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Accepted Manuscript

Migraine affects 1 in 10 people worldwide featuring recent rise: A


systematic review and meta-analysis of community-based studies
involving 6 million participants

Yohannes W. Woldeamanuel, Robert P. Cowan

PII: S0022-510X(16)30774-2
DOI: doi: 10.1016/j.jns.2016.11.071
Reference: JNS 14983
To appear in: Journal of the Neurological Sciences
Received date: 22 September 2016
Revised date: 19 November 2016
Accepted date: 29 November 2016

Please cite this article as: Yohannes W. Woldeamanuel, Robert P. Cowan , Migraine
affects 1 in 10 people worldwide featuring recent rise: A systematic review and meta-
analysis of community-based studies involving 6 million participants. The address for
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appropriate. Jns(2016), doi: 10.1016/j.jns.2016.11.071

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Title

Migraine affects 1 in 10 people worldwide featuring recent rise: a systematic review and meta-

analysis of community-based studies involving 6 million participants

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Author names and affiliations

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Yohannes W. Woldeamanuela,*

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a
Stanford Headache and Facial Pain Program, Department of Neurology and Neurological
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Sciences, Stanford University School of Medicine, 213 Quarry Road, Palo Alto, CA 94304, USA

email: ywoldeam@stanford.edu
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*Corresponding Author: Tel: +1-650-933-3560


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Robert P. Cowanb
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b
Stanford Headache and Facial Pain Program, Department of Neurology and Neurological

Sciences, Stanford University School of Medicine, 213 Quarry Road, Palo Alto, CA 94304, USA
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email: rpcowan@stanford.edu

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Abstract

Objective: To study the weighted average global prevalence of migraine at the community level.

Study Design and Setting: A systematic review using advanced search strategies employing

PubMed/MEDLINE, Scopus, and Web of Science was conducted for community-based and non-

clinical studies by combining the terms „„migraine‟‟, „„community-based‟‟, and names of every

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country worldwide spanning all previous years from January 1, 1920 until August 31, 2015.

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Methods were in accordance with PRISMA and MOOSE guidelines. A meta-analysis with

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subgroup analysis was performed to identify pooled migraine prevalence and examine cohort

heterogeneity.

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Results: A total of 302 community-based studies involving 6,216,995 participants (median age
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35 years, male-to-female ratio of 0.91) were included. Global migraine prevalence was 11.6%

(95% CI 10.7-12.6%; random effects); 10.4% in Africa, 10.1% in Asia, 11.4% in Europe, 9.7%
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in North America, 16.4% in Central and South America. When the pooled cohort was stratified,
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the prevalence was 13.8% among females, 6.9% among males, 11.2% among urban residents,

8.4% among rural residents, and 12.4% among school/college students. Our result showed a
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pattern of rising global migraine prevalence.


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Conclusion: Migraine affects one in ten people worldwide featuring recent rise. Higher

prevalence was found among females, students, and urban residents.


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Keywords: Migraine; Epidemiology; Community-Based Studies; Systematic Review; Meta-

analysis; Prevalence

Running Title: Global Migraine Prevalence: a Systematic Review and Meta-analysis

Abstract Word Count: 189 words

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Highlights

 Global migraine prevalence was 11.6% (95% CI 10.7-12.6%; random effects); 10.4%

in Africa, 10.1% in Asia, 11.4% in Europe, 9.7% in North America (NA), 16.4% in

Central and South America (CSA).

 When the pooled cohort was stratified, the prevalence was 13.8% among females,

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6.9% among males, 11.2% among urban residents, 8.4% among rural residents, and

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12.4% among school/college students.

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 There was a pattern of rising global migraine prevalence.

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It can be deduced that rapid urbanization is associated with the recent rise in migraine

prevalence; higher student and urban affliction can lower academic and economic
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performance.

 Improving awareness, early treatment access-points, research and training, and healthy
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urban lifestyles are important to tackle this costly prevalence rising worldwide.
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1. Introduction

Community-based and centralized population-based neuroepidemiological studies are an

accurate representation of estimating true incidence and prevalence of public health burdens. 1

Such studies serve as a crucial source of information for planning, policy-making, and research

prioritization in health care.1 Neuroepidemiological studies can enhance understanding, identify

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risk and prognostic factors, identify comorbidities and correlates, and stratify phenotyping.2, 3

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These studies allow sociodemographic subanalysis of population characteristics such as age-

group, gender, and area of residency (urban or rural).2, 4


Socioeconomic impact of headache

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disorders has been assessed utilizing neuroepidemiological studies.5 Capturing such big data

allows researchers to conduct longitudinal prospective studies to identify causal factors. While
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longitudinal prospective studies provide the best evidence base for data accrual, repeated cross-
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sectional studies can be regarded as quasilongitudinal providing less costly but useful

epidemiologic clues.6
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Migraine is a common cause of public health and socioeconomic burden worldwide; it is under-

or misdiagnosed and under- or mistreated.7-9 It can negatively affect quality of life and
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productivity both at work and at home.5 When not appropriately managed, migraine is a
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progressive neurological disorder that has the potential to chronify.5 Migraine is more common

among the productive workforce segment of the population.4, 10 Many countries in the Global

South are at the crossroads of rapidly improving socioeconomic mobility and shifting disease

epidemiology; mortality from communicable diseases is either declining or stabilizing, and

greater numbers of people are living longer.1, 4 Thus, morbidity and disability causing disorders

such as migraine have become important causes of global health burden.1, 4, 11


However, in

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developing countries, the health care delivery system is designed to tackle infectious diseases,

and has not yet adapted to accommodate the growing health demands of chronic conditions such

as migraine.11, 12

Since the 1930‟s, beginning with classic studies by Balyeat13 and later by Valqhuist14, large

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number of community-based studies have been conducted in different countries worldwide to

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study migraine prevalence. The 2010 Global Burden of Disease (GBD) Study revealed that

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global years lived with disability (YLD) for migraine has steadily increased since 1990, making

primary headache disorders the leading causes of sequelae of up to 35.5% (10.7% in males,

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18.8% in females for migraine).1, 11 However, to the best of our knowledge, there is no study that
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combined data from all community-based studies to present a weighted average global migraine

prevalence. We are now able to analyze these accruing results and identify important time series
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trends. Using a comprehensive systematic review and meta-analysis, we studied the global
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migraine prevalence at the community level, examine population cohorts with varying

prevalences, and study inter-generational variations.


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2. Methods

2.1. Screening and Inclusion


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A combination of the following search strategies using different search databases was employed

to capture our topic of interest, i.e. community- or population-based or non-clinical studies on

migraine prevalence. Clinical or healthcare facility-based studies were excluded because clinical

population is made of convenience sampling where cohorts are created by recruiting only those

patients presenting at clinical facilities.15

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1. A PubMed/MEDLINE® search was employed for Clinical Studies Categories and

Systematic Reviews on the PubMed Clinical Queries tool combining the terms

„„community- or population-based, migraine prevalence‟‟; the Boolean logic operator

„„AND‟‟ was applied to connect the search terms. The Clinical Studies Category was

selected for „„Etiology‟‟, „„Diagnosis‟‟, „„Prognosis‟‟, „„Clinical Prediction Guides‟‟,

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“Therapy” and the scope of the search was made specific to „„Broad‟‟ to enable

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sensitivity and specificity search values of 99% and 70% (63), respectively.16

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2. A second PubMed/MEDLINE® search was employed without using the Clinical Queries

Tool. Search terms used were „„community- or population-based studies AND migraine

prevalence.‟‟
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3. Advanced PubMed/MEDLINE® search was used by implementing search builder of auto-

suggested MeSH Terms and Boolean logic operator „„AND‟‟ as „„(migraine[MeSH


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Terms]) AND prevalence[MeSH Terms].‟‟


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4. A Web of ScienceTM Advanced Search was employed by using the field tag „„TS‟‟ for

topic, the Boolean operator „„AND,‟‟ and parentheses to create our query as „„TS =
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(migraine AND prevalence)‟‟ on Indexes CPCI (Conference Proceedings Citation Index),


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Science Citation Index Expanded (SCI-EXPANDED), Timespan = All years. Databases

were refined to MEDLINE®, Web of ScienceTM Core Collection, and Current Contents
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Connect®. Results included all languages, all Countries/Territories, all Research Areas,

all Research Domains, and all Document Types.

5. A Scopus Advanced Search was employed by using Search Terms as TITLE-ABS-

KEY("migraine" AND prevalence).

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6. A PubMed/MEDLINE search was employed using the words “migraine, country”. For

“country”, the name of every country worldwide (196 countries) was entered, for e.g.

“migraine, China”.

7. Scientific abstracts and a relevant reference hand search were exhaustively conducted

using Google and Google Scholar. This enabled us to locate and capture unpublished

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studies from the gray literature (e.g. conference abstracts) on our topic of interest.

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A PRISMA17 (Preferred Reporting Items for Systematic Reviews and Meta-analysis: the

PRISMA Statement) flowchart depicting the selection of studies is shown on Figure 1a. Methods

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were in accordance with MOOSE18 (Meta-analysis of Observational Studies in Epidemiology
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guidelines) (Appendix A). Community-based and non-clinical studies were included. Clinical-

based studies and studies not related to our primary interest, i.e. migraine prevalence, were
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excluded. All language publications were included, and non-English articles were translated
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using the assistance from scientific colleagues with respective first languages. The search

spanned all studies which are available in the medical literature in previous years from January 1,
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1920 up to August 31, 2015. YWW (first author in this study) is an expert on literature search
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strategies and has previously contributed several related publications of systematic reviews and

meta-analysis.4, 19, 20
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2.2. Data Extraction

The following data were extracted from each included study: first author, year of publication,

country of origin, average age of total participants, total sample size, number of female

participants, number of male participants, number of migraineurs. Prevalence and 95% CI were

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obtained for the overall pooled data, and stratified data for sex, study setting (urban, rural,

school-based), time period for prevalence (3-months, 6-months, one-year, two-years, lifetime),

method of migraine diagnosis (Ad Hoc Criteria 196221, ICHD criteria22-24, ID-Migraine25,

clinical interview and examination by clinicians and/or neurologists), method of data collection

(door-to-door, telephone interview, mail of self-reported questionnaires), and responder rate. The

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studies were stratified according to region of origin i.e. Africa, Asia, Europe, North America

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(NA), and Central and South America (CSA). The studies were tabulated in chronological order

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in order to observe time series trend and intergenerational differences.

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2.3. Statistical Analysis

Extracted data were pooled to combine prevalence data into one weighted magnitude. StatsDirect

v2.7.9 (StatsDirect Ltd., Altrincham, Cheshire, UK) was used to analyze the results, develop

pooled prevalence rates and prepare forest plots. Pooled prevalence rates and 95% CIs were

generated using random-effects (DerSimonian-Laird26) meta-analysis model. Inter-study

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heterogeneity was explored using I2 and 95% CI.27 By virtue of being robust to outliers and to

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nonparametric distribution, median and its interquartile range was selected to describe

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continuous data. Where available, subgroup analysis was made to compare prevalence

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differences among male-female, rural-urban, students, and among different diagnostic methods

and prevalence periods. Subgroup analysis was also performed by comparing prevalence results
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for studies using ICHD diagnostic criteria against all included studies, and similarly for studies

with prevalence period of lifetime and one-year against all studies. In order to statistically test
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the differences among the subgroups, Cochran‟s chi-square or Q-test was applied using a
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significance p-value level of 0.05. Correlation analysis was conducted between the prevalences
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and the study years to identify if there was a trend of migraine prevalence change among the

different regions and overall globally. Statistical analysis of correlation was appropriately
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selected based on parametric or non-parametric nature of the prevalence distribution in each

region; Pearson‟s r and Spearman‟s rho (with 95% CI and p-values) were selected for parametric
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and non-parametric data, respectively. Missing data were excluded from the final analysis.

Microsoft Excel (Version 15.18 (160109) Microsoft, Redmond, WA, USA, 2015) was utilized

for data compilation and computations.

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3. Results

302 studies involving 6,216,995 participants were included (Figure 1b, Appendix B). Median age

was 35 years (Interquartile Range or IQR 30.2-38.9). Male-to-female ratio among total number

of participants was 0.91 (47.6% males, 52.4% females); male-to-female ratio among non-

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responders was not available. The geographic distribution of the studies was as follows: 33

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(10.9%) studies were from Africa involving combined sample size of 178382, 63 (20.9%) from

Asia involving combined sample size of 4331237, 44 (14.6%) from CSA involving combined

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sample size of 72893, 22 (7.3%) from NA involving combined sample size of 825734, and 140

(46.3%) from Europe involving combined sample size of 808749 (Figure 2a, Appendix B).
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Ninety-two studies (30.5%) were school-based. Eighty-seven % (263) studies were from the
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post-ICHD era (International Classification of Headache Disorders 1988), and 82% (216) of
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these studies applied ICHD criteria. Seventy (23.2%) studies were from urban setting and 24

(8%) studies were from rural setting; the rest 94 (68.8%) studies were either mixed urban-rural.
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Data were mostly collected using door-to-door or face-to-face questionnaire method or through

postal mails of self-administered questionnaires. Telephone interviews were also used by some
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studies. Some studies used physician or neurologist assessment along with questionnaires.
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Median responder rate was 83.4%. Prevalence period used ranged from lifetime prevalence in 73

(28.5%) studies, one-year prevalence in 149 (58.2%) studies, two-year prevalence in 4 (1.6%)

studies, 6-month prevalence in 18 (4.7%) studies, 3-month prevalence in 12 (7%) studies (Figure

2A). Median age of migraineurs was 32 years (IQR 24.6-38.7).

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Pooled crude migraine prevalence was found to be 11.6% (95% CI 10.7-12.6%; random effects);

10.4% in Africa, 10.1% in Asia, 11.4% in Europe, 9.7% in NA, 16.4% in CSA (Figure 2b,

Appendix C). There was a statistically significant difference between the prevalence in CSA

compared to all the other regions; there was no statistically significant difference among the

other four regions (Table 1). When the pooled-cohort was stratified by sex, the prevalence was

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13.8% among females (Appendix D), 6.9% among males (Appendix E); this difference was

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statistically significant (p = 0.0001). When the pooled-cohort was stratified by area of residency

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(urban vs rural setting), the prevalence was 11.2% among urban residents (Appendix F), 8.4%

among rural residents (Appendix G), and 12.4% among school/college students (Appendix H).

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Urban-rural and school-rural prevalence difference was statistically significant at p = 0.002 and p
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= 0.001, respectively.
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Subgroup analysis showed similar random-effects weighted prevalence (p = 0.31) between the
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studies that applied ICHD criteria (11.2%) and all included studies (11.6%). Similarly, subgroup

analysis showed no statistically significant difference (p = 0.35) of random-effects weighted


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prevalence between studies that used one-year period (11.9%) and all included studies (11.6%).
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There was observable increase in migraine prevalence within the last decade in the African,

European and South American regions. Inter-study heterogeneity was found to be moderate with
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an I2 of 48% (95% CI 30-58%).

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Global migraine prevalence changes between the years 1930 and 2015 showed the regions of

Europe (Figure 3d), Asia (Figure 3b), CSA (Figure 3c), and Africa (Figure 3a) to have

statistically significant increment (in a descending order), i.e. migraine prevalence increased as

the years progressed. The NA region (Figure 3e) did not show statistically significant increase.

Overall, the global migraine prevalence (Figure 3f) showed statistically significant increase.

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4. Discussion

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Overall, migraine affects 11.6% people worldwide. When this crude estimate was stratified to

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different sociodemographic cohorts, female gender, school/college goers and urban residents

decreasingly were more affected compared to male gender, rural residents and the overall
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population. Urban residents were 1.3 times more likely to have migraine compared to rural

residents. Migraine was twice as common among females compared to males. These results were
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in agreement with most previous studies on migraine epidemiology. With a total sample size of
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more than 6 million people globally, this study provided the largest sample size and study power
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presently available; it can be assumed that 1 in 1000 people were crudely represented globally,

given the global population of 7 billion28 and a sampling fraction of 0.1%. However, the
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different years when the studies were conducted has to be taken into account as the global
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population has progressively increased. Our study was representative of all continents

worldwide. Male-to-female ratio of participants (0.91) was similar to that of the global (1.01)

population gender ratio estimates.28 The median age of 35 was comparable to current global

median age of 30 years.28 Migraineurs were slightly younger with a median age of 32 years; this

was in accordance to literature evidence that migraine primarily affects the younger and

productive demographic. The 2010 GBD study estimated global prevalence of migraine in both

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sexes to be 14.7% (10.7% in males, 18.8% in females); this was marginally higher than what we

found in our study. The reason for this disparity could be the fact that GBD data sources included

a mixture of published studies, disease registries, hospital discharge data, household surveys,

other surveys, and cohort studies1; in our study, we strictly used community-based and non-

clinical studies to provide a closer approximate to the true prevalence of migraine. According to

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the 2010 GBD, disability caused by migraine in terms of DALYs (Disability-adjusted Life

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Years) have increased by 20% from the year 2000 (15 million) to 2012 (18 million).1

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With regards to geography, the Asian region had the highest sample size of 4,331,237

participants with 20.9% of the total number of studies included (Figure 1b, Figure 2a). Given that
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the Asian region housed the largest target population of over 4.4 billion 28, the Asian sample size

within this study had a sampling fraction of around 0.1% similar to the overall global sampling
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fraction (Figure 1b). Although nearly half of the studies included in this study were from Europe,
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the European sample size (808,749) had a similar sampling fraction of 0.1% - given its target

population of over 742.5 million (Figure 1b).28 The NA sample size (825,734) had the highest
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sampling fraction of 0.23% to its target population of over 355 million (Figure 1b) , despite
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having the lowest number of studies. The African sample size (178,382) had a sampling fraction

of 0.016% to its target population over 1.1 billion (Figure 1b).28 The CSA sample size (72,893)
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had the lowest sampling fraction of 0.011% to its target population of over 626 million (Figure

1b).28 These differences created unintentional overrepresentation where some regions were

overpowered while others were underpowered. In order to control for this effect, we stratified the

results into the different regions. Overall, regional prevalence ranged from 9.7% in NA to 16.4%

in CSA; the other regions of Africa, Asia, and Europe had a comparable prevalence of 10.1-

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11.4%. It was noteworthy to find higher regional prevalence in CSA region compared to other

regions; factors explaining this disparity need to be examined. However, one reason could be the

fact that the combined sample size of the CSA region is at least twice less than the second

combined sample size in Africa. The Asian region featured the highest combined sample size

involving more than 4 million participants. Europe and NA had similar combined sample size of

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around 800,000 participants. Considering the fact that Africa and CSA both feature a growing

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population of around 1 billion, the combined sample sizes for these two regions found in this

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study were under-representative compared to the other three regions ratio of sample size to

regional population size. In Africa, Asia, Europe, and CSA, the increase of migraine prevalence

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was indicative of either genuine intergenerational differences in prevalence or in pain perception
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and tolerance or in increasing awareness and accurate diagnosis. Another plausible reason might

be increase in urbanization with urban population recently surpassing rural population.28


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In comparison to previously published study29, we found some prevalence differences compared

to our results. However, it has to be noted that none of the previously published studies
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employed weighted average; all previously published results were produced by using arithmetic
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averages. Besides, our study is up-to-date with recent studies. For instance, one previously

published study showed arithmetic average migraine prevalence of 11% globally, 5% in Africa,
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9% in Asia, 22% in Australia, 9% in CSA, 15% in Europe, and 13% in NA; the data from

Australia comprised of females only, and all these prevalences included time period of 1 year, 3

months, and „time frame not stated‟.29 For a lifetime prevalence, the same study showed

arithmetic average migraine prevalence of 15% globally, 5% in Africa, 9% in Asia, 17% in

Europe, 13% in NA, and 16% in CSA.29 Our study‟s overall 11.6% global prevalence, 6.9%

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prevalence in men, and 13.8% prevalence in women were comparable to 11%, 6%, and 14%

published in the aforementioned study29, respectively. The higher African prevalence in our

study was because of the weight from our inclusion of recently published studies with prevalence

of up to 22%30; this increasing prevalence was not due to ascertainment bias because the

majority of the studies (75%) in the African region were conducted door-to-door. The higher

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CSA prevalence from our study compared to that in the aforementioned study could be because

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of our study‟s inclusion of 14 recent studies with prevalence as high as 51%31 and probably

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because the latter study separated lifetime results unlike our study. Another point is that

Australia was included under the Asian region in our study unlike the above-mentioned study

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which reported Australian data distinctly from the Asian region. A graphical representation
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comparing these results to our results is displayed on Figure 4.
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Close to a third of the studies included were school-/college-based. Results from these were also
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stratified to examine the prevalence characteristics from this cohort. School-/college-students

had higher migraine prevalence than the overall general prevalence. This suggests migraine‟s
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potential burden on academic performance, because migraine attacks are associated with
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increased absenteeism or presenteeism.32 Rural residents had lower prevalence of migraine

compared to urban residents. This may be associated with the disparity between lifestyles (sleep
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schedules, exercise, stress levels, and meal schedules) in urban versus rural settings.

Our result showed a pattern of increasing global migraine prevalence; when this result was

stratified among the different regions, Europe, Asia, CSA, and Africa had significant rise. There

was no statistically significant change in the NA region; this could be a genuine pattern or due to

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the lower number of studies available in the NA region. The migraine prevalence rise in Asia,

CSA, and Africa should be regarded within the context of the general increase in non-

communicable diseases in these regions which are home to the majority of developing

economies; this correlates with the rapid urbanization rates occurring within these regions33

accompanied by unfavorable lifestyle changes such as low levels of physical activity and sleep

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dysregulation, both of which lower threshold for a migraine attack.34 The European prevalence

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increment could be due to a combination of inadequate attention and suboptimal prioritization

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given to public health policy changes with regards to headache awareness and management,

substandard headache care resource utilization and ineffective strategies, and unfavorable

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lifestyle changes mentioned above.35 Implementing such public health policy changes requires
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the participation of an inter-disciplinary team at different levels of every community, and

actively involving governments and authorities.36 These temporal changes and disparities also
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indicate the need for healthy and favorable lifestyle modification as important self-management
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tools to lower migraines prevalence, particularly in the urban setting.34 Self-management tools

not only help lower prevalences but also return the locus of control back to the sufferer.37
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The claim of increasing prevalence in our study is in line with other recent reports such as that

from the Global Burden Disease (2015) which revealed statistically significant increment of
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global migraine prevalence from 14.7% in 2005 to 15.3% in 201538. The 2015 GBD study

similarly reported that migraine was among the top ranking conditions with age-specific years

lived with disability in adolescents and young adults. The recent rise of migraine needs to be

viewed within the context of the recent rise in non-communicable diseases worldwide; increasing

prevalence in chronic health conditions such as chronic pain, sleep disorders, depression, and

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hypertension38 can lead to increment in migraine prevalence because of the known

multimorbidity between migraine and these chronic health conditions39-41. Biobehavioral factors

such as increasing stress levels also contribute to migraine prevalence42. Migraine and

depression/anxiety/pain catastrophization are bidirectional40, 41; depression is among the top 3

common health problem worldwide38. A rise in one of these health conditions can fuel an

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increment in migraine prevalence. Studies show that pain reporting and pain-related traits such as

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hyperalgesia and pain thresholds are heritable phenotypes43, 44. In addition, epigenetic interaction

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with different environmental stimuli can increase pain susceptibility39, 44. Most of the risk factors

responsible for the increment in migraine prevalence are modifiable. Active pain-coping

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strategies such as exercise were found to be three times more powerful in lowering pain-related
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disability45.
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The number of school-based studies found from North American region was low, suggesting
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unmet need to adequately measure and address the costly burden of migraine in school environs.

National surveillance reports from the NHIS (National Health Interview Survey)26 in USA did
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not use valid and accurate migraine diagnostic criteria; this underscores the importance of
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employing ICHD diagnostic criteria in epidemiologic studies. Fortunately, diagnostic methods


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applied were in accordance to ICHD criteria in the majority of studies. A door-to-door approach

was used to reach participants, and this is recognized as the best modality to examine community

prevalence. Nearly 60% of studies assessed prevalence data of a one-year period. While recall

bias cannot be completely eliminated, a one-year recall fares better than a lifetime recall.

Previous studies have shown that the difference in recall bias between a one-year, a 6-month, and

a 3-month period is not significant.46 Lifetime prevalence is preferably used when studying more

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severe and rarer headache attacks such as cluster headache which is more likely not to be

remembered by the sufferer.46 The overall responder rate of more than 80% was remarkable and

this supported the representativeness of the final pooled results. That recruitment methods

included convenience sampling, cluster sampling, entire population, multistage stratified,

sampling, random sampling, and stratified sampling provided a useful mixed method of

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sampling.

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When performing meta-analysis, fixed-effects model (inverse variance weighting) assumes one

true effect size underlying all studies included.47 Fixed-effects model accepts that there is no real

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difference between studies other than that from pure random error or chance.47 Fixed-effects
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model does not recognize heterogeneity factors such as study settings, studies done in different

years, studies involving different populations and countries; these factors can influence
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prevalence among the different studies included.47 Since heterogeneity makes a fixed-effect
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model implausible for our study, we selected random-effects meta-analysis model. Random-

effects model assumes that the combined study effect is from a distribution of study effects; by
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so doing, random-effects model recognizes heterogeneity factors.26 Random-effects permits


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factoring of study design covariates from one study to another; it incorporates both within and

between study variance.26 Although both approaches were used in our study, we reported results
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from the latter to allow factoring of study variations within the meta-analysis.

Our study strengths include the undertaking and completeness of the first large-scale global

meta-analysis in headache research involving more than 6 million participants. Additionally, our

study provides the first ever weighted analysis of migraine prevalence worldwide. Our study

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delivers a valuable and landmark baseline foundation for conducting similar successive weighted

analysis in a periodical manner so as to assess accruing population-based global migraine data.

Our study not only offers data-driven approaches in understanding epidemiological variations in

migraine, but also can help identify risk factors and speculate intergenerational key differences

(e.g. low levels of physical activity, unhealthy rapid urbanization) that can be used to implement

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a public health policy change. Careful examination of repeated cross-sectional studies can

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provide an alternative to conducting highly costly prospective longitudinal studies.

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Our study limitations are those that are inherent in performing meta-analyses i.e. the

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heterogeneity aspects in variable methods of the studies included. Possible reasons for the
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moderate heterogeneity we found could be the regional differences, the different years, the

prevalence period variations, non-ICHD diagnoses (18%), and differing sample sizes. However,
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we have attempted to minimize these by stratifying major variations of sociodemographic


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cohorts to create a more homogenous participant population. Other limitations include lack of

complete metadata for all studies, and we are aware of the unintended attrition bias related to
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this. All missing data were excluded from the final analysis; such data may be non-random
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missing data and it is known that analysis solely restricted to available data may tend to create

biased results.
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We recommend that future studies report complete sociodemographic and related characteristics

of their findings. Similar pooled meta-analysis studies on other types of headaches such as

tension-type, cluster, and other secondary headaches will shed more light into salient

neuroepidemiologic features. Few studies mentioned that their sample were biologically

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unrelated48, 49; accrued results from such efforts and similar twin studies will contribute to the

understanding of migraine genetics.

5. Conclusions

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Migraine affects one in ten people worldwide; it is twice common in females. Geographical

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variations were observed with Central and South American region featuring higher prevalence

compared to other regions with comparable prevalence; however, this has to be interpreted

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within the context of lower combined sample size within this region compared to other regions.

It can be deduced that rapid urbanization is associated with the recent rise in migraine
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prevalence. The significance of these and other factors to the evolution of the global migraine
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prevalence need to be examined prospectively. Higher student and urban affliction can lower

academic and economic performance. Improving awareness, early treatment access-points,


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research and training, and healthy urban lifestyles are important to tackle this costly prevalence
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rising worldwide. Large-scale and centralized databases and data streaming need to exist for

more efficient community-based mega-data collection. Our study provides the first proper global
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estimation of migraine prevalence. By so doing, our study offers a granular detail of worldwide
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migraine prevalence at the community level. These are applicable for public health policy

changes such as increasing awareness of migraine prevalence and for early management; if not

properly managed, migraine can become chronic and disabling, and this can have wide

socioeconomic consequences.

Acknowledgements

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The authors are indebted to Associate Professor Tomomi Kawakami and Dr. Yuko Nakamura,

from Department of Pediatric Dentistry, The Nippon Dental University School of Life Dentistry

at Tokyo for assistance in Japanese translation.

Funding

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This research received no specific grant from any funding agency in the public, commercial, or

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not-for-profit sectors.

Conflict of interest: None declared.


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References
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1. Vos T, Flaxman AD, Naghavi M, Lozano R, Michaud C, Ezzati M, et al. Years lived with
ED

disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: a systematic analysis for the
Global Burden of Disease Study 2010. Lancet. 2012;380(9859):2163-96.
2. Lipton RB, Bigal ME. Ten lessons on the epidemiology of migraine. Headache. 2007;47 Suppl
PT

1:S2-9.
3. Merikangas KR. Contributions of epidemiology to our understanding of migraine. Headache.
2013;53(2):230-46.
CE

4. Woldeamanuel YW, Andreou AP, Cowan RP. Prevalence of migraine headache and its weight on
neurological burden in Africa: a 43-year systematic review and meta-analysis of community-based
studies. Journal of the neurological sciences. 2014;342(1-2):1-15.
5. Lipton RB, Stewart WF, Scher AI. Epidemiology and economic impact of migraine. Current
AC

medical research and opinion. 2001;17 Suppl 1:s4-12.


6. Corsi DJ, Neuman M, Finlay JE, Subramanian SV. Demographic and health surveys: a profile.
International journal of epidemiology. 2012;41(6):1602-13.
7. Miller S, Matharu MS. Migraine is underdiagnosed and undertreated. The Practitioner.
2014;258(1774):19-24, 2-3.
8. Minen MT, Loder E, Tishler L, Silbersweig D. Migraine diagnosis and treatment: A knowledge
and needs assessment among primary care providers. Cephalalgia : an international journal of headache.
2015.
9. Miller VA. Misunderstood and misdiagnosed: the agony of migraine headache. Advance for
nurse practitioners. 2005;13(10):55-6, 8-60, 2.
10. Hazard E, Munakata J, Bigal ME, Rupnow MF, Lipton RB. The burden of migraine in the United
States: current and emerging perspectives on disease management and economic analysis. Value in health

21
ACCEPTED MANUSCRIPT

: the journal of the International Society for Pharmacoeconomics and Outcomes Research. 2009;12(1):55-
64.
11. Murray CJ, Vos T, Lozano R, Naghavi M, Flaxman AD, Michaud C, et al. Disability-adjusted life
years (DALYs) for 291 diseases and injuries in 21 regions, 1990-2010: a systematic analysis for the
Global Burden of Disease Study 2010. Lancet. 2012;380(9859):2197-223.
12. Kruk ME, Nigenda G, Knaul FM. Redesigning primary care to tackle the global epidemic of
noncommunicable disease. American journal of public health. 2015;105(3):431-7.
13. Balyeat R, Rinkel H. Further Studies in Allergic Migraine:: Based On a Series of Two Hundred
and Two Consecutive Cases. Ann Intern Med 1931;5(6):713-28
14. Vahlquist B. Migraine in children. Triangle; the Sandoz journal of medical science. 1961;5:89-94.

T
15. Chen H, Hailey D, Wang N, Yu P. A review of data quality assessment methods for public health
information systems. Int J Environ Res Public Health. 2014;11(5):5170-207.

IP
16. Haynes RB, McKibbon KA, Wilczynski NL, Walter SD, Werre SR, Hedges T. Optimal search
strategies for retrieving scientifically strong studies of treatment from Medline: analytical survey. Bmj.

CR
2005;330(7501):1179.
17. Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for systematic
reviews and meta-analyses: the PRISMA statement. PLoS medicine. 2009;6(7):e1000097.
18. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, et al. Meta-analysis of

US
observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies
in Epidemiology (MOOSE) group. Jama. 2000;283(15):2008-12.
19. Woldeamanuel Y, Rapoport A, Cowan R. The place of corticosteroids in migraine attack
AN
management: A 65-year systematic review with pooled analysis and critical appraisal. Cephalalgia.
2015;35(11):996-1024.
20. Woldeamanuel YW, Girma B. A 43-year systematic review and meta-analysis: case-fatality and
risk of death among adults with tuberculous meningitis in Africa. J Neurol. 2014;261(5):851-65.
M

21. Classification of Headache. The Ad Hoc Committee on Classification of Headache. Arch Neurol
1962;6(3):173-6.
22. Olesen J. The international classification of headache disorders. 2nd edition (ICHD-II). Revue
ED

neurologique. 2005;161(6-7):689-91.
23. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain.
Headache Classification Committee of the International Headache Society. Cephalalgia : an international
PT

journal of headache. 1988;8 Suppl 7:1-96.


24. Headache Classification Committee of the International Headache S. The International
Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia : an international journal of
CE

headache. 2013;33(9):629-808.
25. Lipton RB, Dodick D, Sadovsky R, Kolodner K, Endicott J, Hettiarachchi J, et al. A self-
administered screener for migraine in primary care: The ID Migraine validation study. Neurology.
2003;61(3):375-82.
AC

26. DerSimonian R, Kacker R. Random-effects model for meta-analysis of clinical trials: an update.
Contemp Clin Trials. 2007;28(2):105-14.
27. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med.
2002;21(11):1539-58.
28. United Nations Department of Economic and Social Affairs/Population Division. World
Urbanization Prospects: The 2014 Revision. ST/ESA/SER.A/366.
29. Stovner L, Hagen K, Jensen R, Katsarava Z, Lipton R, Scher A, et al. The global burden of
headache: a documentation of headache prevalence and disability worldwide. Cephalalgia.
2007;27(3):193-210.
30. Mbewe E, Zairemthiama P, Yeh HH, Paul R, Birbeck GL, Steiner TJ. The epidemiology of
primary headache disorders in Zambia: a population-based door-to-door survey. J Headache Pain.
2015;16:515.

22
ACCEPTED MANUSCRIPT

31. Rocha-Filho PA, Santos PV. Headaches, quality of life, and academic performance in
schoolchildren and adolescents. Headache. 2014;54(7):1194-202.
32. Antonaci F, Voiticovschi-Iosob C, Di Stefano AL, Galli F, Ozge A, Balottin U. The evolution of
headache from childhood to adulthood: a review of the literature. The journal of headache and pain.
2014;15:15.
33. Kojima R. Introduction: population migration and urbanization in developing countries. Dev
Econ. 1996;34(4):349-69.
34. Woldeamanuel YW, Cowan RP. The impact of regular lifestyle behavior in migraine: a
prevalence case-referent study. J Neurol. 2016;263(4):669-76.
35. Diener HC, Steiner TJ, Tepper SJ. Migraine--the forgotten epidemic: development of the

T
EHF/WHA Rome Declaration on Migraine. J Headache Pain. 2006;7(6):433-7.
36. Bosu WK. Learning lessons from operational research in infectious diseases: can the same model

IP
be used for noncommunicable diseases in developing countries? Adv Med Educ Pract. 2014;5:469-82.
37. Fan J, Kong Y, Shi S, Cheng Y. Positive correlations between the health locus of control and self-

CR
management behaviors in hemodialysis patients in Xiamen. International Journal of Nursing Sciences.
2016. j.ijnss.2016.02.002.
38. Disease GBD, Injury I, Prevalence C. Global, regional, and national incidence, prevalence, and
years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global

US
Burden of Disease Study 2015. Lancet. 2016;388(10053):1545-602.
39. van Hecke O, Torrance N, Smith BH. Chronic pain epidemiology and its clinical relevance. Br J
Anaesth. 2013;111(1):13-8.
AN
40. Wang SJ, Chen PK, Fuh JL. Comorbidities of migraine. Front Neurol. 2010;1:16.
41. Buse DC, Silberstein SD, Manack AN, Papapetropoulos S, Lipton RB. Psychiatric comorbidities
of episodic and chronic migraine. J Neurol. 2013;260(8):1960-9.
42. Wober C, Wober-Bingol C. Triggers of migraine and tension-type headache. Handb Clin Neurol.
M

2010;97:161-72.
43. Norbury TA, MacGregor AJ, Urwin J, Spector TD, McMahon SB. Heritability of responses to
painful stimuli in women: a classical twin study. Brain. 2007;130(Pt 11):3041-9.
ED

44. Nielsen CS, Stubhaug A, Price DD, Vassend O, Czajkowski N, Harris JR. Individual differences
in pain sensitivity: genetic and environmental contributions. Pain. 2008;136(1-2):21-9.
45. Blyth FM, March LM, Nicholas MK, Cousins MJ. Self-management of chronic pain: a
PT

population-based study. Pain. 2005;113(3):285-92.


46. Stovner LJ. Headache epidemiology: how and why? J Headache Pain. 2006;7(3):141-4.
47. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of
CE

disease. J Natl Cancer Inst. 1959;22(4):719-48.


48. Katsarava Z, Dzagnidze A, Kukava M, Mirvelashvili E, Djibuti M, Janelidze M, et al. Primary
headache disorders in the Republic of Georgia: prevalence and risk factors. Neurology.
2009;73(21):1796-803.
AC

49. Katsarava Z, Kukava M, Mirvelashvili E, Tavadze A, Dzagnidze A, Djibuti M, et al. A pilot


methodological validation study for a population-based survey of the prevalences of migraine, tension-
type headache and chronic daily headache in the country of Georgia. J Headache Pain. 2007;8(2):77-82.

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PRISMA Flow Diagram

Records identified through database


searching
Method 1: n = 1344 Additional records identified
Method 2: n = 570 through other sources
Identification

Method 3: n = 981 Method 7: n = 25


Method 4: n = 10634
Method 5: n = 4271

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Method 6: n = 1960

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Records after duplicates removed
(n = 1975)
Screening

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Records excluded: studies not
Records screened related to our primary interest
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(n = 1975) i.e. migraine prevalence
(n = 1523)
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Eligibility

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Full-text articles assessed


Full-text articles excluded,
for eligibility
reasons: studies based in clinical
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(n = 452)
setting
(n = 150)
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Included

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Studies included in quantitative


synthesis (meta-analysis)
(n = 302)

Figure 1a. PRISMA Flow Diagram depicting the identification, screening, eligibility, and

inclusion stages. A total of 302 studies were included in the final quantitative meta-analysis.

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Sample size, sampling fractions, and


populations

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8 Sampling Fraction (of thousands)

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7 Sample Size (millions)

6 Population (billions)

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5

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3

2
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1
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0
Africa Asia CSA NA Europe Global
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Figure 1b. Sample size, sampling fractions, and population size of the different regions. With a
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total sample size of more than 6 million people globally, this study provides the largest sample
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size and study power presently available; it can be assumed that 1 in 1000 people were crudely

represented globally, given the global population of 7 billion[28] and a sampling fraction of

0.1%. The Asian region had the highest sample size of 4,331,237 participants with 20.9% of the

total number of studies included. Given that the Asian region housed the largest target

population of over 4.4 billion [28], the Asian sample size within this study had a sampling

fraction of around 0.1% similar to the overall global sampling fraction. Although nearly half of

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the studies included in this study were from Europe, the European sample size (808,749) had a

similar sampling fraction of 0.1% - given its target population of over 742.5 million[28]. The NA

sample size (825,734) had the highest sampling fraction of 0.23% to its target population of

over 355 million [28], despite having the lowest number of studies. The African sample size

(178,382) had a sampling fraction of 0.016% to its target population over 1.1 billion.[28] The

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CSA sample size (72,893) had the lowest sampling fraction of 0.011% to its target population of

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over 626 million.[28]

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Study characterisitics
Three-month
Six-month
Two-year
One-year
Lifetime

Median responder rate

School-based

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Mixed

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Urban
Rural

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ICHD used
Post-ICHD era

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Europe
NA
CSA
Asia
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Africa
0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%
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Figure 2. Characteristics of the studies included. Nearly 60% of the studies applied a one-year
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prevalence. Responder rate was over 80%. Seventy (23.2%) studies were from urban setting and 24 (8%)

studies were from rural setting; the rest 94 (68.8%) studies were either mixed urban-rural. Eighty-seven %
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studies were from the post-ICHD era (International Classification of Headache Disorders 1988), and 82%

of these studies applied ICHD criteria. The geographic distribution of the studies was as follows: 33
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(10.9%) studies were from Africa involving combined sample size of 178382, 63 (20.9%) from Asia

involving combined sample size of 4331237, 44 (14.6%) from CSA involving combined sample size of
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72893, 22 (7.3%) from NA involving combined sample size of 825734, and 140 (46.3%) from Europe

involving combined sample size of 808749. Pooled crude migraine prevalence was found to be 11.6%

(95% CI 10.7-12.6%; random effects); 10.4% in Africa, 10.1% in Asia, 11.4% in Europe, 9.7% in NA,

16.4% in CSA.

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Figure 3. Global migraine prevalence changes between the years 1930 and 2015. These
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results showed the regions of Europe (Figure 3d), Asia (Figure 3b), CSA (Figure 3c), and Africa

(Figure 3a) to have statistically significant increment (in a descending order), i.e. migraine

prevalence increased as the years progressed. The NA region (Figure 3e) did not show

statistically significant increase. Overall, the global migraine prevalence (Figure 3f) showed

statistically significant increase.

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Comparison to previous results


18%
Woldeamanuel 2016
16%

Stovner 2007
14%

Stovner 2007 (lifetime)


12%

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10%

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8%

6%

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4%
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2%

0%
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Global Africa Asia CSA Europe NA Male Female


prevalence
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Figure 4. Comparison of our study results to previously published study[29]. The previously
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published study by Stovner et al. showed arithmetic average migraine prevalence of 11%

globally, 5% in Africa, 9% in Asia, 22% in Australia, 9% in CSA, 15% in Europe, and 13% in
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NA; the data from Australia comprised of females only, and all these prevalences included time
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period of 1 year, 3 months, and „time frame not stated‟.[29] For a lifetime prevalence, the same

study showed arithmetic average migraine prevalence of 15% globally, 5% in Africa, 9% in

Asia, 17% in Europe, 13% in NA, and 16% in CSA.[29] Our study‟s overall 11.6% global

prevalence, 6.9% prevalence in men, and 13.8% prevalence in women were comparable to 11%,

6%, and 14% published in the aforementioned study[29], respectively. The higher African

prevalence in our study was because of the weight from our inclusion of recently published

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studies with prevalence of up to 22%.[30] The higher CSA prevalence from our study compared

to that in the aforementioned study could be because of our study‟s inclusion of 14 recent studies

with prevalence as high as 51%[31] and probably because the latter study separated lifetime

results unlike our study. Another point is that Australia was included under the Asian region in

our study unlike the above-mentioned study which reported Australian data distinctly from the

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Asian region.

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Heterogeneity
Comparisons

Q-value p-value

Africa vs. Asia 0.077 0.781


Africa vs. CSA 7.845 0.005
Africa vs. Europe 0.948 0.330

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Africa vs. NA 0.006 0.937
Asia vs. CSA 7.080 0.008

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Asia vs. Europe 1.253 0.263
Asia vs. NA 0.053 0.818

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Europe vs. NA 1.652 0.199
Europe vs. CSA 10.009 0.002
NA vs. CSA 10.667 0.001

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Table 1. Statistical differences among the regional subgroups. There was a statistically
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significant difference between the prevalence in CSA compared to all the other regions; there
was no statistically significant difference among the other four regions. Cochran‟s chi-square or
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Q-test was applied using a significance p-value level of 0.05. Statistically significant differences
are displayed in bold.
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