Case-control study of migraine and risk of ischaemic stroke in young women.

OBJECTIVE--To determine whether migraine is a risk factor for ischaemic stroke in young women. DESIGN--A case-control study. SETTING--Five hospitals in Paris and suburbs. SUBJECTS--72 women aged under 45 with ischaemic stroke and 173 controls randomly selected from women hospitalised in the same centres. MAIN OUTCOME MEASURES--Ischaemic stroke confirmed by cerebral computerised tomography or magnetic resonance imaging; history of headache recorded with structured interview, and diagnosis of migraine assessed by reproducibility study. RESULTS--Ischaemic stroke was strongly associated with migraine, both migraine without aura (odds ratio 3.0 (95% confidence interval 1.5 to 5.8)) and migraine with aura (odds ratio 6.2 (2.1 to 18.0)). The risk of ischaemic stroke was substantially increased for migrainous women who were using oral contraceptives (odds ratio 13.9) or who were heavy smokers (> or = 20 cigarettes/day) (odds ratio 10.2). CONCLUSIONS--These results indicate an independent association between migraine and the risk of ischaemic stroke in young women. Although the absolute risk of ischaemic stroke in young women with migraine is low, the reduction of known risk factors for stroke, in particular smoking and use of oral contraceptives, should be considered in this group.     

Migraine and stroke in young women: case-control study

ObjectiveTo investigate the association between migraine and ischaemic or haemorrhagic stroke in young women.DesignHospital based case-control study.SettingFive European centres participating in the World Health Organisation Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception.Subjects291 women aged 20-44 years with ischaemic, haemorrhagic, or unclassified arterial stroke compared with 736 age and hospital matched controls.InterventionQuestionnaire.ResultsAdjusted odds ratios associated with a personal history of migraine were 1.78 (95% confidence intervals, 1.14 to 2.77), 3.54 (1.30 to 9.61), and 1.10 (0.63 to 1.94) for all stroke, ischaemic stroke, and haemorrhagic stroke respectively. Odds ratios for ischaemic stroke were similar for classical migraine (with aura) (3.81, 1.26 to 11.5) and simple migraine (without aura) (2.97, 0.66 to 13.5). A family history of migraine, irrespective of personal history, was also associated with increased odds ratios, not only for ischaemic stroke but also haemorrhagic stroke. In migrainous women, coexistent use of oral contraceptives or a history of high blood pressure or smoking had greater than multiplicative effects on the odds ratios for ischaemic stroke associated with migraine alone. Change in the frequency or type of migraine on using oral contraceptives did not predict subsequent stroke. Between 20% and 40% of strokes in women with migraine seemed to develop directly from a migraine attack.ConclusionsMigraine in women of childbearing age significantly increases the risk of ischaemic but not haemorrhagic stroke. The coexistence of oral contraceptive use, high blood pressure, or smoking seems to exert a greater than multiplicative effect on the risk of ischaemic stroke associated with migraine.

Key messages

• A personal history of migraine was associated with increased risk of ischaemic but not haemorrhagic stroke
• Coexistence of risk factors—use of oral contraceptives, high blood pressure, or smoking had more than multiplicative effects on odds ratios for ischaemic stroke associated with migraine alone
• A family history of migraine, irrespective of a personal migraine history, was associated with increased risk of ischaemic and haemorrhagic stroke
• Up to 40% of strokes in migrainous women develop directly out of a migraine attack—so called migrainous strokes
• A change in type or frequency of migraine with use of oral contraceptives did not predict subsequent stroke

     

Selectivity in Genetic Association with Sub-classified Migraine in Women

Migraine can be sub-classified not only according to presence of migraine aura (MA) or absence of migraine aura (MO), but also by additional features accompanying migraine attacks, e.g. photophobia, phonophobia, nausea, etc. all of which are formally recognized by the International Classification of Headache Disorders. It remains unclear how aura status and the other migraine features may be related to underlying migraine pathophysiology. Recent genome-wide association studies (GWAS) have identified 12 independent loci at which single nucleotide polymorphisms (SNPs) are associated with migraine. Using a likelihood framework, we explored the selective association of these SNPs with migraine, sub-classified according to aura status and the other features in a large population-based cohort of women including 3,003 active migraineurs and 18,108 free of migraine. Five loci met stringent significance for association with migraine, among which four were selective for sub-classified migraine, including rs11172113 (LRP1) for MO. The number of loci associated with migraine increased to 11 at suggestive significance thresholds, including five additional selective associations for MO but none for MA. No two SNPs showed similar patterns of selective association with migraine characteristics. At one extreme, SNPs rs6790925 (near TGFBR2) and rs2274316 (MEF2D) were not associated with migraine overall, MA, or MO but were selective for migraine sub-classified by the presence of one or more of the additional migraine features. In contrast, SNP rs7577262 (TRPM8) was associated with migraine overall and showed little or no selectivity for any of the migraine characteristics. The results emphasize the multivalent nature of migraine pathophysiology and suggest that a complete understanding of the genetic influence on migraine may benefit from analyses that stratify migraine according to both aura status and the additional diagnostic features used for clinical characterization of migraine.     

Vascular gene polymorphisms (EDNRA -231 G>A and APOE HhaI) and risk for migraine

Migraine is a neurovascular disorder, and hence, any alteration in vascular endothelial function by either the endothelin system or the apolipoproteins may contribute to its pathophysiology. Thus, we investigated the role of EDNRA -231 G>A and APOE HhaI polymorphism for a possible association with migraine. Genotyping of 613 subjects consisting of 217 migraine subjects, 217 healthy controls (HC), and 179 subjects with tension-type headache was performed using the standard PCR-RFLP method. Data were analyzed by taking the Bonferroni-corrected p-values into account. We found significant difference in the frequency of EDNRA AA genotype between migraine subjects when compared with HC (p-value?=?0.005; OR?=?2.542; confidence interval [CI]?=?1.329-4.863). A similar trend was shown by female migraine subjects at genotype and allele levels. The association of EDNRA -231 G>A polymorphism with migraine fit a recessive model (migraine vs. HC, p-value?=?0.002; OR?=?1.917; CI?=?2.268-2.898). Female migraineurs without aura (MO) followed a similar trend. In the case of APOE HhaI polymorphism, E3E4 and E2E3 genotypes conferred risk when taken together in case of migraine versus HC (p-value?=?0.005; OR?=?2.715; CI?=?1.342-5.490) and migraine with aura (MA) versus HC (p-value?=?0.004; OR?=?3.422; CI?=?7.992). The risk was also seen after stratification on the basis of gender in female migraineurs (total migraine and MA). The interaction of EDNRA and APOE genotypes did not show further significance. The AA genotype and A allele of EDNRA -231 G>A polymorphism conferred risk for total migraine and MO. In APOE HhaI polymorphism, E3E4 and E2E3 conferred risk when taken together in total migraine and MA.     

Factors for short-term outcomes in patients with a minor stroke: results from China National Stroke Registry

Several studies suggest that perceived psychosocial stress is associated with increased risk of stroke; however results are inconsistent with regard to definitions and measurement of perceived stress, features of individual study design, study conduct and conclusions drawn and no meta-analysis has yet been published. We performed a systematic review and meta-analysis of studies assessing association between perceived psychosocial stress and risk of stroke in adults.The results of the meta-analysis are presented. Systematic searches of MEDLINE, EMBASE, CINAHL, PsycInfo, and Cochrane Database of Systematic Reviews were undertaken between 1980 and June 2014. Data extraction and quality appraisal was performed by two independent reviewers. Hazard ratios (HR) and odds ratios (OR) were pooled where appropriate. 14 studies were included in the meta-analysis, 10 prospective cohort, 4 case–control design. Overall pooled adjusted effect estimate for risk of total stroke in subjects exposed to general or work stress or to stressful life events was 1.33 (95 % confidence interval [CI], 1.17, 1.50; P < 0.00001). Sub-group analyses showed perceived psychosocial stress to be associated with increased risk of fatal stroke (HR 1.45 95 % CI, 1.19,1.78; P = 0.0002), total ischaemic stroke (HR 1.40 95 % CI, 1.00,1.97; P = 0.05) and total haemorrhagic stroke (HR 1.73 95 % CI, 1.33,2.25; P > 0.0001).A sex difference was noted with higher stroke risk identified for women (HR 1.90 95 % CI, 1.4, 2.56: P < 0.0001) compared to men (HR 1.24 95 % CI, 1.12, 1.36; P < 0.0001). Current evidence indicates that perceived psychosocial stress is independently associated with increased risk of stroke.     

Snoring as a risk factor for ischaemic heart disease and stroke in men.

The association of snoring with ischaemic heart disease and stroke was studied prospectively in 4388 men aged 40-69. The men were asked, in a questionnaire sent to them, whether they snored habitually, frequently, occasionally, or never. Hospital records and death certificates were checked for the next three years to establish how many of the men developed ischaemic heart disease or stroke: the numbers were 149 and 42, respectively. Three categories of snoring were used for analysis: habitual and frequent snorers (n = 1294), occasional snorers (n = 2614), and non-snorers (n = 480). The age adjusted relative risk of ischaemic heart disease between habitual plus frequent snorers and non-snorers was 1.91 (p less than 0.01) and for ischaemic heart disease or stroke, or both, 2.38 (p less than 0.001). There were no cases of stroke among the non-snorers. Adjustment for age, body mass index, history of hypertension, smoking, and alcohol use did not significantly decrease the relative risks, which were 1.71 (p greater than 0.05) for ischaemic heart disease and 2.08 (p less than 0.01) for ischaemic heart disease and stroke combined. At the beginning of follow up in 1981, 462 men reported a history of angina pectoris or myocardial infarction. For them the relative risk of ischaemic heart disease between habitual plus frequent snorers and non-snorers was 1.30 (NS); for men without previous ischaemic heart disease 2.72 (p less than 0.05). Snoring seems to be a potential determinant of risk of ischaemic heart disease and stroke.     

Molecular genetics of migraine

Migraine is an episodic neurovascular disorder that is clinically divided into two main subtypes that are based on the absence or presence of an aura: migraine without aura (MO) and migraine with aura (MA). Current molecular genetic insight into the pathophysiology of migraine predominantly comes from studies of a rare monogenic subtype of migraine with aura called familial hemiplegic migraine (FHM). Three FHM genes have been identified, which all encode ion transporters, suggesting that disturbances in ion and neurotransmitter balances in the brain are responsible for this migraine type, and possibly the common forms of migraine. Cellular and animal models expressing FHM mutations hint toward neuronal hyperexcitability as the likely underlying disease mechanism. Additional molecular insight into the pathophysiology of migraine may come from other monogenic syndromes (for instance cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, which is caused by NOTCH3 mutations), in which migraine is prominent. Investigating patients with common forms of migraine has had limited successes. Except for 5′,10′-methylenetetrahydrolate reductase, an enzyme in folate metabolism, the large majority of reported genetic associations with candidate migraine genes have not been convincingly replicated. Genetic linkage studies using migraine subtypes as an end diagnosis did not yield gene variants thus far. Clinical heterogeneity in migraine diagnosis may have hampered the identification of such variants. Therefore, the recent introduction of more refined methods of phenotyping, such as latent-class analysis and trait component analysis, may be certainly helpful. Combining the new phenotyping methods with genome-wide association studies may be a successful strategy toward identification of migraine susceptibility genes. Likely the identification of reliable biomarkers for migraine diagnosing will make these efforts even more successful.     

Migraine and risk of ischaemic stroke: a case-control study.

OBJECTIVES--To determine whether migraine is a risk factor for ischaemic stroke. DESIGN--A case-control study. SETTING--Two hospitals in Paris. SUBJECTS--212 patients with stroke (137 men and 75 women) and 212 controls matched for sex, age (to within five years), and history of hypertension. MAIN OUTCOME MEASURES--Ischaemic stroke, confirmed by brain computed tomography or magnetic resonance imaging, and history of headache, recorded with structured questionnaire during interview. RESULTS--Prevalence of migraine did not differ between patients with stroke and controls: 18/137 v 17/137 for men (odds ratio 1.1 (95% confidence interval 0.5 to 2.2), p = 0.86); 23/75 v 17/75 for women (odds ratio 1.6 (0.7 to 3.5), p = 0.24); and 41/212 v 34/212 for both sexes (odds ratio 1.3 (0.8 to 2.3), p = 0.33). When subjects were split into two age groups, however, prevalence of migraine was significantly higher among younger women (aged < 45) with stroke compared with their controls (13/20 v 6/20, odds ratio 4.3 (1.2 to 16.3), p = 0.03). Furthermore, the risk of ischaemic stroke was higher among younger women who smoked (7/20 v 1/20, odds ratio 10.2 (1.1 to 93.3)). CONCLUSIONS--Prevalence of migraine was not different between patients with stroke and matched controls except among women aged < 45, when migraine and stroke were significantly associated.     

Physical activity and stroke in British middle aged men.

OBJECTIVES--To assess the relation between physical activity and stroke and to determine the overall benefit of physical activity for all major cardiovascular events. DESIGN--Prospective study of a cohort of men followed up for 9.5 years. SETTING--General practices in 24 towns in England, Wales, and Scotland (British regional heart study). SUBJECTS--7735 men aged 40-59 at screening, selected at random from one general practice in each of 24 towns. MAIN OUTCOME MEASURES--Fatal and non-fatal strokes and heart attacks. RESULTS--128 major strokes (fatal and non-fatal) occurred. Physical activity was inversely associated with risk of stroke independent of coronary risk factors, heavy drinking, and pre-existing ischaemic heart disease or stroke (relative risk 1.0 for inactivity, 0.6 moderate activity, and 0.3 vigorous activity; test for trend p = 0.008). The association remained after excluding men reporting regular sporting (vigorous) activity. However, vigorous physical activity was associated with a marginally significant increased risk of heart attack compared with moderate or moderately vigorous activity in men with no pre-existing ischaemic heart disease or stroke (relative risk 1.6%; 95% confidence interval 0.96 to 2.8). In men with symptomatic ischaemic heart disease or stroke those doing moderately vigorous or vigorous activity had a risk of heart attack slightly higher than that in inactive men (relative risk = 1.6; 0.8 to 3.3). CONCLUSIONS--Moderate physical activity significantly reduces the risk of stroke and heart attacks in men both with and without pre-existing ischaemic heart disease. More vigorous activity did not confer any further protection. Moderate activity, such as frequent walking and recreational activity or weekly sporting activity, should be encouraged without restriction.     

Influence of total cholesterol,high density lipoprotein cholesterol,and triglycerides on risk of cerebrovascular disease: the Copenhagen City Heart Study.

OBJECTIVE--To estimate the influence of plasma total cholesterol, high density lipoprotein cholesterol, and triglycerides on risk of cerebrovascular disease. DESIGN--The Copenhagen City Heart Study is a prospective observational survey with two cardiovascular examinations at five year intervals. Non-fasting plasma lipids were measured in participants once at each examination, along with other variables. The Cox regression model was used to establish the effect of the factors recorded on cerebrovascular events of mostly, but not exclusively, ischaemic origin. SUBJECTS--19,698 women and men at least 20 years old, randomly selected after age stratification from an area of central Copenhagen. MAIN OUTCOME MEASURES--Initial cases of stroke and transient ischaemic attack recorded from hospital records and death certificates from 1976 through 1988. RESULTS--660 non-haemorrhagic and 33 haemorrhagic events were recorded. Total cholesterol was positively associated with risk of non-haemorrhagic events, but only for levels > 8 mmol/l, corresponding to the upper 5% of the distribution in the study population. For lower plasma cholesterol values the relative risk remained nearly constant. Plasma triglyceride concentration was significantly, positively associated with risk of non-haemorrhagic events. The relative risk corresponding to an increase of 1 mmol/l was 1.12 (95% confidence interval 1.07 to 1.16). There was a negative, log linear association between high density lipoprotein cholesterol and risk of non-haemorrhagic events (0.53 (0.34 to 0.83)). There was no indication that the effects of plasma lipids were different in women and men. CONCLUSIONS--The pattern of the association between plasma cholesterol and risk of ischaemic cerebrovascular disease was not log linear, and the increased risk was confined to the upper 5% of the cholesterol distribution. Further studies should concentrate on the association between plasma cholesterol and verified haemorrhagic stroke.     

Spinal Cord Injury and Migraine Headache: A Population-Based Study

Migraine headaches are a common neurological condition, negatively impacting health and quality of life. Among potential risk factors for migraine headache, risk of migraine headaches was elevated in individuals with spinal cord injury (SCI). The association between migraines and SCI is intriguing to consider from the perspective that migraine headaches may be acquired in response to damage in the spinal cord. The primary objective of this study was to further examine the association between SCI and migraine headache, controlling for potential confounding variables. A secondary objective was to determine the impact of migraine headaches on self-perceived health. Data from a sample of 61,047 participants were obtained from the cross-sectional Canadian Community Health Survey. Multivariable logistic regression was used to explore the association between SCI and migraine headache using probability weights and adjusting for confounders. The multivariable age- and sex-adjusted model revealed a strong association between SCI and migraine headache, with an adjusted odds ratio for migraine of 4.82 (95% confidence interval [3.02, 7.67]) among those with SCI compared to those without SCI. Further, individuals who experienced both SCI and migraine tended to report poorer perceived general health compared with the other groups (i.e., SCI and no migraine). In conclusion, this study established a strong association between SCI and migraine headache. Further research is needed to explore the possible mechanisms underlying this relationship. Improvements in clinical practice to minimize this issue could result in significant improvements in quality of life.     

Trait components provide tools to dissect the genetic susceptibility of migraine

The commonly used "end diagnosis" phenotype that is adopted in linkage and association studies of complex traits is likely to represent an oversimplified model of the genetic background of a disease. This is also likely to be the case for common types of migraine, for which no convincingly associated genetic variants have been reported. In headache disorders, most genetic studies have used end diagnoses of the International Headache Society (IHS) classification as phenotypes. Here, we introduce an alternative strategy; we use trait components--individual clinical symptoms of migraine--to determine affection status in genomewide linkage analyses of migraine-affected families. We identified linkage between several traits and markers on chromosome 4q24 (highest LOD score under locus heterogeneity [HLOD] 4.52), a locus we previously reported to be linked to the end diagnosis migraine with aura. The pulsation trait identified a novel locus on 17p13 (HLOD 4.65). Additionally, a trait combination phenotype (IHS full criteria) revealed a locus on 18q12 (HLOD 3.29), and the age at onset trait revealed a locus on 4q28 (HLOD 2.99). Furthermore, suggestive or nearly suggestive evidence of linkage to four additional loci was observed with the traits phonophobia (10q22) and aggravation by physical exercise (12q21, 15q14, and Xp21), and, interestingly, these loci have been linked to migraine in previous studies. Our findings suggest that the use of symptom components of migraine instead of the end diagnosis provides a useful tool in stratifying the sample for genetic studies.     

Assessing possible hazards of reducing serum cholesterol.

OBJECTIVE--To assess whether low serum cholesterol concentration increases mortality from any cause. DESIGN--Systematic review of published data on mortality from causes other than ischaemic heart disease derived from the 10 largest cohort studies, two international studies, and 28 randomised trials, supplemented by unpublished data on causes of death obtained when necessary. MAIN OUTCOME MEASURES--Excess cause specific mortality associated with low or lowered serum cholesterol concentration. RESULTS--The only cause of death attributable to low serum cholesterol concentration was haemorrhagic stroke. The excess risk was associated only with concentrations below about 5 mmol/l (relative risk 1.9, 95% confidence interval 1.4 to 2.5), affecting about 6% of people in Western populations. For noncirculatory causes of death there was a pronounced difference between cohort studies of employed men, likely to be healthy at recruitment, and cohort studies of subjects in community settings, necessarily including some with existing disease. The employed cohorts showed no excess mortality. The community cohorts showed associations between low cholesterol concentration and lung cancer, haemopoietic cancers, suicide, chronic bronchitis, and chronic liver and bowel disease; these were most satisfactorily explained by early disease or by factors that cause the disease lowering serum cholesterol concentration (depression causes suicide and lowers cholesterol concentration, for example). In the randomised trials nine deaths (from a total of 687 deaths not due to ischaemic heart disease in treated subjects) were attributed to known adverse effects of the specific treatments, but otherwise there was no evidence of an increased mortality from any cause arising from reduction in cholesterol concentration. CONCLUSIONS--There is no evidence that low or reduced serum cholesterol concentration increases mortality from any cause other than haemorrhagic stroke. This risk affects only those people with a very low concentration and even in these will be outweighed by the benefits from the low risk of ischaemic heart disease.     

Reduced Fractional Anisotropy of Corpus Callosum Modulates Inter-Hemispheric Resting State Functional Connectivity in Migraine Patients without Aura

Background

Diffusion tensor imaging (DTI) study revealed reduced fractional anisotropy (FA) values in the corpus callosum (CC) in migraine patients without aura. Abnormalities in white matter integrity, particularly in the CC, may affect inter-hemispheric resting state functional connectivity (RSFC). Unfortunately, relatively little is known about the alterations in functional interactions between the cerebral hemispheres during resting state in migraine patients without aura, and even less about how the inter-hemispheric RSFC are affected by the abnormalities of the CC.

Methods and findings

Twenty-one migraine patients without aura and 21 healthy controls participated in this study, age-, sex-, and education-matched. Tract-based spatial statistics (TBSS) was employed to investigate the white matter alterations of the CC. Meanwhile, voxel-mirrored homotopic connectivity (VMHC) was used to compare the inter-hemispheric RSFC differences between the patients and controls. TBSS analysis revealed reduced FA values in the genu and the splenium of CC in patient group. VMHC analysis showed decreased inter-hemispheric RSFC of anterior cingulate cortex (ACC) in migraine patients without aura relative to that of the controls. Furthermore, in migraine patients without aura, the reduced FA values of the genu of CC correlated with the decreased inter-hemispheric RSFC of the ACC.

Conclusions

Our findings demonstrated that the migraine patients without aura showed reduced FA values of the genu of CC and decreased inter-hemispheric RSFC of the ACC. The correlation between the above structural and functional changes suggested that the reduced fractional anisotropy (FA) of CC modulates inter-hemispheric VMHC in migraine patients without aura. Our results demonstrated that the VMHC alterations of ACC can reflect the FA changes of the genu of CC in migraine patients without aura.     

Progestogens and cardiovascular reactions associated with oral contraceptives and a comparison of the safety of 50- and 30-microgram oestrogen preparations.

Progestogens probably have metabolic effects that may contribute to the increased risk of cardiovascular reactions associated with combined oestrogen-progestogen oral contraceptives. This possibility was investigated by a study of nearly 2000 reports to the Committee on Safety of Medicines from 1964 to 1977. The reports concerned preparations in which norethisterone acetate in doses of 1.0, 2.5, 3.0, or 4.0 mg was combined with 50 microgram of ethinyloestradiol and those in which levonorgestrel in doses of 150 or 250 microgram was combined with 30 microgram of ethinyloestradiol. Observed and expected numbers of reports were compared, using retail pharmacy purchase figures as a measure of the use of different preparations. There was a significant positive association between the dose of norethisterone acetate and deaths from stroke and ischaemic heart disease (IHD); this association was also found for all cases of these two conditions, fatal plus non-fatal. There were no associations of dose of norethisterone acetate with hypertension or venous thrombosis. The higher dose of levonorgestrel was associated with a possible excess of deaths, non-venous plus venous, and an excess of strokes. There was no association between dose of levonorgestrel and hypertension or venous thrombosis. The reports were also used to assess the relative safety of 30-microgram and 50-microgram oestrogen preparations. Those with 30 microgram of oestrogen were associated with significantly fewer reports of death and IHD (both fatal, and fatal plus non-fatal) than those with 50 microgram of oestrogen. In view of the large-scale move towards preparations with progressively lower oestrogen doses, there are no grounds for major changes in oral contraceptive practice. Within the range of preparations currently in use, however, there is a case for minimising the dose of progestogen to reduce the chances of thromboembolism.     

Risk of venous thromboembolism among users of third generation oral contraceptives compared with users of oral contraceptives with levonorgestrel before and after 1995: cohort and case-control analysis

ObjectiveTo compare the risk of idiopathic venous thromboembolism among women taking third generation oral contraceptives (with gestodene or desogestrel) with that among women taking oral contraceptives with levonorgestrel.DesignCohort and case-control analyses derived from the General Practice Research Database.SettingUK general practices, January 1993 to December 1999.ParticipantsWomen aged 15-39 taking third generation oral contraceptives or oral contraceptives with levonorgestrel.ResultsThe adjusted estimates of relative risk for venous thromboembolism associated with third generation oral contraceptives compared with oral contraceptives with levonorgestrel was 1.9 (95% confidence interval 1.3 to 2.8) in the cohort analysis and 2.3 (1.3 to 3.9) in the case-control study. The estimates for the two types of oral contraceptives were similar before and after the warning issued by the Committee on Safety of Medicines in October 1995. A shift away from the use of third generation oral contraceptives after the scare was more pronounced among younger women (who have a lower risk of venous thromboembolism) than among older women. Fewer cases of venous thromboembolism occurred in 1996 and later than would have been expected if the use of oral contraceptives had remained unchanged.ConclusionsThese findings are consistent with previously reported studies, which found that compared with oral contraceptives with levonorgestrel, third generation oral contraceptives are associated with around twice the risk of venous thromboembolism.     

Mortality among oral contraceptive users: 20 year follow up of women in a cohort study.

OBJECTIVE--To see whether the use of oral contraceptives influences mortality. DESIGN--Non-randomised cohort study of 17,032 women followed up on an annual basis for an average of nearly 16 years. SETTING--17 Family planning clinics in England and Scotland. SUBJECTS--Women recruited during 1968-74. At the time of recruitment each woman was aged 25-39, married, a white British subject, willing to participate, and either a current user of oral contraceptives or a current user of a diaphragm or intrauterine device (without previous exposure to the pill). MAIN OUTCOME MEASURES--Overall mortality and cause specific mortality. RESULTS--238 Deaths occurred during the follow up period. The main analyses concerned women entering the study while using either oral contraceptives or a diaphragm or intrauterine device. The overall relative risk of death in the oral contraceptive users was 0.9 (95% confidence interval 0.7 to 1.2). Though the numbers of deaths were small in most individual disease categories, the trends observed were generally consistent with findings in other reports. Thus the relative risk of death in the oral contraceptive users was 4.9 (95% confidence interval 0.7 to 230) for cancer of the cervix, 3.3 (95% confidence interval 0.9 to 17.9) for ischaemic heart disease, and 0.4 (95% confidence interval 0.1 to 1.2) for ovarian cancer. There was a linear trend in the death rates from cervical cancer and ovarian cancer (in opposite directions) with total duration of oral contraceptive use. Death rates from breast cancer (relative risk 0.9; 95% confidence interval 0.5 to 1.4) and suicide and probable suicide (relative risk 1.1; 95% confidence interval 0.3 to 3.6) were much the same in the two contraceptive groups. In 1981 the relative risk of death in oral contraceptive users from circulatory diseases as a group was reported to be 4.2 (95% confidence interval 2.3 to 7.7) in the Royal College of General Practitioners oral contraception study. The corresponding relative risk in this study was only 1.5 (95% confidence interval 0.7 to 3.0). CONCLUSIONS--These findings contain no significant evidence of any overall effect of oral contraceptive use on mortality. None the less, only small numbers of deaths occurred during the study period and a significant adverse (or beneficial) overall effect might emerge in the future. Interestingly, the mortality from circulatory disease associated with oral contraceptive use was substantially less than that found in the Royal College of General Practitioners study.     

Increased risk of stroke in oral contraceptive users carried replicated genetic variants: a population-based case–control study in China

Combined oral contraceptives (COC) use is a unique risk factor for stroke in women, and may modify the associations between genetic polymorphisms and stroke. To investigate whether the genetic variants identified in a recent genome-wide association study (GWAS) could be replicated in Chinese women, as well as, whether related risk was different in COC users, 451 stroke cases and 831 age- and region-matched controls were recruited from our cohort. Genotyping of 3 SNPs (rs700651, rs10958409, and rs1333040) was performed by the polymerase chain reaction assay with TaqMan probes. The history of contraceptive use and relevant information were obtained from a face-to-face interview. Odds ratios (OR) with 95 % confidence interval (CI) were estimated under conditional logistic regression model after adjustment for cardiovascular covariates. Our study replicated the associations of rs10958409 and rs1333040, with the risk of stroke, especially hemorrhagic subtype, but failed to confirm association of rs700651. COC use was associated with a 1.56-fold (OR 1.56, 95 % CI 1.21-2.01) increased risk of stroke. COC users with rs10958409 GA/AA or rs1333040 CT/TT genotypes had an increased risk of overall stroke by 1.59-fold (OR 2.59, 95 % CI 1.59-4.19) and 3.24-fold (OR 4.24, 95 % CI 1.71-10.49), respectively, compared with the non-users with wild-type genotypes. Moreover, the risk of hemorrhagic stroke increased by 4.81- and 15.06-fold when risk allele carriers of rs10958409 or rs1333040 who took COC. Our results confirmed the associations of two GWAS SNPs, also suggested combination effects of these genetic variants and COC use on stroke risk.