Recent findings suggest an association between the renin-angiotensin system and migraine. However, genetic studies are scarce and controversial.
To investigate the association between the AGTR1 1166A>C and AGT Met235Thr polymorphisms with migraine and migraine aura status.
We performed an association study among 25,000 Caucasian U.S. women, participating in the Women's Health Study, with information on the AGTR1 1166A>C and AGT Met235Thr polymorphisms. Migraine and migraine aura status were self-reported. We distinguished between any history of migraine, active migraine with aura, active migraine without aura, and prior migraine (history of migraine, but not in the year prior to baseline). We used logistic regression to investigate the genotype-migraine association.
At baseline, 4,577 (18.3%) women reported any history of migraine; 39.5% of the 3,226 women with active migraine indicated aura. The polymorphisms were not associated with migraine or migraine specific subgroups. We also did not find a significant interaction between the polymorphisms.
Data from this large cohort of Caucasian women do not suggest an association of polymorphisms in the renin-angiotensin system with migraine or aura status. Future studies should focus on haplotype analyses and additional gene-gene as well as gene-environment interactions.
migraine; renin-angiotensin system; polymorphism; women
Previous cross-sectional studies evaluating the relationship between diabetes prevalence and migraine status have found conflicting results. We examined the relationship between migraine and incident type 2 diabetes (T2D) in a cohort of adult women.
Prospective cohort study conducted among participants in the Women’s Health Study who provided information on migraine and did not have diabetes at baseline. Our four exposure groups were migraine with aura, migraine without aura, past history of migraine and no history of migraine. Cox proportional hazards models were used to determine the hazard ratio for incident T2D.
Among the 38,620 women included in this study, 5062 (13.1%) women had migraine, of whom 2014 (39.8%) reported migraine with aura, and 2,087 (5.4%) women had a past history of migraine. During a mean of 14.6 years of follow-up, there were 3,032 cases of incident T2D. After adjustment for confounders, the hazard ratio (95% confidence interval) for developing diabetes was 1.06 (0.91–1.24) for women with migraine with aura, 1.01 (0.89–1.16) for women with migraine without aura, 1.13 (0.98–1.30) for women with a past history of migraine compared to women with no history of migraine.
Results of this prospective study in women do not support an association between migraine and incident T2D.
migraine; diabetes; epidemiology
Objectives To examine the association between migraine and migraine aura status with risk of haemorrhagic stroke.
Design Prospective cohort study.
Setting Women’s Health Study, United States.
Participants 27 860 women aged ≥45 who were free from stroke or other major disease at baseline and had provided information on self reported migraine, aura status, and lipid values.
Main outcome measures Time to first haemorrhagic stroke and subtypes of haemorrhagic stroke.
Results At baseline, 5130 (18%) women reported any history of migraine; of the 3612 with active migraine (migraine in the previous year), 1435 (40%) described having aura. During a mean of 13.6 years of follow-up, 85 haemorrhagic strokes were confirmed after review of medical records. Compared with women without a history of migraine, there was no increased risk of haemorrhagic stroke in those who reported any history of migraine (adjusted hazard ratio 0.98, 95% confidence interval 0.56 to 1.71, P=0.93). In contrast, risk was increased in women with active migraine with aura (2.25, 1.11 to 4.54, P=0.024). The age adjusted increased risk was stronger for intracerebral haemorrhage (2.78, 1.09 to 7.07, P=0.032) and for fatal events (3.56, 1.23 to 10.31, P=0.02). Four additional haemorrhagic stroke events were attributable to migraine with aura per 10 000 women per year. Women who reported active migraine without aura had no increased risk for haemorrhagic stroke.
Conclusion Migraine with aura might, in addition to ischaemic events, also be a risk factor for haemorrhagic stroke. The relatively low number of events and attributable risk should caution against definitive conclusions and call for further confirmation of these observations.
— Many studies support an association between migraine and cardiovascular disease (CVD). This association appears particularly in migraine with aura and is also modified by additional factors.
— We sought to investigate whether the association between migraine and CVD in addition to aura status is affected by certain migraine features.
— Cohort study among 27,840 women, participating in the Women’s Health Study. We had detailed self-reported information on migraine and migraine features among women with active migraine (migraine during the year prior to baseline). Incident CVD events were confirmed after medical record review. We used Cox proportional hazards models to evaluate the association between migraine and incident CVD. The results have been presented in part before. We ran additional analyses according to migraine features.
– At baseline, 5,125 (18.4%) women reported history of migraine; 39.7% of the 3,610 women with active migraine indicated aura. During a mean of 11.9 years of follow-up, 708 CVD events occurred. Migraine with aura doubled the risk for CVD, ischemic stroke, and myocardial infarction. With regard to ischemic stroke, this association seemed stronger in the absence than in the presence of migraine features. This was most pronounced in the absence (HR=3.27; 95% CI=1.93–5.51; p<0.0001) than in the presence of nausea/vomiting (HR=0.91; 95% CI=0.43–1.93; p=0.80). In contrast, the association with myocardial infarction did not reveal a certain pattern.
— These data suggest that the association between migraine with aura and ischemic stroke may differ by absence or presence of migraine features.
migraine; migraine features; cardiovascular disease; cohort study
Few clinic-based studies report an association between migraine and restless legs syndrome (RLS); however, population-based data are unavailable.
Cohort study among 31,370 women participating in the Women’s Health Study. We had detailed self-reported information on migraine, including aura status, and RLS. RLS was ascertained at the 9-year follow-up. We calculated odds ratios (OR) and 95% confidence intervals (CI) for the association between migraine and RLS. We investigated any indication of migraine until RLS ascertainment as well as migraine with and without aura at baseline, prior migraine before baseline, and new reports of migraine during follow-up.
At baseline or during follow-up 6,857 (21.9%) women reported any migraine. These women had an increased risk for RLS (multivariable-adjusted OR=1.22; 95%CI 1.13–1.32). Further analyses indicated a similar association for migraine with aura (multivariable-adjusted OR=1.27; 95%CI 1.10–1.48) and migraine without aura (multivariable-adjusted OR=1.24; 95%CI 1.09–1.40) as well as for new reports of migraine during follow-up (multivariable-adjusted OR=1.30; 95%CI 1.10–1.54). Prior migraine did not appear to be associated with RLS.
Our data suggest an association between migraine and RLS at the population level. The association is similar for migraine with and without aura and for new reports of migraine during follow-up.
migraine; restless legs syndrome; cohort study; association
Interrelationships between the ACE D/I polymorphism (rs1799752), migraine, and cardiovascular disease (CVD) are biologically plausible but remain controversial.
Association study among 25,000 white U.S. women, participating in the Women's Health Study, with information on the ACE D/I polymorphism. Migraine and migraine aura status were self-reported. Incident CVD events were confirmed after medical record review. We used logistic regression to investigate the genotype-migraine association and proportional hazards models to evaluate the interrelationship between genotype, migraine, and incident CVD.
At baseline, 4,577 (18.3%) women reported history of migraine; 39.5% of the 3,226 women with active migraine indicated aura. During 11.9 years of follow-up, 625 CVD events occurred. We did not find an association of the ACE D/I polymorphism with migraine or migraine aura status. There was a lack of association between the ACE D/I polymorphism and incident major CVD, including ischemic stroke and myocardial infarction. Migraine with aura doubled the risk for CVD (multivariable-adjusted RR=2.07; 95%CI=1.53-2.79; p<0.0001), but only for carriers of the DD/DI genotype. The risk was not significant among carriers of the II genotype (multivariable-adjusted RR=1.47; 95%CI=0.71-3.03), a pattern we observed for myocardial infarction and ischemic stroke.
Data from this large cohort of women do not suggest an association of the ACE D/I polymorphism with migraine, migraine aura status, or CVD. The increased risk for CVD among migraineurs with aura was only apparent for carriers of the DD/DI genotype. Due to limited number of outcome events, however, future studies are warranted to further investigate this association.
 migraine; ACE D/I polymorphism;  cardiovascular disease;  cohort study
To investigate the role of three common polymorphisms in the β2 adrenoceptor gene in migraine.
Migraine has been associated with increased risk of cardiovascular disease and asthma in which β2 adrenoceptors play an important role; β adrenoceptor antagonists are used in migraine prevention. However, the role of variants in the β2 adrenoceptor gene in migraine is unclear.
Association study among 23,753 white women, participating in the Women’s Health Study, for whom we had information on migraine at baseline and genotype status of the polymorphisms rs1042713 (Gly16Arg), rs1042714 (Gln27Glu), rs1800888 (Thr164Ile). Migraine was self-reported and we distinguished between any history of migraine, active migraine with and without aura, and prior migraine (history of migraine but not active migraine) in our analyses.
At baseline 4,339 women reported any history of migraine. Of these 3,041 had active migraine (1,221 migraine with aura, 1,820 migraine without aura) and 1,298 prior migraine. No migraine was reported by 19,414 women. Genotype- and haplotype-based analyses did not show an association of any of the gene variants tested with any history of migraine. The multivariable-adjusted odds ratios (ORs) (95% confidence intervals) for any history of migraine in the additive model were 1.0 (0.96–1.05) for rs1042713, 1.0 (0.95–1.05) for rs1042714, and 0.84 (0.68–1.05) for rs1800888. In the haplotype analysis the ORs ranged from 0.83 (0.67–1.03) to 1.01 (0.94–1.07) with Gly16-Glu27-Thr164 as the reference. We also did not find associations in the genotype- and haplotype-based analyses within migraine-specific subgroups.
Our results do not support a role of three investigated polymorphisms in the β2 adrenoceptor gene in migraine pathophysiology.
migraine; β2 adrenoceptor; ADRB2; women
Population-based studies have established an association between migraine and cardiovascular disease (CVD). We sought to investigate whether genetic variants implicated in CVD are associated with migraine. We performed an association study among 25,713 women, participating in the Women’s Health Study, with information on 77 previously characterized polymorphisms. Migraine and migraine aura status were self-reported. We used logistic regression to investigate the genotype-migraine association. At baseline, 4,705 (18.3%) women reported history of migraine; 39.6% of the 3,306 women with active migraine indicated aura. Regarding any history of migraine, the multivariable-adjusted odds ratios (95% confidence intervals) for TNF rs673 were 0.52 (0.30-0.89), for TGFB1 rs1800469 0.93 (0.89-0.98), and for CCR2 rs1799864 1.12 (1.03-1.21). Among active migraine with aura the odds ratios (95% confidence intervals) were 1.35 (1.0-1.81) for TNF rs1800750, 1.13 (1.02-1.26) for TNF rs1800629, and 1.22 (1.07-1.40) for CCR2 rs1799864; among active migraine without aura 0.9 (0.84-0.97) for TGFB1 rs1800469, 1.13 (1.01-1.27) for NOS3 rs3918226, and 1.12 (1.02-1.24) for IL9 rs2069885. After correction for multiple testing using the false discovery rate, none of the results remained significant. Our data suggest an association of polymorphisms implicated in inflammatory pathways and migraine in women. TNF, CCR2, TGFB1, NOS3, and IL9 warrant further investigation.
This article presents results from an association study of 77 polymorphisms, implicated in CVD, and migraine. Variants in TNF, CCR2, TGFB1, NOS3, and IL9 were found to be associated with migraine, but did not remain significant after adjustment for multiple testing. Variations in these genes warrant further investigation.
epidemiology; genetics of migraine; polymorphisms; cardiovascular disease
A previous cross-sectional study showed an association of migraine with a higher prevalence of magnetic resonance imaging (MRI)–measured ischemic lesions in the brain.
To determine whether women or men with migraine (with and without aura) have a higher incidence of brain lesions 9 years after initial MRI, whether migraine frequency was associated with progression of brain lesions, and whether progression of brain lesions was associated with cognitive decline.
Design, Setting, and Participants
In a follow-up of the 2000 Cerebral Abnormalities in Migraine, an Epidemiological Risk Analysis cohort, a prospective populationbased observational study of Dutch participants with migraine and an age- and sexmatched control group, 203 of the 295 baseline participants in the migraine group and 83 of 140 in the control group underwent MRI scan in 2009 to identify progression of MRI-measured brain lesions. Comparisons were adjusted for age, sex, hypertension, diabetes, and educational level. The participants in the migraine group were a mean 57 years (range, 43–72 years), and 71% were women. Those in the control group were a mean 55 years (range, 44–71 years), and 69% were women.
Main Outcome Measures
Progression of MRI-measured cerebral deep white matter hyperintensities, infratentorial hyperintensities, and posterior circulation territory infarctlike lesions. Change in cognition was also measured.
Of the 145 women in the migraine group, 112 (77%) vs 33 of 55 women (60%) in the control group had progression of deep white matter hyperintensities (adjusted odds ratio [OR], 2.1; 95%CI, 1.0–4.1; P=.04). There were no significant associations of migraine with progression of infratentorial hyperintensities: 21 participants (15%) in themigraine group and 1 of 57 participants (2%) in the control group showed progression (adjusted OR, 7.7; 95% CI, 1.0–59.5; P=.05) or new posterior circulation territory infarctlike lesions: 10 of 203 participants (5%) in the migraine group but none of 83 in the control group (P=.07). There was no association of number or frequency of migraine headaches with progression of lesions. There was no significant association of high vs nonhigh deep white matter hyperintensity load with change in cognitive scores ( 3.7 in the migraine group vs 1.4 in the control group; 95% CI, 4.4 to 0.2; adjusted P=.07).
In a community-based cohort followed up after 9 years, women with migraine had a higher incidence of deep white matter hyperintensities but did not have significantly higher progression of other MRI-measured brain changes. There was no association of migraine with progression of any MRI-measured brain lesions in men.
Interrelationships among the ACE deletion/insertion (D/I) polymorphism (rs1799752), migraine, and cardiovascular disease (CVD) are biologically plausible but remain controversial.
Association study among 25,000 white US women, participating in the Women’s Health Study, with information on the ACE D/I polymorphism. Migraine and migraine aura status were self-reported. Incident CVD events were confirmed after medical record review. We used logistic regression to investigate the genotype-migraine association and proportional hazards models to evaluate the interrelationship among genotype, migraine, and incident CVD.
At baseline, 4,577 (18.3%) women reported history of migraine; 39.5% of the 3,226 women with active migraine indicated aura. During 11.9 years of follow-up, 625 CVD events occurred. We did not find an association of the ACE D/I polymorphism with migraine or migraine aura status. There was a lack of association between the ACE D/I polymorphism and incident major CVD, ischemic stroke, and myocardial infarction. Migraine with aura doubled the risk for CVD, but only for carriers of the DD (multivariable-adjusted relative risk [RR] = 2.10; 95% CI = 1.22–3.59; p = 0.007) and DI genotype (multivariable-adjusted RR = 2.31; 95% CI = 1.52–3.51; p < 0.0001). The risk was not significant among carriers of the II genotype, a pattern we observed for myocardial infarction and ischemic stroke.
Data from this large cohort of women do not suggest an association of the ACE deletion/insertion (D/I) polymorphism with migraine, migraine aura status, or cardiovascular disease (CVD). The increased risk for CVD among migraineurs with aura was only apparent for carriers of the DD/DI genotype. Due to limited number of outcome events, however, future studies are warranted to further investigate this association.
= angiotensin-converting enzyme;
= confidence interval;
= cardiovascular disease;
= hazard ratios;
= International Headache Society;
= myocardial infarction;
= odds ratio;
= Women’s Health Study.
Objectives To evaluate whether the association between migraine with aura and increased risk of cardiovascular disease is modified by vascular risk groups as measured by the Framingham risk score for coronary heart disease.
Design Prospective cohort study.
Setting Women’s health study, United States.
Participants 27 519 women who were free from cardiovascular disease at baseline with available information on the Framingham risk score and migraine status.
Main outcome measures Time to major cardiovascular disease event (non-fatal myocardial infarction, non-fatal ischaemic stroke, death from ischaemic cardiovascular disease), myocardial infarction, and ischaemic stroke.
Results At baseline, 3577 (13.0%) women reported active migraine, of whom 1418 (39.6%) reported migraine with aura. During 11.9 years of follow-up, there were 697 cardiovascular disease events. We stratified participants based on 10 year risk of coronary heart disease estimated from the Framingham risk score (≤1%, 2-4%, 5-9%, and ≥10%). Compared with women without migraine, the age adjusted hazard ratios in women with active migraine with aura were 1.93 (95% confidence interval 1.45 to 2.56) for major cardiovascular disease, 1.80 (1.16 to 2.79) for ischaemic stroke, and 1.94 (1.27 to 2.95) for myocardial infarction. When stratified by Framingham risk score, the association between migraine with aura and major cardiovascular disease was strongest in the lowest risk score group. There was a diametric association pattern for ischaemic stroke and myocardial infarction. Compared with women without migraine, the age adjusted hazard ratios in women who reported migraine with aura in the lowest Framingham risk score group were 3.88 (1.87 to 8.08) for ischaemic stroke and 1.29 (0.40 to 4.21) for myocardial infarction. Hazard ratios in women with migraine with aura in the highest Framingham risk score group were 1.00 (0.24 to 4.14) for ischaemic stroke and 3.34 (1.50 to 7.46) for myocardial infarction. Women with migraine without aura were not at increased risk of ischaemic stroke or myocardial infarction in any of the Framingham risk score groups.
Conclusion The association between migraine with aura and cardiovascular disease varies by vascular risk status. Information on history of migraine and vascular risk status might help to identify women at increased risk for specific future cardiovascular disease events.
Trial registration Clinical trials NCT00000479.
Interrelationships between the MTHFR 677C>T polymorphism (rs1801133), migraine, and cardiovascular disease (CVD) are plausible but remain controversial.
Association study among 25,001 white U.S. women, participating in the Women’s Health Study, with information on MTHFR 677C>T polymorphism. Migraine and migraine aura status were self-reported. Incident CVD events were confirmed after medical record review. We used logistic regression to investigate the genotype-migraine association and proportional hazards models to evaluate the interrelationships of genotype and migraine on incident CVD.
At baseline, 4,577 (18.3%) women reported history of migraine; 39.5% of the 3,226 women with active migraine indicated aura. During a mean of 11.9 years of follow-up, 625 CVD events occurred. Our results suggest a modestly reduced risk for migraine with aura in carriers of the TT genotype. The multivariable-adjusted relative risk (RR) in the recessive model was 0.79 (95%CI=0.65–0.96; p=0.02). The TT genotype did not increase the risk for CVD. In contrast, migraine with aura doubled the risk for CVD (multivariable-adjusted RR=2.06; 95%CI=1.53–2.78; p<0.0001). Co-existence of migraine with aura and the TT genotype selectively raised this risk (RR=3.66; 95%CI=1.69–7.90; p=0.001). This pattern was driven by a 4-fold increased risk for ischemic stroke (multivariable-adjusted RR=4.19; 95%CI=1.38–12.74; p=0.01) and not apparent for myocardial infarction.
Data from this large cohort of women suggest a modest protective effect of the MTHFR 677TT genotype on migraine with aura. The increased risk for CVD among migraineurs with aura was magnified for TT genotype carriers, which was driven by a substantially increased risk of ischemic stroke.
 migraine; MTHFR polymorphism;  cardiovascular disease;  cohort study
Studies have linked migraine with aura to an increased risk of ischemic stroke, particularly among women. Data on the relationship of migraine and functional outcome from ischemic cerebral events are sparse.
Methods and Results
Prospective cohort study among 27,852 women enrolled in the Women’s Health Study for whom we had information on migraine and measured cholesterol values and who had no prior stroke or transient ischemic attack (TIA). Migraine was classified into no history of migraine, active migraine with aura, active migraine without aura, and past history of migraine. Possible functional outcomes were no stroke or TIA, TIA, and stroke with modified Rankin Scale (mRS) score 0–1, mRS 2–3, and mRS 4–6. We used multinomial logistic regression to evaluate the relationship of migraine with functional outcomes after ischemic stroke. During a mean of 13.5 years of follow-up, 398 TIAs and 345 ischemic strokes occurred. Compared with women without history of migraine and who did not experience a TIA or stroke, women who reported migraine with aura had adjusted relative risk (95% confidence interval) of 1.56 (1.03–2.36) for TIA, 2.33 (1.37–3.97) for stroke with mRS 0–1, 0.82 (0.30–2.24) for mRS 2–3, and 1.18 (0.28–4.97) for mRS 4–6. The risk of any outcome was not significantly elevated for women who experienced migraine without aura or who had a past history of migraine.
Results of this large prospective cohort suggest that women with migraine with aura are at increased risk of experiencing TIA or ischemic stroke with good functional outcome.
Migraine; stroke; epidemiology; women
Previous studies on migraine and cognition have shown mixed results. However, many could not assess the relationship between migraine and change in cognitive function or only used a limited number of cognitive tests.
Prospective cohort study among 1170 participants of the Epidemiology of Vascular Aging Study who provided information about migraine status and completed cognitive testing. Participants were classified as having no severe headache, non-migraine headache and migraine. Cognitive functioning was measured at up to four time points using nine different cognitive functioning tests. Linear mixed effects models were used to evaluate the relationship between migraine status and change in cognitive function.
Of the 1170 participants, 938 had no severe headache, 167 had migraine, and 65 had non-migraine headache. After adjusting for age, gender, education, and smoking status, people with migraine or non-migraine headache did not experience a greater rate of cognitive decline than those without headache or migraine in any domain (for the MMSE, p-values were 0.68 for the non-migraine headache and time interaction and 0.85 for the migraine and time interaction) during 4-5 years of follow-up. For the Wechsler, those with migraine declined less over time (p-value=.02).
Migraine was not associated with faster cognitive decline over time.
Migraine; cognitive function; epidemiology
Objective To examine the association of type 2 diabetes with baseline cognitive function and cognitive decline over two years of follow up, focusing on women living in the community and on the effects of treatments for diabetes.
Design Nurses' health study in the United States. Two cognitive interviews were carried out by telephone during 1995-2003.
Participants 18 999 women aged 70-81 years who had been registered nurses completed the baseline interview; to date, 16 596 participants have completed follow up interviews after two years.
Main outcome measures Cognitive assessments included telephone interview of cognitive status, immediate and delayed recalls of the East Boston memory test, test of verbal fluency, delayed recall of 10 word list, and digit span backwards. Global scores were calculated by averaging the results of all tests with z scores.
Results After multivariate adjustment, women with type 2 diabetes performed worse on all cognitive tests than women without diabetes at baseline. For example, women with diabetes were at 25-35% increased odds of poor baseline score (defined as bottom 10% of the distribution) compared with women without diabetes on the telephone interview of cognitive status and the global composite score (odds ratios 1.34, 95% confidence interval 1.14 to 1.57, and 1.26, 1.06 to 1.51, respectively). Odds of poor cognition were particularly high for women who had had diabetes for a long time (1.52, 1.15 to 1.99, and 1.49, 1.11 to 2.00, respectively, for ≥ 15 years' duration). In contrast, women with diabetes who were on oral hypoglycaemic agents performed similarly to women without diabetes (1.06 and 0.99), while women not using any medication had the greatest odds of poor performance (1.71, 1.28 to 2.281, and 1.45, 1.04 to 2.02) compared with women without diabetes. There was also a modest increase in odds of poor cognition among women using insulin treatment. All findings were similar when cognitive decline was examined over time.
Conclusions Women with type 2 diabetes had increased odds of poor cognitive function and substantial cognitive decline. Use of oral hypoglycaemic therapy, however, may ameliorate risk.
Migraine has been linked with several measures of socioeconomic status (SES). However, results are inconsistent and data on the association between SES and non-migraine headache, migraine subtypes and migraine frequency are sparse.
We conducted a cross-sectional study among 36,858 participants in the Women’s Health Study. As proxy for SES, we calculated an SES index using annual household income and education. Migraine, migraine aura, and non-migraine headache were self-reported with good validation rates. Multinomial logistic regression models were used to evaluate the association between SES index and the various headache forms.
12,140 (32.9%) women reported any history of headache, 6,801 women (18.4%) reported any history of migraine and 5,339 (14.5%) reported non-migraine headache. Women with low SES had an increased risk for all headache forms. The multivariable-adjusted OR (95% CI) were 1.22 (1.10–1.36) for non-migraine headache, 1.40 (1.28–1.54) for any migraine, 1.44 (1.23–1.69) for migraine with aura, and 1.38 (1.21–1.58) for migraine without aura. Among active migraineurs, low SES was associated with an increased OR for ≥weekly attack frequency (1.77, 1.26–2.49).
In this large cohort of female health professionals, low SES was associated with an increased prevalence for all headache forms and an increased migraine attack frequency.
Migraine; non-migraine headache; migraine frequency; socioeconomic status
Data on the association of the MTHFR 677C>T and ACE D/I polymorphisms with migraine severity, measured by attack frequency, are scarce. We performed an association study among 24,961 women, participating in the Women's Health Study. Migraine, aura status, and attack frequency were self-reported. We used multinomial logistic regression to investigate the genotype-migraine association. Among the 3,186 migraineurs with complete genotype and attack frequency data, 1,270 reported migraine with aura (attack frequency: 76 ≥weekly; 219 monthly; 123 every other month; 852 <6 times/year) and 1,916 migraine without aura (attack frequency: 85 ≥weekly; 414 monthly; 208 every other month; 1,209 <6 times/year). The MTHFR 677TT genotype was associated with a reduced risk for migraine with aura, which only appeared for attacks <6 times/year (age-adjusted odds ratio=0.78; 95% confidence interval=0.61-0.99). We did not find a specific pattern of association of the ACE D/I polymorphism with attack frequency for migraine with or without aura.
migraine; migraine severity; attack frequency; MTHFR 677C>T polymorphism; ACE D/I polymorphism
The prospective Nurses’ Health Study II (NHS-II), which enrolled over 116,000 female nurses, provides a unique opportunity to test the hypothesis of whether migraine is associated with MS and to explore the temporal aspects of the interrelationship.
To calculate relative risk of MS among NHS-II participants with and without migraine; to estimate odds ratio of being diagnosed with migraine in women with and without pre-existing MS.
Cox proportional hazards regression was used to estimate rate ratios and 95% CIs of being diagnosed with MS in women with and without pre-existing migraine adjusted for potential confounders. Multi-variate adjusted odds ratio of being diagnosed with migraine in women with and without pre-existing MS were estimated using logistic regression.
The prevalence of migraine in women with MS at baseline (26%, p=0.11) and those diagnosed with MS after enrolment (29%, p<0.0001) was higher than in the non-MS cases (21%). The relative risk of developing MS in migraineurs was 1.39 times higher than in non-migraineurs (95% CI: 1.10-1.77 (p= 0.008)). The absolute risk of developing MS in women-migraineurs over a 15-year follow-up was 0.47%, and 0.32% among non-migraineurs. The odds of being diagnosed with migraine was higher in women with pre-existing MS compared to those without MS, but did not reach statistical significance (OR=1.57, 95% CI: 0.97-2.52; p=0.06).
Using a large, population-based cohort of women-nurses, history of migraine was associated with an increased risk of MS. However, the difference in absolute risk of MS in migraineurs and non-migraineurs was small.
Multiple Sclerosis ; Migraine ; Natural history studies (prognosis) ; Risk factors in epidemiology 
Migraine has a wide clinical spectrum. Our aim was to group information on migraine characteristics into meaningful components and to identify key components of the migraine phenotype.
We performed two principal component analyses, one among participants in the Women's Health Study enrolment cohort and one in a sub-cohort with additional migraine-specific information.
Among the 9,427 women with migraine attack-related information at enrolment, the three most important components pertained to central nervous system (CNS) sensitization, attack frequency/pain location, and aura/visual phenomena. In the sub-group of 1,675 women with more detailed information, food triggers and unspecific symptoms constituted two principal components that explain more of the variance of the migraine phenotype than the three attack-related components.
Our results indicate that information on migraine-associated features, symptoms, and triggers is highly correlated allowing the extraction of principal components. Migraine attack-related symptoms are best summarized by symptoms related to CNS sensitization, attack frequency/pain location, and aura/visual phenomena. Taking a more general view, unspecific symptoms and food triggers appear to carry stronger importance in characterizing the migraine phenotype. These components are useful for future research on the pathophysiology and genetics of migraine and may have implications for diagnosing and treating patients.
migraine; features; triggers; sensitization; principal component analysis
To describe the medical care use and costs associated with migraine.
Retrospective case-control design in which migraine case status was ascertained via validated telephone interview and linked with comprehensive claims data. Unadjusted and adjusted use and cost differences by migraine status were evaluated using exponential score tests and generalized estimating equations.
SETTING AND PATIENTS
We interviewed 8,579 individuals to identify migraine cases (N = 1,265) and a random sample of nonmigraine controls (N = 1,178) among eligible health plan enrollees aged 18 to 55.
Survey responses were used to categorize individuals meeting the International Headache Society's diagnostic criteria for migraine with or without aura as migraine cases and to collect information on comorbid psychiatric symptoms. Claims data were used to compile annual medical and pharmaceutical use and costs, presence of migraine diagnosis, and other diagnosed comorbidities.
Interview-ascertained migraine cases used more outpatient visits (9.1 vs 6.8; P < .01), were more likely to be seen in the emergency department (20.7% vs 17.6%; P < .05), and were admitted to the hospital more (4.5% vs 2.8%; P < .05) compared to nonmigraine controls. Cases incurred significantly higher medical care costs ($2,761 vs $2,064; P < .01). Multivariable model results indicate that much of this increase in costs is due to the presence of major depressive symptoms as well as other diagnosed comorbidities that are more common among those with migraine.
By combining validated telephone survey information to identify migraine cases and controls with comprehensive claims data, we found migraine cases incur higher medical care costs compared to controls. These increased costs are associated with the presence of psychiatric symptoms and other comorbidities.
migraine; migraine headache; medical care cost; utilization; claims data
Migraine is a common headache disorder that is increasingly being evaluated in population-based studies. The American Migraine Study II and the Women’s Health Study (WHS) have successfully used “modified” International Classification of Headache Disorders - I (ICHD-I) criteria to classify patients. Investigating agreement of self-reported migraine in large epidemiological studies with the criteria of the revised version (ICHD-II) is sparse. We have investigated 1,675 women with self-reported migraine participating in the WHS, who provided additional information on a detailed migraine questionnaire, which allowed us to apply all ICHD-II criteria. In this sub-cohort we confirmed self-reported migraine in over 87% of women when applying the ICHD-II criteria for migraine (71.5%) and probable migraine without aura (16.2 %). In conclusion, there is excellent agreement between self-reported migraine and ICHD-II based migraine classification in the WHS. In addition, questionnaire-based migraine assessment according to full ICHD-II criteria in large population-based studies is feasible.
migraine; epidemiology; questionnaire; ICHD-I; ICHD-II
Migraine has been associated with risk of cardiovascular disease (CVD). Data on the association between migraine frequency and CVD are sparse.
Prospective cohort study of 27,798 US women aged ≥45 years, who were free of CVD, and for whom we had information on lipids and migraine frequency. We categorized migraine frequency as < monthly, monthly, and ≥ weekly. Incident CVD was confirmed after medical record review.
Of the 3,568 women with active migraine at baseline, 75.3% reported a migraine frequency of < monthly, 19.7% monthly, and 5.0% ≥ weekly. During 11.9 years of follow-up, 706 CVD events occurred. Compared with women without migraine, the multivariable-adjusted hazard ratios (HRs) (95% confidence intervals) among active migraineurs for CVD were 1.55 (1.22–1.97), 0.65 (0.31–1.38), and 1.93 (0.86–4.33) for an attack frequency of < monthly, monthly, and ≥ weekly, respectively. The association between migraine frequency and CVD was only apparent among migraineurs with aura. Among those, the multivariable-adjusted HRs for women with a migraine frequency < monthly ranged from 1.81 (1.30–2.50) for coronary revascularizations to 2.43 (1.58–3.74) for myocardial infarction. For women with active migraine with aura and migraine frequencies of ≥ weekly, we only found significant increased risk of ischemic stroke (HR = 4.25 [1.36–13.29]).
In our data, the association between migraine and cardiovascular disease varies by migraine frequency. Significant associations were only found among women with migraine with aura. Ischemic stroke was the only outcome associated with a high-attack frequency while a low-attack frequency was associated with any vascular event. Low number of outcome events should caution the interpretation.
= confidence interval;
= cardiovascular disease;
= hazard ratio;
= myocardial infarction;
= Women’s Health Study.
Intimate partner violence (IPV) among women is a global public health problem. The association between childhood maltreatment and migraine is well established, but not the association between IPV and migraine. The aim of this cross-sectional study was to evaluate the relationship between type and severity of IPV and migraine in a large cohort of Peruvian women.
Women who delivered singleton infants (N=2,066) at the Instituto Nacional Materno Perinatal, Lima, Peru were interviewed during their post-partum hospital stay. Participants were queried about their lifetime experiences with headaches and migraine, and with physical and sexual violence. The International Classification of Headache Disorders (ICHD-2) diagnostic criteria were used to classify participants according to their migraine status. Questions on physical and sexual violence were adapted from the protocol of Demographic Health Survey Questionnaires and Modules: Domestic Violence Module and the World Health Organization (WHO) Multi-Country Study on Violence against Women. Depressive symptoms were assessed using the nine-item Patient Health Questionnaire Depression Subset. Logistic regression was used to estimate multivariate adjusted odds ratios (aOR) and 95% confidence intervals (CI).
Compared with women without a history of violence, women with experiences of lifetime physical or sexual violence (aOR=1.44, 95% CI 1.19–1.75), physical violence only (aOR=1.36, 95% CI 1.10–1.68), sexual violence only (aOR=1.76, 95% CI 0.97–3.21) and both physical and sexual violence (aOR=1.61, 95% CI 1.12–2.31) had increased odds of any migraine after adjusting for maternal age, parity and access to basic foods. There was no gradient of increased odds of any migraine with severity of physical violence. The relationship between IPV and any migraine was strongest among women with depressive symptoms. The odds of any migraine was increased 2.25-fold (95% CI 1.75–2.28) among abused women who also had depressive symptoms compared with non-abused and non-depressed women. Associations from sensitivity analyses that segregated women according to probable migraine (ICHD-2 category 1.6.1) and migraine (ICHD-2 category 1.1) diagnoses were of similar magnitudes as those reported here for women with any migraine diagnoses. IPV, particularly sexual violence, appears to be a risk factor for migraine.
Our findings suggest the potential importance of considering a history of violence among migraineurs.
Migraine has been associated with sleep disorders in men and non-pregnant women, but little is known about sleep complaints among pregnant migraineurs.
A cohort of 1,334 women was interviewed during early pregnancy. At the time of interview we ascertained participants' migraine diagnosis status and collected information about sleep duration before and during early pregnancy, daytime sleepiness, vital exhaustion and perceived stress during early pregnancy. Multivariable logistic regression procedures were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of short/long sleep duration, excessive daytime sleepiness, vital exhaustion and elevated perceived stress associated with a history of migraine.
Approximately 19.4% of the cohort (n = 259) reported having a medical diagnosis of migraine prior to the study pregnancy. Compared with women without migraine, the multivariable-adjusted ORs (95% CI) among migraineurs for short sleep duration before and during early pregnancy were 1.51 (1.09-2.09), and 1.57 (1.11-2.23), respectively. The corresponding OR (95% CI) for long sleep duration before and during pregnancy were 1.33 (0.77-2.31) and 1.31 (0.94-1.83), respectively. A modest and statistically insignificant association between migraine history and excessive daytime sleepiness in early pregnancy was noted (OR = 1.46; 95% CI 0.94-2.26). Migraineurs had an increased risk of vital exhaustion (OR = 2.04; 95% CI 1.52-2.76) and elevated perceived stress (OR = 1.57; 95% CI 1.06-2.31). Observed associations were more pronounced among overweight migraineurs.
These data support earlier research documenting increased risks of sleep disorders among migraineurs; and extends the literature to include pregnant women. Prospective studies are needed to more thoroughly explore factors that mediate the apparent migraine-sleep comorbidity among pregnant women.
Migraine with aura (MA) has been associated with increased risk of cardiovascular disease (CVD). The role of aspirin on this association remains unclear.
Post-hoc subgroup analyses of the Women’s Health Study, a randomized trial testing 100mg aspirin on alternate days in primary prevention of CVD among 39,876 women aged ≥45.
During 10 years, 998 major CVD events were confirmed in 39,757 women with complete migraine information. Aspirin reduced risk of ischemic stroke (RR=0.76; 95%CI=0.63–0.93) but not other CVD. Migraine or MA did not modify the effect of aspirin on CVD except for myocardial infarction (MI) (p-interaction=0.01). Women with MA on aspirin had increased risk of MI (RR=3.72, 95%CI=1.39–9.95). Further exploratory analyses indicate this is only apparent among women with MA on aspirin who ever smoked or had history of hypertension (p-interaction<0.01).
In post-hoc subgroup analyses, aspirin had similar protective effects on ischemic stroke for women with or without migraine. By contrast, our data suggest that women with MA on aspirin had increased risk of MI. The small number of outcome events in subgroups, the exploratory nature of our analyses, and lack of plausible mechanisms raise the possibility of a chance finding, which must caution the interpretation.