, we conducted an emulated repeated cross-sectional study, randomizing participants into either the exposure period (after the 2017 WHI study) or the non-exposure period (before the 2017 WHI study). As a result of this random assignment, interval-censored characteristics such as the onset and cessation of menopause were anticipated to be distributed similarly between both groups. Healthcare utilization was assessed during the study period. Additional information is provided in " Study design " section.

The study received approval from the Institutional Review Board (IRB) of National Yang Ming Chiao Tung University (IRB number: NYCU112074A). It adhered to the 1964 Declaration of Helsinki and its subsequent amendments, as well as the Strengthening the Reporting of Observational Studies in Epidemiology guidelines.

Data source

Data was sourced from the National Health Insurance Research Database of the Health and Welfare Data Science Center, Ministry of Health and Welfare. Taiwan’s NHI is a form of social insurance that enrolls nearly 100% of the population. We used a dataset that included the Registry for Beneficiaries database, Ambulatory Care Expenditures by Visits database, Details of Ambulatory Care Orders database, Inpatient Expenditures by Admissions database, and Details of Inpatient Orders database. The Registry for Beneficiaries database contains personal insurance information including birth year, health insurance category, and insurance amounts. The other four datasets contain all medical claims of insured individuals, including disease diagnoses, procedures performed, and prescriptions dispensed during inpatient, outpatient, and emergency visits.

Study design

The study employed a 6-month repeated cross-sectional design, spanning June 2017 to December 2017. This timeframe included the 3 months before and 3 months after September 2017, denoted as the month of information exposure (Fig.  1 A). From a female population aged 50–60 years (as described in " Study population " section), 10,000 women were randomly selected and assigned to a specific month. This procedure was repeated six times with replacement to establish six independent monthly groups (Fig.  1 B) for emulating the randomization of information exposure.

Study design and sampling approach. A Diagram illustrating the emulated cross-sectional study design. WHI Women’s Health Initiative. B Profile of sampling and randomization. We assume that the study population exists in each month of the study period

Study population

Our target population comprised women aged 50–60 years with continuous NHI coverage between January and December 2017. We initially identified 10,914,840 women who had uninterrupted NHI coverage during the study period (Fig.  2 ). Of these, 1,907,084 were within 50–60 years of age. After excluding 38,134 women who underwent oophorectomy between January 1, 2000 and December 31, 2017, our final eligible study population comprised 1,869,050 women. We employed simple random sampling with replacement to select 10,000 study participants for each of the 6 months, resulting in a total of 60,000 participants for analysis.

Flowchart for selection of the study participants. NHI National Health Insurance

Exposure to the 2017 WHI study

The variable "exposure to the 2017 WHI study" was defined in relation to its publication month, specifically, September 2017, a pivotal period for information dissemination. The exposure status for each participant was determined based on their assignment month relative to September 2017, with study participants categorized as "yes" if assigned after that month and "no" if assigned before.

In the present study, we assessed two primary outcome variables. The first one was outpatient visits related to menopausal symptoms; we investigated whether women aged 50–60 years had any outpatient visits for menopause-related symptoms during the designated month. The second was HT use; we examined whether women who had outpatient visits for menopausal symptoms were prescribed HT.

Regarding the first outcome, we identified an outpatient visit for menopause-related symptoms when women were diagnosed with primary diagnostic codes that included either the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code 627 or the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes N92.4 and N95. Regarding the second outcome, we defined HT prescription as the receipt of any medications associated with the Anatomical Therapeutic Chemical codes G03C and G03F during the designated month.

Covariates potentially associated with HT use included demographic factors, medical history, healthcare provider attributes, and time trends. The demographic factors included age, income-related insurance premium amounts, health insurance category, and geographic location. The study participants were divided into two age groups: 50–54 and 55–60 years. NHI enrolment salary and health insurance category were determined based on the status in the assigned month. The income-related insurance premium amounts were divided into five categories: < NT$30,000, NT$30,001–NT$50,000, NT$50,001–NT$80,000, NT$80,001–NT$120,000, and ≥ NT$120,001 or above. Health insurance was classified into five categories following the National Health Insurance Act: Category 1: civil servants or employees of publicly or privately owned enterprises or institutions; Category 2: members of an occupational union who have no particular employers; Category 3: members of the Farmers’ Association or the Irrigation Association; Category 5: members of a household of low-income families; and Category 6: veterans and others (Category 4 is not available through the NHI database). Geographic location was determined based on the medical institutions most frequently visited by the study participants within 1 year before the first day of the randomly assigned month (index date) and was divided into six categories: north, central, south, east, outlying islands, and unknown.

Medical history included the following conditions: cardiovascular diseases (ICD-9-CM: 410–414, 430–437; ICD-10-CM: I20-I22, I24-I25, G45.0-G46.8, I60-I68), diabetes mellitus (ICD-9-CM: 250, 251.8, 357.2, 362.01, 362.02, 366.41, 583.81; ICD-10-CM: E08-E13), hyperlipidemia (ICD-9-CM: 272; ICD-10-CM: E71.30, E75.21-E75.22, E75.24, E75.3-E75.6, E77, E78.0-E78.6, E78.70, E78.79, E78.8-E78.9, E88), hypertension (ICD-9-CM: 401–405; ICD-10-CM: I10-I15, N26.2), liver diseases (ICD-9-CM: 570–573; ICD-10-CM: K70-K77), osteoporosis (ICD-9-CM: 733.01–733.09; ICD-10-CM: M81.0, M81.6, M81.8), breast cancer (ICD-9-CM: 174, 233.0, 238.3, 239.3; ICD-10-CM: C50, D05, D48.6, D49.3, Z51.12), and gynecological cancer (ICD-9-CM: 180, 182.0, 183.0; ICD-10-CM: C53, C54.1, C54.2, C54.3, C54.9, C56). Furthermore, medical history was defined as a history of more than two outpatient visits or more than one hospitalization record related to a specific condition in the 5 years preceding the index date.

Healthcare provider attributes included physician specialty, sex, and hospital ownership. These attributes were determined based on the characteristics of most outpatient visits for menopause-related symptoms during the assigned month. Time trend was defined as the natural progression of time during the study period, with each month serving as a unit of time.

Statistical analysis

We employed descriptive statistics to describe the baseline characteristics of study participants (1) before and after the 2017 WHI study and (2) for each month. We evaluated the statistical significance of the differences between the study groups using the standardized mean difference (SMD), where SMD > 0.1 signified a significant difference.

We utilized logistic regression to investigate the impact of the 2017 WHI study on outpatient visits for menopause-related symptoms and HT use among women with outpatient visits. The variables of interest comprised a binary variable indicating exposure to the 2017 WHI report ( \({\text{X}}_{1}\) ) and its interaction with the time trend ( \({\text{X}}_{1}\) t). The binary variable " \({\text{X}}_{1}\) " signifies the immediate level change associated with the study publication; the interaction term " \({\text{X}}_{1}\) t " represents the change over time following the study. In examining outpatient visits for menopause-related symptoms, we controlled for demographic factors, medical history, and time trend. In the analysis of HT use, the covariates included demographic factors, medical history, healthcare provider attributes, and time trend. SAS (version 9.4; SAS Institute, Inc., Cary, NC, USA) and R (version 4.2.2; R Foundation for Statistical Computing, Vienna, Austria) were used for data analysis.

Sensitivity and scenario analyses

Sensitivity and scenario analyses were conducted to assess the robustness of the study design. The first sensitivity analysis involved random selection of a monthly sample of 30,000 participants over 6 months and logistic regression to assess the impact of the 2017 WHI study. In the second sensitivity analysis, bootstrapping was performed 100 times, following the same sampling method as in the first analysis, and 30,000 participants were randomly selected each month. This approach provided insights into the robustness of our effect estimates.

We performed a scenario analysis based on the 2002 WHI HT trial findings, which closely mirrored our base case study in design and statistical analysis. The study period spanned from January 2002 to January 2003, excluding the exposure month (July 2002), covering the 6 months before and after the exposure. This scenario serves as a positive control to validate our study design.

Demographic characteristics

The baseline characteristics of the study participants ( N  = 60,000 women) before and after the 2017 WHI study are summarized in Table  1 and those for each month are presented in Additional File 1. The average age of the study participants was approximately 55 years. Over 80% of the study participants reported an NHI enrolment salary below NT$50,000, and nearly half of them belonged to the first category of health insurance, which includes those employed by the government, schools, or privately operated public utility enterprises. Most study participants lived in the northern region, followed by the southern and central regions. Regarding medical history, < 25% of the study participants had an existing condition, such as hyperlipidemia, hypertension, diabetes mellitus, liver disease, cardiovascular disease, and breast or gynecological cancer. The observed baseline characteristics among the included participants were similar and comparable (SMD < 0.1) before and after the 2017 WHI study, as well as for each month.

Base case analysis

Tables  2  and 3  show the results of logistic regressions assessing the impact of the 2017 WHI study on outpatient visits for menopause-related symptoms and HT use among women who had outpatient visits, respectively. Crude and adjusted models consistently demonstrated that the 2017 report did not have a significant impact on outpatient visits for menopause-related symptoms (adjusted odds ratio [aOR] of level change: 1.20, 95% CI: 0.85–1.71; aOR of slope change: 1.11, 95% CI: 0.92–1.35; Table  2 ) or HT use among women who had outpatient visits (aOR of level change: 1.08, 95% CI: 0.49–2.4; aOR of slope change: 1.37, 95% CI: 0.88–2.12; Table 3 ).

Base case sensitivity analysis

The two sensitivity analyses involving (1) sampling of 30,000 participants each month and (2) sampling of 30,000 participants each month with bootstrapping for 100 iterations consistently indicated that the 2017 WHI study did not have a significant effect on outpatient visits for menopause-related symptoms (sensitivity analysis (1): aOR of level change: 0.95, 95% CI: 0.78–1.15; aOR of slope change: 1.03, 95% CI: 0.95–1.11; sensitivity analysis (2): aOR of level change: 0.99, 95% CI: 0.77–1.21; aOR of slope change: 0.96, 95% CI: 0.87–1.06) or HT use among participants who had outpatient visits (sensitivity analysis (1): aOR of level change: 0.92, 95% CI: 0.59–1.43; aOR of slope change: 1.07, 95% CI: 0.83–1.38; sensitivity analysis (2): aOR of level change: 1.03, 95% CI: 0.67–1.55; aOR of slope change: 0.99, 95% CI: 0.8–1.26; Table 4 ). These results are consistent with those of the base case analysis.

Scenario analysis

In our scenario analysis, we adopted an identical study design to validate our findings by assessing the effects of the 2002 WHI HT trial. The 2002 report was associated with reduced likelihood of outpatient visits for menopause-related symptoms among women aged 50–60 years, with an aOR of 0.67 (95% CI: 0.62–0.73) and a negative change over time (aOR: 0.95, 95% CI: 0.93–0.98; Additional File 2). However, the 2002 report was associated with increased odds of HT use among women who had outpatient visits, with an aOR of 2.08 (95% CI: 1.6–2.69) and a positive change over time (aOR: 1.24, 95% CI: 1.15–1.35; Additional File 2).

Summary of key findings

We introduced an emulated cross-sectional study design to investigate the impact of the 2017 WHI study on HT use in Taiwan. Our findings show that the 2017 WHI study had no significant impact on the level or slope of menopause-related outpatient visits among middle-aged women and their use of HT. The sensitivity analysis further underscored the robustness of these estimates. There are two possible explanations for the lack of a significant effect of the 2017 WHI study on outpatient visits or HT use among women who had outpatient visits. First, although the updated information released in the 2017 WHI study reduced concerns about the overall mortality associated with HT, its impact remained limited and did not fully counteract negative health risks, such as cancer incidence, as highlighted in the 2002 WHI study [ 27 , 28 ]. Second, there was a temporal gap between the publication of the study results and the update of Taiwan’s menopausal treatment guidelines. The Taiwanese Menopause Society released updated guidelines in 2019, incorporating the 2017 WHI study findings into their recommendations [ 10 ]. Although this time lag may not affect the treatment choice of healthcare providers, it may reduce the demand for HT use among women experiencing menopausal symptoms, particularly those with mild symptoms.

Our scenario analysis revealed a significant negative effect of the 2002 WHI HT trial findings on overall HT use among women aged 50–60 years, consistent with the results of previous studies ([ 16 , 17 , 18 , 19 , 20 ] (Additional File 3). This reduction in HT use can be primarily attributed to a decrease in menopause-related outpatient visits. Notably, the 2002 WHI HT trial had a negative effect on outpatient visits among women aged 50–60 years but a positive effect on HT use among women who had outpatient visits (Additional File 2). One possible explanation is that the risks associated with HT have long been discussed by various women's health associations and have received extensive media coverage in Taiwan before the 2002 WHI publication [ 29 ]. Consequently, women may have been more inclined not to visit physicians [ 29 ]. Those who sought menopause-related outpatient care may have experienced more severe menopausal symptoms, thereby exhibiting a greater tendency to opt for HT for symptom management.

Limitations

This study had two limitations, which are related to the database and research design. Firstly, because of the inherent constraints of the NHI claims database in identifying women with menopausal symptoms, we used women aged 50–60 years as proxies for those with menopausal symptoms. Consequently, women without menopausal symptoms may have been included in this study. Secondly, we excluded women who had a history of oophorectomy between January 1, 2000, and December 31, 2017. This exclusion criterion may have resulted in cases where individuals had not yet undergone oophorectomy at the time of assignment for a given month, leading to their unintended exclusion from the observation.

Although these limitations may influence sample selection, the approach of random sampling and assignment employed in this study may ensure that a potential selection bias is randomly distributed across the study periods, including 3 months before and after the publication of the 2017 WHI study. Furthermore, the sensitivity analysis results derived from 100 bootstrapped iterations were consistent with the base case analysis results, emphasizing the robustness of the research findings. Therefore, these measurement errors are unlikely to introduce a significant bias in estimating the impact of the 2017 WHI study findings.

This study introduced an innovative approach to emulate a cross-sectional study for simulating the randomization of information shock, aimed at addressing two methodological challenges. The first challenge arose from the limitation of the NHI database in identifying the study population, resulting from variations in menopausal symptoms among women and unavailability of records in claims data in cases where women do not seek medical attention for these symptoms. The second challenge relates to the natural development of menopause, which evolves over time. If we had employed a conventional cohort, monitoring study participants before and after the publication of the 2017 WHI study, it would have been difficult to distinguish whether the observed changes were due to the natural development of menopause or the impact of the 2017 WHI study findings. These issues may have affected the internal validity of the study.

To address these challenges, we adopted an emulated repeated cross-sectional design with random sampling and assignments to emulate the randomization of the 2017 information shock. This research design randomized women aged 50–60 years and accounted for unobserved confounders before and after the publication of the 2017 WHI study findings. Additionally, descriptive statistics highlighted that the distribution of baseline characteristics among the study participants, generated through random sampling and assignments, was similar. The inferential statistics indicated minimal differences between the crude and adjusted models. These results confirmed the robustness of the study design.

Recommendations for future studies

Because of constraints related to the accessibility of NHI claims data during the study, the primary emphasis was evaluation of the short-term impact of the 2017 WHI study. Considering Rogers' diffusion of innovation theory, which suggests that the dissemination of innovative information takes time, it is possible that a time lag effect exists [ 30 ]. To gain a more comprehensive understanding, future research should aim to investigate the long-term effects of the 2017 WHI study findings.

In addition, it is noteworthy that a temporal gap existed between the publication of the 2017 WHI study and the release of updated treatment guidelines in Taiwan. Therefore, subsequent studies can investigate whether a significant shift occurred in 2019 in response to the updated guidelines.

Furthermore, for future observational follow-up studies, it may be beneficial to consider the approach employed in this study, which involved emulating cross-sectional data to simulate a randomization of information shock. This methodology proves particularly useful when dealing with interval-censored data and addressing the challenges of distinguishing the effect of an intervention effect from the natural progression of a disease.

The 2017 WHI study had no demonstrable effect on the level and rate of change in outpatient visits among middle-aged menopausal women and HT use within this group. This implies that the updated findings of the 2017 WHI HT study may not have fully counteracted the enduring negative effect of the 2002 WHI HT trial on HT use. In future observational studies involving interval-censored data, researchers may consider employing the emulated randomization approach used in this study to establish a repeated cross-sectional design for before-and-after comparisons.

Availability of data and materials

The data supporting the findings of this study are available from the Ministry of Health and Welfare, Taiwan; however, restrictions apply to the availability of these data, which were used under the license for the current study and are not publicly available. The code supporting the findings of this study is available from the corresponding authors upon request.

Abbreviations

• Hormone therapy
• Women’s Health Initiative

Randomized controlled trial

National Health Insurance

Institutional Review Board

International Classification of Diseases, Ninth Revision, Clinical Modification

International Classification of Diseases, Tenth Revision, Clinical Modification

Standardized mean difference

Adjusted odds ratio

Woods NF, Mitchell ES. Symptoms during the perimenopause: prevalence, severity, trajectory, and significance in women’s lives. Am J Med. 2005;118(Suppl 12B):14–24.

Article   PubMed   Google Scholar  

Bromberger JT, Schott LL, Kravitz HM, Sowers M, Avis NE, Gold EB, et al. Longitudinal change in reproductive hormones and depressive symptoms across the menopausal transition: results from the Study of Women’s Health across the Nation (SWAN). Arch Gen Psychiatry. 2010;67:598–607.

Article   CAS   PubMed   PubMed Central   Google Scholar  

Bromberger JT, Kravitz HM, Chang Y, Randolph JF, Avis NE, Gold EB, et al. Does risk for anxiety increase during the menopausal transition? Study of women’s health across the nation. Menopause. 2013;20:488–95.

Article   PubMed   PubMed Central   Google Scholar  

Ripa P, Ornello R, Degan D, Tiseo C, Stewart J, Pistoia F, et al. Migraine in menopausal women: a systematic review. Int J Womens Health. 2015;7:773–82.

PubMed   PubMed Central   Google Scholar  

Nappi RE, Kokot-Kierepa M. Vaginal health: insights, views & attitudes (VIVA) – results from an international survey. Climacteric. 2012;15:36–44.

Article   CAS   PubMed   Google Scholar  

van Staa TP, Dennison EM, Leufkens HG, Cooper C. Epidemiology of fractures in England and Wales. Bone. 2001;29:517–22.

Polo-Kantola P. Sleep problems in midlife and beyond. Maturitas. 2011;68:224–32.

Joffe H, Massler A, Sharkey KM. Evaluation and management of sleep disturbance during the menopause transition. Semin Reprod Med. 2010;28:404–21.

Currie H, Moger SJ. Menopause – understanding the impact on women and their partners. Post Reprod Health. 2019;25:183–90.

The Taiwanese Menopause Society. Guidelines for the management and treatment of menopausal women in Taiwan. 2019;2019.

Health Promotion Administration. Hormone therapy education manual for menopause. 2002.

Google Scholar  

Cagnacci A, Venier M. The controversial history of hormone replacement therapy. Medicina (Kaunas). 2019;55: 602.

Design of the Women’s Health Initiative clinical trial and observational study. The Women’s Health Initiative Study Group. Control Clin Trials. 1998;19:61–109.

Article   Google Scholar  

Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288:321–33.

Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Black H, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA. 2004;291:1701–12.

Hersh AL, Stefanick ML, Stafford RS. National use of postmenopausal hormone therapy: annual trends and response to recent evidence. JAMA. 2004;291:47–53.

Guay MP, Dragomir A, Pilon D, Moride Y, Perreault S. Changes in pattern of use, clinical characteristics and persistence rate of hormone replacement therapy among postmenopausal women after the WHI publication. Pharmacoepidemiol Drug Saf. 2007;16:17–27.

Menon U, Burnell M, Sharma A, Gentry-Maharaj A, Fraser L, Ryan A, et al. line in use of hormone therapy among postmenopausal women in the United Kingdom. Menopause. 2007;14:462–7.

Wu CY, Wu SL, Lin SJ, Chu CM. Changes in hormone therapy prescriptions among middle-aged women in Taiwan: implications for health needs at menopause. Womens Health Issues. 2011;21:153–9.

Burkard T, Moser M, Rauch M, Jick SS, Meier CR. Utilization pattern of hormone therapy in UK general practice between 1996 and 2015: a descriptive study. Menopause. 2019;26:741–9.

Haas JS, Kaplan CP, Gerstenberger EP, Kerlikowske K. Changes in the use of postmenopausal hormone therapy after the publication of clinical trial results. Ann Intern Med. 2004;140:184–8.

Usher C, Teeling M, Bennett K, Feely J. Effect of clinical trial publicity on HRT prescribing in Ireland. Eur J Clin Pharmacol. 2006;62:307–10.

Johansen LL, Thinggaard M, Hallas J, Osler M, Christensen K. Postmenopausal hormone therapy and mortality before and after the Women’s Health Initiative study. Sci Rep. 2023;13:539.

Manson JE, Aragaki AK, Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, et al. Menopausal hormone therapy and long-term all-cause and cause-specific mortality: the Women’s Health Initiative randomized trials. JAMA. 2017;318:927–38.

Alsugeir D, Wei L, Adesuyan M, Cook S, Panay N, Brauer R. Hormone replacement therapy prescribing in menopausal women in the UK: a descriptive study. BJGP Open. 2022;6:0126.

Sundell M, Brynhildsen J, Spetz Holm AC, Fredrikson M, Hoffmann M. Trends in the incidence, prevalence and sales volume of menopausal hormone therapy in Sweden from 2000 to 2021. Maturitas. 2023;175:107787.

Natari RB, Hollingworth SA, Clavarino AM, Dingle KD, McGuire TM. Long term impact of the WHI studies on information-seeking and decision-making in menopause symptoms management: a longitudinal analysis of questions to a medicines call centre. BMC Womens Health. 2021;21:348.

Huang KE, Xu L, I NN, Jaisamrarn U. The Asian Menopause Survey: knowledge, perceptions, hormone treatment and sexual function. Maturitas. 2010;65:276–83.

Kuo DJ, Lee YC, Huang WF. Hormone therapy use and prescription durations of menopausal women in Taiwan: a 5 years’ national cohort study. Maturitas. 2007;58:259–68.

Rogers EM. Diffusion of innovations. 5th ed. New York: Free Press; 2003.

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Acknowledgements

We would like to thank Editage ( www.editage.com ) for English language editing.

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Author information

Chen-Han Chueh, Pei-Kuan Ho and Ming-Neng Shiu contributed equally to this work.

Authors and Affiliations

Institute of Health and Welfare Policy, National Yang Ming Chiao Tung University, Taipei, Taiwan

Chen-Han Chueh, Pei-Kuan Ho, Wai-Hou Li, Ming-Neng Shiu, I.-Ting Wang & Yi-Wen Tsai

Department of Obstetrics and Gynecology, Chen Hsin General Hospital, Taipei, Taiwan

Department of Pharmacy, National Yang Ming Chiao Tung University, Taipei, Taiwan

Ming-Neng Shiu

Department of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan

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Contributions

Chen-Han Chueh: Methodology, Validation, Visualization, Writing—original draft, Writing—review & editing. Pei-Kuan Ho: Data curation, Formal analysis, Software, Visualization, Writing—original draft, Writing—review & editing. Wai-Hou Li: Conceptualization, Supervision, Writing—original draft, Writing—review & editing. Ming-Neng Shiu: Conceptualization, Project administration, Supervision, Writing—review & editing. I-Ting Wang: Methodology, Writing—original draft. Yu-Wen Wen: Conceptualization, Methodology, Supervision, Writing—review & editing. Yi-Wen Tsai: Conceptualization, Methodology, Project administration, Resources, Supervision, Writing—original draft, Writing—review & editing. All the authors have read and approved the final version of the manuscript.

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Correspondence to Chen-Han Chueh or Yi-Wen Tsai .

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Supplementary Information

Additional file 1: baseline characteristics of the study participants for each month ( n  = 60,000)., 12889_2024_19089_moesm2_esm.docx.

Additional File 2: Scenario analysis of the impact of the 2002 WHI study on outpatient visits for menopause-related symptoms and HT use among women aged 50–60 years.

12889_2024_19089_MOESM3_ESM.docx

Additional File 3: Scenario analysis of the impact of the 2002 WHI study on the overall use of HT among women aged 50–60 years ( N  = 120,000).

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Chueh, CH., Ho, PK., Li, WH. et al. The 2017 Women’s Health Initiative study and use of hormone therapy: an emulated repeated cross-sectional study. BMC Public Health 24 , 1674 (2024). https://doi.org/10.1186/s12889-024-19089-2

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Honors Scholar Theses

Pandemic impacts on women’s mental health: a literature review.

Wenqi Gong Follow

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For many years, women's mental health has been a topic of discussion in the research field, and these problems are usually regarded as the result of gender inequality. This study identifies mental health differences among women in different family structures in the context of a pandemic, by citing scenario-based research from 2020 to 2023. More specifically, by comparative analysis, disparities in a series of variables are observed between married and unmarried women. These findings figure out risk factors that tend to distress women. The literature review emphasizes the huge challenges confronting women today, and the root causes of the psychological differences between men and women that need further study, to help improve women's mental health.

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Gong, Wenqi, "Pandemic Impacts on Women’s Mental Health: A Literature Review" (2023). Honors Scholar Theses . 1042. https://digitalcommons.lib.uconn.edu/srhonors_theses/1042

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• Published: 20 June 2024

Genetically predicted high sex hormone binding globulin was associated with decreased risk of polycystic ovary syndrome

• Xiaofeng Guo 1 ,
• Langlang Chen 1 ,
• Jianhua He 1 ,
• Xiaozhi Zhang 1 &
• Shui Xu 1  

BMC Women's Health volume  24 , Article number:  357 ( 2024 ) Cite this article

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Previous observational studies have indicated an inverse correlation between circulating sex hormone binding globulin (SHBG) levels and the incidence of polycystic ovary syndrome (PCOS). Nevertheless, conventional observational studies may be susceptible to bias. Consequently, we conducted a two-sample Mendelian randomization (MR) investigation to delve deeper into the connection between SHBG levels and the risk of PCOS.

We employed single-nucleotide polymorphisms (SNPs) linked to serum SHBG levels as instrumental variables (IVs). Genetic associations with PCOS were derived from a meta-analysis of GWAS data. Our primary analytical approach relied on the inverse-variance weighted (IVW) method, complemented by alternative MR techniques, including simple-median, weighted-median, MR-Egger regression, and MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) testing. Additionally, sensitivity analyses were conducted to assess the robustness of the association.

We utilized 289 SNPs associated with serum SHBG levels, achieving genome-wide significance, as instrumental variables (IVs). Our MR analyses revealed that genetically predicted elevated circulating SHBG concentrations were linked to a reduced risk of PCOS (odds ratio (OR) = 0.56, 95% confidence interval (CI): 0.39–0.78, P  = 8.30 × 10 –4 ) using the IVW method. MR-Egger regression did not detect any directional pleiotropic effects ( P intercept = 0.626). Sensitivity analyses, employing alternative MR methods and IV sets, consistently reaffirmed our results, underscoring the robustness of our findings.

Conclusions

Through a genetic epidemiological approach, we have substantiated prior observational literature, indicating a potential causal inverse relationship between serum SHBG concentrations and PCOS risk. Nevertheless, further research is needed to elucidate the underlying mechanism of SHBG in the development of PCOS.

Peer Review reports

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of childbearing age, characterized by hyperandrogenism, menstrual disorders, and polycystic ovarian changes [ 1 , 2 ]. It was estimated that in 2019, approximately 66.0 million individuals were affected by PCOS worldwide and the overall prevalence rate was 829.6 per 100,000 [ 3 ]. Patients with PCOS may not only have a higher rate of infertility but also have an increased risk of developing diabetes and cardiovascular diseases, which poses a great challenge to public health management [ 2 ].

While the exact cause and development of PCOS remain unclear, evidence suggests that a combination of genetic and environmental factors significantly contribute to its etiology and pathogenesis. Established risk factors for PCOS encompass genetic susceptibility, obesity, and insulin resistance [ 4 , 5 , 6 , 7 ]. Sex hormone binding globulin (SHBG) acts as a carrier for sex hormones, binding with both testosterone and estrogen, and holds a crucial role in various physiological and pathological contexts [ 8 ]. Observational studies have consistently shown lower circulating SHBG levels in PCOS patients when compared to healthy controls. For instance, in a study involving 200 PCOS patients and 200 controls, peripheral SHBG levels were significantly higher in the control group than in the PCOS group [ 9 ]. Another study, which included 585 women with PCOS and 171 controls, similarly observed lower serum SHBG levels in PCOS patients compared to controls [ 10 ]. However, since findings from traditional observational epidemiological studies are susceptible to bias such as confounding and reverse causation, it remains unclear whether the observed association was causal or not.

Mendelian randomization (MR) is a genetic epidemiological approach that utilizes single nucleotide polymorphisms (SNPs) strongly linked to the exposure as instrumental variables (IVs) to assess potential causal relationships between the exposure and the outcome [ 11 ]. Since genotypes are assumed to be randomly distributed during gamete formation, the application of instrumental variable models effectively addresses the issue of confounding in observational studies, particularly the potential bias caused by unmeasured confounding variables in causal inference [ 12 , 13 ]. Furthermore, as genotypes precede the onset of disease, MR studies can effectively mitigate the issue of reverse causation. Consequently, in this study, we conducted a two-sample MR investigation to explore the potential link between circulating SHBG levels and the risk of PCOS.

Selection of genetic variants

The overall design of this study is shown in Fig.  1 . The IVs for serum SHBG were obtained from a recent genome-wide association study (GWAS) involving 425,097 individuals of European descent [ 14 ]. A total of 305 independent SNPs (r 2 threshold < 0.001, kb = 10,000) associated with circulating SHBG levels at genome-wide significance level ( P  < 5 × 10 −8 ) were identified. Of these, 16 were not present in the primary outcome dataset. Consequently, we ultimately utilized 289 SNPs associated with circulating SHBG concentrations as instrumental variables (IVs) in the subsequent MR analyses. The details of GWAS studies and datasets used in the present study are listed in Supplementary Table 1, and the detailed information of the selected SNPs used as IVs is displayed in Supplementary Table 2.

An overall design of the present study. Abbreviations: IVW, inverse-variance weighted; GWAS, Genome-wide association study; MR, Mendelian randomization; MR-PRESSO, MR pleiotropy residual sum and outlier test; PCOS, polycystic ovary syndrome; SHBG, sex hormone binding globulin; SNP, single nucleotide polymorphism

Furthermore, as body mass index (BMI) has been shown to be correlated with both circulating SHBG levels and PCOS risk, we selected 462 independent SHBG-associated SNPs (with an r 2 threshold < 0.001 and kb = 10,000) from the same GWAS meta-analysis, after adjusting for BMI ( P  < 5 × 10 −8 ). Among them, 22 SNPs were not available in the outcome dataset. Finally, 440 SNPs associated with circulating SHBG concentrations adjusted by BMI were used as IVs in the primary analyses. The detailed information of the selected SNPs used as IVs is displayed in Supplementary Table 3.

Outcome dataset

The genetic association data for PCOS were sourced from a GWAS meta-analysis, which encompassed 10,074 cases and 103,164 controls of European ancestry [ 15 ]. This represents the most extensive GWAS meta-analysis of PCOS to date, incorporating participants from seven cohorts, including Rotterdam, EGCUT, deCODE, UK (London/Oxford), Chicago, Boston, and 23andMe [ 15 ]. However, due to unavailability of data from 23andMe, the final study population for this investigation comprised 4,138 PCOS patients and 20,129 controls [ 15 ]. Comprehensive details of these studies have been previously documented in published articles, and all participating studies received approval from their respective ethical committees. Furthermore, we selected another summary data associated with PCOS involving 1,424 cases and 200,581 controls from the Finland consortium ( https://www.finngen.fi/fi ), which collected and analyzed genetic and health related data from about 500,000 participants to replicate our findings.

Statistical analysis

We first calculated F-statistics to quantify the strength of the IVs, with the equation of F = beta 2 /se 2 [ 16 ]. A F-statistic greater than 10 suggests the IVs are unlikely to suffer from weak instrument bias.

Our primary analysis employed the inverse-variance weighted (IVW) method to investigate the potential causal association between circulating SHBG concentrations and PCOS risk. This method initially derives causal effect estimates from individual genetic instrumental variables, namely, the effect estimates of each SNP on both SHBG and PCOS. These estimates are then aggregated through meta-analysis to yield a consolidated causal effect estimate [ 17 ]. The estimated value from the IVW method is essentially equivalent to the regression coefficient in weighted regression with zero intercept term [ 18 , 19 ]. In addition, we conducted a series of alternative MR methods to analyze the effect of potential pleiotropy on causal estimation. For instance, MR-Egger regression was used to evaluate influence of potential directional pleiotropy. In MR-Egger regression analysis, the intercept term signifies the average pleiotropic effect of genetic variation [ 20 ]. If the intercept is different from zero, there is evidence of directed pleiotropy [ 20 ]. Under the assumption that the correlation between genetic variation and exposure is unrelated to the direct impact of genetic variation on the outcomes, the slope coefficient in MR-Egger regression provides a consistent estimate of the causal effect [ 20 ]. Furthermore, we employed both the simple-median and weighted-median methods, which involve combining either unweighted or weighted estimates using the median. As long as the weight of the causal effect calculated by the effective instrumental variable reaches 50%, a consistent estimation of the causal effect can be obtained [ 21 ]. Moreover, the likelihood-based method was used to evaluate the linear relationship between the exposure and the outcome, and the likelihood-based estimator expresses the causal increase in the outcome per unit change in the risk factor assuming a linear association between the risk factor and the outcome variables [ 22 ]. Lastly, we employed the Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) method to identify and address horizontal pleiotropic outliers. This method conducts a global heterogeneity test by regressing the SNP-outcome (PCOS) associations against the SNP-exposure (SHBG) associations and then comparing the actual distance of each SNP from the regression line with the expected distance under the null hypothesis of no pleiotropy [ 23 ].

All statistical analyses were performed using R (version 3.6.3) with packages “MendelianRandomization” and “MR-PRESSO”, unless otherwise noted. An observed P -value < 0.013(0.05/2/2) was considered as statistically significant evidence for a causal association by using Bonferroni correction. A P -value ranging from 0.013 to 0.05 was considered as suggestive evidence.

In the present study, a total of 289 and 440 independent SNPs associated with SHBG and SHBG adjusted BMI achieving genome-wide significance were used as IVs in the primary analysis. The F-statistic for SHBG and SHBG adjusted BMI was 21.77–1857.13, satisfying the threshold of > 10.

As shown in Table  1 , genetically predicted higher levels of circulating SHBG were significant associated with a decreased risk of PCOS. For one standard deviation (SD) (approximately 30.3 nmol/L) increment of SHBG levels, the odds ratio (OR) of PCOS was 0.56 [95% confidence interval (CI): 0.39–0.78, P  = 8.30 × 10 –4 ]. The causal effect estimate was consistent in the sensitivity analyses using the simple-median (OR = 0.51, 95% CI: 0.30–0.87, P  = 0.013), weighted-median (OR = 0.60, 95% CI: 0.35–1.03, P  = 0.066) and Maximum-likelihood (OR = 0.55, 95% CI: 0.39–0.78, P  = 7.28 × 10 –4 ) methods. One outlier SNPs were detected using MR-PRESSO test, and the causal effect estimate between SHBG and PCOS was similar (OR = 0.54, 95% CI: 0.39–0.76, P  = 4.07 × 10 –4 ). MR-Egger regression did not suggest evidence of potential directional pleiotropy ( P for intercept = 0.626) (Fig.  2 ). Since BMI has been reported to be associated with both risk of PCOS and levels of circulating SHBG, we repeated our MR analysis using SHBG associated SNPs with adjustments for BMI as IVs to further evaluate the robustness of our main analyses. The causal effect of circulating SHBG adjusted for BMI with risk of PCOS remained consistent (OR = 0.53, 95% CI: 0.38–0.73, P  = 4.07 × 10 –4 , by IVW method) (Fig.  2 ).

Association between genetically predicted SHBG levels, SHBG adjusted BMI levels and risk of PCOS based on different MR methods. Abbreviations: BMI, Body mass index; IVW, inverse-variance weighted; MR, Mendelian randomization; SHBG, sex hormone binding globulin; SNP, single nucleotide polymorphism

When replicating the findings in the Finnegan consortium dataset, we observed consistent results for the association between SHBG and SHBG-adjusted BMI using the IVW method (OR = 0.45, 95% CI: 0.30–0.68, P  = 1.83 × 10 –4 for SHBG and OR = 0.50, 95% CI: 0.33–0.75, P  = 8.87 × 10 –4 for SHBG-adjusted BMI). The results of the other sensitivity analyses are listed in Supplementary Table 4.

In this study, a two-sample MR approach was employed to assess the potential causal link between circulating SHBG levels and PCOS risk. The analysis revealed that genetically predicted high SHBG levels were linked to a reduced PCOS risk. Our findings remained consistent across various sensitivity analyses using different MR methods and alternative instrumental variable sets, underscoring their robustness.

SHBG, a serum protein linked to sex hormones, plays a critical role in facilitating the action and transport of these hormones [ 24 ]. Its levels have been documented to correlate with PCOS development, as well as with complications and long-term outcomes in PCOS patients. A reduced serum SHBG level in PCOS patients serves as a significant risk factor for hyperandrogenemia and serves as a crucial predictor of insulin resistance, as well as disturbances in glucose and lipid metabolism [ 25 ]. Observational epidemiological studies have provided evidence of an association between SHBG and PCOS risk. Cross-sectional studies have further indicated that SHBG levels are lower in the PCOS group compared to the control group [ 26 , 27 ]. In a case–control study, the mean SHBG concentration was notably lower in the PCOS group compared to the control group, with statistically significant differences observed ( P  = 0.004) [ 28 ]. In addition, in a recent meta-analysis comprising 5,121 cases and 5,059 controls, it was reported that circulating SHBG levels were lower in PCOS patients compared to controls (SMD = -0.83, 95%CI = -1.01 to -0.64) [ 29 ]. Consistently, our findings support the notion of a protective effect of circulating SHBG levels against the development of PCOS.

While the precise molecular mechanism by which SHBG contributes to PCOS development remains unclear, various studies have indicated potential biological pathways involved in the pathogenesis of PCOS. For instance, the reduction in SHBG levels among PCOS patients results in elevated free and bioactive androgen levels, increased luteinizing hormone secretion, and reduced follicle-stimulating hormone secretion. These factors collectively lead to a high rate of follicle atresia and ultimately contribute to ovulation disorders [ 30 , 31 ]. Moreover, insulin resistance (IR) stands out as a prominent characteristic of PCOS [ 32 ]. In a study by Fu Chen et al., SHBG was identified as an independent influential factor for HOMA-IR and could serve as a valuable predictive marker for IR in PCOS patients [ 33 ]. Feng C et al. conducted in vitro studies using a human insulin-resistant cell model, demonstrating that SHBG may down-regulate the Phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT) pathway. This pathway is known to be associated with the development of both local and systemic insulin resistance, which is considered to play a role in the connection between metabolic disorders and reproductive dysfunction in PCOS [ 34 ]. While these explanations hold biological plausibility, further studies are needed to clarify the precise role of SHBG in PCOS development.

Prior investigations have also indicated an association between BMI and both SHBG levels and PCOS risk. For instance, in a population-based cohort study, it was observed that women who were overweight or obese at both 14 and 31 years of age had a heightened risk of PCOS development [relative risk (RR) = 1.71, 95% CI = 1.30–2.24] [ 35 ]. Another study reported that SHBG correlated negatively with BMI in both PCOS ( P  < 0.0001) and non-PCOS groups ( P  = 0.001) [ 36 ]. Hence, in this study, we conducted a sensitivity analysis by employing IVs adjusted for BMI and reran the MR analysis. The causal association between SHBG and PCOS risk remained consistent, bolstering confidence in the potential causal role of SHBG in PCOS development.

There are some strengths in our study when compared with previous studies [ 14 , 37 ]. To ensure three fundamental assumptions, we selected SNPs from independent loci related to circulating SHBG levels with more rigorous criterion ( P  < 5 × 10 −8 , r 2 threshold < 0.001, kb = 10,000) from the largest GWAS to date as our IVs [ 13 ]. Second, MR analyses employing genetic variants as IVs largely address the issue of confounding inherent in traditional observational studies because genotypes are randomly allocated during gamete formation. We also performed different MR methods to test for potential pleiotropy. We did not observe evidence of directional pleiotropy for the causal association between SHBG and risk of PCOS in any of the above MR approaches. Lastly, we replicated our findings using another set of summary data, yielding consistent results. Nonetheless, this study also encounters limitations. While the majority of participants in the GWAS meta-analysis were of European descent, it's important to acknowledge the potential confounding effects arising from population stratification. Consequently, the results of this study may not be entirely applicable to individuals of non-European descent. Furthermore, we could not assess the potential nonlinear effects of serum SHBG on the risk PCOS by using the MR method. While we try our best to avoid pleiotropy, we cannot totally rule out the possibility of pleiotropy. Canalization plays a crucial role in complex organisms and should be considered when investigating genetic causality through two-sample MR analysis. However, the association between SHBG and the risk of PCOS needs further validation through additional studies due to the absence of individual data.

In conclusion, our study revealed a genetic association between high SHBG levels and reduced PCOS risk, implying a potential causal role for SHBG in PCOS development. Further investigations are needed to elucidate the underlying mechanisms by which SHBG influences the development of PCOS.

Availability of data and materials

Datasets used for the analysis are available under reasonable requests. Data on SHBG were contributed by Katherine S Ruth et al., (2020) and were downloaded from https://www.nature.com/articles/s41591-020-0751-5#Sec19 . Data on PCOS was contributed by Felix Day et al., (2018) and were downloaded from https://doi.org/10.17863/CAM.27720.

Abbreviations

Body mass index

Confidence interval

Insulin resistance

Instrumental variables

Inverse-variance weighted

Genome-wide association study

• Mendelian randomization

Mendelian randomization pleiotropy residual sum and outlier

• Polycystic ovary syndrome

Standard deviation

Sex hormone binding globulin

Single nucleotide polymorphisms

Uncertainty interval

Meier RK. Polycystic Ovary Syndrome. Nurs Clin North Am. 2018;53(3):407–20. https://doi.org/10.1016/j.cnur.2018.04.008 .

Article   PubMed   Google Scholar  

Louwers YV, Laven JSE. Characteristics of polycystic ovary syndrome throughout life. Ther Adv Reprod Health. 2020;14:2633494120911038. https://doi.org/10.1177/2633494120911038 .

Article   PubMed   PubMed Central   Google Scholar  

Diseases GBD, Injuries C. Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the global burden of disease study 2019. Lancet. 2020;396(10258):1204–22. https://doi.org/10.1016/S0140-6736(20)30925-9 .

Article   Google Scholar  

Vink JM, Sadrzadeh S, Lambalk CB, Boomsma DI. Heritability of polycystic ovary syndrome in a Dutch twin-family study. J Clin Endocrinol Metab. 2006;91(6):2100–4. https://doi.org/10.1210/jc.2005-1494 .

Article   CAS   PubMed   Google Scholar  

Barbieri RL, Sluss PM, Powers RD, McShane PM, Vitonis A, Ginsburg E, Cramer DC. Association of body mass index, age, and cigarette smoking with serum testosterone levels in cycling women undergoing in vitro fertilization. Fertil Steril. 2005;83(2):302–8. https://doi.org/10.1016/j.fertnstert.2004.07.956 .

Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr Rev. 1997;18(6):774–800. https://doi.org/10.1210/edrv.18.6.0318 .

Traub ML. Assessing and treating insulin resistance in women with polycystic ovarian syndrome. World J Diabetes. 2011;2(3):33–40. https://doi.org/10.4239/wjd.v2.i3.33 .

Fortunati N. Sex hormone-binding globulin not only a transport protein What news is around the corner. J Endocrinol Invest. 1999;22(3):223–34. https://doi.org/10.1007/BF03343547 .

Bhatnager R, Senwal A, Nanda S, Dang AS. Association of rs6259 polymorphism with SHBG levels and Poly Cystic Ovary Syndrome in Indian population: a case control study. Mol Biol Rep. 2019;46(2):2131–8. https://doi.org/10.1007/s11033-019-04665-2 .

Schweighofer N, Lerchbaum E, Trummer O, Schwetz V, Pilz S, Pieber TR, Obermayer-Pietsch B. Androgen levels and metabolic parameters are associated with a genetic variant of F13A1 in women with polycystic ovary syndrome. Gene. 2012;504(1):133–9. https://doi.org/10.1016/j.gene.2012.04.050 .

Katan MB. Commentary: mendelian randomization, 18 years on. Int J Epidemiol. 2004;33(1):10–1. https://doi.org/10.1093/ije/dyh023 .

Stukel TA, Fisher ES, Wennberg DE, Alter DA, Gottlieb DJ, Vermeulen MJ. Analysis of observational studies in the presence of treatment selection bias: effects of invasive cardiac management on AMI survival using propensity score and instrumental variable methods. JAMA. 2007;297(3):278–85. https://doi.org/10.1001/jama.297.3.278 .

Article   CAS   PubMed   PubMed Central   Google Scholar  

Davies NM, Holmes MV, Davey SG. Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ. 2018;362:k601. https://doi.org/10.1136/bmj.k601 .

Ruth KS, Day FR, Tyrrell J, Thompson DJ, Wood AR, Mahajan A, Beaumont RN, Wittemans L, Martin S, Busch AS, et al. Using human genetics to understand the disease impacts of testosterone in men and women. Nat Med. 2020;26(2):252–8. https://doi.org/10.1038/s41591-020-0751-5 .

Day F, Karaderi T, Jones MR, Meun C, He C, Drong A, Kraft P, Lin N, Huang H, Broer L, et al. Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria. PLoS Genet. 2018;14(12):e1007813. https://doi.org/10.1371/journal.pgen.1007813 .

Chong M, Sjaarda J, Pigeyre M, Mohammadi-Shemirani P, Lali R, Shoamanesh A, Gerstein HC, Pare G. Novel drug targets for ischemic stroke identified through mendelian randomization analysis of the blood proteome. Circulation. 2019;140(10):819–30. https://doi.org/10.1161/CIRCULATIONAHA.119.040180 .

Lawlor DA, Harbord RM, Sterne JA, Timpson N, Davey SG. Mendelian randomization: using genes as instruments for making causal inferences in epidemiology. Stat Med. 2008;27(8):1133–63. https://doi.org/10.1002/sim.3034 .

Burgess S, Butterworth A, Thompson SG. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol. 2013;37(7):658–65. https://doi.org/10.1002/gepi.21758 .

Thompson SG, Sharp SJ. Explaining heterogeneity in meta-analysis: a comparison of methods. Stat Med. 1999;18(20):2693–708. https://doi.org/10.1002/(sici)1097-0258(19991030)18:20%3c2693::aid-sim235%3e3.0.co;2-v .

Bowden J, Davey Smith G, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol. 2015;44(2):512–25. https://doi.org/10.1093/ije/dyv080 .

Bowden J, Davey Smith G, Haycock PC, Burgess S. Consistent estimation in mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol. 2016;40(4):304–14. https://doi.org/10.1002/gepi.21965 .

Burgess S, Scott RA, Timpson NJ, Davey Smith G, Thompson SG, Consortium E-I. Using published data in Mendelian randomization: a blueprint for efficient identification of causal risk factors. Eur J Epidemiol. 2015;30(7):543–52. https://doi.org/10.1007/s10654-015-0011-z .

Wu F, Huang Y, Hu J, Shao Z. Mendelian randomization study of inflammatory bowel disease and bone mineral density. BMC Med. 2020;18(1):312. https://doi.org/10.1186/s12916-020-01778-5 .

Tawfeek MA, Alfadhli EM, Alayoubi AM, El-Beshbishy HA, Habib FA. Sex hormone binding globulin as a valuable biochemical marker in predicting gestational diabetes mellitus. BMC Womens Health. 2017;17(1):18. https://doi.org/10.1186/s12905-017-0373-3 .

Yasui T, Tomita J, Miyatani Y, Yamada M, Uemura H, Irahara M, Arai M, Kojimahara N, Okabe R, Ishii Y, et al. Associations of adiponectin with sex hormone-binding globulin levels in aging male and female populations. Clin Chim Acta. 2007;386(1–2):69–75. https://doi.org/10.1016/j.cca.2007.08.001 .

Zhu Q, Zhou H, Zhang A, Gao R, Yang S, Zhao C, Wang Y, Hu J, Goswami R, Gong L, et al. Serum LBP Is Associated with Insulin Resistance in Women with PCOS. PLoS ONE. 2016;11(1):e0145337. https://doi.org/10.1371/journal.pone.0145337 .

Jayagopal V, Kilpatrick ES, Jennings PE, Hepburn DA, Atkin SL. The biological variation of testosterone and sex hormone-binding globulin (SHBG) in polycystic ovarian syndrome: implications for SHBG as a surrogate marker of insulin resistance. J Clin Endocrinol Metab. 2003;88(4):1528–33. https://doi.org/10.1210/jc.2002-020557 .

Sieminska L, Marek B, Kos-Kudla B, Niedziolka D, Kajdaniuk D, Nowak M, Glogowska-Szelag J. Serum adiponectin in women with polycystic ovarian syndrome and its relation to clinical, metabolic and endocrine parameters. J Endocrinol Invest. 2004;27(6):528–34. https://doi.org/10.1007/BF03347474 .

Deswal R, Yadav A, Dang AS. Sex hormone binding globulin - an important biomarker for predicting PCOS risk A systematic review and meta-analysis. Syst Biol Reprod Med. 2018;64(1):12–24. https://doi.org/10.1080/19396368.2017.1410591 .

Cho LW, Jayagopal V, Kilpatrick ES, Holding S, Atkin SL. The LH/FSH ratio has little use in diagnosing polycystic ovarian syndrome. Ann Clin Biochem. 2006;43(Pt 3):217–9. https://doi.org/10.1258/000456306776865188 .

Chang RJ. The reproductive phenotype in polycystic ovary syndrome. Nat Clin Pract Endocrinol Metab. 2007;3(10):688–95. https://doi.org/10.1038/ncpendmet0637 .

Cassar S, Misso ML, Hopkins WG, Shaw CS, Teede HJ, Stepto NK. Insulin resistance in polycystic ovary syndrome: a systematic review and meta-analysis of euglycaemic-hyperinsulinaemic clamp studies. Hum Reprod. 2016;31(11):2619–31. https://doi.org/10.1093/humrep/dew243 .

Chen F, Liao Y, Chen M, Yin H, Chen G, Huang Q, Chen L, Yang X, Zhang W, Wang P, et al. Evaluation of the Efficacy of Sex Hormone-Binding Globulin in Insulin Resistance Assessment Based on HOMA-IR in Patients with PCOS. Reprod Sci. 2021;28(9):2504–13. https://doi.org/10.1007/s43032-021-00535-0 .

Feng C, Jin Z, Chi X, Zhang B, Wang X, Sun L, Fan J, Sun Q, Zhang X. SHBG expression is correlated with PI3K/AKT pathway activity in a cellular model of human insulin resistance. Gynecol Endocrinol. 2018;34(7):567–73. https://doi.org/10.1080/09513590.2017.1411474 .

Laitinen J, Taponen S, Martikainen H, Pouta A, Millwood I, Hartikainen AL, Ruokonen A, Sovio U, McCarthy MI, Franks S, et al. Body size from birth to adulthood as a predictor of self-reported polycystic ovary syndrome symptoms. Int J Obes Relat Metab Disord. 2003;27(6):710–5. https://doi.org/10.1038/sj.ijo.0802301 .

Yasmin E, Balen AH, Barth JH. The association of body mass index and biochemical hyperandrogenaemia in women with and without polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol. 2013;166(2):173–7. https://doi.org/10.1016/j.ejogrb.2012.09.025 .

Day FR, Hinds DA, Tung JY, Stolk L, Styrkarsdottir U, Saxena R, Bjonnes A, Broer L, Dunger DB, Halldorsson BV, et al. Causal mechanisms and balancing selection inferred from genetic associations with polycystic ovary syndrome. Nat Commun. 2015;6:8464. https://doi.org/10.1038/ncomms9464 .

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The author sincerely thanks the researchers and participants of the original GWAS for their collection and management of large-scale data resources, as well as those who actively participated in this study.

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XFG and SX performed the literature review, conducted data analysis, interpreted findings, and drafted the manuscript. LLC, JHH and XZZ carried on data analysis and interpreted findings. XFG, LLC and SX mainly conducted on the data collation and checked the manuscript. XFG and SX directed analytic strategy, supervised the study from conception to completion and revised drafts of the manuscript. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work to take public responsibility for appropriate portions of the content and agreed to be accountable for all aspects of the work in ensuring that questions related to its accuracy or integrity.

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Guo, X., Chen, L., He, J. et al. Genetically predicted high sex hormone binding globulin was associated with decreased risk of polycystic ovary syndrome. BMC Women's Health 24 , 357 (2024). https://doi.org/10.1186/s12905-024-03144-6

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4 Methodologic Issues in Women’s Health Research

In reviewing and evaluating research on women’s health, the committee considered not only conditions 1 and health determinants but also the types of research conducted. This chapter addresses methodologic issues with respect to women’s health, looking at study design, subject sampling, outcome measures, and analysis. The Women’s Health Initiative (WHI) is then discussed as an example of what has been learned about methods of women’s health research from the studies already conducted. The information in this chapter helps the committee address question 4 from Box 1-4 , whether the most appropriate research methods are being used to study women’s health.

• STUDY DESIGN

Research can be conducted on molecules, cells, and animals (basic research); on individuals or populations (clinical or observational studies); and on health systems (health-services and health-policy research). Each type of study has strengths and weaknesses, and progress generally requires congruence of evidence from multiple studies of different designs. For example, progress in breast and cervical cancer came through basic and experimental clinical research and other epidemiologic studies that provided support for similar conclusions (see Chapters 2 and 3 ).

Two major types of clinical studies are observational studies and clinical trials. An observational study is a study in which investigators do not manipulate the use of or deliver an intervention (that is, they do not assign subjects to treatment and control groups) but only observe and measure outcomes in subjects who are (or are not, in the case of a comparison group) exposed to an intervention (for example, a smoking ban that decreases secondhand smoke exposure) (Rosenbaum, 2002). Such studies have less control of potential confounders than do experimental studies, such as randomized controlled trials, and are more prone to selection bias and to bias in the choice of comparison populations. Observational studies provide information for identifying associations and are especially useful for generating hypotheses for further testing; they are less useful for determining causality. The Nurses’ Health Study (NHS) and the Study of Women’s Health Across the Nation (SWAN) are examples of large observational studies. The NHS was originally intended to investigate the potential long-term consequences of oral contraceptives and later adapted to investigate factors that influence women’s health, especially in preventing cancer (NHS, 2008). SWAN was designed to collect information on the natural history of menopause (SWAN, 2010).

A randomized clinical trial is a prospective experiment in which investigators assign an eligible sample of people randomly to one or more treatment groups and a control group and follow subjects’ outcomes. Randomized clinical trials are usually considered the best for testing the efficacy of a treatment or intervention (Rosenbaum, 2002). The Women’s Health Study (WHS) was a randomized clinical trial in which the interventions were aspirin and vitamin E (WHS, 2009). The WHI consisted of both an observational study and three blinded, randomized clinical trial components that had hormone therapy, calcium and vitamin D, or dietary and exercise modification as the interventions (WHI, 2010). The randomized clinical trial in the WHI identified a risk of heart disease to be associated with combination estrogen hormone therapy, which was previously thought to be cardioprotective, and it confirmed the risk of breast cancer, venous thromboembolism, and stroke. Confidence in those results facilitated a decision to halt the study and led to a rapid change in prescribing practices (WHI, 2010).

Randomized clinical trials, however, have limitations of their own. Because of the expense and number of subjects needed to assess a given drug or other treatment, it is not possible to change key variables. The ability to extrapolate the results to a larger population might also be limited (Rosenbaum, 2002). In addition, ethical and practical considerations of the studies, including the ethics of placebo controls, need to be taken into account.

• SUBJECT SAMPLING

If study results are to be extrapolated to the general population, the research sample needs to reflect the general population. Ensuring that research can be applied to the general population requires more than simply incorporating members of a subpopulation as part of the overall sample; it requires adequate numbers to ensure the statistical power to evaluate effects in that subpopulation. It is important to note that using gender or sex as a control variable is not the same as examining the effects of gender or sex on a given outcome. Thus, the issue is not simply including women in trials but including sufficient numbers to test effects on both women and men. To be fully informative, findings need to be reported separately by sex or gender. If a subpopulation, such as women in this case, is excluded or underrepresented in the sample, it is difficult to know whether the results will apply to the subpopulation or whether it would have responded differently. For example, that lack of data can delay translation of research findings on effective treatments to the excluded or underrepresented subpopulation or can lead to adverse outcomes because of inappropriate application to one population of treatments developed on another.

It might seem obvious that poor clinical outcomes can occur if it is presumed that there are no sex or gender differences when they do exist, but false inferences and bad outcomes can also result from a presumption of sex or gender differences when such differences do not exist (Baumeister, 1988). For example, the first randomized clinical trial of estrogen therapy, the Coronary Drug Project, was done in men. That study was discontinued prematurely because of a lack of evidence of a positive effect and a trend toward increased cardiovascular mortality in the treated group (The Coronary Drug Project Research Group, 1973). The doses in the trial were much higher than those given to women, so the results were thought not to be relevant to women, and estrogen therapy continued to be prescribed to women to reduce cardiovascular risks. More than 20 years after the study, postmenopausal hormones were still among the top-selling drugs in the United States—an estimated 15 million women were taking them (Hersh et al., 2004). Conversely, statins (that is, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) were first shown to be effective in lowering cholesterol in a Scottish trial in men (Shepherd et al., 1995). Of 5 randomized controlled trials published in 1994–1998, the Scottish trial was in men only, and the other 4 included 14–19% women. That small number of women in statin trials limited conclusions for women and led to questions about the extrapolation of the data to women. LaRosa and colleagues (1999) conducted a meta-analysis of data from those trials and concluded that the risk reduction from statins is similar in men and women. 2 Meta-analyses, however, are not optimal, especially when evaluating the leading cause of mortality in women, and more recently the efficacy and safety of statins, especially for primary prevention, has been questioned and is still being evaluated (Abramson and Wright, 2007; Mascitelli and Pezzetta, 2007; McPherson and Kavaslar, 2007; Ridker, 2010).

Before 1987, women were underrepresented in key randomized controlled trials because of policies that limited or prevented their participation mainly owing to concern about potential exposures of fetuses. Changes in National In stitutes of Health (NIH) and Food and Drug Administration (FDA) regulations and policies, starting in 1987, addressed that underrepresentation and aimed to increase the enrollment of women and analysis of data on women in clinical trials (GAO, 1992, 2000; Merkatz and Junod, 1994). Progress has been made since then in increasing enrollment of women. Women made up 51.7% and 60.0% of participants in NIH extramural and intramural clinical research in 1995 and 2008, respectively (HHS, 2009). The highest percentage, 64.2%, was seen in 2002; that corresponds to when large women-only studies related to breast cancer, menopause, and cardiovascular diseases (the WHS, the WHI, and SWAN) were conducted (HHS, 2009). The sex distribution in all the minority-group participants in 2008 was similar to that in the nonminority population; women made up 59.15% of minority-group participants (HHS, 2009). 3

Data from clinical trials that looked at specific end points have provided additional insight into the participation of women and minorities. A recent analysis of FDA clinical trials found that although the number of trials enrolling women and the proportion of participants who are female participating in phase I trials have increased since 2001, women are still underrepresented (Pinnow et al., 2009). Stewart and colleagues (2007) found higher enrollments of women than of men in their study of cooperative group surgical oncology trials, primarily because of the large number of breast-cancer trials. Members of racial and ethnic minorities and older persons were less likely to be enrolled in the trials than were whites and younger subjects.

Human immunodeficiency virus (HIV) research historically has had low representation of women. Of the women who were eligible to participate in the largest cohort study of HIV-infected women in the United States (the Women’s Interagency HIV Study), about half would have been ineligible, on the basis of exclusion criteria, to participate in 20 of the AIDS Clinical Trials Group studies, which are among the largest HIV clinical-trial groups in the United States (Gandhi et al., 2005). Those results are consistent with an earlier meta-analysis published in abstract form that found that in 49 randomized controlled trials of antiretrovirals in 1990–2000, women averaged only 12.25% of the participants (Pardo et al., 2002).

In studies of cardiovascular disease, clinical-trial subjects have not been representative of the general population (Lloyd-Jones et al., 2001; Pedone and Lapane, 2003); one study discussed the predominance of men in cardiovascular trials (Sharpe, 2002). In 19 randomized controlled trials open to both men and women that examined myocardial infarction, stroke, or death, the mean percentage of female subjects was only 27%. 4 Only 13 of those studies presented sex-based analyses (Kim and Menon, 2009). A review of the literature by the Agency for Healthcare Research and Quality indicated that studies of coronary heart disease rarely included women in adequate numbers for analysis of the data by sex (Grady et al., 2003).

Part of the reason for the low participation of women is that many cardiovascular-disease clinical trials had inclusion criteria that were more appropriate for men than for women (Grady et al., 2003). Such inclusion criteria as early age of onset of myocardial infarction and chest pain as a presenting symptom will favor enrollment of men because women are on the average older at disease onset, are less likely than men to report chest pain during a heart attack, and are more likely to report other symptoms (Bairey Merz et al., 2006; Canto et al., 2007).

Even when women are included in clinical trials, having too few of them can be a barrier to obtaining statistically significant results related to women. Freedman and colleagues (1995) suggested conducting large clinical trials for conditions in which there is a priori evidence of sex differences. The NIH guidelines require inclusion of women and minorities in phase III clinical trials unless there is substantial evidence that sex differences do not exist (Bennett and the Board on Health Sciences Policy of the Institute of Medicine, 1993; Freedman et al., 1995). That implies that earlier research—including cells, animals, and phase I and II clinical trials—must have addressed potential sex differences sufficiently to support a choice not to include women in phase III clinical trials in numbers adequate for assessing sex differences. Underrepresentation of women in earlier phases could lead to interventions or treatments that are less effective or more toxic in women. For example, dose regimens are determined in phase I clinical trials, and conducting such studies mostly in men would result in drug doses based on male anatomy (Chen et al., 2000). Data indicate that women continue to be underrepresented in trials. For example, Jagsi (2009) found that women comprised only 38.8% of participants in non–sex-specific prospective clinical studies.

Because women might not be included in studies in adequate numbers to obtain a valid statistical analysis, another potential method of obtaining useful data on women is to perform meta-analysis of aggregated published data. That, however, requires that multiple studies be sufficiently similar in design (for example, having similar inclusion criteria and dosing regimens) and in clinical outcomes to be aggregated and also that the studies provide data on women separately (Berlin and Ellenberg, 2009). However, most clinical trials do not publish results on key subgroups of interest. Even when results on subgroups are published, the data are typically presented in different ways among studies and difficult to combine in a meta-analysis (Berlin and Ellenberg, 2009).

Combining data on individual subjects from randomized trials is another approach for enhancing statistical power that increases the number of subjects available for analysis in clinical subgroups. Pooling of data on individual subjects overcomes the limitations of meta-analysis and allows use of more sensitive statistical methods, including analysis of survival times, multivariable models, and tests for treatment-by-covariate interactions (Samsa et al., 2005). It also enables the assessment of the combined effect of treatment for multiple end points—combining benefits and risks to capture net “value” (Antithrombotic Trialists Collaboration, 2009). However, the technique poses logistical challenges and requires collaboration among trial groups and support from funding agencies (Bravata et al., 2007).

A Bayesian approach could also be used to determine whether sex or gender differences exist, and that information could form the basis of further research. The Bayesian approach is an iterative one that adds more subjects from a subgroup on the basis of probabilities estimated from previous or preliminary results (Berry, 2006). In Bayesian analysis, the effect in a small number of women could be compared with the effect in a larger sample of men (or vice versa). If the distribution of results for several outcomes is the same between the sexes or genders, the study can proceed and continue to include a small number of women and to conduct periodic analyses to determine whether sex or gender differences are evident. If the distributions are different, the next phase of the clinical trial would incorporate larger numbers of women to assess the differences. This method could be applied to individual and pooled trials.

An alternative to executing clinical trials with women and men and analyzing sex- or gender-specific data is to conduct women-only studies, particularly in cases in which there are gaps in knowledge about women. That has been done in a few men-only studies that demonstrated the benefit of a drug. For example, the original Physicians Health Study was a randomized controlled trial in men that found that daily aspirin led to a significant reduction in myocardial infarction but not in cardiovascular death (Hennekens and Buring, 1989; Hennekens and Eberlein, 1985). It was not known whether the results would be the same in women. Later the women-only WHS had slightly different results: daily aspirin lowered the risk of stroke but did not affect the risk of myocardial infarction or cardiovascular death (Ridker et al., 2005). Sex differences were then examined in a study that pooled individual-level data from 6 primary-prevention randomized trials and 16 secondary-prevention randomized trials (looking for prevention after a coronary event), including both the sex-specific trials discussed above. No sex differences in the effect of aspirin on overall serious cardiovascular events were seen, and the risk of cardiovascular events was reduced in both men and women. However, there were slight sex differences in aspirin’s value in primary prevention (depending on the statistical analysis): less primary prevention of major coronary events and more primary prevention of strokes were seen in women than in men. No sex differences were seen in secondary prevention of either end point—aspirin was protective in both sexes (Antithrombotic Trialists Collaboration, 2009). Overall, the authors concluded that aspirin is beneficial for protecting against secondary events in both women and men but that protection against primary events needs to be weighed against the risks posed by daily aspirin for both sexes.

• OUTCOME MEASURES

Female-Appropriate End Points

Sex and gender differences need to be considered not only for inclusion and exclusion criteria but also when determining the end points to be studied. If study end points are based on male pathophysiology, clinical outcomes relevant to women will be missed. For example, women are more likely to have unstable angina (DeCara, 2003), unrecognized myocardial infarction (Sheifer et al., 2001), and stroke as cardiovascular outcomes than men (Lloyd-Jones et al., 2009; Tow-fighi et al., 2007). If a clinical trial looking at a cardiovascular-disease treatment assesses fatal and nonfatal myocardial infarction as its outcome but does not assess such events as unstable angina that are more common in women, it will underestimate the prevalence of cardiovascular disease in women and be biased against finding a treatment effect in women.

Quality of Life as an End Point

Incidence and 5-year survival rates are often the end points evaluated in clinical trials, including studies of women’s health; fewer studies assess morbidity or health-related quality-of-life (HRQoL) end points. The focus of research on mortality is also reflected in the relative lack of attention paid to conditions associated more closely with morbidity than with mortality, such as autoimmune disease, thyroid disease, and nonmalignant gynecologic disorders. Many of those chronic disabling disorders and depressive and anxiety disorders affect women more than men (Rieker and Bird, 2005), and women, when surveyed, generally report worse health than men even though men have shorter life expectancy and lower age of onset of such diseases as cardiovascular disease (Rieker and Bird, 2005). In addition, women rank quality-of-life end points high when considering what aspects of health matter to them, and this points to the need to assess HRQoL end points in women (Fryback et al., 2007).

One challenge in including HRQoL end points in studies is the need for consistent and accurate metrics for them. In particular for women’s health, including metrics that measure what matters to women is important. Metrics for HRQoL end points have been developed as interest in assessing them in observational studies, clinical trials, and health-services research has increased. Measures of HRQoL end points can reflect specific symptoms, constellations of symptoms associated with specific conditions, or the combined effects on overall well-being that reflect symptoms that affect HRQoL (that is, quantify a global measure of quality of life) (Gold et al., 2002). HRQoL metrics, such as the SF-36 , which is a short-form health survey with 36 questions, quantify quality of life in terms of domains (for example, physical, psychologic, economic, spiritual, and social) and allow comparisons among conditions, but some may lack sensitivity to sex- and gender-specific issues (such as menopause and premenstrual-syndrome symptoms), and some are affected by sex and gender (Fleishman and Lawrence, 2003). Research is beginning to identify and improve understanding of those differences to capture quality-of-life end points for women better (Fryback et al., 2007). Improved measures of HRQoL in women will help not only in assessing women’s health but in communicating risks and benefits associated with treatment and intervention options to women and to facilitate informed decision making for female patients—an important aspect of translating research into practice, which is discussed further in Chapter 5 .

Including adequate numbers of women in clinical trials is necessary but not sufficient to ensure that results are applicable to women. Despite improved inclusion of women in trials funded by NIH and reviewed by FDA, there has been a lag in the routine analysis and reporting of data by sex (GAO, 2000, 2001). Often there is no mention of separate male and female analysis in publications, and it is not possible to know whether an analysis by sex was not conducted or was conducted but not reported, especially inasmuch as negative findings are often not reported. Many trials are designed to test an intervention, not to test whether the intervention is safe and effective in both men and women.

Another consideration is that the volume of health-research data is expanding, and new initiatives are underway to capture those data. The initiatives include developing a health-information-technology infrastructure and large databases, including the i2b2, the Cancer Biomedical Informatics Grid, improvement in the Medicare and Medicaid claims databases, and use of distributed data networks for an FDA sentinel system to detect adverse drug events (Bach et al., 2002; Kakazu et al., 2004; Murphy et al., 2006; Platt et al., 2009). If those technologies are to achieve their full potential in improving women’s health, the ability to capture and analyze sex- and gender-specific data needs to be considered during the design of such systems (Brittle and Bird, 2007; McKinley et al., 2002; Weisman, 2000). Additionally, data relevant to women’s health needs to be captured better in health-services research (for example, by using metrics of care quality specific to women) so that there can be more accurate measures of the translation of research findings into health-care services and delivery (Chou et al., 2007a,b; Correa-de-Araujo, 2004; NCQA, 2010).

METHODOLOGIC LESSONS FROM THE WOMEN’S HEALTH INITIATIVE

Much has been learned from the WHI about how to design women’s health research (see Appendix C for details of this study). The WHI, which is the largest clinical study done exclusively on women, was designed as a study of primary prevention of diseases of aging (coronary heart disease, breast and colorectal cancer, and hip and other fractures), but it also assessed other end points (stroke, venous and pulmonary emboli, ovarian and endometrial cancer, gall bladder disease, cognition, and death). A global index was developed as a summary measure of the effect of treatment for potentially life-threatening events (Resnick et al., 2006, 2009). The WHI consisted of an observational study that was designed to identify predictors of disease in women and a clinical trial that consisted of three randomized components (Anderson et al., 2003):

trials that evaluated the effects of the postmenopausal hormone therapy, conjugated equine estrogen (Premarin™) on heart disease, fractures, and breast and colorectal cancer in 10,739 postmenopausal women who did not have uteruses, or conjugated equine estrogen plus medroxyprogesterone (Prempro™) in 16,608 postmenopausal omen who had uteruses;

a trial that assessed whether a calcium and vitamin D supplement reduces the risk of colorectal cancer and the frequency of hip and other fractures in over 36,000 postmenopausal women; and

a trial that assessed the effects of a diet low in fat and high in fruits, vegetables, and grains on breast cancer, colorectal cancer, and heart disease in almost 49,000 postmenopausal women.

The hormone-therapy component of the WHI was initiated to assess the risks and benefits associated with menopausal hormone therapy (estrogen or estrogen plus progestin) and to help to settle controversies about the efficacy of those therapies in preventing cardiovascular disease (HHS, 2010). Basic research had suggested a cardioprotective effect of estrogen in animals (Gerhard-Herman et al., 2000); data from individual studies and pooled data from observational studies, such as the NHS, found a significantly lower risk of coronary heart disease in postmenopausal women who were on estrogen alone (Barrett-Connor and Grady, 1998; Grady et al., 1992; Grodstein et al., 1996, 2000; Stampfer and Colditz, 1991); and data from a randomized controlled trial (the Postmenopausal Estrogen/Progestin Interventions [PEPI]) that examined intermediate end points (lipid profiles) as proxies for coronary heart disease found a somewhat beneficial effect of PEPI (reducing low-density–lipoprotein cholesterol and increasing high-density–lipoprotein cholesterol by 10–15%) (Espeland et al., 1998). The NHS specifically showed decreased rates of coronary heart disease and of death from cardiovascular disease, but no effect on the rate of stroke, with estrogen therapy (Stampfer et al., 1991). At the time, hormone therapy was routinely prescribed from menopause on, and many thought it likely that the WHI would be halted prematurely because the beneficial effects of such therapy on cardiovascular disease would be demonstrated early in the study (IOM, 1993).

At the same time, however, other randomized controlled trials—such as the Heart and Estrogen/Progestin Replacement Study (HERS), which examined heart attacks and death from coronary heart disease (Herrington et al., 2000), and the Estrogen Replacement and Atherosclerosis (ERA) study, which examined lipid concentrations, angiographic end points, and cardiovascular events—did not show that estrogen plus progestin prevented further heart attacks or death from coronary heart disease in postmenopausal women who had heart disease and, in the case of HERS, actually resulted in a higher rate of coronary heart disease soon after initiation of treatment (Grady et al., 2000; Herrington et al., 2000; Hulley et al., 1998). Earlier, the Framingham Study, the only prospective observational study designed specifically to measure coronary–heart-disease end points, did not show beneficial effects of estrogen on mortality from all causes or from cardiovascular disease (Wilson et al., 1985). The Framingham Study differed from other observational studies in its inclusion of angina and systematic ascertainment of silent myocardial infarction through routine electrocardiography. Those examples highlight the importance of including study end points that reflect both female and male physiology. It is noteworthy that the observational studies showed effects similar to those in the WHI of both hormone treatments for disease outcomes other than cardiovascular disease (that is, breast, colorectal, and endometrial cancer; stroke; and venous thromboembolism) (WHI, 2010).

Because the WHI was a large, randomized controlled trial that looked at multiple end points, it provided more definitive results than the previous conflicting findings. That design helped to detect an increased risk of stroke and a lack of effect (increase or decrease) on heart disease in the estrogen-only portion of the WHI, and it enabled scientific confidence in those results (Anderson et al., 2004). That led to the halting of the studies for safety reasons (HHS, 2004).

The conflicting results on coronary heart disease in the NHS and the WHI led to exploration of new statistical methods to adjust for potential confounders in the use of nonrandomized observational data. One method, the use of propensity scores, was able to replicate the WHI’s findings on coronary heart disease better when applied to the observational data (Hernán et al., 2008; Tannen et al., 2007).

The WHI illustrates the utility of developing a composite score to assess benefits and risks together and among diseases. The WHI’s “global index” gave equal weight to the effects of hormone therapy on specific monitored outcomes— coronary heart disease, stroke, pulmonary embolism, breast and colorectal cancer, hip fractures, and death. It was helpful in understanding the net effect of hormone therapy on those clinical outcomes. One limitation of the index, however, is in making decisions about treatment for menopause symptoms. The index does not include the effect of hormone therapy on menopausal symptoms, because the hormone-therapy component of the WHI was designed to evaluate effects on diseases of aging, not on menopause symptoms. The index also did not include dementia, urinary incontinence, and other end points that might affect treatment decisions. To be most useful for treatment decisions, a global measure of net effect should include all clinically relevant end points, especially those of greatest importance to women. The end points need to be weighted (either equally or differently) in an index; this can be done by using analytic decision models in which end points can be weighted implicitly according to their likelihood of occurrence, effect on mortality, and effect on HRQoL. The WHI recruited a large number of older, postmenopausal women and was relatively successful in meeting not only its overall recruitment goals but also its recruitment goals for minority women (Hays et al., 2003), and lessons can be learned from its recruitment strategies (Limacher, 2003). In addition, the lack of information on the social roles of the women in the WHI (for example, marital history) limits the ability to assess barriers to behavioral change, especially for the dietary arm.

The WHI also pointed to the importance of considering the timing and duration of treatment in observational studies. Some researchers pointed to the treatment of older postmenopausal women and questioned the generalizability of the findings to women who take hormone therapy at earlier stages for menopausal symptoms (Harman et al., 2004). A reanalysis of the data from the NHS demonstrated the importance of accounting for age, timing and duration of treatment, and the onset of adverse events in observational studies, with the reanalysis yielding results for the NHS closer to WHI than originally reported (Hernán et al., 2008). That reanalysis generated some controversy (Stampfer, 2008), but does point to the importance of timing issues in studies and the potential for novel analytical techniques to shed light on study differences (Hernán and Robins, 2008; Hernán et al., 2008; Hoover, 2008; Prentice, 2008; Wilcox and Wacholder, 2008; Willet et al., 2008).

There are several lessons to be learned regarding methodologic and statistical approaches to women’s health research. Etiology and risk factors can be investigated with well-designed and well-executed observational studies that measure and adjust for known confounders, ensure appropriate ascertainment of end points (especially coronary heart disease, whose ascertainment is more challenging), and use appropriate statistical techniques to analyze data. Caution needs to be exercised in extrapolating from studies that use biomarkers rather than clinical outcomes. In using biomarkers for clinical outcomes, it is crucial that the measures selected be relevant to women, especially in clinical studies that involve both women and men. For example, the results of observational studies that reported on the effect of hormone therapy on lipids were interpreted as proxy evidence of their effect on coronary–heart-disease end points, but this was not confirmed or supported in randomized controlled trials that examined these end points.

Single-sex studies like the WHI can provide valuable information and fill in research gaps—especially in, for example, coronary heart disease—in clinical trials where women have been underrepresented. Most clinical trials, however, now include both women and men, and it will be critical to develop new methods and approaches to analysis of data by subgroup. After many years, the analysis of data by sex is still inadequate, and it is unclear whether adequate numbers of women are being enrolled in clinical trials to allow adequate analysis (GAO, 2000, 2001).

The limitations of randomized controlled trials, such as expense and the number of subjects needed, are reflected in questions that arose regarding the randomized controlled trials of the WHI. One question was related to the choice of hormone therapy—conjugated equine estrogen with progestin (Prempro™) and without progestin (Premarin™). Conjugated equine estrogen is a complex compound, and it is not known whether these results would apply to estradiol alone. It is also not known whether other routes of administration—dermal or intranasal—would have produced different results or whether different types of progestin would have different effects on coronary heart disease.

• CONCLUSIONS
• Women need to be considered in the design, inclusion and exclusion criteria, recruitment, outcome measures, and analysis of research. Adequate numbers of women need to be enrolled in studies to allow statistically significant sex-based analyses, study outcomes need to include symptoms and effects seen in women, analyses need to be conducted to determine sex or gender differences, and the results of the analyses need to be published. A number of design and analytic techniques can be explored to improve sex-specific analyses while limiting the increase in sample size.
• Much research focuses on improving disease survival; insufficient attention has been paid to improving disease-related morbidity (for example, autoimmune diseases that affect a large number of women and the health effects that follow breast-cancer treatment and recovery) and especially to wellness and quality of life as health outcomes.
• RECOMMENDATIONS
• Basic research should include analysis of effects in females. Information from this basic research can guide the focus of sex and gender differences in clinical studies.
• Sex and gender differences in the manifestation of disease should be considered in the design of research to incorporate the spectrum of outcomes that are relevant to women. Government and other funding agencies should ensure adequate participation of women and reporting of sex-stratified analyses in health research. One possible mechanism would be to expand the role of data-safety monitoring boards to monitor participation, efficacy, and adverse outcomes by sex.
• Given the practical limitations in the size of research studies, research designs and statistical techniques that facilitate analysis of data on subgroups—without substantially increasing the overall size of a study population—should be explored. Conferences or meetings with a specific goal of developing consensus guidelines or recommendations on such study methods (for example, the use of Bayesian statistics and the pooling of data across study groups) should be convened by NIH and other federal agencies and relevant professional organizations.
• To gain knowledge from existing studies that individually do not have sufficient numbers of female subjects for separate analysis, the director of the Department of Health and Human Services Office of the National Coordinator for Health Information Technology should support development and application of mechanisms for pooling patient and subject data to answer research questions that are not definitively answered by single studies.
• For approval of medical products (drugs, devices, and biologics) coming to market, FDA should enforce compliance with the requirement for sex-stratified analyses of efficacy and safety and should take these analyses into account in regulatory decisions.
• When it is possible, analysis of clinical research should be stratified by sex and should include power calculations to prevent type II errors in interpretation that might lead to withholding of therapy from women.
• The International Committee of Medical Journal Editors and editors of relevant journals not represented on that committee should adopt as a guideline that all papers that report the outcomes of clinical trials report outcomes in men and women separately except for trials involving sex-specific conditions (such as endometrial cancer and prostatic cancer). NIH should sponsor a meeting to facilitate establishment of such guidelines.
• The federal government should ensure that a data infrastructure is designed to capture data in forms that facilitate its analysis by sex and gender.
• Research should be conducted on women’s quality of life, including the development of better measures to compare effects not only of health conditions but of interventions and treatments on quality of life. The end points or outcomes examined in studies should include quality-of-life outcomes (for example, functional status, mobility, and pain) in addition to mortality.
• Abramson, J., and J. M. Wright. 2007. Are lipid-lowering guidelines evidence-based? Lancet 369(9557):168–169. [ PubMed : 17240267 ]
• Anderson, G., J. Manson, R. Wallace, B. Lund, D. Hall, S. Davis, S. Shumaker, C. Y. Wang, E. Stein, and R. L. Prentice. 2003. Implementation of the women’s health initiative study design . Annals of Epidemiology 13(9 Suppl.):S5–S17. [ PubMed : 14575938 ]
• Anderson, G., M. Limacher, A. Assaf, T. Bassford, S. Beresford, H. Black, D. Bonds, R. Brunner, R. Brzyski, B. Caan, R. Chlebowski, D. Curb, M. Gass, J. Hays, G. Heiss, S. Hendrix, B. Howard, J. Hsia, A. Hubbell, R. Jackson, K. Johnson, H. Judd, J. Kotchen, L. Kuller, A. LaCroix, D. Lane, R. Langer, N. Lasser, C. Lewis, J. Manson, K. Margolis, J. Ockene, M. O’Sullivan, L. Phillips, R. Prentice, C. Ritenbaugh, J. Robbins, J. Rossouw, G. Sarto, M. Stefanick, L. Van Horn, J. Wactawski-Wende, R. Wallace, and S. Wassertheil-Smoller. 2004. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: The women’s health initiative randomized controlled trial . Journal of the American Medical Association 291(14):1701–1712. [ PubMed : 15082697 ]
• Antithrombotic Trialists Collaboration. 2009. Aspirin in the primary and secondary prevention of vascular disease: Collaborative meta-analysis of individual participant data from randomised trials . Lancet 373(9678):1849–1860. [ PMC free article : PMC2715005 ] [ PubMed : 19482214 ]
• Bach, P. B., E. Guadagnoli, D. Schrag, N. Schussler, and J. L. Warren. 2002. Patient demographic and socioeconomic characteristics in the SEER-Medicare database applications and limitations . Medical Care 40(8 Suppl.):IV19–IV25. [ PubMed : 12187164 ]
• Bairey Merz, C. N., L. J. Shaw, S. E. Reis, V. Bittner, S. F. Kelsey, M. Olson, B. D. Johnson, C. J. Pepine, S. Mankad, B. L. Sharaf, W. J. Rogers, G. M. Pohost, A. Lerman, A. A. Quyyumi, and G. Sopko. 2006. Insights from the NHLBI-sponsored Women’s Ischemia Syndrome Evaluation (WISE) study: Part II: Gender differences in presentation, diagnosis, and outcome with regard to gender-based pathophysiology of atherosclerosis and macrovascular and microvascular coronary disease . Journal of the American College of Cardiology 47(3 Suppl.):S21–S29. [ PubMed : 16458167 ]
• Barrett-Connor, E., and D. Grady. 1998. Hormone replacement therapy, heart disease, and other considerations . Annual Review of Public Health 19:55–72. [ PubMed : 9611612 ]
• Baumeister, R. F. 1988. Should we stop studying sex differences altogether? [editorial]. American Psychologist 43:1092–1095.
• Bennett, J. C., and the Board on Health Sciences Policy of the Institute of Medicine. 1993. Inclusion of women in clinical trials—policies for population subgroups . New England Journal of Medicine 329(4):288–292. [ PubMed : 8316288 ]
• Berlin, J. A., and S. S. Ellenberg. 2009. Inclusion of women in clinical trials . BMC Medicine 7:56. [ PMC free article : PMC2763864 ] [ PubMed : 19818115 ]
• Berry, D. A. 2006. Bayesian clinical trials . Nature Reviews Drug Discovery 5(1):27–36. [ PubMed : 16485344 ]
• Bravata, D. M., A. L. Gienger, K. M. McDonald, V. Sundaram, M. V. Perez, R. Varghese, J. R. Kapoor, R. Ardehali, D. K. Owens, and M. A. Hlatky. 2007. Systematic review: The comparative effectiveness of percutaneous coronary interventions and coronary artery bypass graft surgery . Annals of Internal Medicine 147(10):703–716. [ PubMed : 17938385 ]
• Brittle, C., and C. E. Bird. 2007. Literature Review on Effective Sex- and Gender-Based Systems/Mod els of Care . Arlington, VA: Uncommon Insights.
• Canto, J. G., R. J. Goldberg, M. M. Hand, R. O. Bonow, G. Sopko, C. J. Pepine, and T. Long. 2007. Symptom presentation of women with acute coronary syndromes: Myth vs reality . Archives of Internal Medicine 167(22):2405–2413. [ PubMed : 18071161 ]
• Chen, M. L., S. C. Lee, M. J. Ng, D. J. Schuirmann, L. J. Lesko, and R. L. Williams. 2000. Pharmacokinetic analysis of bioequivalence trials: Implications for sex-related issues in clinical pharmacology and biopharmaceutics . Clinical Pharmacology and Therapeutics 68(5):510–521. [ PubMed : 11103754 ]
• Chou, A. F., S. H. Scholle, C. S. Weisman, A. S. Bierman, R. Correa-de-Araujo, and L. Mosca. 2007. a. Gender disparities in the quality of cardiovascular disease care in private managed care plans . Women’s Health Issues 17(3):120–130. [ PubMed : 17448685 ]
• Chou, A. F., L. Wong, C. S. Weisman, S. Chan, A. S. Bierman, R. Correa-de-Araujo, and S. H. Scholle. 2007. b. Gender disparities in cardiovascular disease care among commercial and medicare managed care plans . Women’s Health Issues 17(3):139–149. [ PubMed : 17481918 ]
• The Coronary Drug Project Research Group. 1973. The Coronary Drug Project: Findings leading to discontinuation of the 2.5-mg/day estrogen group . Journal of the American Medical Associa tion 226(6):652–657. [ PubMed : 4356847 ]
• Correa-de-Araujo, R. 2004. A wake-up call to advance women’s health . Women’s Health Issues 14(2):31–34. [ PubMed : 15120412 ]
• DeCara, J. M. 2003. Noninvasive cardiac testing in women . Journal of the American Medical Women’s Association 58(4):254–263. [ PubMed : 14640257 ]
• Espeland, M. A., S. M. Marcovina, V. Miller, P. D. Wood, C. Wasilauskas, R. Sherwin, H. Schrott, and T. L. Bush. 1998. Effect of postmenopausal hormone therapy on lipoprotein(a) concentration. PEPI investigators. Postmenopausal estrogen/progestin interventions . Circulation 97(10): 979–986. [ PubMed : 9529266 ]
• Fleishman, J. A., and W. F. Lawrence. 2003. Demographic variation in SF-12 scores: True differences or differential item functioning? Medical Care 41(7 Suppl.):III75–III86. [ PubMed : 12865729 ]
• Freedman, L. S., R. Simon, M. A. Foulkes, L. Friedman, N. L. Geller, D. J. Gordon, and R. Mowery. 1995. Inclusion of women and minorities in clinical trials and the NIH revitalization act of 1993—the perspective of NIH clinical trialists . Controlled Clinical Trials 16(5):277–285; discussion 286,–289, 293–309. [ PubMed : 8582146 ]
• Fryback, D. G., N. C. Dunham, M. Palta, J. Hanmer, J. Buechner, D. Cherepanov, S. A. Herrington, R. D. Hays, R. M. Kaplan, T. G. Ganiats, D. Feeny, and P. Kind. 2007. US norms for six generic health-related quality-of-life indexes from the National Health Measurement Study . Medical Care 45(12):1162–1170. [ PMC free article : PMC2647803 ] [ PubMed : 18007166 ]
• Gandhi, M., N. Ameli, P. Bacchetti, G. B. Sharp, A. L. French, M. Young, S. J. Gange, K. Anastos, S. Holman, A. Levine, and R. M. Greenblatt. 2005. Eligibility criteria for HIV clinical trials and generalizability of results: The gap between published reports and study protocols . AIDS 19(16):1885–1896. [ PubMed : 16227797 ]
• GAO (General Acounting Office). 1992. Women’s Health: FDA Needs to Ensure More Study of Gen der Differences in Prescription Drug Testing: Report to Congressional Requesters. Washington, DC: GAO.
• ———. 2000. Women’s Health: NIH Has Increased Its Efforts to Include Women in Research: Report to Congressional Requesters . Washington, DC: GAO.
• ———. 2001. Women’s Health: Women Sufficiently Represented in New Drug Testing, but FDA Oversight Needs Improvement . Washington, DC: GAO.
• Gerhard-Herman, M., N. Hamburg, and P. Ganz. 2000. Hormone replacement therapy and cardiovascular risk . Current Cardiology Reports 2(4):288–292. [ PubMed : 10953261 ]
• Gold, M. R., D. Stevenson, and D. G. Fryback. 2002. HALYS and QALYS and DALYS, oh my: Similarities and differences in summary measures of population health . Annual Review of Public Health 23(1):115–134. [ PubMed : 11910057 ]
• Grady, D., S. M. Rubin, D. B. Petitti, C. S. Fox, D. Black, B. Ettinger, V. L. Ernster, and S. R. Cummings. 1992. Hormone therapy to prevent disease and prolong life in postmenopausal women . Annals of Internal Medicine 117(12):1016–1037. [ PubMed : 1443971 ]
• Grady, D., N. K. Wenger, D. Herrington, S. Khan, C. Furberg, D. Hunninghake, E. Vittinghoff, and S. Hulley. 2000. Postmenopausal hormone therapy increases risk for venous thromboembolic disease. The Heart and Estrogen/Progestin Replacement Study . Annals of Internal Medicine 132(9):689–696. [ PubMed : 10787361 ]
• Grady, D., L. Chaput, and M. Kristof. 2003. Results of systematic review of research on diagnosis and treatment of coronary heart disease in women . In Evidence Report/Technology Assessment . No. 80. (Prepared by the University of California, San Francisco—Stanford Evidence-based Practice Center under Contract No 290-97-0013.) AHRQ Publication No. 03-0035. Rockville, MD: Agency for Healthcare Research and Quality.
• Grodstein, F., M. J. Stampfer, J. E. Manson, G. A. Colditz, W. C. Willett, B. Rosner, F. E. Speizer, and C. H. Hennekens. 1996. Postmenopausal estrogen and progestin use and the risk of cardiovascular disease . New England Journal of Medicine 335(7):453-461. [ PubMed : 8672166 ]
• Grodstein, F., J. E. Manson, G. A. Colditz, W. C. Willett, F. E. Speizer, and M. J. Stampfer. 2000. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease . Annals of Internal Medicine 133(12):933–941. [ PubMed : 11119394 ]
• Harman, S. M., E. A. Brinton, T. Clarkson, C. B. Heward, H. S. Hecht, R. H. Karas, D. R. Judelson, and F. Naftolin. 2004. Is the WHI relevant to HRT started in the perimenopause? Endocrine 24(3):195–202. [ PubMed : 15542885 ]
• Hays, J., J. R. Hunt, F. A. Hubbell, G. L. Anderson, M. Limacher, C. Allen, and J. E. Rossouw. 2003. The Women’s Health Initiative recruitment methods and results . Annals of Epidemiology 13(9 Suppl.):S18–S77. [ PubMed : 14575939 ]
• Hennekens, C. H., and J. E. Buring. 1989. Methodologic considerations in the design and conduct of randomized trials: The US Physicians’ Health Study . Controlled Clinical Trials 10(4 Suppl.):142S–150S. [ PubMed : 2605963 ]
• Hennekens, C. H., and K. Eberlein. 1985. A randomized trial of aspirin and beta-carotene among US Physicians . Preventive Medicine 14(2):165–168. [ PubMed : 3900975 ]
• Hernán, M. A., and J. M. Robins. 2008. Authors’ response, part I: Observational studies analyzed like randomized experiments: Best of both worlds . Epidemiology 19(6):789–792.
• Hernán, M. A., A. Alonso, R. Logan, F. Grodstein, K. B. Michels, W. C. Willett, J. E. Manson, and J. M. Robins. 2008. Observational studies analyzed like randomized experiments: An application to postmenopausal hormone therapy and coronary heart disease . Epidemiology 19(6):766–779. [ PMC free article : PMC3731075 ] [ PubMed : 18854702 ]
• Herrington, D. M., D. M. Reboussin, K. B. Brosnihan, P. C. Sharp, S. A. Shumaker, T. E. Snyder, C. D. Furberg, G. J. Kowalchuk, T. D. Stuckey, W. J. Rogers, D. H. Givens, and D. Waters. 2000. Effects of estrogen replacement on the progression of coronary-artery atherosclerosis . New England Journal of Medicine 343(8):522–529. [ PubMed : 10954759 ]
• Hersh, A. L., M. L. Stefanick, and R. S. Stafford. 2004. National use of postmenopausal hormone therapy: Annual trends and response to recent evidence . Journal of the American Medical As sociation 291(1):47–53. [ PubMed : 14709575 ]
• HHS (US Department of Health and Human Services). 2004. NHLBI Advisory for Physicians on the WHI Trial of Conjugated Equine Estrogens Versus Placebo . http://www ​.nhlbi.nih ​.gov/whi/e-a_advisory.htm (accessed April 12, 2010).
• ———. 2009. Monitoring Adherence to the NIH Policy on the Inclusion of Women and Minorities as Subjects in Clinical Research .
• ———. 2010. Women’s Health Initiative. http://orwh ​.od.nih.gov ​/inclusion/FinalAnnualReport2007.pdf (accessed May 6, 2010).
• Hoover, R. N. 2008. The sound and the fury: Was it all worth it? Epidemiology 19(6):780–782; discussion 789–793. [ PubMed : 18813016 ]
• Hulley, S., D. Grady, T. Bush, C. Furberg, D. Herrington, B. Riggs, and E. Vittinghoff. 1998. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group . Journal of the American Medical Association 280(7):605–613. [ PubMed : 9718051 ]
• IOM (Institute of Medicine). 1993. An Assessment of the NIH Women’s Health Initiative . Washington, DC: National Academy Press. [ PubMed : 25144041 ]
• Jagsi, R., A. R. Motomura, S. Amarnath, A. Jankovic, N. Sheets, and P. A. Ubel. 2009. Under-representation of women in high-impact published clinical cancer research . Cancer 115(14): 3293–3301. [ PubMed : 19507175 ]
• Kakazu, K. K., L. W. Cheung, and W. Lynne. 2004. The cancer biomedical informatics grid (caBIG): Pioneering an expansive network of information and tools for collaborative cancer research . Hawaii Medical Journal 63(9):273–275. [ PubMed : 15540527 ]
• Kim, E. S., and V. Menon. 2009. Status of women in cardiovascular clinical trials . Arteriosclerosis, Thrombosis, and Vascular Biology 29(3):279–283. [ PubMed : 19221204 ]
• LaRosa, J. C., J. He, and S. Vupputuri. 1999. Effect of statins on risk of coronary disease: A meta-analysis of randomized controlled trials . Journal of the American Medical Association 282(24):2340–2346. [ PubMed : 10612322 ]
• Limacher, M. C. 2003. Recruitment and retention: Lessons learned from the Women’s Health Initiative. In Science Meets Reality: Recruitment and Retention of Women in Clinical Studies, and the Critical Role of Relevance. A Report of the Task Force Sponsored by the NIH Office of Women’s Health , edited by HHS. Washington, DC.
• Lloyd-Jones, D., R. Adams, M. Carnethon, G. De Simone, T. B. Ferguson, K. Flegal, E. Ford, K. Furie, A. Go, K. Greenlund, N. Haase, S. Hailpern, M. Ho, V. Howard, B. Kissela, S. Kittner, D. Lackland, L. Lisabeth, A. Marelli, M. McDermott, J. Meigs, D. Mozaffarian, G. Nichol, C. O’Donnell, V. Roger, W. Rosamond, R. Sacco, P. Sorlie, R. Stafford, J. Steinberger, T. Thom, S. Wasserthiel-Smoller, N. Wong, J. Wylie-Rosett, and Y. Hong. 2009. Heart disease and stroke statistics—2009 update: A report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee . Circulation 119(3):480–486. [ PubMed : 19171871 ]
• Lloyd-Jones, D. M., C. J. O’Donnell, R. B. D’Agostino, J. Massaro, H. Silbershatz, and P. W. F. Wilson. 2001. Applicability of cholesterol-lowering primary prevention trials to a general population: The Framingham Heart Study . Archives of Internal Medicine 161(7):949–954. [ PubMed : 11295957 ]
• Mascitelli, L., and F. Pezzetta. 2007. Statins for primary prevention of coronary artery disease . Lancet 369(9567):1078–1079; author reply 1079. [ PubMed : 17398298 ]
• McKinley, E. D., J. W. Thompson, J. Briefer-French, L. S. Wilcox, C. S. Weisman, and W. C. Andrews. 2002. Performance indicators in women’s health: Incorporating women’s health in the health plan employer data and information set (HEDIS) . Women’s Health Issues 12(1):46–58. [ PubMed : 11786292 ]
• McPherson, R., and N. Kavaslar. 2007. Statins for primary prevention of coronary artery disease . Lancet 369(9567):1078; author reply 1079. [ PubMed : 17398299 ]
• Merkatz, R. B., and S. W. Junod. 1994. Historical background of changes in FDA policy on the study and evaluation of drugs in women . Academic Medicine 69(9):703–707. [ PubMed : 8074759 ]
• Murphy, S. N., M. E. Mendis, D. A. Berkowitz, I. Kohane, and H. C. Chueh. 2006. Integration of clinical and genetic data in the i2b2 architecture . AMIA Annual Symposium Proceedings :1040. [ PMC free article : PMC1839291 ] [ PubMed : 17238659 ]
• NCQA (National Committee for Quality Assurance). 2010. HEDIS 2010 Measures . http://www ​.ncqa.org/tabid/59/Default ​.aspx (accessed March 23, 2010).
• NHS (Nurse’s Health Study). 2008. History of the Nurse’s Health Study . http://www ​.channing.harvard ​.edu/nhs/index.php/history/ (accessed March 9, 2010).
• Pardo, M., M. Ruiz, A. Gimeno, L. Navarro, A. Garcia, M. Tarazona, and M. Aznar. 2002. Gender Bias in Clinical Trials of AIDS Drugs . Paper read at International Conference on AIDS, July 7–12, 2002; Barcelona, Spain.
• Pedone, C., and K. Lapane. 2003. Generalizability of guidelines and physicians’ adherence. Case study on the Sixth Joint National Committee’s Guidelines on Hypertension . BMC Public Health 3(1):24. [ PMC free article : PMC183849 ] [ PubMed : 12873353 ]
• Pinnow, E., P. Sharma, A. Parekh, N. Gevorkian, and K. Uhl. 2009. Increasing participation of women in early phase clinical trials approved by the FDA . Women’s Health Issues 19(2):89–93. [ PubMed : 19272558 ]
• Platt, R., M. Wilson, K. A. Chan, J. S. Benner, J. Marchibroda, and M. McClellan. 2009. The new sentinel network—improving the evidence of medical-product safety . New England Journal of Medicine 361(7):645–647. [ PubMed : 19635947 ]
• Prentice, R. L. 2008. Data analysis methods and the reliability of analytic epidemiologic research . Epidemiology 19(6):785–788; discussion 789–793. [ PMC free article : PMC2711000 ] [ PubMed : 18813015 ]
• Resnick, S. M., P. M. Maki, S. R. Rapp, M. A. Espeland, R. Brunner, L. H. Coker, I. A. Granek, P. Hogan, J. K. Ockene, and S. A. Shumaker. 2006. Effects of combination estrogen plus progestin hormone treatment on cognition and affect . Journal of Clinical Endocrinology and Metabolism 91(5):1802–1810. [ PubMed : 16522699 ]
• Resnick, S. M., M. A. Espeland, Y. An, P. M. Maki, L. H. Coker, R. Jackson, M. L. Stefanick, R. Wallace, and S. R. Rapp. 2009. Effects of conjugated equine estrogens on cognition and affect in postmenopausal women with prior hysterectomy . Journal of Clinical Endocrinology and Metabolism 94(11):4152–4161. [ PMC free article : PMC2775644 ] [ PubMed : 19850684 ]
• Ridker, P. M. 2010. Statin therapy for low-LDL, high-hsCRP patients: From JUPITER to CORONA. Clinical Chemistry 56(4):505–507. [ PubMed : 20185617 ]
• Ridker, P. M., N. R. Cook, I. M. Lee, D. Gordon, J. M. Gaziano, J. E. Manson, C. H. Hennekens, and J. E. Buring. 2005. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women . New England Journal of Medicine 352(13):1293–1304. [ PubMed : 15753114 ]
• Rieker, P. P., and C. E. Bird. 2005. Rethinking gender differences in health: Why we need to integrate social and biological perspectives . Journals of Gerontology . Series B , Psychological Sciences and Series B, Psychological Sciences and Social Sciences 60(Special Issue 2):S40–S47. [ PubMed : 16251589 ]
• Rosenbaum, P. R. 2002. Observational Studies . 2nd ed. New York: Springer-Verlag.
• Samsa, G., G. Hu, and M. Root. 2005. Combining information from multiple data sources to create multivariable risk models: Illustration and preliminary assessment of a new method . Journal of Biomedicine and Biotechnology 2005(2):113–123. [ PMC free article : PMC1184042 ] [ PubMed : 16046816 ]
• Sharpe, N. 2002. Clinical trials and the real world: Selection bias and generalisability of trial results . Cardiovascular Drugs and Therapy 16(1):75–77. [ PubMed : 12085983 ]
• Sheifer, S. E., T. A. Manolio, and B. J. Gersh. 2001. Unrecognized myocardial infarction . Annals of Internal Medicine 135(9):801–811. [ PubMed : 11694105 ]
• Shepherd, J., S. M. Cobbe, I. Ford, C. G. Isles, A. R. Lorimer, P. W. MacFarlane, J. H. McKillop, and C. J. Packard. 1995. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group . New England Journal of Medicine 333(20):1301–1307. [ PubMed : 7566020 ]
• Stampfer, M. J. 2008. ITT for observational data: Worst of both worlds? Epidemiology 19(6):783–784; discussion 789–793. [ PubMed : 18813017 ]
• Stampfer, M. J., and G. A. Colditz. 1991. Estrogen replacement therapy and coronary heart disease: A quantitative assessment of the epidemiologic evidence . Preventive Medicine 20(1):47–63. [ PubMed : 1826173 ]
• Stampfer, M. J., G. A. Colditz, W. C. Willett, J. E. Manson, B. Rosner, F. E. Speizer, and C. H. Hennekens. 1991. Postmenopausal estrogen therapy and cardiovascular disease. Ten-year follow-up from the Nurses’ Health Study . New England Journal of Medicine 325(11):756–762. [ PubMed : 1870648 ]
• Stewart, J. H., A. G. Bertoni, J. L. Staten, E. A. Levine, and C. P. Gross. 2007. Participation in surgical oncology clinical trials: Gender-, race/ethnicity-, and age-based disparities . Annals of Surgical Oncology 14(12):3328–3334. [ PubMed : 17682824 ]
• SWAN (Study of Women’s Health Across the Nation). 2010. Swan History . http://www ​.swanstudy.org/history.asp (accessed April 9, 2010).
• Tannen, R. L., M. G. Weiner, D. Xie, and K. Barnhart. 2007. Estrogen affects post-menopausal women differently than estrogen plus progestin replacement therapy . Human Reproduction 22(6):1769–1777. [ PubMed : 17347166 ]
• Towfighi, A., J. L. Saver, R. Engelhardt, and B. Ovbiagele. 2007. A midlife stroke surge among women in the United States . Neurology 69(20):1898–1904. [ PubMed : 17581944 ]
• Weisman, C. S. 2000. Advocating for gender-specific health care: A historical perspective . Journal of Gender-Specific Medicine 3(3):22–24. [ PubMed : 11252822 ]
• WHI (Women’s Health Initiative). 2010. About Women’s Health Initiative. http://whi ​.org/about/ (accessed April 8, 2010).
• WHS (Women’s Health Study). 2009. Women’s Health Study (WHS): A Randomized Trial of Low- dose Aspirin and Vitamin E in the Primary Prevention of Cardiovascular Disease and Cancer . http://clinicaltrials.gov/ct/show/NCT00000479 (accessed April 9, 2010).
• Wilcox, A., and S. Wacholder. 2008. Observational data and clinical trials: Narrowing the gap? Epidemiology 19(6):765. [ PubMed : 18854701 ]
• Willet, W. C., J. E. Manson, and F. Grodstein. 2008. Author’s response, part II . Epidemiology 19(6):793.
• Wilson, P. W., R. J. Garrison, and W. P. Castelli. 1985. Postmenopausal estrogen use, cigarette smoking, and cardiovascular morbidity in women over 50. The Framingham Study . New England Journal of Medicine 313(17):1038–1043. [ PubMed : 2995808 ]

For brevity, the committee uses the term conditions to mean diseases, disorders, and conditions.

LaRosa and colleagues (1999) searched the Medline database from 1966 to 1998. Therefore, most of the studies found were probably designed and initiated before the enactment of Public Law 103-43.

Although these findings should be interpreted with caution because the Office of Management and Budget (OMB) changed minority classifications between 1995 and 2007 (HHS, 2009), data indicate that minority enrollment was 36.7% in 1995. It peaked in 2006 at 43.1% and dropped to 28.6% in 2008 (HHS, 2009). The aggregated extramural and intramural data from 2008 (using the 1977 OMB standards in a combined race–ethnicity format) show that “Black or African American” had the highest proportion of participation (15.8% of enrollees), followed by “Asian/Pacific Islander” (2.6%) and “Hispanic not White” (4.6%).

The studies were funded by the National Heart, Lung, and Blood Institute and published in 1997–2006. Sex-specific studies were excluded.

• Cite this Page Institute of Medicine (US) Committee on Women's Health Research. Women’s Health Research: Progress, Pitfalls, and Promise. Washington (DC): National Academies Press (US); 2010. 4, Methodologic Issues in Women’s Health Research.
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Women's health from a woman's point of view: a review of the literature

• PMID: 3522518
• DOI: 10.1080/07399338609515739

PIP: The literature on the current health problems of women is reviewed, clarifying the conditions and updating present knowledge of women's health within the context of medical and social research. Both medical professionals and women have begun to address women's health issues with 4 major issues receiving particular emphasis: the charge that physicians fail to take women's complaints seriously; the allegation that the population of women is being drugged; the accusation that women experience excessive surgical procedures; and the notion that sexism is inherent in American medical education. Focus on these issues is not the answer. Women, individually and collectively, need to clarify issues of women's health within the context of modern research and understanding. The literature is reviewed in the categories of prepubescent females, adolescence and the young woman, women's reproductive lives, life styles of the middle years, external and internal abuse, and aged women. The estimated annual occurrence of 60,000-100,000 cases of incest and/or sexual abuse among prepubescent females makes it a women's health issue of serious dimension. The victims are overwhelmingly female with a ratio of 10 females to 1 male child. Appetite disorders, known as patharexia, are a major public health problem of female adolescents. After depression, they represent the most common emotional illness among young girls and women. Anorexia nervosa, bulimarexia, and bulimia all are characterized by body image and distortion and the victim's obsessive desire to be thin. A more conforming, but still inappropriately adapted, response to social expectations for women is teen pregnancy. Teenagers who decide to have their babies often are those with the fewest options. Voluntary childlessness, late age childbirth, and issues of reproductive freedom are having social, political, and economic impact on the lives of all women. The prevailing social context of sexism and inequality contributes to the origin and persistence of problems of women patients, as demonstrated by the correlation between subordinate group status and mental health. Many changes have been initiated as a result of pressure from individual women and from the women's health care movement. For example, medical schools are reforming their training in values, ethics, and human relations. Women have begun to assume more control over their own lives and well being. Women's groups such as the Boston Women's Health Collective have set the pattern for a proliferation of self-help manuals available to the general readership. Recent media attention has focused on such women's health issues as family violence, incest, and battering. Women have challenged the medical professionals in their treatments, and medical professionals need to see beyond individual symptoms to the context of illness in women. Complete health for women can be a new model for other social movements.

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