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Executive Summary

Perspectives From Advancing National Institutes of Health Research to Inform and Improve the Health of Women

A Conference Summary

Temkin, Sarah M. MD; Noursi, Samia PhD; Regensteiner, Judith G. PhD; Stratton, Pamela MD; Clayton, Janine A. MD

Author Information
Obstetrics & Gynecology: June 9, 2022 - Volume - Issue - 10.1097/AOG.0000000000004821
doi: 10.1097/AOG.0000000000004821
  • Open
  • PAP

The health of women remains understudied, despite a compelling need that more evidence-based information would lead to better outcomes. In their fiscal year 2021 reports, the House and Senate Appropriations Committees requested that the National Institutes of Health (NIH) convene a conference to evaluate research currently underway related to women's health and provide an update as part of the Fiscal Year 2022 Congressional Justification that identifies priority areas for additional study to advance women's health research, including reproductive science. Three high-priority areas were identified: 1) rising rates of maternal morbidity and mortality, 2) rising rates of chronic debilitating conditions in women, and 3) stagnant cervical cancer survival rates. In response to Congress, the NIH Office of Research on Women's Health developed a strategy to obtain input on the three priority areas from experts in women's health; members of the public; representatives from NIH Institutes, Centers, and Offices; and members of the NIH Advisory Committee on Research on Women's Health, a Federal Advisory Committee Act committee whose role it is to advise and prioritize issues affecting women's health. A Women's Health Conference Working Group was formed by the Advisory Committee on Research on Women's Health to review and discuss data on current NIH activities, plan the women's health conference, and prepare a report. On October 20, 2021, the Office of Research on Women's Health and the Advisory Committee on Research on Women's Health co-hosted a conference titled, “Advancing NIH Research on the Health of Women: A 2021 Conference.” The meeting proceedings revealed that, although exciting advances in women's health research have taken place, significant gaps in questions and knowledge remain in critical areas. Identifying these gaps can inform future research that will ultimately result in improved health for women.

The three focused topics designated by Congress represent significant public health crises in women's health in the United States. In 2019, 754 women died of maternal causes in the United States, for an overall maternal mortality rate of 20.1 deaths per 100,000 live births.1 These rates of maternal mortality are considerably higher in the United States than those of peer countries, and they continue to rise.2 Significant racial disparities in this rate exist with maternal mortality for non-Hispanic Black patients (44.0 deaths per 100,000 live births), 2.5 times the rate for non-Hispanic White patients.1 Second, women in the United States more commonly have a diagnosis of a chronic debilitating condition as well as multimorbidity—the simultaneous occurrence of two or more diseases that may or may not share a causal link.3 And third, despite the widespread availability of effective cervical cancer screening and prevention with the human papillomavirus (HPV) vaccine, the age-adjusted death rate from cervical cancer fell by only 0.7% annually between 2009 and 2018. This survival improvement is less than recent survival benefits observed in other cancers that affect women.4 Furthermore, significant racial inequities persist in this disease site, as Black women remain 30% more likely to be diagnosed and 75% more likely to die of cervical cancer compared with White women.5

CURRENT NATIONAL INSTITUTES OF HEALTH ACTIVITIES

In response to the Congressional request, three internal “group clusters” corresponding to the specifically requested topics and a fourth cluster to harmonize the data, were formed. Co-led by a subject matter expert from the Office of Research on Women's Health and an NIH scientist from a relevant institute, each cluster was comprised of subject matter experts from the NIH and other Department of Health and Human Services agencies, including the Centers for Disease Control and Prevention, the U.S. Food and Drug Administration, the Centers for Medicare & Medicaid Services, the U.S. Department of Veterans Affairs, and the Health Resources and Services Administration. Each cluster completed focused assessments and reviews of the relevant NIH research portfolios, held discussions on its respective topic area, and presented analyses, findings, and recommendations to the Advisory Committee on Research on Women's Health Women's Health Conference Working Group. Wherever possible, as the official system of record for annual NIH funding on specific research topics, the NIH's Research, Condition, and Disease Categorization system was used as a metric of funding. The Research, Condition, and Disease Categorization system is the NIH system of categorization and publicly reporting funding in each of more than 280 reported categories of disease, condition, or research area. The purpose of this system is to provide consistent and transparent information to the public about research funded by the NIH.6

Research on Women's Health

As measured by the Manual Categorization System-Women's Health reporting module, women's health research accounted for 10.8% of the NIH budget in fiscal year 2020 ($4,466 million).7 As shown in Figure 1, in fiscal year 2020, the Institutes, Centers, and Offices with the largest absolute funding directed toward women's health research included the Institutes, Centers, and Offices with the largest overall budgets: National Cancer Institute; National Institute of Allergy and Infectious Diseases; and National Heart, Lung, and Blood Institute. When evaluated by percentage, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institute of Arthritis and Musculoskeletal and Skin Diseases, and National Institute on Minority Health and Health Disparities allocated the largest fraction of their budgets to women's health (29%, 28%, and 25%, respectively).

F1
Fig. 1.:
National Institutes of Health (NIH) total budget and women's health research spending by institute or center, fiscal year 2020 (NIH women's health research total: $4,466 million). NCI, National Cancer Institute; NIAID, National Institute of Allergy and Infectious Diseases; NHLBI, National Heart, Lung, and Blood Institute; NIA, National Institute on Aging; NIGMS, National Institute for General Medical Sciences; NINDS, National Institute of Neurological Disorders and Stroke; OD, Office of the Director; NIDDK, National Institute of Diabetes and Digestive and Kidney Diseases; NIMH, National Institute of Mental Health; NICHD, Eunice Kennedy Shriver National Institute of Child Health and Human Development; NIDA, National Institute on Drug Abuse; NIEHS, National Institute of Environmental Health Sciences; NCATS, National Center for Advancing Translational Sciences; NEI, National Eye Institute; NIAMS, National Institute of Arthritis and Musculoskeletal and Skin Diseases; NHGRI, National Human Genome Research Institute; NIAAA, National Institute on Alcohol Abuse and Alcoholism; NIDCD, National Institute on Deafness and Other Communication Disorders; NIDCR, National Institute of Dental and Craniofacial Research; NLM, National Library of Medicine; NIBIB, National Institute of Biomedical Imaging and Bioengineering; NIMHD, National Institute on Minority Health and Health Disparities; NINR, National Institute of Nursing Research; NCCIH, National Center for Complementary and Integrative Health; FIC, Fogarty International Center. Data from women's health spending data derived from NIH Research, Condition, and Disease Categorization data system frozen file and Institute or Center total budget exclude buildings and facilities costs; data derived from NIH Office of Budget “Appropriations History by Institute or Center” file, https://officeofbudget.od.nih.gov/approp_hist.html.

As the Congressionally mandated focal point for coordinating research on the health of women at the NIH (per Public Law 103–43, section 486), the Office of Research on Women's Health collaborates with the 27 constituent NIH Institutes and Centers and the broader scientific community to ensure that sex and gender are integrated into an interdisciplinary scientific framework at NIH and throughout the biomedical research enterprise. In fiscal year 2020, the Office of Research on Women's Health budget was $45 million, which has remained largely unchanged since 2003 ($41 million).

Since the passage of the NIH Revitalization Act in 1993, representation of women in clinical research has improved, and today roughly half of NIH-supported clinical trial participants are women.8 In 2016, the NIH Sex as a Biologic Variable policy required justification from the scientific literature, preliminary data, or other relevant considerations for applications proposing to study only one sex.9 However, substantial underrepresentation of female enrollment in clinical trials persists in several disease categories, including human immunodeficiency virus (HIV), acquired immunodeficiency syndrome (AIDS), chronic kidney diseases, and cardiovascular diseases.10 Fewer than one third of phase III clinical trials supported by the NIH report results disaggregated by sex.8 For diseases that afflict primarily one sex, the funding patterns show greater fiscal investment for conditions that predominantly affect males when compared with burden of the disease within the population. The disparity between funding and burden of disease favoring conditions that occur predominantly in males is nearly twice as large as for conditions more common in females.11

Maternal Morbidity and Mortality

In 2017, as a response to the maternal morbidity and mortality public health crisis, the NIH established a Research, Condition, and Disease Categorization category for maternal health that includes projects focused on prepregnancy through 1 year postpartum. In 2020, an additional Research, Condition, and Disease Categorization category for maternal morbidity and mortality was created to capture the subset of topics within maternal health, specifically related to pregnancy complications and deaths associated with pregnancy (Fig. 2). In fiscal year 2020, the largest investment in maternal morbidity and mortality came from the NICHD ($76 million), followed by the National Heart, Lung, and Blood Institute ($40 million), the National Institute for Diabetes and Digestive and Kidney Diseases ($19 million), and the National Institute of Mental Health ($18 million).

F2
Fig. 2.:
Maternal health and maternal morbidity and mortality (MMM), National Institutes of Health, fiscal year 2020.

Current NIH activities specific to maternal morbidity and mortality include, but are not limited to, basic and translational science that investigates the underlying physiology of pregnancy, as well as the pathophysiology of pregnancy-associated disorders through programs such as the Human Placenta Project (Weinberg DH, Signore C, Spong CY. The Human Placenta Project: current progress and future directions [abstract]. Placenta 2016;45:71. doi: 10.1016/j.placenta.2016.06.041). Prospective clinical trials research investigating interventions to reduce maternal and infant morbidity, deaths, and complications is performed through the NICHD's Maternal-Fetal Medicine Units Network.12 Other NIH institutes support maternal health research relevant to their institutes' mission areas. For example, the National Heart, Lung, and Blood Institute supports projects that target maternal cardiovascular health such as postpartum cardiomyopathy; the National Institute for Diabetes and Digestive and Kidney Diseases addresses gestational diabetes; the National Institute of Environmental Health Sciences focuses on the environmental effect on maternal health; the National Institute of Mental Health addresses maternal psychiatric conditions; the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism address substance and alcohol use disorders in pregnant and birthing people; and the National Institute on Minority Health and Health Disparities focuses on racial and ethnic disparities in maternal health. Additionally, the NIH Maternal Mortality Task Force was created early in fiscal year 2020 to generate tailored, evidence-based solutions to the maternal morbidity and mortality crisis; it is led by the NIH Office of the Director, NICHD, and the Office of Research on Women's Health. The Maternal Mortality Task Force established the IMPROVE Initiative (Implementing a Maternal health and Pregnancy Outcomes Vision for Everyone) to support research aimed at reducing preventable maternal deaths and improve health for women before, during, and after delivery.13 Reducing inequities related to factors such as race, age, and geographic region is prioritized. Furthermore, a new collaboration between the Office of Research on Women's Health and the National Institute for General Medical Sciences focused on women's health in the IDeA (Institutional Development Award) Program, supported 13 awards on maternal morbidity and mortality in fiscal year 2020.14 This program is Congressionally mandated and administered by the National Institute of General Medicine, with the goal of building research capacity in states that historically have had low levels of NIH funding (23 states and Puerto Rico).15

Rising Rates of Chronic Debilitating Diseases in Women

The NIH supports a wide range of research on chronic diseases—covering screening and prevention, diagnostics, treatment and therapeutics, health disparities, and other aspects of fundamental biology such as disease mechanisms and pathogenesis. However, no single NIH Research, Condition, and Disease Categorization category for reporting medical research funding to the public encompasses the research area of chronic debilitating conditions. In 2010, the Department of Health and Human Services defined chronic illnesses as “conditions that last a year or more and require ongoing medical attention and/or limit activities of daily living”16 was used to describe chronic debilitating conditions in women. A framework (Table 1) was created for the purposes of planning this women's health conference and conducting an NIH portfolio analysis that categorized chronic debilitating conditions in women into the following categories: 1) female-specific, 2) more common in women or morbidity is greater for women or both, 3) occur in both sexes but potentially understudied in women, and 4) high morbidity in women. Disability-adjusted life-years were used as a metric to measure the burden of disease in women. Disability-adjusted life-years are defined by the World Health Organization as “the loss of the equivalent of one year of full health. Disability-adjusted life-years for a disease or health condition are the sum of the years of life lost to due to premature mortality and the years lived with a disability due to prevalent cases of the disease or health condition in a population.”17 For conditions with an associated Research, Condition, and Disease Categorization category, within this framework funding estimates were used to calculate approximate spending per disability-adjusted life-years among those in the U.S. female population. The ratio of fiscal year 2020 NIH spending to 2019 disability-adjusted life-years for U.S. women varied widely with $17 per disability-adjusted life-years for lower back pain to $25,936 per disability-adjusted life-years for HIV at either extreme. When calculated in this manner, NIH spending was not aligned with the burden of diseases among women.

T1
Table 1.:
Fiscal Year 2020 National Institutes of Health Spending Per Disability-Adjusted Life-Year in Women for Chronic Debilitating Conditions by Research, Condition, and Disease Categorization*

Additionally, a qualitative assessment of Institute, Center and Office priorities related to chronic debilitating conditions in women was performed. Each Institute, Center and Office represented within the conference planning clusters was invited to submit their three highest-funded projects related to chronic debilitating conditions in women from fiscal year 2018 to fiscal year 2020. A total of 184 priority projects were submitted by 11 Institutes, Centers, and Offices. The associated Research, Condition, and Disease Categorization categories from these submitted projects confirmed that all chronic conditions relevant to women, as defined in the Women's Health Conference chronic debilitating conditions in women framework, are included in ongoing NIH-supported research. The largest proportion of projects was focused on conditions more common in women or having greater morbidity for women or both (49%), followed by conditions potentially understudied in women (25%), conditions with high morbidity in women (15%), and female-specific conditions (11%).

Cervical Cancer

The Research, Condition, and Disease Categorization category for cervical cancer includes basic research, translation and clinical studies, premalignant and invasive cervical diseases, HPV biology, prevention, screening, vaccination, treatment, and related health services. In fiscal year 2020, the NIH invested about $113 million in cervical cancer research, with most projects funded by the National Cancer Institute ($91 million) and that amount represents 1.4% of the overall the National Cancer Institute budget. As measured by funding to lethality score—a metric that accounts for differences in the mortality, incidence, and effect on person-years of life lost—gynecologic cancers, including cervical cancer, rank in the bottom half of funding allocation from the National Cancer Institute.18 The National Institute of Allergy and Infectious Diseases, National Institute on Minority Health and Health Disparities, and the NICHD also fund research on cervical cancer, primarily focused on research on HPV biology, screening and prevention of preinvasive cervical disease, and reducing disparities in screening and prevention in historically underrepresented communities.

Comparably, more NIH-supported projects are classified as investigating etiology, prevention, early detection, and cancer control than research directly on invasive cervical cancer treatment. Robust basic and translational research on cervical cancer at the National Cancer Institute includes a Specialized Programs of Research Excellence with a focus on the development of the next generation of novel preventive and therapeutic vaccines, research to understand the carcinogenesis of HPV and mechanistic studies of the virally mediated tumor microenvironment, and tumor specific immune responses.19 The Cancer Genome Atlas has molecularly characterized primary cancer and matched normal samples creating a publicly available genomic, epigenomic, transcriptomic, and proteomic data set on 33 cancer types including cervical cancer.20

Cervical cancer screening and prevention efforts are concentrated in projects directed toward self-sampling and one-dose HPV vaccination efficacy. Ongoing clinical trials researching innovative care in cervical cancer treatment include studies listed in Table 2. The most recent, active NIH-supported clinical trial in advanced, persistent, or metastatic disease, GOG 240, closed to patient accrual in 2010.21 These trials are supported by the National Cancer Institute's clinical research networks: the Experimental Therapeutics Clinical Trials Network, National Clinical Trials Network, and the National Cancer Institute Community Oncology Research Program.22,23

T2
Table 2.:
Ongoing Clinical Trials on the Treatment of Invasive Cervical Cancer

PUBLIC COMMENTS

On July 1, 2021, the Office of Research on Women's Health published a Request for Information in the Federal Register (Federal Register Notice [FRN 2021-14151]) to inform the Women's Health Conference. The Request for Information invited comments and testimonies from the extramural scientific community, professional societies, and the general public to assist with identifying research gaps, describing pitfalls in clinical practices, and obtaining real-life testimonial experiences (direct or indirect) related to any or all of the three Congressionally specified public health issues.

Of 247 comments received, 104 addressed maternal morbidity and mortality, 182 discussed chronic debilitating conditions in women, and 27 mentioned cervical cancer. Most comments were submitted by researchers or research groups (n=56), followed by members of the public (n=49), awareness and advocacy groups (n=36), patients (n=40), and health care professionals (n=34). The 10 most frequently identified keywords from the manual coding in order of frequency were: 1) maternal morbidity and mortality, 2) racial disparities, 3) access to care, 4) health care professional training, 5) mental health, 6) Black or African American women, 7) screening, 8) quality of care, 9) time to diagnosis, and 10) social determinants of health.

ADVANCING NIH RESEARCH ON THE HEALTH OF WOMEN: A 2021 CONFERENCE PROCEEDINGS

Thirty-two speakers were invited to discuss a wide range of topics related to research on the health of women and the three focused public health needs identified by Congress (maternal morbidity and mortality, chronic debilitating conditions in women, stagnant cervical cancer survival). After overview talks outlining the return on investment from women's health research and overcoming bias in women's health research, the specific topics from the Congressional request were addressed. Breakout sessions on each of the topics addressed prevention, basic and translational research opportunities, health services research opportunities, and research to improve equity. A final talk on innovation in women's health research concluded the Women's Health Conference. Additional resources, slides, and talks are available at https://orwh.od.nih.gov/research/2021-womens-health-research-conference.

RESEARCH GAPS AND OPPORTUNITIES

Research to improve the health of women is embedded into the work and mission of all NIH Institutes, Centers, and Offices. The Office of Research on Women's Health acts as the focal point in coordinating this research and ensures that sex and gender are integrated into an interdisciplinary scientific framework at the NIH and throughout the broader scientific enterprise to inform and improve the health of women.

The following crosscutting themes emerged from the talks and presentations of stakeholders participating in the Advancing NIH Research on Women's Health Conference, including speakers, Advisory Committee on Research on Women's Health, and Coordinating Committee on Research for Women's Health members:

  • •The need for implementation research that addresses the health of women. Research to understand how best practices can be applied to women's health topics is urgently needed. The quality of care received by women varies tremendously by factors that include, but are not limited to, geographic location, insurance status, educational attainment, and other social factors. Interventions such as safety bundles have demonstrated large-scale improvements in pregnancy outcomes, yet such interventions remain unimplemented in many hospitals.24,25 The stigma surrounding menstrual issues and lack of recognition of women's pain have resulted in limited scientific innovation for female-specific conditions such as endometriosis.26 Vaccines that prevent cervical cancer have been approved for use in the United States since 2006, yet just more than half of adolescents have completed the HPV vaccine series.27 Research to “scale up” these and other successful interventions that have demonstrated improvements in the health of women should be prioritized. Innovative trial design, outreach and “big data” studies that use population health records, and incorporation of advances in disease modeling could all be used toward the goal that all women receive high quality and evidence-based care.
  • •Research that addresses inequities in care that affect the health of women. Although race, ethnicity, and sex or gender reporting from applicable NIH-defined phase III clinical trial results is required, identifying outcomes for populations with overlapping identities (eg, Black women) remains challenging, limiting data on the health consequences of intersectionality. The disproportionate burden of disease on women from historically underserved, understudied, and underrepresented populations of maternal morbidity and mortality and cervical cancer is notable. Black, Alaska Native, and American Indian people die at a rate almost three times as high as White women from pregnancy-related causes.28 The burden of chronic debilitating disease on women from underserved and underrepresented populations is not well described in the current medical evidence base; and in addition, lower socioeconomic status and lower educational attainment are additional risk factors for multimorbidity.3 Despite similar rates of cervical cancer screening and HPV vaccination, incidence and mortality remain higher in Black populations, which is likely due to delays in diagnosis after abnormal screening results, advanced stage at diagnosis, and lower rates of receipt of guideline adherent care.5,29,30 Attention to populations of women at higher risk of disease (including, but not limited to, women with historically underrepresented racial and ethnic identities, people with disabilities, sexual and gender minorities, rural populations, and those from socioeconomically disadvantaged backgrounds) through community-engaged research is an urgent need.
  • •Intentional research on the health of women. Historically, research findings from clinical trials that disproportionately enrolled men were subsequently applied to women. Since the creation of the Office of Research on Women's Health, significant advances in research focused on the health of women through collaborative efforts with the NIH's Institutes, Centers, and Offices and extramural stakeholders. Today women are enrolled into NIH-supported clinical research at similar rates to men. Yet work remains to be done. Despite women being included in clinical research and trials, such studies are rarely specifically designed to address the health of women nor are hypotheses centered around the particular needs of women. As a result, fundamental basic and translational knowledge gaps persist in many diseases that affect women and men, as well as female-specific conditions. The trigger for the initiation of labor, the underlying cause of preeclampsia, basic physiology of the uterus and of typical and atypical menstruation, the innate differences between male and female systems pathogenesis of chronic diseases, and the discrepant carcinogenesis of various HPV types are unknown. Without this foundational knowledge, gaps remain in providing evidence-based, high-quality care to women. Significant gaps in our current evidence base remain regarding disorders and diseases that occur in women, including effects on functioning and quality of life throughout their life course. Sex-disaggregated clinical outcomes data from clinical research including clinical trials—tied to critical life course windows such as menarche and menopause—from a diverse population of women are needed to fill these gaps.

The NIH Sex as a Biologic Variable policy has led to increased attention to the influences of sex preclinical research with the potential to accelerate advancement of new knowledge about underlying mechanisms of many diseases that affect women. Despite the policy, gaps remain in basic and translational understanding of sex differences. Continued attention to, application, and enforcement of this policy among investigators, funders, and publishers will allow for improved disease prevention and treatment strategies in the multitude of conditions that present differently and require different treatment in women and men.31

Clinical research on female-specific and relevant conditions, disorders, and diseases has been and remains limited.10,11 The “networks” of morbidity are different in women, with multimorbidity more likely to cross multiple organ systems compared with men. Additionally, the pattern of accumulation of morbidity, meaning what initial chronic conditions are diagnosed and how conditions are additive, differs by sex and gender.32 Scientific inquiry on conditions such as menopause, endometriosis, and leiomyomas falls under the purview of multiple Institutes and Centers, and there are fewer standing funding opportunities compared with other research topics.

To fill evidence gaps related to women's health, clinical trials networks with the following attributes were proposed: a specific multidisciplinary emphasis on women (including pregnant people), tools to design trials that answer questions specific to women, and capacity to enroll women into studies. Large-scale prospective cohort studies of women might likewise begin to fill some of our gaps in understanding the specific pathophysiology of women with chronic debilitating diseases.

There are currently limited numbers of the NIH funding opportunities for women's health and female-specific conditions issued across NIH's Institutes, Centers, and Offices. However, intentional funding opportunities could expand the breadth of research support for, and the knowledge base generated on women's health. The creation of standing study sections on sex differences and women's health research within the NIH Center for Scientific Review and the inclusion of researchers with women's health expertise on additional study sections could enhance the review process. Intentional funding of studies of women's health leveraging existing NIH resources such as cohorts, biobanks, and bioinformatics can accelerate progress by advancing the growth and comprehensiveness of the NIH women's health research portfolio.

CONCLUSION

Improving the health of women benefits all members of our society.33 Increasing research on the health of women has been demonstrated to produce significant returns on investment.34 The 5-year, 2019–2023 Trans-National Institutes of Health Strategic Plan for Women's Health Research sets out an ambitious vision for a world in which the biomedical research enterprise thoroughly integrates sex and gender influences through the following five strategic goals:

  1. Advance rigorous research that is relevant to the health of women.
  2. Develop methods and leverage data sources to consider sex and gender influences that enhance research for the health of women.
  3. Enhance dissemination and implementation of evidence to improve the health of women.
  4. Promote training and careers to develop a well-trained, diverse, and robust workforce to advance science for the health of women.
  5. Improve evaluation of research that is relevant to the health of women.35

Realization of the NIH mission of “turning discovery into health” requires that biomedical research findings and innovations generated apply to women as well as men. For every woman to receive evidence-based disease prevention and treatment tailored to her own needs, circumstances, and goals, robust investment in women's health research incorporating sex and gender considerations is required. Despite progress in biomedical research, women in the United States continue to experience high rates of illness and physical disability compared with women in other high-income countries. Broad support for increased prioritization of research on women's health was expressed by members of the public, NIH stakeholders, Advisory Committee on Research on Women's Health members, and the participants of the Advancing NIH Research on Women's Health Conference. Research that uses a life-course approach is informed by gender considerations, and incorporates systematic consideration of sex differences from the beginning to the end aligns with a global agenda for women's health.36 Exciting possibilities exist when important research on the health of women is undertaken. Such research has the potential to greatly improve human health.

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