Advancing Research on Chronic Conditions in Women (2024)

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4 Impact of Select Chronic Conditions in Women This chapter describes the impact of female-specific and gynecologic conditions and conditions that predominantly impact or affect women differently. The conditions listed are not exhaustive and are meant to provide an idea of the magnitude of the effect these conditions have on women, the difference between women and men, and differences by age and racial and ethnic groups when data are readily available. They also reflect what is known about diagnosis, treatment, prevention, and management (see Chapter 5 and 6). In addition, this chapter highlights where more needs to be learned about the impact these conditions have on women and describes the economic burden these conditions have on both individuals and society and effects on quality of life. As mentioned in Chapter 3, several measures of impact exist. To describe these conditions, the committee focused on prevalence, given that it is a common, widely reported measure. Another measure of impact is economic burden. As mentioned in Chapter 3, this reflects both health care or direct costs and other related, indirect costs as they pertain to aspects such as employment and labor. When available, this chapter also provides information on quality of life to reflect the effect these conditions have on a woman’s life. The committee notes that the conditions selected and discussed here are extremely heterogeneous. Human immunodeficiency virus (HIV) for example has one etiologic factor while other conditions are not a single entity but rather a collection of various conditions such as cardiometabolic conditions and pelvic floor disorders. Further, some conditions lack diagnostic specificity or are difficult to confirm such as chronic pain and vulvodynia. This heterogeneity and varying measurement precision affect data on the prevalence of these conditions and other measures of impact. One important feature of these conditions is that many of them have a relatively early onset (see Table 4-1). More specifically, of the 25 conditions described in this chapter, nine— dysmenorrhea, endometriosis, and chronic pelvic pain (CPP), vulvodynia, depression, substance use disorder (SUD), HIV, migraine/headache, multiple sclerosis (MS), and systemic lupus erythematosus (SLE)—typically develop in early adulthood. Thus, these conditions will have a lifelong effect on quality of life. Overall, the multimorbid presentation of many of these conditions in women highlights the challenges and complexities of living with chronic conditions. PREPUBLICATION COPY: UNCORRECTED PROOFS 

2 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN TABLE 4-1 Life Course Stage of Onset of Chronic Conditions Affecting Women. No. Conditions Estimated Age of Source Onset (Average Years or Range) Female-Specific and Gynecologic Conditions 1 Dysmenorrhea Adolescence and ACOG, 2018 within 6 –12 months of onset of menarche 2 Endometriosis Adolescence ACOG, 2018 3 Uterine Leiomyomas/Uterine Adulthood ACOG, 2021a; De La Fibroids Cruz and Buchanan, 2017; Hartmann et al., 2017 4 Infertility Adolescence Phillips et al., 2023 5 Vulvodynia Adolescence Reed et al., 2012 6 Pelvic Floor Disorders Adulthood Committee on Practice Bulletins—Gynecology and American Urogynecologic Society, 2017 7 Menopausal Symptoms Adulthood Committee on Practice Bulletins—Gynecology, 2014 Chronic Conditions That Predominantly Impact Women 8 Major Depressive Disorder Adolescence APA, 2013 9 Postpartum Depression Adolescence and APA, 2013 during pregnancy or 4 weeks post- delivery 10 Substance Use Disorder Adolescence APA, 2013 11 HIV Adulthood CDC, 2023 12 Migraine/Headache Adolescence International Headache Society, 2018 13 Multiple Sclerosis Adulthood Mayo Clinic,2022 14 Systemic Lupus Erythematosus Adolescence Hochberg et al. 2011 15 Chronic Pain (including lower Adulthood Owiredua et al., 2020 back pain) Cardiometabolic Conditions 16 Cardiovascular Disease Adulthood Tsao et al., 2023 17 Stroke Adulthood Tsao et al., 2023 18 Type 2 Diabetes Adolescence Tsao et al., 2023 PREPUBLICATION COPY: UNCORRECTED PROOFS 

IMPACT OF SELECT CHRONIC CONDITIONS IN WOMEN 3 19 Obesity Childhood Tsao et al., 2023 20 Metabolic Syndrome Adolescence Tsao et al., 2023 21 Fibromyalgia Adulthood Arnold et al., 2019 22 Myalgic Adulthood IOM, 2015 Encephalomyelitis/Chronic Fatigue Syndrome 23 Alzheimer’s disease Adulthood Alzheimer's Association, 2024 24 Osteoporosis Adulthood ACOG, 2021b; Sarafrazi et al., 2021 25 Sarcopenia Older Adulthood Cruz-Jentoft et al., 2019 IMPACT OF FEMALE-SPECIFIC AND GYNECOLOGIC CONDITIONS Dysmenorrhea Dysmenorrhea, pain resulting from menstrual cramps, is classified into two types: primary, which has no known cause, and secondary dysmenorrhea, which is results from a known cause, such as endometriosis, uterine fibroids, and pelvic inflammatory disease (ACOG, 2018; Proctor and Farquhar, 2006). Primary dysmenorrhea typically occurs during adolescence and within 6–12 months of onset of menarche and secondary dysmenorrhea can occur any time after onset of menarche, usually after 2 years depending on the on the cause or condition (ACOG, 2018; Iacovides et al., 2015; Proctor and Farquhar, 2006). Two literature reviews report the prevalence of dysmenorrhea based on both non-U.S. and U.S. studies (Armour et al., 2019; Ju et al., 2013). For U.S. studies, the prevalence of dysmenorrhea varied: from 65 percent in a sample of predominantly African American adolescent girls (12–21 years of age) (Houston et al., 2006) to 85 percent in a sample comprised predominantly of Hispanic adolescent girls (Banikarim et al., 2000). In adult women, the prevalence ranged from at least 21 percent in women aged 36–44 years (Abenhaim and Harlow, 2006) to 20–22 percent with moderate dysmenorrhea in a sample of nurses mostly 25 years or older (Weisman et al., 2004). Prevalence estimates vary among ethnic groups, partly reflecting different cultural attitudes of women with respect to menstruation (Francavilla et al., 2023). Endometriosis Endometriosis is an inflammatory gynecologic disease marked by the presence of endometrial-like tissue outside the uterus. Prevalence estimates are inconsistent or lacking (Christ et al., 2021), and the accuracy of reported measures is uncertain given the variability in diagnostic approaches and the population of interest (Shafrir et al., 2018). For example, prevalence ranged from as low as 1.9 percent of women aged 16–60 in a 2015 study based on Kaiser Permanent Washington electronic health records, 11.0 percent in women 18–44 years of age undergoing laparoscopy or laparotomy, to a high of 62.0 percent in adolescent girls diagnosed laparoscopically (Buck Louis et al., 2011; Christ et al., 2021; Janssen et al., 2013). Prevalence by race and ethnicity were not reported in these studies. Delays in diagnosing endometriosis appear to be common. One study reported an average diagnosis delay of 6.7 years, and another study reported a delay of 4.7 years (Greene et al., 2009; PREPUBLICATION COPY: UNCORRECTED PROOFS 

4 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN Nnoaham et al., 2011). In a study of women who received a surgical diagnosis of endometriosis (Greene et al., 2009), women who first experience symptoms during adolescence waited longer to seek medical attention (6 years) compared to women who first experience symptoms as adults (2 years). In addition, 58.7 percent of women consulted three or more physicians before receiving a diagnosis (Greene et al., 2009). Several barriers contribute to delay in diagnosis. These include an array of individual factors (e.g. distinguishing pathological symptoms from normal menstruation), interpersonal influences (e.g. menstrual stigma) and health care system factors (e.g. delayed referrals to specialist services), and factors specific to endometriosis (e.g. lack of a noninvasive method for definitive diagnosis) (Davenport et al., 2023). Uterine Fibroids Uterine fibroids are the most common benign tumor of the woman’s pelvic area (Bulun, 2013). In a literature review of 60 studies, one group reported a prevalence range of 4.5–68.6 percent, depending on the characteristics of the study, such as geography, follow-up time, and methodological approach (Stewart et al., 2017). Prevalence estimates may be underreported given that most studies focus on symptomatic women (Baird et al., 2003; Giuliani et al., 2020), but one study reported the cumulative incidence as greater than 70.0 percent by the age of 50 (Baird et al., 2003). Individuals who self-identify as Black have higher prevalence and incidence and a younger age of onset (Baird et al., 2003; Huang et al., 2023; Marsh et al., 2013). Female Infertility According to the Practice Committee of the American Society for Reproductive Medicine, “Infertility is a disease, defined by the failure to achieve a successful pregnancy after 12 months, or more of appropriate, timed unprotected intercourse or therapeutic donor insemination” (Practice Committee of the American Society for Reproductive Medicine, 2013). National estimates come from two surveys. The National Survey of Family Growth is designed to be nationally representative of women and men aged 15–49 in U.S. households. Data from 2015–2019 showed that 8.5 percent of married women aged 15–49 years who had at least 12 consecutive months of unprotected intercourse without pregnancy reported infertility (Nugent and Chandra, 2024). The survey also reported data on impaired fertility, which includes all women regardless of marital status who report difficulty conceiving or carrying to term, and found that for same population, 13.4 percent of women had impaired fertility (Nugent and Chandra, 2024). The National Health and Nutrition Examination Survey (NHANES) also captures data on infertility. 1 Data from the NHANES 2013–2016 survey cycles showed that 12.5 percent of women aged 20–44 years, reported infertility (Kelley et al., 2019), with a significant association between age and infertility: as age increased, so did infertility prevalence. The study found no significant differences in prevalence of infertility among racial and ethnic groups. 1 Women were asked to respond to two questions, “Have you ever attempted to become pregnant over a period of at least a year without becoming pregnant?” and “Have you ever been to a doctor or other medical provider because you were unable to become pregnant?” PREPUBLICATION COPY: UNCORRECTED PROOFS 

IMPACT OF SELECT CHRONIC CONDITIONS IN WOMEN 5 Vulvodynia The most recent consensus 2015 guidelines 2 state that vulvodynia—ongoing pain at the opening of the vagina—is “vulvar pain of at least three months’ duration, without clear identifiable cause, which may have potential associated factors.” Given these “potential associated factors,” the guidelines added that vulvodynia may be multifactorial and that factors can occur and overlap, suggesting the heterogeneous aspects of the experience (Bornstein et al., 2016). Given the unknown etiology and multiple associated factors, it is challenging to capture the prevalence, and what estimates are available may be too low. One report noted lifetime prevalence estimates of 10–28 percent in reproductive-aged women (Pukall et al., 2016) and another study placed the estimated 4–16 percent (Eppsteiner et al., 2014). The impact of vulvodynia is difficult to assess, given that approximately 50 percent of those affected fail to seek treatment and less than 2.0 percent of women in one study predicted to have vulvodynia obtained a diagnosis (Reed et al., 2012). In addition, care-seeking behaviors vary by patient characteristics, including education, marital status, body mass index (BMI), and number of comorbid gynecological conditions (Bond et al., 2022). A true diagnosis also requires clinical confirmation to rule out other known causes for vulvar pain such as dermatological conditions. Two population-based studies report prevalence of vulvodynia. A 2012 study based in southeastern Michigan found a prevalence of 8.3 percent among women aged 18 years and older who responded to a self-administered survey (Reed et al., 2012). A 2014 survey in Boston and Minneapolis/St. Paul found a similar prevalence of 7.0–8.0 percent in women by the age of 40 years (Harlow et al., 2014). The Michigan study also found that prevalence remained constant through age 70, after which it declined. Almost 17.0 percent of those surveyed had their symptoms resolve after an average of 12.5 years (Reed et al., 2012). Vulvodynia affected 4.3 percent of Black women compared to 9.3 percent of White and 15.6 percent of Hispanic women (Reed et al., 2012). These findings are consistent with other studies showing that the prevalence of vulvodynia is reported highest in Hispanic women and lowest in Black women (Harlow et al., 2014; Harlow and Stewart, 2003; Reed et al., 2014). Pelvic Floor Disorders Pelvic floor disorders (PFD) include urinary incontinence, fecal incontinence, and pelvic organ prolapse. Based on 2005–2010 NHANES data, the prevalence in women was 25.0 percent, with 17.1 percent of women experiencing moderate to severe urinary incontinence, 9.4 percent experiencing fecal incontinence, and 2.9 percent having pelvic organ prolapse (Wu et al., 2014). Urinary incontinence is associated with lower urinary track symptoms (LUTS) with symptoms falling in three areas: symptoms with storage of urine, voiding of urine, and after voiding (Abrams et al., 2003). One study using data from the Boston Area Community Health Survey, found that 22.9 percent of women aged 30-80 years reported LUTS and LUTS interference with activities such as travel, exercise, and social activities. About 59.6 percent of women reported some LUTS and/or interference with activities, and 17.5 percent reported no LUTS or interference with activities (Sutcliffe et al., 2019). Risk factors associated with PFD include high BMI, having given birth to more children, and hysterectomy (Wu et al., 2014). The prevalence increases significantly by age, from 6.3 percent in women aged 20–29 to 52.7 percent in women 2 2015 consensus guidelines of the International Society for the Study of Vulvovaginal Disease, the International Society for the Study of Women’s Sexual Health, and the International Pelvic Pain Society PREPUBLICATION COPY: UNCORRECTED PROOFS 

6 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN 80 and older (Wu et al., 2014). In addition, racial and ethnic groups showed a significant difference: non-Hispanic White women had a higher prevalence of one or more pelvic floor disorder at 26.4 percent compared to Hispanic, Mexican American women at 24.0 percent, and other Hispanic and non-Hispanic Black women, both at 20.0 percent (Wu et al., 2014). With respect to urinary incontinence, a more recent study based on NHANES 2015–2018 data reported 61.8 percent of women 20 years or older experienced urinary incontinence and 22.1 percent experienced moderate to severe urinary incontinence (Patel et al., 2022). 3 Menopausal Symptoms Approximately 1.3 million U.S. women enter menopause each year (McCarthy and Raval, 2020). Natural or spontaneous menopause typically occurs between ages 45 and 51, with variability in the age of onset, duration, and degree of perceived symptoms (Harlow et al., 2012). In a progress report of menopause transition-related results from studies associated with the Study of Women’s Health Across the Nation (SWAN), the investigators summarized findings on symptoms (El Khoudary et al., 2019): • Up to 80 percent reported vasomotor symptoms (VMS) or hot flashes, with the highest reporting during the transition from early to late perimenopause (El Khoudary et al., 2019; Gold et al., 2006). White women had the highest unadjusted percentage of VMS of greater than 6 days at baseline at 43.5 percent, followed by African American women at 38.0 percent, Hispanic women at 10.5 percent, Chinese or Chinese American women at 4.7 percent and Japanese or Japanese American women at 3.3 percent. However, in models adjusting for a number of sociodemographic factors, African American women had a higher adjusted odds ratio (1.63) of VMS than White women in this longitudinal cohort. In addition, during menopausal transitions (e.g., premenopause to perimenopause, perimenopause to postmenopause), African American women had the highest reported unadjusted percentage of any VMS (Gold et al., 2006). • Women in late perimenopause and natural postmenopause reported more sleep difficulties (43.2–45.4 percent), compared to premenopausal women (31.4 percent) (Kravitz et al., 2003). In addition, in pre or early perimenopausal women, White women were significantly more likely and Hispanic women less likely to wake up several times than women of other racial and ethnic groups. (Kravitz et al., 2008). In a more recent study of sleep difficulties (e.g., sleep duration, awake after sleep onset) in postmenopausal women, White women reported better sleep quality, than Black or Hispanic women. Differences were mediated by factors, such as the number of medical issues, financial problems, and stressors (Matthews et al., 2019). 3 Both Wu and colleagues (2014) and Patel and colleagues (2022) use the Sandvik Severity Index as a measure of the severity of urinary incontinence. SSI is based on responses to two questions: episode frequency (<once per month, a few times a month, a few times a week, or every day and/or night) and leakage amount (drops, splashes, or more). Responses were multiplied to obtain a total severity score that ranges from 0 to 12 and divided into five symptom categories. Wu and colleagues applied three categories based on symptoms scores: 1-2: mild or slight, 3-6: moderate; 7-12: severe. Patel and colleagues applied four categories to symptom scores in the following way: 1-2: slight; 3-6: moderate; 8-9: severe; 12: very severe. PREPUBLICATION COPY: UNCORRECTED PROOFS 

IMPACT OF SELECT CHRONIC CONDITIONS IN WOMEN 7 • Several studies examined depression and major depressive episode (MDE). In one study, 23.8 percent of women had a diagnosis of at least one MDE 4. African American women had the highest percentage of MDE diagnosis (33.8 percent) compared to White women (29.9 percent). In addition, the study reported that postmenopausal women had 3.86 higher odds of MDE, compared to premenopausal women (Bromberger et al., 2011). A more recent study used the Center for Epidemiology Studies-Depression Scale (CES-D) to indicate severity of depressive symptoms; a CES-D score of 16 or higher indicated high depressive symptom levels. Study results suggested postmenopausal women had higher odds of high depressive symptoms levels compared to premenopausal women (Odds ratio: 1.49. 95% Confidence interval: 1.09-2.04) (Kravitz et al., 2022). • Approximately 60.0 percent of midlife women report problems with memory during late perimenopause and early menopause (Fuh et al., 2006; Greendale et al., 2009; Greendale et al., 2010; Sullivan Mitchell and Fugate Woods, 2001). Results of one study suggest that memory problems improved postmenopause, and memory returned to premenopausal levels (Greendale et al., 2009). • During menopausal transition stages, the incidence of urinary incontinence varied. Postmenopausal women had the lowest incidence (8.2 per 100-woman years), compared to women in late perimenopause (14.5 per 100-woman years) or early perimenopause (17.8 per 100,000) (Waetjen et al., 2009). • At baseline, when all women participating in the study were either pre- or early perimenopausal, 19.6 percent of women reported vaginal dryness. By the time the women were postmenopausal, or at the study’s end, about 34.0 percent of all women reported vaginal dryness (Waetjen et al., 2018). • Menopausal stage was not associated with frequency of sexual intercourse, emotional satisfaction with partner, or physical pleasure (Avis et al., 2009). IMPACT OF CHRONIC CONDITIONS THAT PREDOMINANTLY IMPACT WOMEN OR AFFECT WOMEN DIFFERENTLY Major Depressive Disorder, Including Postpartum Depression Depression disproportionately affects women in the United States (Hasin et al., 2018). According to the Diagnostic and Statistical Manual, Fifth Ed. (DSM-V), major depressive disorder (MDD) diagnostic criteria includes having at least five specific symptoms for at least 2 weeks and require a symptom of “depressed mood” and/or “markedly diminished interest or pleasure in all or most daily activities.” Other symptoms could include weight loss, insomnia, agitation, fatigue, feelings of worthlessness, decreased concentration or indecisiveness, and/or recurrent deaths or suicidal ideation (APA, 2013). Researchers have noted that determining prevalence trends for MDD is challenging because most published prevalence studies are based on the DSM-IV definition of MDD, which was replaced in 2013 and differs from the DSM-V (Hasin et al., 2018). 4 Major depressive episode diagnosis was based on the Structured Clinical Interview for Diagnostic and Statistical Manual, Fourth Ed. (DSM-IV) Axis I Disorders, and the interview was conducted during the course of the study (Bromberger et al., 2011). PREPUBLICATION COPY: UNCORRECTED PROOFS 

8 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN One study based on the 2012-2013 National Epidemiology Survey on Alcohol and Related Conditions III and using the DSM-V MDD definition found that the prevalence of experiencing MDD for at least 12 months was higher in women at 13.4 percent compared to men at 7.2 percent (Hasin et al., 2018). The same study measured lifetime MDD at 26.1 percent in women and 14.7 percent in men. The Behavioral Risk Factor Surveillance System (BRFSS) relies on self-report of lifetime diagnosis of depression, 5 which includes MDD and depression, dysthymia, and minor depression, and found that the prevalence in U.S. women was 30.7 percent compared to 16.3 percent in men (Lee et al., 2023). Although reporting on major depressive episode (MDE) as opposed to MDD, the 2022 National Survey on Drug Use and Health (NSDUH) (SAMHSA, 2023), an annual survey representative of the U.S. population, found that women had a higher prevalence of at least one MDE 6 at 10.4 percent compared to men at 7.0 percent. The survey also demonstrated that the prevalence of MDE in women decreased with increasing age as did the difference in prevalence between women and men. For example, the gender difference in those aged 18–25 was 25.2 percent for women versus 15.1 percent for men, 11.2 percent in women versus 8.2 percent in men at aged 26–49, and 4.0 percent in women compared to 1.1 percent in men aged 65 and older (SAMHSA, 2023). Reports on major depression prevalence by race and ethnicity in women were not readily available in NSDUH published reports. A subset of MDD occurs with pregnancy and/or the postnatal period. The DSM-V defines MDD with peripartum onset when symptoms occur during pregnancy or in the 4 weeks after delivery (APA, 2013). Three studies examining depressive symptoms in a small, non- representative sample of U.S. women during and after pregnancy found that the prevalence of depressive symptoms ranged from 3.0–25.2 percent (Haas et al., 2005; Herring et al., 2008; Rich-Edwards, 2006). One study using data from the 2018 Pregnancy Risk Assessment Monitoring System 7 had an estimated prevalence of self-reported postpartum depressive symptoms (PDS) 8 of 13.2 percent with prevalence decreasing from 22.2 percent in women aged 19 and younger versus 10.8 percent in women aged 35 and older (Bauman et al., 2020). American Indian and Alaska Native, non-Hispanic women had the highest prevalence at 22.0 percent, followed by 19.2 for 5 Survey participants were asked the following question to capture lifetime depression: “Has a doctor, nurse, or other health professional ever told you that you had a depressive disorder, including depression, major depression, dysthymia, or minor depression?” 6 In the 2021 NSDUH, respondents were classified as having MDE in the past 12 months if (1) they had at least one period of 2 weeks or longer in the past year when for most of the day nearly every day, they felt depressed or lost interest or pleasure in daily activities; and (2) they also had problems with sleeping, eating, energy, concentration, self-worth, or recurrent thoughts of death or recurrent suicidal ideation. 7 According to the article, “[Pregnancy Risk Assessment Monitoring System] collects site-specific, population-based data on self-report maternal behaviors and experiences before, during, and shortly after pregnancy. From each of the 50 continuously participating sites, a stratified, random sample of women with a recent live birth (singleton or multiple births) is selected monthly from birth certificate files. and these women are surveyed 2–6 months postpartum (average = 4 months) using a standardized protocol and questionnaire” (Bauman et al., 2020). 8 Self-report PDS were based on questions adapted from the Patient Health Questionnaire-2. “1) Since your new baby was born, how often have you felt down, depressed, or hopeless? And 2) Since your new baby was born, how often have you had little interest or little pleasure in doing things? Women responding ‘always’ or ‘often’ to either question were classified as experiencing PDS.” PREPUBLICATION COPY: UNCORRECTED PROOFS 

IMPACT OF SELECT CHRONIC CONDITIONS IN WOMEN 9 Asian American and Pacific Islander women, non-Hispanic women, 18.2 percent for non- Hispanic Black women, 16.3 percent for other non-Hispanic women, 12.0 percent for Hispanic women, and 11.4 percent for non-Hispanic White women. Substance Use Disorder Substance use disorder (SUD), also known as “substance-related and addictive disorders” in DSM-V, reflects excess use of: alcohol, caffeine, cannabis, hallucinogens, inhalants, opioids, sedatives, hypnotics and anxiolytics, stimulants, tobacco, and other or unknown substances and use associated with 11 symptoms, including larger amounts of the substance taken than intended; craving; interference with work, home, or school responsibilities; and negative effects on social interactions with people, tolerance, and withdrawal (APA, 2013). NSDUH reports data on substance use, including SUD, and mental health (SAMHSA, 2023). In the 2022 survey, the prevalence of SUD in the past year was higher in men 12 years or older at 20.0 percent compared to women at 14.7 percent (SAMHSA, 2024). The prevalence in women displays in inverted U shape by age, rising from 9.9 percent of women aged 12–17 to 26.7 percent of women aged 18– 25 and then declining to 13.3 for aged 26 and older (SAMHSA, 2024). NSDUH does not report data by gender and race and ethnicity. Human Immunodeficiency Virus According to the Centers for Disease Control and Prevention (CDC), human immunodeficiency virus (HIV) is a virus that attacks the body’s immune system. If untreated, it can lead to acquired immunodeficiency syndrome (AIDS) (CDC, 2022a). Most states and Territories are required by law or regulations to report all confirmed HIV diagnoses, which provides a picture of U.S. HIV incidence and prevalence (CDC, 2023a). 9 The data described next provides detailed information on HIV (both incidence and prevalence) including by age and race and ethnicity. In addition, individuals newly diagnosed and living with HIV by transgender groups are also available. Although women represent a small proportion of new HIV cases and the U.S population living with HIV/AIDS, there are important and distinct characteristics of HIV infection in women versus men. New HIV Diagnoses The CDC National HIV Surveillance System reports a rate of new U.S. HIV diagnoses in 2021 of 12.7 per 100,000 or 35,716 new HIV diagnoses (CDC, 2023b). Females assigned sex at birth 10 who were 13 years and older accounted for approximately 18 percent of these in 2021, representing a rate of new HIV diagnoses of 4.6 per 100,000 (CDC, 2023b). Males assigned sex at birth11 accounted for a majority of new diagnoses of HIV and a higher rate at 21.1 per 100,000. The rate of new HIV diagnoses initially increased with age, from 1.9 per 100,000 in females assigned sex at birth aged 15–19 to 8.4 per 100,000 in females assigned sex at birth aged 9 According to the CDC, as of November 2022, 49 states, the District of Columbia, and Puerto Rico had laws for requiring all CD4 and viral load data to be reported. Of these, 29 states and Puerto Rico also explicitly required molecular data reporting. Idaho and the Virgin Islands do not meet the criteria for reporting all viral load and CD4 count data (CDC, 2023a). CDC estimates that about 12.7 percent of individuals with HIV are undiagnosed (CDC, 2023c). 10 According to CDC (2023b), data include transgender and additional gender identity persons. PREPUBLICATION COPY: UNCORRECTED PROOFS 

10 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN 30–34 and 35–39 but decreased from 7.3 per 100,000 in females assigned sex at birth aged 40– 44 to 2.6 per 100,00 in women aged 60–64. Black and African American females assigned sex at birth had the highest rate at 19.5 per 100,000, followed by multiracial females assigned sex at birth at 7.5 per 100,000, Hispanic females assigned sex at birth and Latinas at 4.8 per 100,000, American Indian and Alaska Native females assigned sex at birth at 4.4 per 100,000, Native Hawaiian and Pacific Islander females assigned sex at birth at 3.9 per 100,000, White females assigned sex at birth at 1.8 per 100,000, and Asian American females assigned sex at birth at 1.1 per 100,000. Although HIV is reported for transgender women, transgender men, and other gender identity groups, the rate per 100,000 was not reported. 2021 had 811 new HIV diagnoses in transgender women, 56 in transgender men, and 44 in individuals with other gender identities. 11 Persons Living with Diagnosed HIV Infection CDC’s National HIV Surveillance System reported that the rate of persons living with diagnosed HIV infection was 382.2 per 100,000, or 1.1 million individuals. Males assigned sex at birth aged 13 and older accounted for the majority with a rate of 598.1 per 100,000 compared to 172.9 per 100,000 for women (CDC, 2023b). The rate increased by age from 12.1 per 100,000 in females assigned sex at birth aged 15–19 to a peak of 343.3 per 100,000 in females assigned sex at birth aged 55–59 and decreased to 274.3 per 100,000 in females assigned sex at birth aged 60–64. Black and African American females assigned sex at birth living with HIV had the highest rate, at 781.6 per 100,000, followed by multiracial females assigned sex at birth at 483.6 per 100,000, Hispanic/Latino females assigned sex at birth at 188.6 per 100,000, American Indian and Alaska Native females assigned sex at birth at 76.5 per 100,000, Native Hawaiian and Pacific Islander females assigned sex at birth at 59.9 per 100,000, White females assigned sex at birth at 46.8 per 100,000, and Asian females assigned sex at birth at 32.3 per 100,000. In 2021, 13,110 transgender females assigned sex at birth were living with HIV, along with 574 transgender men and 361 individuals with other gender identity (CDC, 2023b). Migraine/Headache The third edition of the International Classification of Headache Disorders organizes headaches as primary headaches, secondary headaches, and painful cranial neuropathies (International Headache Society, 2018). Migraine is a primary headache disorder with two major types, with and without aura. Migraine without aura for adults is defined as a headache lasting a minimum of 4 hours with specific symptoms of photophobia, phonophobia and nausea. Migraine with aura is identified by transient neurological symptoms that accompany or precedes the headache. Using 2021 National Health Interview Survey (NHIS) data, researchers determined that headache or migraine 12 prevalence in adults was 4.3 percent. Women reported a higher prevalence of 6.2 percent compared to 2.2 percent for men (NCHS, 2023). NHIS data from 2018 11 According to CDC (2023b), “’transgender woman’ includes individuals who were assigned ‘male’ sex at birth but have ever identified as ‘female’ gender, ‘transgender man’ includes individuals who were assigned ‘female’ sex at birth but have ever identified as ‘male’ gender. Additional gender identity examples include ‘bigender,’ ‘gender queer,’ and “two-spirit.’ Adults 18 years or older who reported being “bothered a lot by headache or migraine in the past three 12 months.” PREPUBLICATION COPY: UNCORRECTED PROOFS 

IMPACT OF SELECT CHRONIC CONDITIONS IN WOMEN 11 showed the prevalence of women “who had a severe headache or migraine in the past three months” was 20.1 percent compared to 10.6 percent for men, though this difference decreased by age (NCHS, 2020). The prevalence of severe headache or migraine was 25.5 percent in women aged 18–44 compared to 7.6 in women 75 years or older. One group used NHIS data and reported similar age-adjusted prevalence of severe headache or migraine over time from 2005– 2018 for both women and men (Burch, 2020). In 2018, American Indian and Alaska Native adults had the highest prevalence at 22.1 percent, compared to White adults at 16.3 percent, Black or African American adults at 15.6 percent, and Asian American adults at 9.1 percent; this study did not report race and ethnicity data by gender. Cardiometabolic Conditions This section describes the impact of cardiometabolic conditions. Cardiovascular disease (CVD) includes coronary heart disease, heart failure, stroke, and hypertension. Risk factors for cardiovascular disease and stroke include Type 2 diabetes, obesity, and cardiometabolic syndrome. CVD CVD is a disease of heart and blood vessels and causes significant U.S. mortality and morbidity. Each year the American Heart Association (AHA), in collaboration with the National Institutes of Health (NIH), summarizes the most recent health data, including heart disease and stroke (Tsao et al., 2023). Using NHANES 2017–2020 data, investigators estimated the prevalence pf CVD (which includes coronary heart disease, heart failure, stroke, and hypertension) in adults 20 years or older was 48.6 percent. Women reported a lower prevalence of 44.8 percent compared to men at 52.4 percent. Among women aged 20–29, the prevalence of CVD with hypertension was 20.0 percent compared to 76.3 percent in women aged 60–79 years, and highest among those 80 years and older, with a similar age trend for men. Non-Hispanic Black women had the highest prevalence of cardiovascular disease at 59.0 percent, followed by non-Hispanic White women at 44.6 percent, non-Hispanic Asian American women at 38.5 percent, and Hispanic women and Latinas at 37.3 percent (Tsao et al., 2023). NHANES 2017–2020 data showed that the prevalence of CVD without hypertension was 9.9 percent, with women at 9.2 percent compared to 10.9 percent for men. The prevalence of was 1.6 percent in women aged 20–39 years compared to 19.6 percent in women aged 60–70, and 32.8 percent in women aged 80 years and older. Non-Hispanic Black women had the highest prevalence at 11.1 percent, followed by non-Hispanic White women at 9.2 percent, Hispanic women and Latinas at 8.4 percent, and Asian American women at 4.9 percent (Tsao et al., 2023). Stroke Based on NHANES 2017–2020, the prevalence of stroke in adults aged 20 and older was 3.3 percent (Tsao et al., 2023). Women had a slightly higher prevalence of 3.6 percent compared to 2.9 percent for men. Women aged 20–39 had the lowest prevalence at 0.6 percent, and women aged 80 years and older had the highest prevalence at 14.0 percent. Men had a similar increase in stroke prevalence with age. Non-Hispanic Black women had the highest prevalence (5.4 percent), followed by non-Hispanic White women at 3.6 percent, Hispanic women at 2.5 percent, and Asian American women at 1.5 percent. PREPUBLICATION COPY: UNCORRECTED PROOFS 

12 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN Type 2 Diabetes Diabetes influences health outcomes across the life course in both men and women. It is estimated that 38.1 million U.S. adults 18 years and older have diabetes. About 90–95 percent of diabetes cases are Type 2 diabetes 13 (CDC, 2024). Data from the most recent National Diabetes Statistic Report which uses NHANES data (CDC, 2024) shows a crude diabetes prevalence of 15.4 percent for men and 14.1 percent for women aged 18 years and older (Bullard et al., 2018), which includes both diagnosed and undiagnosed diabetes. Individuals classified as “diagnosed diabetes” self-reported having ever received a diagnosis of diabetes from a physician and those diagnosed as having “undiagnosed diabetes” were based on fasting plasma glucose of greater than 126 mg/dl and HbA1C of 6.5 percent or higher among people self-reporting no diabetes. Considering the distribution of diagnosis by race and ethnicity, American Indian and Alaska Native women had the highest prevalence of diagnosed diabetes at 13.7 percent, followed by 12.5 percent of non-Hispanic Black women, 11.3 percent of Hispanic women and Latinas, 7.8 percent of Asian American, and 6.1 percent of non-Hispanic White women (CDC, 2024). In addition, considering education and income, diabetes prevalence was highest in lower socioeconomic groups. Specifically, the highest prevalence of diabetes was found in 14.8 percent of women with less than a high school education and 13.6 percent of women with incomes less than 100 percent of the federal poverty level. By region, the prevalence of diabetes was higher for women living in non-metropolitan areas (8.6 percent) (CDC, 2024). The incidence of Type 2 diabetes among children and adolescents aged 10–19 was 17.9 per 100,000 in 2017–2018, based on the SEARCH for Diabetes in Youth study. 14 The incidence with girls at 21.6 and boys at 14.3 per 100,000, a significant increase from 11.1 and 7.0 per 100,000 respectively in 2002–2003 (Wagenknecht et al., 2023). Obesity Obesity is based on BMI, 15 an indirect measure of body fat based on weight and height. NHANES measures BMI through a household interview and physical examination obtaining both weight and height measures. Based on NHANES 2017–2018 data, the prevalence of obesity in adults 20 years and older was 42.4 percent. Women had a slightly lower prevalence at 41.9 percent compared to 43.0 percent for men (Hales et al., 2020). Among women, the prevalence was 39.7 percent in women aged 20–39 years and 43.3 percent in women aged 40–59 years and 60 and older. Non-Hispanic Black women had the highest prevalence of obesity at 56.9 percent, followed by Mexican American women at 49.6 percent, Hispanic women and Latinas at 43.7 percent, non-Hispanic White women at 39.8 percent, and non-Hispanic Asian American women at 17.2 percent. For children and adolescents, obesity is defined as a BMI value at the 95th percentile or greater. Based on NHANES 2017–2018, the prevalence in children and adolescents aged 2–19 was 19.3 percent (Fryar et al., 2020). In girls, the prevalence was 18.0 percent versus 20.5 13 Other forms of diabetes are Type 1 diabetes and gestational diabetes however, most of the data presented reflects Type 2 diabetes unless otherwise specified (CDC, 2024). 14 SEARCH for Diabetes in Youth study is a population-based surveillance study on the incidence of Type 1 and Type 2 diabetes in U.S. children and young people conducted over the 17-year period from 2002–2018 (Wagenknecht et al., 2023). 15 BMI is reported as weight status, underweight (BMI below 18.5), healthy weight (BMI 18.5–24.9), overweight (BMI 25.0–29.9) and obesity (BMI 30.0 and above) (CDC, 2022b). PREPUBLICATION COPY: UNCORRECTED PROOFS 

IMPACT OF SELECT CHRONIC CONDITIONS IN WOMEN 13 percent in boys. Girls aged 2–5 years had the lowest prevalence of obesity at 12.2 percent, compared to 19.2 percent of 6–11–year-olds and 19.9 percent of 12–19–year-olds Non-Hispanic Black girls had the highest prevalence of obesity at 29.1 percent, followed by Mexican American girls at 24.9 percent, Hispanic girls and Latinas at 23.0 percent, non-Hispanic White girls at 14.8 percent, and non-Hispanic Asian American girls at 5.1 percent. Metabolic Syndrome The accumulation of fat within the abdominal cavity is a key component of the metabolic syndrome, which is defined as any combination of three of the following: abdominal obesity, elevated fasting glucose levels, high circulating lipid levels, and hypertension. Metabolic syndromes reflect a grouping of risk factors for cardiovascular disease and Type 2 diabetes. A diagnosis of metabolic syndrome requires elevated levels of at least three of five clinical measures: waist circumference, triglycerides, blood pressure, fasting glucose, and high density lipoprotein-cholesterol (Alberti et al., 2009). Based on 2017-2018 NHANES survey data, the overall prevalence for metabolic syndrome was 37.1 percent (Yang et al., 2022). The prevalence of metabolic syndrome in women was 35.6 percent versus 38.7 percent in men (Yang et al., 2022). Multiple Sclerosis Diagnosis of multiple sclerosis (MS) is based on clinical presentation of the number of attacks and the evidence of lesions in at least two separate areas of the central nervous system (CNS), including the brain, spinal cord and optic nerves (Thompson et al., 2018), although additional information such as lesions in other areas of the CNS or the development of new CNS lesions over time to confirm diagnosis (Thompson et al., 2018). Using data from multiple health care claim sources, one group reported a 10-year cumulative U.S. prevalence was 309.2 per 100,000 in 2010 (Wallin et al., 2019). It was 450.1 per 100,000 in women compared to 159.7 per 100,000 in men. The prevalence in women aged 18–24 was 50.9 per 100,000, compared to a peak of 703.8 per 100,000 for women aged 55–64 and 228.5 per 100,000 for women aged 75 or older. Using 2010 claims data from Kaiser Permanente Southern California, another group found similar results for prevalence by gender (Langer-Gould et al., 2022). This study reported a prevalence of 352.6 per 100,000 in non-Hispanic White women, 337.4 per 100,000 in Black women, 99.9 per 100,000 in Hispanic women and Latinas, and 35.8 per 100,000 in Asian American and Pacific Islander women. In addition, the prevalence of MS in non-Hispanic White women peaked at 538.5 per 100,000 between the ages of 55 and 64 years compared to a peak of 452.4 per 100,000 in Black women over the same age range. Another study demonstrated similar results using 2010 data from multiple health claim sources (Hittle et al., 2023), women had a prevalence rate of 468.9 per 100,000 compared to 163.0 per 100,000 in men. The prevalence in non-Hispanic White women was 543.3 per 100,000 followed by non-Hispanic Black women at 429.8 per 100,000, women of other non-Hispanic racial and ethnic groups at 290.6 per 100,000, and Hispanic women and Latinas at 235.3 per 100,000. This study also found that women aged of 45–54 had the highest MS prevalence for every race and ethnic group. PREPUBLICATION COPY: UNCORRECTED PROOFS 

14 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN Systemic Lupus Erythematosus Systemic lupus erythematosus (SLE) is a rare autoimmune disease. The 2019 European League Against Rheumatism and American College of Rheumatology (ACR) developed a complicated classification criteria for SLE based on a set of immunological and clinical assessment (Aringer et al., 2019).The criteria are based on the presence of “antinuclear antibodies (ANA) at a titer of >=1:80 HEp-2 cells or an equivalent positive test” along with at least the presence of one clinical criteria and a score that equals 10 or more points. These criteria include clinical (constitutional, hematologic, neuropsychiatric, mucocutaneous, serosal, musculoskeletal, renal) and immunological (antiphospholipid antibodies, complement proteins, and SLE-specific antibodies) domains. A criterion is not considered toward the score if another explanation is possible. CDC supports multiple population-based SLE registries. A meta-analysis of registry data from Michigan, Georgia, New York, and California estimated an overall 2018 age-standardized prevalence of 72.8 per 100,000 persons. The estimated prevalence was higher in women (128.7 per 100,000) compared to men (14.6 per 100,000). In addition, by race, American Indian and Alaska Native women had the highest prevalence (270.6 per 100,000) followed by Black women (230.9 per 100,000), White women (84.7 per 100,000), and Asian and Pacific Islander women (84.4 per 100,000) (Izmirly et al., 2021). In a study of patients for over 40 years (1976–2018) in Olmsted County, Minnesota, the investigators noted an increasing prevalence over the decades, rising from 30.7 per 100,000 in 1985 in men and women combined to 97.4 per 100,000 in 2015 (Duarte-García et al., 2022) and also increasing trends in incidence, although that is difficult to measure given diagnostic challenges. A study utilizing data from the 2016–2018 Medical Expenditure Panel Survey (MEPS) identified adults who self-reported SLE and had either a record of SLE-related medication or a rheumatologist visit within the calendar year. The prevalence of SLE was estimated at 195.0 per 100,000 adults. The prevalence rate for women was higher at 90.8 per 100,000, compared to 9.2 per 100,000 for men (Grabich et al., 2022). Chronic Pain Pain is defined as “an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage” 16; in the 2020 definition from the International Association for the Study of Pain (IASP) (Raja et al., 2020). Chronic pain is defined as lasting longer than 3 months and causing significant effects on daily life and physical and mental health (Treede et al., 2019). Based on NHIS data, the age-adjusted prevalence in 2021 was 20.5 percent in women and 18.8 percent in men (Rikard et al., 2023). Duca and colleagues (2023) reviewed several surveillance systems that monitor pain and concluded that 16 Included in the IASP pain definition are the accompanying notes: “Pain is always a personal experience that is influenced to varying degrees by biological, psychological, and social factors. Pain and nociception are different phenomena. Pain cannot be inferred solely from activity in sensory neurons. Through their life experiences, individuals learn the concept of pain. A person’s report of an experience as pain should be respected. Although pain usually serves an adaptive role, it may have adverse effects on function and social and psychological well-being. Verbal description is only one of several behaviors to express pain; inability to communicate does not negate the possibility that a human or non-human animal experiences pain” (Raja et al., 2020). PREPUBLICATION COPY: UNCORRECTED PROOFS 

IMPACT OF SELECT CHRONIC CONDITIONS IN WOMEN 15 NHIS is the best source for pain data given various attributes, such as the questions were tested cognitively, representative of the U.S. population, timely given that the survey is administered annually, data collection is standardized. Fibromyalgia The ACR 2010 diagnostic criteria for fibromyalgia includes the following three conditions: having widespread pain and severe symptoms, 17 symptoms present for at least 3 months, and no other disorders that would explain the pain (Wolfe et al., 2010). The Widespread Pain Index (WPI) lists 19 areas in the body where pain may exist, and symptom severity examines fatigue, sleep, and cognition and symptoms severity and magnitude. Although these diagnostic criteria are established, challenges arise in measuring prevalence, given that symptoms are broad and may overlap with other conditions (Vincent et al., 2013). These challenges likely contribute to the paucity of national studies reporting fibromyalgia prevalence. One study demonstrated the challenges in interpreting fibromyalgia prevalence data. NHIS collects information on fibromyalgia diagnosis based on self-report. The authors then compare that data to a NHIS-derived measure that serves as the clinical proxy, based on the ACR diagnostic criteria. The study found that 1.8 percent of individuals self-reported fibromyalgia, but nearly 73.5 percent of them did not meet the proxy, suggesting potential misclassification between self-reported and clinically determined fibromyalgia (Walitt et al., 2016). A study of prevalence in Olmstead County, Minnesota employed two methods. One approach reviewed medical records of individuals with diagnosed fibromyalgia and determined the age-adjusted prevalence was 1.1 percent, with an age-adjusted prevalence of 2.0 percent in women and 0.2 percent in men (Vincent et al., 2013). The second approach used a mailed survey and determined the age-adjusted prevalence as 6.4 percent, with 7.7 percent of women reporting they had fibromyalgia versus 4.9 percent of men. The investigators noted that the prevalence may be underestimated given that a standard clinical approach to assessing and diagnosing fibromyalgia does not exist. They also pointed out that observed gender differences may be affected by greater health-care-seeking behavior in women than men and differences in symptoms of pain and tender areas reported between women and men. They did not report fibromyalgia prevalence by gender, race, or ethnicity. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating condition with unknown etiology and symptoms. Results from studies examining fibromyalgia and ME/CFS are limited in their interpretation because diagnostic criteria overlap, they do not state the definition used for diagnosis, or they employed limited comparison or control groups. A 2015 Institute of Medicine (IOM) 18 report proposed diagnostic criteria for ME/CFS that requires three symptoms: a significant reduction in the performance of activities for more than 6 months that is not relieved by rest and not initiated by overexertion; malaise following exertion; and 17 WPI >=7 and symptom severity (SS) scale score >=5 or WPI 3–6 and SS scale score >=9. 18 As of March 2016, the Health and Medicine Division of the National Academies of Sciences, Engineering and Medicine (the National Academies) continues the consensus studies and convening activities previously carried out by the IOM. The IOM name is used to refer to reports issued prior to July 2015. PREPUBLICATION COPY: UNCORRECTED PROOFS 

16 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN “unrefreshing” sleep (IOM, 2015). A diagnosis also requires at least one of two additional criteria or manifestations, either cognitive impairment or orthostatic intolerance, which refers to experiencing a fall in blood pressure that resolves when the individual sits or lies down. In addition, for malaise, sleep, and cognitive impairment, the symptoms should occur more than half of the time, and their intensity should be moderate, substantial, or severe. The committee authoring that report did not require pain as a symptom in its proposed ME/CFS diagnostic criteria because although individuals commonly experience pain, no evidence suggests that it is different than those experienced by healthy individuals or those with other conditions. A recent study using NHIS data reported an overall ME/CFS prevalence of 1.3 percent, with a prevalence of 1.7 percent in women compared to 0.9 percent in men (Vahratian et al., 2023). The study also reported a prevalence of 2.1 percent in adults aged 60–69 compared to 0.7 percent in adults aged 18–39. The study, which did not report data on gender, and race and ethnicity by gender, found that non-Hispanic White individuals had the highest prevalence at 1.5 percent, compared to non-Hispanic Black individuals at 1.2 percent; Hispanic and Latina/Latino individuals at 0.8 percent, and non-Hispanic Asian American individuals at 0.7 percent. Alzheimer’s Disease Alzheimer’s disease (AD) is a neurological, degenerative disorder characterized by brain pathological changes over many years that eventually give rise to behavioral alterations, cognitive deficits, and dementia (also referred to as “Alzheimer dementia”). As with many neurodegenerative diseases, its progression represents as a continuum of pathological changes in the brain that accumulate over decades and result in behavioral and cognitive impairments. It has three stages: preclinical, with at least one biomarker without overt cognitive issues; prodromal, also referred to as “mild cognitive impairment,” marked by the onset of memory loss in addition to pathological biomarkers; and dementia, the final stage that impairs activities of daily living (Ferretti et al., 2018). In 2023, approximately 6.7 million U.S. individuals aged 65 and older had Alzheimer’s dementia, equivalent to 1 in 9 adults in this age group (Alzheimer's Association, 2023; Rajan et al., 2021). A study of Medicare data that included Medicare Advantage encounter data and traditional Medicare claims data reported a prevalence of 7.9 percent for beneficiaries aged 65 years and older in 2017. The prevalence was only slightly higher in women than men after age adjustment 7.6 versus 6.5 percent (Haye et al., 2023). In the nationally representative Health and Retirement Study, the age-standardized prevalence in persons aged 65 and older was 8.5 percent in 2016, and 9.3 percent in women versus 6.8 percent in men (Hudomiet et al., 2022). The study also reported a decline in prevalence from 2000–2016 in both men and women (Hudomiet et al., 2022). This difference in prevalence number and overall lifetime risk between women and men is believed to be related to the longer life expectancy in women, but remains controversial (Ferretti et al., 2018). These studies did not report by gender and racial and ethnic groups. Osteoporosis The 2020 American Association of Clinical Endocrinologists/American College of Endocrinology Clinical Practice Guidelines for the Diagnosis and Treatment of Postmenopausal Osteoporosis states that the diagnosis is based on fragility fractures without other metabolic bone disorders, even with a normal bone mineral density as measured by a T-score. Osteoporosis is also diagnosed based on a T-score of −2.5 or lower in the lumbar spine, femoral neck, or 33 PREPUBLICATION COPY: UNCORRECTED PROOFS 

IMPACT OF SELECT CHRONIC CONDITIONS IN WOMEN 17 percent radius, even without a prevalent fracture, or a T-score between −1.0 and −2.5 and increased fracture risk using the FRAX® fracture risk assessment tool (Camacho et al., 2020). Similar diagnostic guidance has been developed by the Bone Health and Osteoporosis Foundation (BHOF) in a clinician’s guide to prevent and treat osteoporosis (Leboff et al., 2022). According to BHOF, an estimated 54 million individuals in the United States have low bone mineral density or osteoporosis (BHOF, 2023), but prevalence data for osteoporosis are limited; two sources of prevalence data demonstrate a different range—from 10.8 percent based on Centers for Medicare and Medicaid Services claims data to 19.6 percent in women aged 50 and older reported in NHANES for 2017-2018 (Sarafrazi et al., 2021), based on confirmation by bone mineral density value using dual-energy X-ray absorptiometry (DXA). NHANES data showed that the prevalence was 19.6 percent in women compared to 4.4 percent in men. The prevalence of low bone mass, a precursor to osteoporosis was 51.5 percent in women and 33.5 percent in men. Longitudinal NHANES data showed that the prevalence increased in women from 2007–2008 (14.0 percent) to 2017–2018 (19.6 percent) (Sarafrazi et al., 2021). Data from NHANES 2013–2014 reported prevalence percentages by race and ethnicity in women 50 years and older (Looker et al., 2017). The prevalence was 2.4 percent in non-Hispanic Black women, 17.0 percent in non-Hispanic White women, 20.5 percent for Hispanic women, and 40.0 percent in non-Hispanic Asian women. Limited data are available for ethnic subgroups of Asian American women, but one group compared bone mineral density results between White women and women of Filipino, Chinese, and Japanese ancestry (Lo et al., 2020). The Asian subpopulations were similar, but women in Asian ethnic groups had a 30–50 percent lower bone mineral density than non-Hispanic Back or White women. Low bone mass can be used as a risk factor or indicator for osteoporosis. NHANES data show that the prevalence of low bone mass as measured using DXA was 50.3 percent in women aged 50–65 compared to 33.5 percent in men (Sarafrazi et al., 2021) and 52.9 percent of women 65 years or older compared to 40.7 percent of men (Sarafrazi et al., 2021). Fractures are indicators of osteoporosis. The fractures most likely due to osteoporosis are fractures of the femoral neck, pathologic fractures of the vertebrae, and lumbar and thoracic and vertebral fractures (Warriner et al., 2011). Hip fractures are another osteoporosis-related injury. The majority of hip fractures in both men and women occur among those aged 75–84 (Brauer, 2009). Medicare claims data suggest that hip fracture rates in women aged 65 and older declined each year from 2002–2012 and then plateaued at levels higher than projected for 2013, 2014, and 2015 which is estimated to have resulted in more than 11,000 additional hip fractures over those three years (Lewiecki et al., 2018). Similarly, based on data from commercial and Medicare Advantage plan members aged 50 and older, fracture rates no longer declined between 2007– 2017, and for some specific fracture types, rates were rising (Lewiecki et al., 2020; Lewiecki et al., 2019). Among Medicare beneficiaries, 18 percent of patients who had a fracture died after it compared to 9.3 percent who did not, with death rates at 20 percent for men and 11 percent for women (Williams et al., 2021). Sarcopenia Sarcopenia is a musculoskeletal disease that includes symptoms of loss of muscle mass, weakening muscle strength and function and is more likely to occur in older adults. It is a relatively new condition whose diagnostic code was introduced in 2016 (M62.84) (Anker et al., 2016). Several organizations have developed definitions (Asian Working Group for Sarcopenia, PREPUBLICATION COPY: UNCORRECTED PROOFS 

18 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN European Working Group on Sarcopenia in Older People (EWGSOP), Foundation for the National Institutes of Health (FNIH) Sarcopenia Project, International Working Group on Sarcopenia (IWGS), and the National Institute of Aging (NIA) and FNIH-funded Sarcopenia Definitions and Outcomes Consortium). EWGSOP’s definition, specifically its revised version (EWGSOP2), is the one mostly widely used (Yuan and Larsson, 2023); it provides thresholds reflective of low levels of grip strength, muscle mass, and performance, such as walking speed (Cruz-Jentoft et al., 2019). The FNIH Sarcopenia Project developed evidence-based thresholds for both grip strength and muscle mass, based on a pooled sample of 26,625 participants from nine studies of older individuals (Studenski et al., 2014). A later effort of FNIH and NIA, the Sarcopenia Definition and Outcomes Consortium, developed a similar definition, based on a review of epidemiologic studies (Bhasin et al., 2020). Across these various definitions, thresholds and methods used in the diagnostic criteria differ (Petermann‐Rocha et al., 2022). The lack of an agreed-upon definition and diagnostic criteria makes it difficult to estimate the impact and prevalence of sarcopenia (Petermann‐Rocha et al., 2022). One group conducted a literature review and meta-analysis to estimate the prevalence and found that most studies were in Europe, Asia, or Africa (Petermann‐Rocha et al., 2022). Depending on which diagnostic criteria a study used, the prevalence was 10.0–27.0 percent. For women, it was 2–21 percent, compared to 11.0 –21.0 percent for men. Studies using EWGSOP criteria reported that it was 2.0 percent in women and 11.0 percent in men, but studies using the IWGS criteria reported a prevalence of 17.0 percent for women compared to 12.0 percent for men. The meta-analysis did not report prevalence by gender for race and ethnicity. ECONOMIC BURDEN In addition to the magnitude of the impact these conditions have on women, it is important to understand the economic burden of these conditions. The effect both directly on health care costs and indirectly on productivity provides an additional dimension of the burden on the individual and society. The following section describes examples of the economic burden of five female-specific and gynecologic conditions (vulvodynia, endometriosis, uterine fibroids, PFD, and menopausal symptoms), two conditions that affect women during and after pregnancy (maternal mental health conditions and delivery preterm as a risk factor for cardiovascular disease), and those conditions with a high prevalence in women (migraines, osteoporosis, and sarcopenia). Vulvodynia Data are limited on the economic burden of vulvodynia. One Web-based survey of 300 respondents examined the direct cost of vulvodynia, estimating that it that totaled nearly $9,000 per patient over 6 months. Of this, 68 percent was related to direct health care costs. The study further estimated that the annual cost of $17,724.80 per woman was much higher than the estimated mean expenditure for medical care per woman of $3,219 in the 2000 MEPS. The study estimated the national economic burden of vulvodynia was in the range of $31–$72 billion (Xie et al., 2012). PREPUBLICATION COPY: UNCORRECTED PROOFS 

IMPACT OF SELECT CHRONIC CONDITIONS IN WOMEN 19 Endometriosis The annual U.S. total cost for endometriosis was estimated at approximately $22 billion in 2002 based on a systematic review of available literature from 1990 through 2006. (Simoens et al., 2007). Since that time several researchers have explored different aspects of the costs associated with endometriosis. One group analyzed commercial claims data from 2000–2010 to compare the costs between women with endometriosis versus matched women without the condition (Fuldeore et al., 2015). Overall, in the first year after diagnosis, mean total health care cost, including inpatient, outpatient, emergency department, and pharmacy costs, was $13,199 compared to $3,747 for their matched pairs. In addition, women with endometriosis had higher health care use before and after diagnosis. An earlier study also found higher cost and use in women with endometriosis compared to those without (Mirkin et al., 2007), and reported that 64 percent of women with endometriosis underwent related surgical procedure, such as hysterectomy or laparotomy, contributing to an average of approximately 13 days of lost time at work per procedure (Mirkin et al., 2007). Productivity, both household and in employment, is also affected. One group surveyed women aged 18–49 with endometriosis and examined reported productivity at both work and at home (Soliman et al., 2017). Overall, with a mean of 37.7 hours in a work week, experienced 6.3 hours of reduced productivity. For household work, with a mean of 15.6 hours, they had a mean of 4.9 hours of reduced productivity. An increase in lost productivity was associated with greater severity and number of symptoms. Delays in diagnosis also influence health care costs. Analyzing commercial and Medicare Advantage claims data, one group found that women with diagnostic delays of less than 1year had average health care cost of $21,489 compared to $34,460 for women who experienced delays of 3–5 years (Surrey et al., 2020). Dysmenorrhea is closely linked to endometriosis; despite some estimates of economic consequences of dysmenorrhea in countries other than the United States, little U.S.-specific evidence exists. Uterine Fibroids A systematic review of the literature was conducted to estimate the number of women seeking treatment for uterine fibroids each year and the associated direct and indirect costs (Cardozo et al., 2012). The estimated annual direct costs (including surgery, hospital admissions, outpatient visits, and medications), ranged from $4.1–$9.4 billion. The estimated annual costs of lost work ranged from $1.5–$17.2 billion. Obstetric outcomes attributed to fibroids incurred costs between $238 million–$7.76 billion each year. Overall, uterine fibroids were estimated to cost the U.S. $5.9 –$34.4 billion annually (in 2010 dollars). Pelvic Floor Disorders Limited studies have examined the economic burden of PFD. One study evaluated the costs of ambulatory care related to female PFD based on data from the U.S. National Ambulatory Medical Care Survey. The estimated average annual cost of ambulatory physician services related to PFD (adjusting for deductibles and copayments) was $412 million in 2005– 2006 compared to $262 million in 1996–1997 (Sung et al., 2010). Another study examined the economic impact of surgical treatment for fecal incontinence in women based on data from the Nationwide Inpatient Sample, an all-payer national database, from 1998–2003 (Sung et al., PREPUBLICATION COPY: UNCORRECTED PROOFS 

20 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN 2007). The total inpatient hospital cost was estimated at $29.5 million in 2003, up from $22.8 million in 2001. In addition, the actual cost per surgical admission was about $6,980 in 2003, up from $6,500 in 2001. In a multivariable regression, factors significantly associated with cost per surgical admission were length of stay, number of procedures, age, and non-White racial group (Sung et al., 2007). Menopausal Symptoms Using 2000–2002 MEPS data, one group examined the economic burden of menopausal symptoms and gynecologic conditions, including menstrual disorders, endometriosis, and prolapse of female genital organs (Kjerulff et al., 2007). This study estimated the annual health care cost related to menopausal symptoms and gynecologic conditions at $3.0 billion and $10.5 billion, respectively. Other investigators examined the effect of menopausal symptoms on work productivity (Faubion et al., 2023). Based on an estimate of 10.8 percent of women missing a day of work per year and with a mean of 3 days of missed work annually, the researchers estimated the cost to be $1.8 billion per year. Major Depressive Disorder and Maternal Mental Health Conditions Data on the economic burden of MDD on women across the life course is limited. A recent study offers a detailed analysis of the societal costs associated with MDD among U.S. adults in 2019 (Greenberg et al., 2023). The study estimated that approximately 19.8 million adults in the U.S. were affected by MDD. Of these, 62.7 percent were women, and 32.9 percent were individuals classified as severe. The study calculated the additional societal economic burden of MDD to be approximately $16,854 per affected adult. The main factors contributing to these costs included healthcare expenses, costs related to household maintenance, presenteeism, 19 and absenteeism. The study did not provide data on the incremental costs specific to women. One study examined the economic burden of mental health conditions in women giving birth in Texas in 2019 and compiled the cost related to both mother and child for the next 5 years, producing an estimate of $2.2 billion related to untreated mental health conditions in women in 2019 (Margiotta et al., 2022). Maternal-related indirect and direct cost account for 55 percent. The remaining 45 percent was related to child outcomes, including health care use. Another study examined the societal costs of untreated perinatal mood and anxiety disorders. Societal costs were examined in three areas: maternal productivity loss, greater use of public sector services such as Medicaid costs, and higher health care costs attributable to worse maternal and child health. It estimated that the societal cost of untreated perinatal mood and anxiety disorders to the U.S. for all births in 2017, following mother and child pairs from pregnancy through 5 years postpartum, is $14.2 billion, with mothers incurring 65 percent of the costs (Luca et al., 2020). Presenteeism refers to workers being on the job but because of illness or other medical conditions, 19 are not fully functioning. PREPUBLICATION COPY: UNCORRECTED PROOFS 

IMPACT OF SELECT CHRONIC CONDITIONS IN WOMEN 21 Cardiovascular Risk Factors Studies examining the economic burden of cardiovascular risk factors that provide data by gender are limited. One study reported that overweight and obesity in women contributed to $10.25 billion to CVD-related costs and suggested that excess bodyweight could be about 17 percent of this cost (Wang et al., 2002). Another study examined the lifetime direct medical costs of treating Type 2 diabetes and diabetic complications in men and women newly diagnosed with Type 2 diabetes by age. Women diagnosed at 25–44 years had estimated lifetime direct medical costs of $130,8000 and $56,600 when diagnosed at age 65 years or older. Men had lower costs at $124,700 and $54,700 respectively (Zhuo et al., 2013). Migraines Estimates of the economic burden of migraines in women are limited. One study estimated the disability and economic costs of migraine in the U.S. The estimated annual economic loss attributable to migraine related to absenteeism and reduced productivity was $10,688.8 million in women and $2,660.3 million in men (Hu et al., 1999). Another study examined the economic burden of migraines (Edmeads and Mackell, 2002). Based on a population-based sample of 1,087 individuals, of which 80 percent were women, individuals with migraines experienced higher health care costs ($522) and work productivity loss ($709) compared to those without migraines ($415 and $500 respectively). Osteoporosis Osteoporosis is the second most expensive condition treated at U.S. hospitals, costing $16 billion in 2013 (Torio and Moore, 2016). One study examined the cost of osteoporotic fractures based on hospital discharge data (Cunningham et al., 2016); about 72,900 patients (76 percent women) were admitted for osteoporotic fracture (2008–2014). The mean total hospital charge, reflecting charges for the facility, diagnostics, and pharmacy and after adjusting factors such as age, sex, race, and comorbid conditions, was approximately $47,386. In comparison, other common conditions such as septicemia, congestive heart failure, pneumonia, urinary tract infection, and cardiac dysrhythmias had lower mean total hospital charges ranging from about $6,000 for septicemia to $28,000 cardiac dysrhythmias. Another study using Optum claims data 2007–2017 of about 300,000 patients, of which 72 percent were women, estimated the osteoporosis-related health care costs at least 12 months or more after the fracture was about $19,500. Total health care costs were $34,900, with rehabilitation adding another $18,000 (Williams et al., 2020). Another study examined the cost of osteoporosis-related fractures in Medicare patients using the Chronic Conditions Data Warehouse for the Medicare Fee for Service population. About 886,000 Medicare beneficiaries with fractures were identified with women comprising about 94 percent of this group. Beneficiaries with fractures had a mean all- cause costs of $47,163 compared to $16,034 for those without a fracture (Williams et al., 2021). In a modeling study, one group used NHANES data, population estimates from the U.S. Census, and other data sources to estimate fracture risk in women aged 65 and older and related indirect and direct costs. The model projected that fractures would increase from 1.9 million in 2018 to 3.2 million in 2040, representing a 68 percent increase (Lewiecki et al., 2019). In addition, related costs were projected to increase from $57 billion in 2018 to $95 billion in 2040. PREPUBLICATION COPY: UNCORRECTED PROOFS 

22 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN Sarcopenia One group examined the economic cost of hospitalization for individuals with sarcopenia, using data from NHANES, the Healthcare Cost and Utilization Project, and the U.S. Census. For women with sarcopenia aged 40 or older, the total cost in 2014 was $21.7 billion or an average of $266 per person. By age group, the average per person cost was $380 for women aged 65 or older compared to $205 per person for women aged 40–64. In the 65 year or older group, Hispanic women had the highest average per person cost at $817, followed by women of other races at $787 per person, White women at $342 per person, and Black women at $54 per person (Goates et al., 2019). In summary, although data are limited for most conditions, the studies indicate that the economic costs of chronic conditions in women are high. The estimated cost of these conditions to society ranged from $412 million for fecal incontinence to $22 billion for endometriosis. Moreover, health care costs to manage and treat chronic conditions are substantial, from $9,000 per 6 months for vulvodynia to $47,386 for osteoporosis. In addition to these costs, women experience lower productivity at both home and work. One economic impact simulation found that increasing investments in women’s health research could yield substantial cost savings for society. A RAND study estimated the impact on societal costs by increasing research funding for AD and/or Alzheimer dementia, coronary artery disease, and rheumatoid arthritis. The analysis projected societal cost savings of $932 million for Alzheimer’s disease, with approximately 40 percent of the savings stemming from fewer nursing home stays, if an additional $288 million were invested to address questions about women with Alzheimer's disease. Additionally, investing $20 million in research on coronary artery disease and women's health could result in $1.9 billion in savings, primarily from improved quality of life and fewer lost years of work productivity. Furthermore, an investment of about $6 million in research on rheumatoid arthritis in women could yield savings of $10.5 billion, with around 90 percent of the cost reductions attributed to improved quality of life (Baird et al., 2021; Bird, 2022). QUALITY OF LIFE The studies reported so far highlight the magnitude of the conditions affecting women and the cost of managing them from a health-care and work-related perspective for both the individual and society. Another dimension to consider is the effect on quality of life. Health- related quality of life is defined as a measure of health outcome that reflects “functioning and well-being in physical, mental, and social domains of life” (Kaplan and Hays, 2022). Domains of functioning include physical, such as self-care; role, including work and home responsibilities; and social––interacting with others (Kaplan and Hays, 2022). One study, which did not focus specifically on women, noted an increase in research studies including “quality of life” as a keyword from about 10,000 in 2010 to about 17,000 in 2019 (Kaplan and Hays, 2022). Although researchers have published more on quality of life, they used a variety of measures that may represent different constructs, so interpreting the findings across studies is challenging. In 2010, an IOM report, Women’s Health Research: Progress Pitfalls, and Progress, reviewed the progress made following the investment of research dollars and the passage of policies over 20 years (IOM, 2010). The authoring committee noted that conditions such as endometriosis, chronic pain, CFS, and fibroids, which significantly affect quality of life, were understudied. Within a broad array of recommendations, the committee emphasized including PREPUBLICATION COPY: UNCORRECTED PROOFS 

IMPACT OF SELECT CHRONIC CONDITIONS IN WOMEN 23 quality of life in women's health research, especially as other measures of disease impact, such as prevalence, had not decreased for women: • research should include the quality of life in women, • research on conditions with high morbidity and that affect quality of life should be increased, • measures should be improved that compare the effects of conditions, interventions, and treatments on the quality of life, and • study end points in research should include quality of life outcomes. Several recent reviews of the literature suggest some progress resulting in a better understanding of the effect that living with chronic conditions has on women, although more research is needed. One systematic review examined the effect of multimorbidity on quality of life, with attention to differences between men and women (Makovski et al., 2019). The authors reviewed 74 studies and concluded that women were well represented in the studies; women were a majority of the participants in 81 percent of those studies. The results demonstrated a strong association between women with multimorbid conditions and lower quality of life than men. One meta-analysis of 14 studies found differences in the quality of life for men versus women dealing with infertility (Almutawa et al., 2023). The analysis found that women with infertility experienced a lower quality of life and more depression and anxiety. Endometriosis is frequently associated with reduced health quality of life, and increased risk of depression and anxiety. A meta-analysis of quality-of-life scores as measured by the Physical and Mental Component Scores assessment tool were on average lower for women with endometriosis compared to those without, suggesting that both physical and mental health aspects are impaired (Wang et al., 2021). It also found nearly twice the odds of depression across 18 studies and anxiety across 11 studies in women with endometriosis compared to women without (Wang et al., 2021). Another systematic review and meta-analysis of studies of postmenopausal women with osteoporosis that included quality of life measures found that postmenopausal osteoporosis and osteoporotic fractures reduced physical and mental health status more than for postmenopausal women with normal bone density (Gao and Zhao, 2023). The impact of fibromyalgia on quality of life is significant. An analysis of affected patients in Spain found that 59 percent expressed difficulty with their partners and 44 percent were dependent on others to accomplish household chores. Their interactions with health care providers were less than stellar, as evidenced by an average score of 4.9 on a scale of 10 regarding their satisfaction with their care (Collado et al., 2014). Quality-of-life assessments after treatments or interventions for chronic conditions can provide valuable insights into the overall well-being and functioning of individuals. In a meta- analysis of 76 studies of women with pelvic organ prolapse, surgical treatments or the use of pessary for pelvic organ prolapse were shown to improve the quality of life for women (Ghanbari et al., 2022). A literature review of 139 studies of women with endometriosis also suggested that surgical treatment improved the quality of life, however these studies were based on convenience samples and have several limitations (Jones et al., 2023). In contrast, the results of a review of five studies that examined endometriosis-related pain suggested that the quality of life remained the same or worsened after surgery and medication (Keukens et al., 2024). One group examined the effect of various psychological interventions, including cognitive behavioral therapy, mindfulness, and acceptance and commitment therapy, on the PREPUBLICATION COPY: UNCORRECTED PROOFS 

24 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN quality of life in women with fibromyalgia. Of the 16 studies included in the analysis, 12 demonstrated an improved quality of life and a reduction in symptoms (Samami et al., 2021). The authors of this study concluded that “besides pharmacological treatments, taking advantage of psychological interventions by health care providers is recommended to reduce the symptoms of fibromyalgia and improve the quality of life in affected patients” (Samami et al., 2021). Authors of these studies noted several challenges to examining the quality of life implications of chronic conditions, including the heterogeneity of the studies, such as variations in the diagnosis of conditions; different lengths of follow-up time used; and the different measures to capture quality of life, such as disease-specific measures of quality of life versus general measures (Almutawa et al., 2023; Gao and Zhao, 2023; Keukens et al., 2024; Makovski et al., 2019). SUMMARY This chapter summarizes available measures of impact—prevalence, economic, and quality of life—for female-specific and gynecologic conditions and chronic conditions that predominantly impact women. Several aspects were identified. First, conditions with unknown etiology, lack of standard criteria for diagnosis, and symptoms that overlap with other conditions hinder the ability to obtain an accurate measure of impact. Chronic conditions characterized by these factors include dysmenorrhea, endometriosis, vulvodynia, chronic pain, fibromyalgia, and ME/CFS, which may contribute to their underreporting and lack of reporting by age, race, and ethnicity. Second, national studies only report some of these chronic conditions, and even if conditions are reported in national databases or studies, many do not report prevalence by age, race, or ethnicity, hindering the ability to improve understanding of the variation that occurs among specific groups. In addition, most studies do not assess economic burden or quality of life, which are additional measures of impact. The committee only identified three conditions for which studies examined economic cost, and many of those studies were conducted almost 20 years ago. REFERENCES Abenhaim, H. A., and B. L. Harlow. 2006. Live births, cesarean sections and the development of menstrual abnormalities. International Journal of Gynaecology & Obstetrics 92(2):111–116. Abrams, P., L. Cardozo, M. Fall, D. Griffiths, P. Rosier, U. Ulmsten, P. Van Kerrebroeck, A. Victor, and A. Wein. 2003. The standardisation of terminology in lower urinary tract function: Report from the standardisation sub-committee of the International Continence Society. Urology 61(1):37–49. ACOG (American College of Obstetrics and Gynecology). 2018. ACOG committee opinion no. 760: Dysmenorrhea and endometriosis in the adolescent. Obstetrics and Gynecology 132(6):e249– e258. ACOG. 2021a. Management of symptomatic uterine leiomyomas: ACOG practice bulletin, number 228. Obstetrics and Gynecology 137(6):e100–e115. ACOG. 2021b. Osteoporosis prevention, screening, and diagnosis: ACOG clinical practice guideline no. 1. Obstetrics and Gynecology 138(3):494–506. Alberti, K. G. M. M., R. H. Eckel, S. M. Grundy, P. Z. Zimmet, J. I. Cleeman, K. A. Donato, J.C. Fruchart, W. P. T. James, C. M. Loria, and S. C. Smith. 2009. Harmonizing the metabolic syndrome. Circulation 120(16):1640–1645. PREPUBLICATION COPY: UNCORRECTED PROOFS 

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