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Echogenic intracardiac foci detection and location in the second-trimester ultrasound and association with fetal outcomes: A systematic literature review

Hope Eleri Jones, Serica Battaglia,  [ ... ], Sinead Brophy

Shroud waving self-determination: A qualitative analysis of the moral and epistemic dimensions of obstetric violence in the Netherlands

Rodante van der Waal, Inge van Nistelrooij

Facilitators and barriers to vaccination uptake in pregnancy: A qualitative systematic review

Mohammad S. Razai, Rania Mansour,  [ ... ], Pippa Oakeshott

Enhanced peer-group strategies to support the prevention of mother-to-child HIV transmission leads to increased retention in care in Uganda: A randomized controlled trial

Alexander Amone, Grace Gabagaya,  [ ... ], Philippa Musoke

Factors associated with bypassing primary healthcare facilities for childbirth among women in Devchuli municipality of Nepal

Manisha Maharjan, Sudim Sharma, Hari Prasad Kaphle

Birth preparedness and complication readiness among recently delivered women in Hargeisa town, Somaliland: A community-based cross-sectional study

Abdeta Muktar Ahmed, Mohamed Abdilahi Ahmed, Mohammed Hassen Ahmed

Impact of COVID-19 on antenatal care provision at public hospitals in the Sidama region, Ethiopia: A mixed methods study

Zemenu Yohannes Kassa, Vanessa Scarf, Sabera Turkmani, Deborah Fox

Histopathologic patterns and factors associated with cervical lesions at Jimma Medical Center, Jimma, Southwest Ethiopia: A two-year cross-sectional study

Birhanu Hailu Tirkaso, Tesfaye Hurgesa Bayisa, Tewodros Wubshet Desta

Multilevel negative binomial analysis of factors associated with numbers of antenatal care contacts in low and middle income countries: Findings from 59 nationally representative datasets

Adugnaw Zeleke Alem, Biresaw Ayen Tegegne,  [ ... ], Tsegaw Amare Baykeda

ex vivo , patient-derived explant model of endometrial cancer">Development of a long term, ex vivo , patient-derived explant model of endometrial cancer

Hannah van der Woude, Khoi Phan,  [ ... ], Claire Elizabeth Henry

Estimates of the incidence, prevalence, and factors associated with common sexually transmitted infections among Lebanese women

Hiam Chemaitelly, Ramzi R. Finan,  [ ... ], Wassim Y. Almawi

Comparison of perinatal outcome and mode of birth of twin and singleton pregnancies in migrant and refugee populations on the Thai Myanmar border: A population cohort

Taco J. Prins, Aung Myat Min,  [ ... ], Rose McGready

Understanding the uptake and determinants of prevention of mother-to-child transmission of HIV services in East Africa: Mixed methods systematic review and meta-analysis

Feleke Hailemichael Astawesegn, Haider Mannan, Virginia Stulz, Elizabeth Conroy

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COVID-19 and Women's Health

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As a result of the Coronavirus disease (COVID-19) pandemic, the world is facing one of the greatest challenges we have experienced in over a century. The economic consequences for society at large are potentially catastrophic. The health and social care sectors have reacted by providing emergency care on an ...

Keywords : COVID-19, Women's Health, Pregnancy

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Exploring Obesity’s Impact on Women and Policy’s Role in Improving Outcomes

Obesity is a significant public health issue in the United States, affecting millions of Americans and costing billions of dollars in health care expenses. Women are disproportionately affected by the obesity epidemic, both in terms of their health outcomes and the economic costs of the disease. There are also notable racial and economic disparities associated with obesity. During this congressional briefing, panelists will explore the disproportionate impact of obesity on women, including obesity risk factors that are unique to women,…

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Join us for the VCU Health of Women Conference 2024 SWHR Pre-conference Symposium! This symposium will discuss the impacts of autoimmune diseases on women’s health across the lifespan, with special emphasis on pregnancy and maternal health, caregiving/parenting.

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SWHR’s Policy Advisory Council will meet for its quarterly closed-door meeting. Council members will have an opportunity to work collaboratively to develop policy positions, promote research, and create materials designed benefit women’s health.

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Kit de Herramientas para la Endometriosis: Guía para Adolescentes

Descargar una copia del Kit de Herramientas para la Endometriosis: Guía para Adolescentes en español, para ayudar a empoderar a las adolescentes que viven con endometriosis y así entender mejor su salud y orientarse en su atención.

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Supporting Children with Narcolepsy at School

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Women’s midlife health: the unfinished research agenda

• Sioban D. Harlow 1 ,
• Lynnette Leidy Sievert 2 ,
• Andrea Z. LaCroix 3 ,
• Gita D. Mishra 4 &
• Nancy Fugate Woods 5  

Women's Midlife Health volume  9 , Article number:  7 ( 2023 ) Cite this article

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Introduction

In 2015 we launched Women’s Midlife Health with the aim of increasing scientific focus on the midlife -- a critical window for preventing chronic disease, optimizing health and functioning, and promoting healthy aging. This life stage, from about age 35–40 years to about 60–65 years, is coincident with the menopausal transition in women, encompassing the late reproductive to late postmenopausal stages of reproductive aging [ 1 , 2 , 3 , 4 ]. As noted in our initial editorial [ 5 ], in addition to the hallmark symptoms of menopause, the midlife is a vulnerable window for onset of gynecologic and hormone-sensitive conditions as well as onset or exacerbation of symptoms, symptom burden and functional limitations. It is also the critical window for interventions to reduce the loss of bone strength associated with menopause, to protect heart health and to promote psychosocial well-being. At the time we started this publication, relatively few journals were interested in manuscripts on midlife aging, except for a handful focused on menopause and reproductive aging. Women’s Midlife Health was designed to fill this gap. We developed an international community of investigators studying the intersection of menopause and midlife health who have contributed to enlarging scientific understanding, developing an international view of the perimenopause and acquainting investigators with studies of menopause around the world. Over the past decade, as scientific knowledge has increased, documenting the importance of the midlife for healthy aging, menopause journals have expanded their scope and aging journals have expanded their breadth. As multiple excellent venues are now available to publish work on midlife health, we have decided to cease publication of this journal. In our closing editorial, we provide reflections on what we have achieved and outline some of the continuing critical gaps in scientific knowledge.

The unfinished research agenda

Scientific terminology for menopause and reproductive aging was initially defined only in 1980 [ 6 ]. At about the same time, social scientists were documenting unexpected variation in symptom experience within and across populations [ 7 , 8 , 9 ], alerting practitioners to a previously unrecognized need to understand the physiology and context of menopause and midlife. Concerted and well-funded research efforts to advance knowledge about the natural history of menopause, including data on its changing physiology and pathophysiology and their related biosocial changes, were initiated in the last decades of the twentieth century [ 10 , 11 , 12 , 13 , 14 ]. In the 1990’s and early 2000’s, the first wave of cohort studies elucidated the hormonal transitions that characterize ovarian aging and the specific symptoms attributable to them while documenting the inter-relationships between ovarian aging and bone, cardiovascular, and musculoskeletal aging. Over the last two decades these insights have led to the establishment of an evidence-based model for staging reproductive aging (i.e., the STRAW + 10 model ) [ 1 , 2 , 3 , 4 ], a developing theory of midlife aging with initial guidance as to critical windows for intervention, and an appreciation of variation in age at menopause and symptom experiences related to the complex interplay across physiologic and sociocultural systems that can influence, adversely or beneficially, the prospects for healthy aging. Moreover, foundational studies over the past three decades have laid the groundwork for understanding ovarian aging and its interface with other aspects of aging in midlife. Critical gaps in scientific knowledge remain that will require a new generation of well-funded studies. Some gaps represent a simple failure to ask basic questions, others signal a need for an expanded global focus encompassing further geographic and population diversity in the midlife experience, while others reflect the new research questions that have arisen from our current studies.

Although considerable information has been generated regarding the nature of ovarian aging for women who experience natural menopause, information for women experiencing surgical menopause (double oophorectomy), hysterectomy [ 15 ] and for women with chronic illnesses (e.g., HIV, cancer or autoimmune disease) that alter the menopause experience, remains lacking. Often excluded from study samples or analyses by design, yet likely to experience more abrupt hormonal changes and symptomatology, and more adverse health consequences, studies addressing the trajectories of ovarian aging and associated symptoms and pathophysiologic changes are warranted. Such studies are of particular importance given the differing risks of hysterectomy and surgical menopause by race, ethnicity and region of residence and the health risks associated with early menopause and premature ovarian insufficiency [ 16 ]. Also, given recent evidence of racial and ethnic differences in the timing of menopause, symptom experience and clustering of risk factors, considerably more focus on the midlife experience of minoritized populations and population specific risk factors, including the impact of structural racism, is of paramount importance [ 17 ].

Similarly, data on the midlife continues to remain limited from low- and middle-income countries, despite the important contribution of chronic diseases to the global burden of disease. As pointed out in our series on Contraception in Midlife, Demographic and Health Surveys, a major source of health information for many countries, only interview women of reproductive age, from ~ 15 to 49 years old [ 18 ]. Here, too, evaluation of context specific health risks common in such settings, such as the impact of high parity, early and late childbirth, increased risk of pelvic floor disorders, anemia, infectious diseases, high parasite load, life-long under-nutrition, and the increasing frequency of natural disasters associated with climate change is lacking. Other population subgroups for whom information on the menopausal transition experience and medical care options is limited are lesbian and transgender individuals.

As the STRAW + 10 model for staging reproductive aging [ 1 , 2 , 3 , 4 ] predates the generation of a substantive literature on the relationships between declines in anti-mullerian hormone (AMH), ovarian reserve and menopause, a revision of the STRAW + 10 model incorporating information on AMH levels across stages of the menopausal transition is overdue.

Also, given the substantive body of literature now published on the natural history of menopause and midlife health, knowledge translation to intervention trials and education of women and their health care providers is urgently needed. For example, the now well documented timing of precipitous bone loss during the late menopausal transition stages [ 19 ] argues for earlier screening of at-risk women and trials aimed at evaluating whether treatment across the trans-menopausal period (from approximately 2 years before until 1 year after the menopause) can prevent this precipitous loss. Similarly, most health care providers remain poorly informed about how to evaluate and treat bothersome menopausal symptoms, while much of what we have learned has yet to be made accessible to women themselves. This gap continues despite the publication of numerous rigorous randomized controlled trials that could easily be clinically translated so that women can choose, based on truthful comparisons and accurate information about the magnitude of benefits and risks, from many pharmacologic therapies that modestly improve vasomotor symptom frequency, severity, midlife sleep problems and menopause-related quality of life [ 20 ].

One intriguing insight gained over the last quarter century, is the complex interplay among symptoms and physiologic risk factors, suggesting that more attentions to bi- and multi-directional relationships among symptoms and heart, cognitive, and psychosocial health is warranted. For example, the relative timing of and feedback across endocrine changes, sleep disturbances, vasomotor symptoms and cognitive health remain poorly understood as does the inter-relationship between sleep, vasomotor symptoms, heart rate variability and cardiovascular risk.

We have learned a great deal about the types of life challenges facing midlife women from studies begun in the 1990s and later. Nonetheless, we need to remain vigilant to the unique and evolving stressors facing midlife women as they provide an important understanding of the social context for women’s health. Recent research about menopause and the workplace is just one dimension needing consideration, along with the pressures of family life (partners, children, and aging parents to name a few) [ 21 , 22 , 23 ].

Some further areas that have received limited attention to date and remain understudied include:

The relationship between the increased menstrual flow experienced by most women during the menopausal transition -- often consistent with definitions of abnormal uterine bleeding -- and classic symptoms of menopause including fatigue, trouble focusing, depression and anxiety, heart palpitations and hot flashes;

Risk factors for and pathophysiologic mechanisms underlying vasomotor symptoms that are not timed to changes in reproductive hormone levels, including those that begin long before and last long after the final menstrual period;

Differences in the risks and consequences of hot flashes versus night sweats, two symptoms that are often combined into vasomotor symptoms but vary dramatically in experience and are identifiably different on ambulatory monitor graphs;

The impact of exposure to endocrine disrupting chemicals, including forever chemicals, heavy metals and other environmental pollutants on endocrine function, musculoskeletal changes, heart health and cognition across the midlife;

The relationship between menstrual disorders prior to midlife and symptoms experienced during menopause, and their impact, or not, on work productivity;

Assessment of menopausal symptoms/outcomes across countries and cultures using both quantitative and qualitative surveys, collecting both symptom presence and symptom bothersomeness in the context of women’s lives;

The role of structural racism, neighborhood conditions, and historical trauma on timing of menopause and risk of menopausal symptoms and on the symptom and health burden women carry as they enter the menopausal transition; and,

Investigation of factors associated with positive menopausal transitions, including research on effects of education about menopause, provision of anticipatory guidance to help women manage the changes they are facing, and their development of attributions helping them sort the menopause-related to life-related factors.

As we approach the next generation of midlife studies, priority should also be given to advancing research methods, including in the following areas:

As serial hormonal testing is not accessible to many women and in many countries, development of a validated bleeding questionnaire for staging reproductive aging;

Building on core outcomes developed for vasomotor symptoms and genitourinary symptoms of menopause, definition of a core outcomes for additional symptoms of menopause and midlife health endpoints ( https://medicine.unimelb.edu.au/school-structure/obstetrics-and-gynaecology/research/COMMA ) [ 24 , 25 ]; and,

Given the complex interplay of multiple pathophysiologic changes that underlie symptoms and disease onset across the midlife, further development of statistical methods that permit simultaneous modeling of both the means and variances of multiple dynamic trajectories.

Finally, collaboration with health professional organizations is necessary to enrich their educational preparation to provide appropriate and helpful care to women in anticipation of and during the peri- menopause and post-menopause.

In closing, Women’s Midlife Health has met its goal of opening opportunities for publications on this critical lifestage and has published several important topical series on contraception, pain, stress, disability and structural racism in addition to innovative papers that have expanded the paradigm of and refocused the research agenda for women’s health. All papers will remain accessible at https://womensmidlifehealthjournal.biomedcentral.com/ and on PubMed https://pubmed.ncbi.nlm.nih.gov/ . We thank all the authors and reviewers who contributed to the success of the journal.

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Hardy C, Thorne E, Griffiths A, et al. Work outcomes in midlife women: the impact of menopause, work stress and working environment. Women’s Midlife Health. 2018;4:3. https://doi.org/10.1186/s40695-018-0036-z .

Lensen S, Bell RJ, Carpenter JS, Christmas M, Davis SR, Giblin K, Goldstein SR, Hillard T, Hunter MS, Iliodromiti S, Jaisamrarn U, Khandelwal S, Kiesel L, Kim BV, Lumsden MA, Maki PM, Mitchell CM, Nappi RE, Niederberger C, Panay N, Roberts H, Shifren J, Simon JA, Stute P, Vincent A, Wolfman W, Hickey M. A core outcome set for genitourinary symptoms associated with menopause: the COMMA (Core Outcomes in Menopause) global initiative. Menopause. 2021;28(8):859–66.

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Harlow, S.D., Sievert, L.L., LaCroix, A.Z. et al. Women’s midlife health: the unfinished research agenda. womens midlife health 9 , 7 (2023). https://doi.org/10.1186/s40695-023-00090-5

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When choosing a topic for your Women's Health essay, consider what interests you the most. Are you drawn to issues like reproductive health, mental wellness, or access to healthcare? Think about what you're passionate about and what you think others should know more about. This will help you narrow down your focus and make your essay more engaging.

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For a thesis statement on Women's Health, consider statements like "Access to comprehensive reproductive healthcare is a fundamental human right," "Societal beauty standards have a detrimental impact on women's mental health," or "Gender biases in medical research have led to disparities in women's healthcare."

When crafting your essay , you might want to start with a compelling statistic or a thought-provoking question. For example, "Did you know that women are 50% more likely to be misdiagnosed following a heart attack?" or "Imagine living in a world where your access to healthcare is determined by your gender."

In your essay , you can reinforce your main points and leave the reader with a call to action or a question to ponder. For example, "It's time to prioritize women's health and work towards a more inclusive and equitable healthcare system," or "What steps can we take to ensure that all women have access to the care they deserve?"

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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.
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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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