Research Submission. ISSN doi: /head Published by Wiley Periodicals, Inc. Headache 2013 American Headache Society

Transcription

1 Headache 2013 American Headache Society ISSN doi: /head Published by Wiley Periodicals, Inc. Research Submission Sex Differences in the Prevalence, Symptoms, and Associated Features of Migraine, Probable Migraine and Other Severe Headache: Results of the American Migraine Prevalence and Prevention (AMPP) Study Dawn C. Buse, PhD; Elizabeth W. Loder, MD, MPH; Jennifer A. Gorman, MS; Walter F. Stewart, PhD; Michael L. Reed, PhD; Kristina M. Fanning, PhD; Daniel Serrano, PhD; Richard B. Lipton, MD Background. The strikingly higher prevalence of migraine in females compared with males is one of the hallmarks of migraine. A large global body of evidence exists on the sex differences in the prevalence of migraine with female to male ratios ranging from 2 : 1 to 3 : 1 and peaking in midlife. Some data are available on sex differences in associated symptoms, headache-related disability and impairment, and healthcare resource utilization in migraine. Few data are available on corresponding sex differences in probable migraine (PM) and other severe headache (ie, nonmigraine-spectrum severe headache). Gaining a clear understanding of sex differences in a range of severe headache disorders may help differentiate the range of headache types. Herein, we compare sexes on prevalence and a range of clinical variables for migraine, PM, and other severe headache in a large sample from the US population. Methods. This study analyzed data from the 2004 American Migraine Prevalence and Prevention Study. Total and demographic-stratified sex-specific, prevalence estimates of headache subtypes (migraine, PM, and other severe headache) are reported. Log-binomial models are used to calculate sex-specific adjusted prevalence ratios and 95% confidence intervals for each across demographic strata. A smoothed sex prevalence ratio (female to male) figure is presented for migraine and PM. Results. One hundred sixty-two thousand seven hundred fifty-six individuals aged 12 and older responded to the 2004 American Migraine Prevalence and Prevention Study survey (64.9% response rate). Twenty-eight thousand two hundred sixty-one (17.4%) reported severe headache in the preceding year (23.5% of females and 10.6% of males), 11.8% met International Classification of Headache Disorders-2 criteria for migraine (17.3% of females and 5.7% of males), 4.6% met criteria for PM (5.3% of females and 3.9% of males), and 1.0% were categorized with other severe headache (0.9% of females and 1.0% of males). Sex differences were observed in the prevalence of migraine and PM, but not for other severe headache. Adjusted female to male prevalence ratios ranged from 1.48 to 3.25 across the lifetime for migraine and from 1.22 to 1.53 for PM. Sex differences were also observed in associated symptomology, aura, headache-related disability, healthcare resource utilization, and diagnosis for migraine and PM. Despite higher rates of migraine diagnosis by a healthcare professional, females with migraine were less likely than males to be using preventive pharmacologic treatment for headache. Conclusions. In this large, US population sample, both migraine and PM were more common among females, but a sex difference was not observed in the prevalence of other severe headache. The sex difference in migraine and PM held true across age and for most other sociodemographic variables with the exception of race for PM. Females with migraine and PM had higher rates of most migraine symptoms, aura, greater associated impairment, and higher healthcare resource utilization than From the Albert Einstein College of Medicine, Bronx, NY, USA (D.C. Buse, R.B. Lipton); Montefiore Headache Center, Bronx, NY, USA (D.C. Buse, R.B. Lipton); Brigham and Women s Hospital, Boston, MA, USA (E.W. Loder); Harvard Medical School, Boston, MA, USA (E.W. Loder); W.L. Gore & Associates, Flagstaff, AZ, USA (J.A. Gorman); Sutter Health, San Francisco, CA, USA (W.F. Stewart); Vedanta Research, Chapel Hill, NC, USA (M.L. Reed, K.M. Fanning, and D. Serrano). Address all correspondence to D. Buse, Montefiore Medical Center Montefiore Headache Center, 1575 Blondell Avenue Suite#225, Bronx, NY 10471, USA, dbuse@montefiore.org Accepted for publication May 11,

2 Headache 1279 males. Corresponding sex differences were not observed among individuals with other severe headache on the majority of these comparisons. Results suggest that PM is part of the migraine spectrum whereas other severe headache types are not. Results also substantiate existing literature on sex differences in primary headaches and extend results to additional headache types and related factors. Key words: migraine, probable migraine, sex differences, headache, headache-related disability, health care resource utilization Abbreviations: AMPP American Migraine Prevalence and Prevention Study, AMS American Migraine Study, CI confidence interval, HCP healthcare professional, HF high-frequency, ICHD International Classification of Headache Disorders, MIDAS Migraine Disability Assessment Questionnaire, OR odds ratio, PM probable migraine, PR prevalence ratio (Headache 2013;53: ) With few exceptions, it is well established that the majority of primary headache disorders have a higher prevalence in females than males. A review of global population estimates of primary headache subtypes of 107 studies from 6 continents reported prevalence of 42% for tension-type headache, 11% for migraine, and 3% chronic daily headache (3%). 1 Although the report found differences in the prevalence of headache across continents, all three of these headache types were more prevalent among females compared to males on every continent.female to male sex prevalence ratios (PRs) are most dramatic in migraine and chronic daily headache but also exist in tension-type headache. In fact, the only primary headache types that have not demonstrated a female preponderance are the trigeminal autonomic cephalalgias. The majority of these headache types are more common in men, especially cluster headache, which has female to male sex prevalence estimates ranging from 1:3.5to1:7. 2 Elevated female to male sex PRs in migraine have been reported from studies around the world with a variety of samples and methodologies The female to male sex PR for migraine has consistently varied across the lifespan ranging from 3 or 4 to 1 in midlife and lowering to 2 to 1 or less at both ends of the age spectrum. In addition to the female prepon- Financial Support: The American Migraine Prevalence and Prevention (AMPP) Study was funded through a research grant to the National Headache Foundation from McNeil-Janssen Scientific Affairs LLC, Raritan, NJ. The AMPP database was donated by McNeil-Janssen Scientific Affairs LLC to the National Headache Foundation for use in various projects. Additional funding and support for this manuscript was provided through a grant to the National Headache Foundation by ENDO Pharmaceuticals, Chadds Ford, PA. Conflict of Interest: Dawn C. Buse, PhD, has received grant support and honoraria from Allergan Pharmaceuticals, MAP Pharmaceuticals, Novartis and NuPathe. Elizabeth W. Loder, MD, MPH, reports receiving salary support from the British Medical Journal in exchange for services as a clinical editor. Jennifer A. Gorman, MS, has nothing to disclose. Walter F. Stewart, PhD, received grants from Allergan Pharmaceuticals, Endo Pharmaceuticals, GlaxoSmithKline, Minster, Merck, Inc., Neuralieve, Novartis, OrthoMcNeil, Pfizer, the National Headache Foundation, and the National Institutes of Health. Michael L. Reed, PhD, has received funding for research and data analysis from Allergan Inc., CoLucid, Endo Pharmaceuticals, GlaxoSmithKline, MAP Pharmaceuticals, Merck, Novartis, NuPathe, Ortho-McNeil, and the National Headache Foundation. Kristina M. Fanning, PhD, has received research support from Allergan Inc., CoLucid, Endo Pharmaceuticals, GlaxoSmithKline, MAP Pharmaceuticals, Merck & Co., Inc., NuPathe, Novartis, Ortho-McNeil, and the National Headache Foundation. Daniel Serrano, PhD, has received research support from Allergan Inc., CoLucid, Endo Pharmaceuticals, GlaxoSmithKline, MAP Pharmaceuticals, Merck & Co., Inc., NuPathe, Novartis, Ortho-McNeil, and the National Headache Foundation. Richard B. Lipton, MD, receives research support from the NIH [PO1 AG03949 (Program Director, Project and Core Leader), RO1AG (Investigator), RO1AG A2 (Investigator), RO1AG (Investigator), RO1AG12101 (Investigator), K23AG (Mentor), K23NS A1 (Mentor), and K23NS47256 (Mentor)], the National Headache Foundation, and the Migraine Research Fund; serves on the editorial board of Neurology, has reviewed for the NIA and NINDS, holds stock options in eneura Therapeutics; serves as consultant, advisory board member, or has received honoraria from: Allergan, American Headache Society, Autonomic Technologies, Boehringer-Ingelheim Pharmaceuticals, Boston Scientific, Bristol Myers Squibb, Cognimed, Colucid, Eli Lilly, ENDO, eneura Therapeutics, GlaxoSmith- Kline, Merck, Novartis, NuPathe, Pfizer, and Vedanta.

3 1280 September 2013 derance in migraine prevalence, some studies have reported that females may experience greater symptomology and headache-related disability. 3,4,8,19,24,25 Sex differences have also been observed in the prevalence of probable migraine (PM), although the direction is not always consistent. 5,9,26,27 Few data are available on sex differences in associated symptomology, frequency, and disability in PM. (See MacGregor et al, 2011, 28 Smitherman et al, 2013, 29 and Merikangas, for detailed reviews of sex-related differences in migraine and other headache types.) Several large scale studies have reported sex prevalence differences in migraine, including the American Migraine Study (AMS) I 20 and II 7,8 and the American Migraine Prevalence and Prevention (AMPP) Study. 31 In 1989, a self-administered questionnaire was sent to 15,000 households as part of the AMS I. 20 Questionnaires collected data on sociodemographics, headache symptomology, frequency, and related disability among other topics. Of 20,468 respondents, 17.6% of females and 5.7% of males were found to have one or more migraine headaches per year (a 3 to 1 female to male sex PR).Researchers also found that females with migraine had more frequent attacks than males but the sexes did not differ substantially in terms of headache-related disability. In 1999, 20,000 households were surveyed as part of the AMS II. 7,8 Of 29,727 respondents,the prevalence of migraine was 18.2% among females and 6.5% among males. Although the reported frequency of severe headache pain was similar for female and male migraineurs, females were somewhat more likely to report severe impairment during migraine, longer duration of impairment, and were more likely to report photophobia, phonophobia, unilateral pain, nausea, vomiting, blurred vision, and aura associated with headache. In 2004, the AMPP Study collected data from 120,000 US households and assessed headache symptomology, frequency, headache-related disability, and other data. Surveys asked about severe headache and second edition of International Classification of Headache Disorders (ICHD-2) 32 criteria, which were applied to determine the 3 most severe headache types experienced by respondents. Data were received from 162,756 individuals aged 12 and older to determine the consistency of sex-specific patterns across 3 defined subgroups of severe headache including migraine, PM, and other (ie, nonmigraine spectrum) severe headache. Previous analyses of AMPP Study data have revealed sex differences in migraine and PM prevalence. 27,31 The prevalence of migraine was found to be 17.1% in females and 5.6% in males, and PM was 5.1% in females and 3.9% in males. However, data on sex differences in symptomology, aura, headache-related disability, health resource utilization, and comorbidities for individuals meeting criteria for migraine, PM, and other types of severe headache have not yet been systematically reported from the 2004 AMPP Study sample. In the current study, sex-specific patterns on multiple variables were examined in the 2004 AMPP Study population overall as well as by major racial subgroups, age groups, and by other sociodemographic variables. We report the sex-specific prevalence of migraine, PM, and other severe headache. We also report the sex-specific occurrence of headache symptoms, reported aura, headache-related disability, healthcare resource utilization (eg, consulting behavior, emergency department/urgent care clinic visits for headache), and healthcare professional (HCP) assigned headache diagnoses, among other variables, by headache subtype. In addition, we will examine prevalence and female to male PRs by age, race, and annual household income for each of the 3 types of severe headache. METHODS Study Design and Sample. The AMPP Study is a 2-phase, longitudinal, population-based investigation. The AMPP Study was modeled on the methods of the AMS I and II. 7,8,20 In 2004, a self-administered questionnaire was mailed to a stratified random sample of 120,000 US households, drawn from a 600,000 household nationwide panel maintained by TNS, a survey sampling firm. TNS maintains panels comprised of sampling blocks, each containing 5000 households, which are constructed to represent the US population in terms of census region, population density, age of head of household, household income, and number of household members. Sociodemographic and census information is obtained from each household during initial contact

4 Headache 1281 and is routinely updated by the survey company. In phase 2, a random sample of 24,000 adults ( 18 years of age) was selected from the 28,261 respondents to the 2004 survey with complete data and who reported experiencing at least one severe headache in the preceding year. These participants were asked to complete annual surveys from 2005 to The current analyses are derived from the 2004 survey data as this population-based sample allows for the calculation of prevalence estimates. Respondents aged 12 who endorsed having at least one severe headache in the preceding year were included in analyses. This study was approved by the Albert Einstein College of Medicine Institutional Review Board AMPP Study Survey. The 2004 AMPP Study survey instructed the head of household to report the total number of household members and the number of household members who suffer from severe headaches. Each household member (up to a total of 3) with severe headaches was asked to complete the remainder of the questionnaire, which included sociodemographic characteristics (age, sex, height, and weight), headache frequency, associated symptoms, and other information necessary to assign an ICHD-2 diagnosis, headache-related disability, average pain of severe headaches, age of onset of severe headache, headache-related emergency department/urgent care clinic visits, acute and preventive headache medication use, and physician diagnosis of headache subtype. Associated Symptoms, Headache Frequency, and Assignment of Headache Diagnosis. Respondents were asked to report the average number of days that they experienced headache in a week, month, or year. They were also asked if they experienced pain-free intervals between attacks. Respondents were asked if they experienced symptoms with severe headache including nausea; vomiting; unilateral head pain; pulsating or throbbing pain; sensitivity to light; sensitivity to noise; blurring of vision in association with headaches; presence of shimmering lights, circles, other shapes, or colors before the eyes before the start of the headache; and presence of numbness of lips, tongue, fingers, or legs before the start of the headache. Respondents were asked to report average pain intensity of severe headaches as: extremely severe pain, severe pain, moderately severe pain, ormild pain. Responses to these items were used to assign headache type based on the ICHD-2. Use of these items to assign a diagnosis was validated in a population sample of subjects with migraine and other types of headache. 7 The items exhibited a sensitivity of 100% and specificity of 82.3% for the diagnosis of migraine. Although this diagnostic module was not revalidated using ICHD-2 criteria, the migraine criteria remained essentially unchanged relative to ICHD-1 criteria. Migraine and PM diagnoses were derived by applying modified ICHD-2 criteria. Respondents satisfied Criterion 1 if they reported one or more of the following associated with headache: severe or extremely severe pain, unilateral headache, or pulsatile or throbbing pain. Respondents satisfied Criterion 2 if they reported one or more of the following associated with headache: nausea or vomiting, photophobia and phonophobia, or visual or sensory aura. A migraine diagnosis was assigned if a respondent met both Criteria 1 and 2. A diagnosis of PM was assigned if a respondent met either Criterion 1 or 2. If neither of these criteria were met, respondents were assigned with other severe headache. This group may logically capture cluster headache, tension-type headache, and other nonmigrainous forms of headache that respondents subjectively rated as severe. Headache-Related Disability. Headache-related disability was assessed with the Migraine Disability Assessment Questionnaire (MIDAS). 33 The MIDAS is a self-administered 5-item questionnaire that assesses days of missed activity or substantially reduced activity due to headache in the preceding 3 months in 3 domains: schoolwork/paid employment, household work or chores, and nonwork (family, social, and leisure) activities. Responses are summed and fall into 1 of 4 grades of headache-related disability: little or none (0-5), mild (6-10), moderate (11-20), or severe (21-40). Respondents were also asked how they are usually affected by severe headaches with the following response options: able to work/function normally, working ability or activity impaired to some degree, working ability or activity severely impaired, and bed rest required. Additionally, respondents were asked Each time you have a severe headache, how

5 1282 September 2013 long are you unable to work or undertake normal activities? with options ranging from 0 days to 6 days. Medication Use and Healthcare Resource Utilization. Respondents were asked how they usually treat their severe headaches, with the following response options: (1) take nonprescription medications; (2) take prescription medications; (3) take both prescription and nonprescription medications; or (4) take no medications. Respondents were asked if they have ever taken a prescription medication on a daily basis for headache prevention, and if so, if they are currently taking it or when they had taken it in the past. Finally, respondents were asked if they were taking any other daily medications, with the following response options: (1) water pill or prescription diuretic for high blood pressure; (2) prescription medicine (other than water pill) for high blood pressure; (3) prescription medicine for seizures, epilepsy, or fits; (4) prescription medicine for diabetes; (5) prescription medicine for cholesterol; (6) prescription medicine for depression or anxiety. Responses to this item were used to estimate comorbid conditions. Respondents were asked to report prior headache diagnoses from a physician or other HCP from the following response options: tension headaches, sinus headaches, cluster headaches, stress headaches, sick headaches, and migraine headaches. Respondents were asked to report age of first migraine diagnosis; belief that their most severe headache was migraine; number of household members with migraine; and usual headache treatment with response options including prescription medication, nonprescription medication, both and neither. Respondents were asked if they had ever used a prescription preventive medication for headache on a daily basis and if they had ever used the emergency department or urgent care facility for severe headache. Sociodemographic Data. Sociodemographic data including race, region of the country, population density, and annual household income were collected by TNS during enrollment.age, sex, height, and weight were gathered from self-report in the questionnaire. For the majority of analyses, respondents were divided into 6 age categories (12-17, 18-29, 30-39, 40-49, 50-59, 60), 4 racial groups (Caucasian, African American, other, or unknown if data were missing), 4 population density groups (<100,000, 100, ,999, 500,000-1,999,999, 2,000,000), 5 annual household income groups (<$22,500, $22,500-$39,999, $40,000- $59,999, $60,000-$89,999, $90,000), and 9 US regions (New England, Middle Atlantic, South Atlantic, East North Central, West North Central, East South Central, West South Central, Mountain, and Pacific). Average headache frequency (reported as the number of days with headache) in a week, month, or year was obtained from respondents in free text. For the purposes of analyses, headache frequency was categorized as days per month within the following categories: <1 per month, 1-4 month, 5-9 per month, and 10 per month. Analyses. Analyses were conducted using SAS Version 9 (Copyright SAS Institute Inc., Cary, NC, USA). Nonresponse bias was examined contrasting differential response rates across demographic strata on: sex, age, race, region of the country, population density of geographic location, annual household income, and household size (ie, number of members in the household) using descriptive statistics. Data were reported for those with and without severe headache. Sex-specific prevalence for those with severe headache was divided by headache type, and sex-specific prevalence rates within each headache type were calculated by age, race, and annual household income. Log-binomial models were used to calculate adjusted sex-stratified PRs by headache type for sociodemographic variables. These models estimated PRs and 95% confidence intervals (CIs) for each individual sociodemographic variable adjusted for all other sociodemographic variables. Adjusted PRs were obtained from adjusted logbinomial models, which were also used to determine female to male adjusted PRs for each headache type stratified on the 5 sociodemographic categories (adjusting for all other sociodemographic variables). Within each headache type, unadjusted sex-specific prevalence and PRs were calculated for the effects of headache symptoms, headache frequency (days per month), average headache pain intensity, headacherelated disability and impairment, headache diagnoses assigned by an HCP, emergency department/

6 Headache 1283 urgent care clinic use, and medication use (acute and preventive for headache and other conditions). Logbinomial models were used to estimate sex PRs and 95% CIs. Data on headache impact, headache-related disability, healthcare resource utilization, and medication use were reported as the percentage of the sample who responded (participants with missing data were not included in the denominator for the items for which they did not respond). RESULTS One hundred twenty thousand households, containing a total of 257,339 household members, were contacted to participate in the AMPP Study survey. Surveys were returned by 77,879 households (64.9% response rate) yielding data for 162,756 individual household members aged 12 years old (Table 1). Respondents were primarily female (52.6%, N = 85,571) and Caucasian (86.6%, N = 140,948). Response rates did not differ substantially between males (62%) and females (64%), but were higher in Caucasians (65%) than in African Americans (56%, P <.01) and in those aged 50 years old (P <.01). Response rates did not differ significantly by geographic region, population density, or annual household income. For additional details on comparisons between respondents and nonrespondents, see Lipton et al. 31 It was not possible to assess reasons for nonparticipation. Thirty thousand seven hundred twenty-one respondents reported experiencing severe headache, of whom 430 were missing sociodemographic data and were not included in the AMPP Study cohort (ie, they were not included in these or any other analyses from the AMPP Study data set). This resulted in 30,291 respondents with severe headache of whom 28,261 reported experiencing severe headache in the preceding year. Of these, 19,189 respondents (11.8%) met criteria for migraine, 7485 (4.6%) met criteria for PM, and 1587 (1.0%) reported experiencing severe headache that did not meet criteria for migraine or PM (ie, other severe headache). Unadjusted, Sex-Specific Prevalence of Migraine, PM, and Other Severe Headache by Sociodemographic Variables. 23.5% of females and 10.6% of males reported experiencing severe headache in the preceding year (Table 2). The unadjusted prevalence of migraine and PM was higher among females than males, whereas the prevalence of other severe headache was similar between sexes. 17.3% of females and 5.7% of males met criteria for migraine, 5.3% of females and 3.9% of males met criteria for PM, and 0.9% of females and 1.0% of males reported headache which was classified as other severe headache. Prevalence of migraine and PM were highest in midlife for both sexes. Among those aged 30-39, the unadjusted prevalence of migraine was 28.4% in females and 9.1% in males. In the same age group, unadjusted prevalence of PM was 6.8% in females and 5.2% in males. Prevalence of other severe headache was fairly consistent across the lifespan, ranging from 0.4% during adolescence to 1.2% among persons age 60 for both sexes. Within race, the unadjusted prevalence of migraine was higher than PM for all races in both sexes with one exception. The prevalence of PM was slightly higher than migraine prevalence among African American males (Table 2). Between races, unadjusted prevalence rates for migraine were highest in females among the other racial category (ie, not Caucasian or African American) (19.3%) followed by Caucasian females (17.5%), whereas unadjusted prevalence rates of PM were highest among African American females (7.6%) compared with 5.0% of Caucasian females. The same pattern held true for males. Rates of migraine were highest in the other racial category (6.9%), and rates of PM were highest among African American males (4.9%) compared with Caucasian males (3.7%). The combined prevalence of migraine and PM was similar for Caucasians and African Americans for both sexes (females: Caucasians 22.6%, African Americans 21.6%; males: Caucasians 9.5%, African Americans 9.2%), demonstrating that the total migrainespectrum (including PM) prevalence is similar between the 2 groups. Unadjusted prevalence of migraine and PM was inversely related to annual household income for both sexes (Table 2) and the number of family members living in a household (data not shown). Prevalence of migraine was highest for both females (20.6%) and males (9.1%) among individuals who

7 1284 September 2013 Table 1. Total Population Surveyed and Respondents (2004 AMPP Study Survey) by Sociodemographic Characteristics Total Population Surveyed (N = 257,339) Total Population Surveyed (%) Survey Respondents (N = 162,756) Response Rate (%) Sex Male 124, , Female 132, , Age , , , , , , , , , , , , Race Caucasian 217, , African American 21, , Asian, Pacific Islander Native American Other Unknown/No Answer Region New England 13, Middle Atlantic 36, , East North Central 41, , West North Central 17, , South Atlantic 47, , East South Central 15, West South Central 28, , Pacific 39, , Mountain 16, , Population Density <100,000 35, , , ,999 43, , ,000-1,999,999 57, , ,000, , , Household Income <$22,500 52, , $22,500-$39,999 49, , $40,000-$59,999 46, , $60,000-$89,999 51, , $90,000 57, , Household Size 1 Member 31, , Members 79, , Members 48, , Members 52, , Members 45, , live in households with an annual average income of $22,500 per year. For both sexes, prevalence decreased as household income increased. In households with an annual income $90,000, 13.6% of females and 4.2% of males met criteria for migraine. A similar pattern was observed in the prevalence of PM for both sexes. Adjusted, Sex-Specific PRs of Migraine, PM, and Other Severe Headache by Sociodemographic Variables. Compared with persons aged (the reference group), PRs for migraine were highest for both males and females in the 30 to 39-year-old age group. Females in this age group were 3.8 times more likely (PR = 3.80, 95% CI = ), and males

8 Headache 1285 Table 2. Unadjusted Sex-Specific Prevalence of Migraine, Probable Migraine, and Other Severe Headache by Sociodemographic Variables Total Sample N = 162,756 Females (N = 85,571; 52.6%) Males (N = 77,185; 47.4%) Severe headache : No 65,498 (76.5%) 68,997 (89.4%) Severe Headache : Yes 20,073 (23.5%) 8188 (10.6%) N Other Severe Headache (N = 805, 0.9%) Probable Migraine (N = 4493, 5.3%) Migraine (N = 14,775, 17.3%) N Other Severe Headache (N = 782, 1.0%) Probable Migraine (N = 2992, 3.9%) Migraine (N = 4414, 5.7%) Age (years) (0.4%) 203 (3.0%) 499 (7.4%) (0.4%) 166 (2.3%) 352 (4.9%) , (0.8%) 643 (5.4%) 2456 (20.6%) 11, (0.9%) 383 (3.5%) 691 (6.3%) , (0.8%) 810 (6.8%) 3376 (28.4%) 10, (1.1%) 562 (5.2%) 976 (9.1%) , (0.8%) 1041 (6.6%) 4052 (25.8%) 13, (0.9%) 695 (5.2%) 1091 (8.1%) , (1.1%) 904 (5.9%) 2824 (18.5%) 13, (1.2%) 652 (4.7%) 845 (6.1%) 60 24, (1.2%) 892 (3.7%) 1568 (6.5%) 20, (1.2%) 534 (2.6%) 459 (2.2%) Race Caucasian 73, (0.9%) 3649 (5.0%) 12,856 (17.5%) 67, (1.0%) 2510 (3.7%) 3891 (5.8%) African American (1.4%) 542 (7.6%) 1001 (14.0%) (1.2%) 235 (4.9%) 209 (4.3%) Other (0.9%) 141 (5.6%) 484 (19.3%) (0.8%) 137 (5.5%) 174 (6.9%) Unknown/Missing (1.2%) 161 (6.1%) 434 (16.3%) (1.2%) 110 (5.1%) 140 (6.4%) Annual Household Income <$22,500 19, (1.5%) 1280 (6.5%) 4084 (20.6%) 13, (1.6%) 813 (6.2%) 1185 (9.1%) $22,500-39,999 16, (0.9%) 936 (5.8%) 2982 (18.4%) 14, (1.0%) 601 (4.1%) 825 (5.6%) $40,000-59,999 15, (0.8%) 757 (5.0%) 2626 (17.4%) 14, (1.1%) 518 (3.6%) 766 (5.3%) $60,000-89,999 16, (0.7%) 733 (4.5%) 2584 (16.0%) 16, (0.9%) 522 (3.2%) 854 (5.2%) $90,000 18, (0.7%) 787 (4.3%) 2499 (13.6%) 18, (0.7%) 538 (2.9%) 784 (4.2%)

9 1286 September 2013 were 1.7 times more likely (PR = 1.72, 95% CI = ) to have migraine compared with teenage respondents (Table 3). Individuals aged 60 were significantly less likely to have migraine than those in adolescence (females: PR = 0.77, 95% CI = ; males: PR = 0.36, 95% CI = ). A similar pattern was observed for PRs of PM by age for both sexes. Individuals in their 30s and 40s had the highest rates of PM. Other severe headache was more likely at all ages compared with the year age group for both sexes and generally increased over the lifespan. However, absolute differences with age were small. Within sex by race, adjusted PRs for African Americans (compared with Caucasians as the reference group) were well below 1.0 for migraine for both sexes (female: PR = 0.69, 95% CI = ; male: PR = 0.65, 95% CI = ), but significantly greater than 1.0 for PM for both sexes (female: PR = 1.38, 95% CI = ; male: PR = 1.20, 95% CI = ) (Table 3). Thus, African Americans of both sexes are less likely to have migraine but more likely to have PM than Caucasians. African Americans had higher risk for other severe headache compared with Caucasians, although this difference was only significant for females (PR = 1.39, 95% CI = ). Adjusted PRs for average annual household income were similar between sexes. Using the lowest annual household income group as the reference, both females and males in the highest income group were significantly less likely to have migraine (female: PR = 0.54, 95% CI = ; male: PR = 0.45, 95% CI = ) and PM (female: PR = 0.64, 95% CI = ; male: PR = 0.48, 95% CI = ) (Table 3). When compared with the lowest income level, the PRs for migraine and PM decreased as household income increased for both sexes. Household size revealed a similar pattern for both sexes as those in households with more members had lower risk of migraine or PM (data not shown). Adjusted Female to Male PRs of Migraine, PM, and Other Severe Headache. Females had higher prevalence of migraine than males at all ages, although the differences varied across the lifespan. Female to male adjusted PRs for migraine peaked at 3.25 (95% CI = ) among those aged Prevalence of migraine was still higher among females at both ends of the age spectrum although the difference was not as pronounced, with a female to male PR during ages of 1.48 (95% CI = ) to 2.91 (95% CI = ) among those aged 60 (Table 4). Female to male adjusted PRs for PM showed a similar pattern across the lifespan, with a peak of 1.53 (95% CI = ) among those aged to 1.35 (95% CI = ) among those aged 60 and 1.28 (95% CI = ) during adolescence. Other severe headache revealed a different pattern with a heightened prevalence among females during adolescence (female to male PR = 1.24, 95% CI = ) but a male preponderance among those aged 18 (Table 4). The Figure shows a graph of smoothed female to male PRs for migraine and PM by age group. Adjusted female to male PRs for migraine were approximately 3 to 1 among all 3 racial groups: Caucasian female to male PR = 2.97 (95% CI = ), African American female to male PR = 3.02 (95% CI = ), other racial group female to male PR = 2.71 (95% CI = ). Significantly elevated adjusted female to male PRs were also seen in PM among Caucasians (PR = 1.30, 95% CI = ) and African Americans (PR = 1.48 (95% CI = ). Among persons with other severe headache, the adjusted female to male PR was 0.84 (95% CI = ) for Caucasians indicating a male preponderance, and nonsignificant for other racial groups indicating the lack of a significant difference between sexes.adjusted female to male PRs for the 3 headache types are also presented by annual household income in Table 4. Headache Symptoms and Frequency by Sex for Migraine, PM, and Other Severe Headache. Females with migraine were significantly more likely than males to report all ICHD-2 criteria and most symptoms commonly associated with migraine including nausea, vomiting, unilateral head pain, pulsing or throbbing pain, photophobia, phonophobia, blurred vision, and visual aura, but not sensory aura (Table 5). Females with PM were also significantly more likely than males to report most of these symptoms including nausea, vomiting, photophobia, phonophobia, and visual aura. Among those

10 Headache 1287 Table 3. Sex-Specific Adjusted Prevalence Ratios by Headache Subtype Females (N = 85,571) Males (N = 77,185) Other Severe Headache PR (95% CI) Probable Migraine PR (95% CI) Migraine PR (95% CI) Other Severe Headache PR (95% CI) Probable Migraine PR (95% CI) Migraine PR (95% CI) Age (years) ref ref ref ref ref ref ( ) 1.70 ( ) 2.74 ( ) 2.08 ( ) 1.39 ( ) 1.19 ( ) ( ) 2.17 ( ) 3.80 ( ) 2.17 ( ) 2.10 ( ) 1.72 ( ) ( ) 2.10 ( ) 3.51 ( ) 1.83 ( ) 2.11 ( ) 1.56 ( ) ( ) 1.80 ( ) 2.51 ( ) 2.15 ( ) 1.85 ( ) 1.14 ( ) ( ) 1.01 ( ) 0.77 ( ) 1.71 ( ) 0.89 ( ) 0.36 ( ) Race Caucasian ref ref ref ref ref ref African American 1.39 ( ) 1.38 ( ) 0.69 ( ) 1.16 ( ) 1.20 ( ) 0.65 ( ) Other 1.12 ( ) 1.06 ( ) 0.97 ( ) 0.80 ( ) 1.30 ( ) 1.02 ( ) Annual Household Income <$22,500 ref ref ref ref ref ref $22,500-39, ( ) 0.88 ( ) 0.81 ( ) 0.67 ( ) 0.68 ( ) 0.63 ( ) $40,000-59, ( ) 0.75 ( ) 0.72 ( ) 0.76 ( ) 0.59 ( ) 0.58 ( ) $60,000-89, ( ) 0.67 ( ) 0.63 ( ) 0.65 ( ) 0.53 ( ) 0.55 ( ) $90, ( ) 0.64 ( ) 0.54 ( ) 0.55 ( ) 0.48 ( ) 0.45 ( ) Adjusted prevalence ratios and 95% confidence limits were estimated using log-binomial models predicting migraine status (within sex). Adjusted for age, race, region of the country, population density, annual household income, and household size. Results are shown for age, race, and annual household income.

11 1288 September 2013 Table 4. Adjusted Sex Prevalence (Female to Male) Ratios (95% CI) by Headache Subtype Other Severe Headache PR (95% CI) Probable Migraine PR (95% CI) Migraine PR (95% CI) Age (years) ( ) 1.28 ( ) 1.48 ( ) ( ) 1.53 ( ) 3.25 ( ) ( ) 1.27 ( ) 3.08 ( ) ( ) 1.24 ( ) 3.12 ( ) ( ) 1.22 ( ) 2.93 ( ) ( ) 1.35 ( ) 2.91 ( ) Race Caucasian 0.84 ( ) 1.30 ( ) 2.97 ( ) African American 1.03 ( ) 1.48 ( ) 3.02 ( ) Other 1.09 ( ) 1.02 ( ) 2.71 ( ) Annual Household Income <$22, ( ) 1.05 ( ) 2.49 ( ) $22,500-39, ( ) 1.38 ( ) 3.25 ( ) $40,000-59, ( ) 1.37 ( ) 3.23 ( ) $60,000-69, ( ) 1.39 ( ) 2.99 ( ) $90, ( ) 1.45 ( ) 3.14 ( ) Adjusted sex prevalence ratios and 95% CIs estimated using log-binomial models predicting migraine status with main covariate sex (within sociodemographic category). Adjusted for age, race, region of the country, population density, annual household income, and household size. with other severe headache, significant sex differences were only seen in rates of photophobia. Among those with migraine, the majority of respondents in both sexes (48.8% of females and Figure. Smoothed sex (female to male) prevalence ratios of migraine and probable migraine by age. 45.3% of males) reported 1-4 days of headache per month (Table 5). Females with migraine were less likely than males to endorse a frequency of <1 day with headache per month although rates only differed by 2.1% (23.5% vs 25.6%, female to male PR = 0.92, 95% CI = ). The majority of individuals of both sexes with PM also endorsed 1-4 days of headache per month (50.4% of females and 47.1% of males), and females were less likely to endorse a frequency of <1 day with headache per month (21.1% vs 23.8%, female to male PR = 0.89, 95% CI = ). Highfrequency (HF) migraine (headache 10 days per month) was more common among males, occurring in 16.7% of males with migraine and 14.9% of females with migraine (female to male PR = 0.90, 95% CI = ). PM shows the same pattern; 16.4% of males and 13.8% of females reported headache on 10 days per month. Reports of average pain associated with severe headache did not form a clear pattern of sex differences for migraine or PM. The majority of respondents of both sexes with migraine endorsed severe pain associated with headache. Males with migraine

12 Headache 1289 Table 5. Sex-Specific Prevalence and Female to Male Prevalence Ratios of Headache Symptoms, Frequency, and Pain Intensity by Headache Subtype Other Severe Headache N = 1587 Probable Migraine N = 7485 Migraine N = 19,189 F M Sex Prevalence Ratio (female to male), 95% CI F M Sex Prevalence Ratio (female to male), 95% CI 50.7% 49.3% 60.0% 40.0% 77.0% 23.0% F M Sex Prevalence Ratio (female to male), 95% CI Associated symptoms during severe headache Nausea 0.0% 0.0% NA 6.9% 3.0% 2.31 ( ) 76.8% 65.8% 1.17 ( ) Vomiting 0.0% 0.0% NA 1.9% 1.2% 1.53 ( ) 31.8% 28.3% 1.12 ( ) Photophobia 11.1% 7.2% 1.54 ( ) 23.4% 17.1% 1.37 ( ) 83.2% 76.4% 1.09 ( ) Phonophobia 7.3% 6.6% 1.10 ( ) 21.9% 17.5% 1.25 ( ) 78.8% 70.7% 1.12 ( ) Blurred vision 4.8% 4.4% 1.11 ( ) 12.8% 11.5% 1.11 ( ) 45.0% 41.2% 1.09 ( ) Visual aura 0.0% 0.0% NA 3.9% 2.8% 1.37 ( ) 37.0% 30.4% 1.22 ( ) Sensory aura 0.0% 0.0% NA 1.1% 0.9% 1.12 ( ) 12.3% 12.2% 1.01 ( ) Average frequency of headache days/month <1 per month 39.0% 47.7% 0.82 ( ) 21.1% 23.8% 0.89 ( ) 23.5% 25.6% 0.92 ( ) 1-4 per month 44.7% 38.9% 1.15 ( ) 50.4% 47.1% 1.07 ( ) 48.8% 45.3% 1.08 ( ) 5-9 per month 8.5% 7.3% 1.16 ( ) 14.7% 12.7% 1.16 ( ) 12.8% 12.4% 1.04 ( ) 10 per month 7.8% 6.1% 1.28 ( ) 13.8% 16.4% 0.84 ( ) 14.9% 16.7% 0.90 ( ) Which statement best describes the pain of your severe headaches? Extremely severe pain 0.0% 0.0% NA 10.8% 12.8% 0.84 ( ) 36.8% 38.3% 0.96 ( ) Severe pain 0.0% 0.0% NA 40.3% 40.1% 1.00 ( ) 47.6% 45.2% 1.05 ( ) Moderately severe pain 57.5% 53.2% 1.08 ( ) 41.6% 38.7% 1.08 ( ) 14.6% 14.8% 0.99 ( ) Mild pain 42.5% 46.8% 0.91 ( ) 7.3% 8.4% 0.87 ( ) 1.0% 1.7% 0.60 ( ) Denominator excludes unknown and missing data. Respondents could check more than one response.

13 1290 September 2013 were slightly more likely to endorse extremely severe pain whereas females were more likely to endorse severe pain, although absolute percentages varied by only 2%. Respondents with PM showed similar results. The majority of females with PM endorsed moderately severe pain and the majority of males endorsed severe pain associated with headache. Males with PM were slightly more likely to endorse extremely severe pain than females although absolute rates were only 2% different (12.8% males vs 10.8% females, female to male PR = 0.84, 95% CI = ). Headache-Related Disability and Impact by Sex for Migraine, PM, and Other Severe Headache. Females with migraine were 1.34 times more likely than males (12.4% vs 9.3%, 95% CI = ) to have the highest level of headache-related disability (MIDAS Grade 4) (Table 6). Females were more likely than males to have moderate (PR = 1.46, 95% CI = ) or mild (PR = 1.46, 95% CI = ) headache-related disability whereas males were significantly more likely to report no headacherelated disability (PR = 0.84, 95% CI = ). Among those with PM, there was not a significant sex difference among those with severe headacherelated disability; however, females with PM were significantly more likely to have moderate (PR = 1.52, 95% CI = ) or mild (PR = 1.47, 95% CI = ) levels of headache-related disability than males and were less likely to report no headache-related disability (PR = 0.93, 95% CI = ). Examination of individual MIDAS items reveal that females with migraine and PM were significantly more likely than males to report inability to do household work on at least 1 day due to headache, work or school productivity reduced by at least 50% on at least 1 day due to headache, and missed family or social activities on at least 1 day due to headache. When asked how they were usually affected by their severe headaches, females with both migraine and PM were significantly more likely than males to report requiring bed rest during an attack, whereas males with migraine and PM were more likely to report being able to work and function normally (Table 6). When asked how long after a headache attack they were unable to work or undertake normal activities, females with migraine were more likely than males to be impaired for 3-<6 days, whereas males with migraine were significantly more likely to report being impaired for 0 or <1 day. Females with PM were significantly more likely than males to be impaired 1-<3 days whereas males with PM were significantly more likely to report no impairment following attacks. Diagnosis, Acute and Preventive Pharmacologic Treatment and Emergency Department/Urgent Care Visits by Sex for Migraine, PM, and Other Severe Headache. Females who met ICHD-2 criteria for migraine at the time of the AMPP Study survey were significantly more likely than males who met these criteria to have been diagnosed with migraine by a HCP (69.8% vs 46.2%; PR = 1.29, 95% CI = ), but also significantly more likely to have been diagnosed with tension headache (33.2% vs 25.5%; PR = 1.30, 95% CI = ), sinus headache (40.7% vs 33.8%; PR = 1.21, 95% CI = ), and stress headaches (30.2% vs 23.7%; PR = 1.27, 95% CI = ) (Table 7). Females were significantly less likely than males with migraine to have been diagnosed with cluster headache (9.8% vs 10.9%; PR = 0.90, 95% CI = ). A similar pattern was seen in PM; females who met criteria for PM were more likely than males with PM to have been diagnosed with migraine (24.0% vs 15.1%; PR = 1.59, 95% CI = ), tension headache (27.1% vs 21.5%; PR = 1.26, 95% CI = ), sinus headache (35.9% vs 31.3%; PR = 1.15, 95% CI = ), and stress headaches (23.9% vs 18.2%; PR = 1.31, 95% CI = ), and less likely to have been diagnosed with cluster headache (4.0% vs 5.0%; PR = 0.81, 95% CI = ). Females with other severe headache were significantly more likely than males to have been diagnosed with every type of headache assessed. Females with migraine were also significantly more likely than males to use prescription medications only for headache (PR = 1.33, 95% CI = ) and to report taking both prescription and nonprescription medications for headache (PR = 1.22, 95% CI = ) (Table 7). Females with migraine were significantly less likely than males to

14 Headache 1291 Table 6. Sex-Specific Prevalence and Female to Male Prevalence Ratios of Headache-Related Disability and Impairment by Headache Subtype Other Severe Headache N = 1587 Probable Migraine N = 7485 Migraine N = 19,189 F M Sex Prevalence Ratio (female to male), 95% CI F M Sex Prevalence Ratio (female to male), 95% CI 50.7% 49.3% 60.0% 40.0% 77.0% 23.0% F M Sex Prevalence Ratio (female to male), 95% CI Headache-Related Disability: MIDAS Grade Grade 1: None 92.6% 95.0% 0.98 ( ) 79.2% 85.4% 0.93 ( ) 60.7% 72.3% 0.84 ( ) Grade 2: Mild 3.4% 2.2% 1.54 ( ) 9.7% 6.6% 1.47 ( ) 15.3% 10.5% 1.46 ( ) Grade 3: Moderate 2.1% 1.3% 1.65 ( ) 6.2% 4.1% 1.52 ( ) 11.5% 7.9% 1.46 ( ) Grade 4: Severe 1.9% 1.5% 1.21 ( ) 4.9% 4.0% 1.24 ( ) 12.4% 9.3% 1.34 ( ) Headache-Related Disability: Individual MIDAS Item Because of your headaches on how many days in the last 3 months...? Missed at least 1 day of work/school 17.0% 9.6% 1.76 ( ) 18.2% 17.7% 1.03 ( ) 32.0% 31.0% 1.03 ( ) Work/school productivity reduced by at least 50% 10.8% 9.3% 1.16 ( ) 25.0% 24.3% 1.03 ( ) 46.1% 44.2% 1.04 ( ) due to headache on at least 1 day Did no household work due to headache on at least 1 day Household productivity reduced by at least 50% due to headache on at least 1 day Missed family or social activity due to headache on at least 1 day 27.9% 14.3% 1.96 ( ) 54.7% 29.7% 1.84 ( ) 75.5% 50.3% 1.50 ( ) 22.7% 11.6% 1.96 ( ) 47.7% 27.8% 1.72 ( ) 66.2% 44.4% 1.49 ( ) 13.2% 12.1% 1.09 ( ) 28.8% 23.7% 1.21 ( ) 50.3% 45.3% 1.11 ( ) Which best describes how you are usually affected by severe headaches? Able to work/function normally 56.1% 60.7% 0.92 ( ) 27.8% 32.6% 0.85 ( ) 6.8% 8.6% 0.79 ( ) Working ability or activity impaired to some degree 33.7% 29.8% 1.13 ( ) 49.9% 45.5% 1.10 ( ) 39.0% 39.0% 1.00 ( ) Working ability or activity severely impaired 3.4% 3.1% 1.09 ( ) 10.3% 11.3% 0.91 ( ) 22.0% 22.6% 0.97 ( ) Bed rest required 6.8% 6.4% 1.07 ( ) 12.1% 10.6% 1.14 ( ) 32.2% 30.0% 1.08 ( ) Each time you have a severe headache, how long are you unable to work or undertake normal activities? 0 days 64.4% 76.9% 0.84 ( ) 44.2% 47.0% 0.94 ( ) 16.1% 19.8% 0.81 ( ) <1 day 28.5% 17.7% 1.61 ( ) 41.2% 42.0% 0.98 ( ) 46.8% 51.2% 0.92 ( ) 1-< 3 days 5.1% 4.0% 1.27 ( ) 12.5% 8.8% 1.42 ( ) 31.4% 24.5% 1.28 ( ) 3-< 6 days 0.7% 0.5% 1.63 ( ) 1.2% 1.5% 0.82 ( ) 4.6% 3.3% 1.39 ( ) 6 days 1.3% 0.9% 1.47 ( ) 0.9% 0.8% 1.21 ( ) 1.1% 1.2% 0.91 ( ) Denominator excludes unknown and missing data.