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Abstract Background Many studies have described the features of menstrually-related migraines (MRM) in the natural cycle and the efficacy of prevention. MRM in combined hormonal contraceptive (CHC) users has scarcely been researched. Estrogen and progestin withdrawal in CHC users are both more abrupt and from higher hormone levels compared with the natural cycle. An advantage for prevention of MRM in CHC users is that the hormone withdrawal is predictable. It is unknown, whether the attacks during the hormone-free interval are associated with the hormone withdrawal or onset of bleeding. Improved understanding of this relation might contribute to better define and shorten the time interval for prevention. Methods For this prospective diary-based trial we collected migraine and bleeding data from CHC users with MRM in at least two of three cycles. We analyzed frequency of migraines over the whole CHC cycle. During the hormone-free phase the relation between onset of migraine and onset of bleeding was studied. We compared pain intensity and identified prolonged-migraine attacks during hormone use and the hormone-free phase. Results During the hormone-free interval the number of migraine days and the pain score/migraine day were significantly higher in comparison with the mean during hormone use. The prevalence of migraine attacks was fourfold on hormone-free days 3–6. Migraine typically started on days 1–4. Migraine in relation to bleeding mostly occurred on days − 1 to + 4. In 78% of the cycles the first migraine day occurred during bleeding days 1 ± 2 and 48% started on days − 1 and day 1. The predictability of the first bleeding day was very high. Conclusion The day of hormone-withdrawal migraine and the first bleeding day are highly predictable in CHC users. Migraine onset is mostly day − 1 and 1 of the bleeding and on days 1–4 of the hormone-free interval. Migraine attacks of CHC users in the hormone-free interval are severe and long lasting. Further trials are necessary to investigate if this knowledge can be used to optimise prevention.

Abstract Objective To develop a robust statistical tool for the diagnosis of menstrually related migraine. Background The International Classification of Headache Disorders (ICHD) has diagnostic criteria for menstrual migraine within the appendix. These include the requirement for menstrual attacks to occur within a 5-day window in at least 23 $\frac {2}{3}$ menstrual cycles ( 23 $\frac {2}{3}$-criterion). While this criterion has been shown to be sensitive, it is not specific. Yet in some circumstances, for example to establish the underlying pathophysiology of menstrual attacks, specificity is also important, to ensure that only women in whom the relationship between migraine and menstruation is more than a chance occurrence are recruited. Methods Using a simple mathematical model, a Markov chain, to model migraine attacks we developed a statistical criterion to diagnose menstrual migraine (sMM). We then analysed a data set of migraine diaries using both the 23 $\frac {2}{3}$-criterion and the sMM. Results sMM was superior to the 23 $\frac {2}{3}$-criterion for varying numbers of menstrual cycles and increased in accuracy with more cycle data. In contrast, the 23 $\frac {2}{3}$-criterion showed maximum sensitivity only for three cycles, although specificity increased with more cycle data. Conclusions While the ICHD 23 $\frac {2}{3}$-criterion is a simple screening tool for menstrual migraine, the sMM provides a more specific diagnosis and can be applied irrespective of the number of menstrual cycles recorded. It is particularly useful for clinical trials of menstrual migraine where a chance association between migraine and menstruation must be excluded.

Abstract Background Menstrual migraine (MM) and premenstrual syndrome (PMS) are two conditions linked to specific phases of the menstrual cycle. The exact pathophysiological mechanisms are not fully understood, but both conditions are hypothesized to be triggered by female sex hormones. Co-occurrence of MM and PMS is controversial. The objective of this population-based study was to compare self-assessed symptoms of PMS in female migraineurs with and without MM. A total of 237 women from the general population who self-reported migraine in at least50% of their menstruations in a screening questionnaire were invited to a clinical interview and diagnosed by a neurologist according to the International Classification of Headache Disorders II (ICHD II), including the appendix criteria for MM. All women were asked to complete a self-administered form containing 11 questions about PMS-symptoms adapted from the Diagnostic and Statistical Manual of Mental Disorders. The number of PMS symptoms was compared among migraineurs with and without MM. In addition, each participant completed the Headache Impact test (HIT-6) and Migraine Disability Assessment Score (MIDAS). Findings A total of 193 women returned a complete PMS questionnaire, of which 67 women were excluded from the analyses due to current use of hormonal contraception (n = 61) or because they did not fulfil the ICHD-criteria for migraine (n = 6). Among the remaining 126 migraineurs, 78 had MM and 48 non-menstrually related migraine. PMS symptoms were equally frequent in migraineurs with and without MM (5.4 vs. 5.9, p = 0.84). Women with MM reported more migraine days/month, longer lasting migraine attacks and higher HIT-6 scores than those without MM, but MIDAS scores were similar. Conclusion We did not find any difference in number of self-reported PMS-symptoms between migraineurs with and without MM.

Abstract We systematically reviewed data about the effect of exogenous estrogens and progestogens on the course of migraine during reproductive age. Thereafter a consensus procedure among international experts was undertaken to develop statements to support clinical decision making, in terms of possible effects on migraine course of exogenous estrogens and progestogens and on possible treatment of headache associated with the use or with the withdrawal of hormones. Overall, quality of current evidence is low. Recommendations are provided for all the compounds with available evidence including the conventional 21/7 combined hormonal contraception, the desogestrel only oral pill, combined oral contraceptives with shortened pill-free interval, combined oral contraceptives with estradiol supplementation during the pill-free interval, extended regimen of combined hormonal contraceptive with pill or patch, combined hormonal contraceptive vaginal ring, transdermal estradiol supplementation with gel, transdermal estradiol supplementation with patch, subcutaneous estrogen implant with cyclical oral progestogen. As the quality of available data is poor, further research is needed on this topic to improve the knowledge about the use of estrogens and progestogens in women with migraine. There is a need for better management of headaches related to the use of hormones or their withdrawal.

Abstract Background In 2016, a large meta-analysis brought the number of susceptibility loci for migraine to 38. While sub-type analysis for migraine without aura (MO) and migraine with aura (MA) found some loci showed specificity to MO, the study did not test the loci with respect to other subtypes of migraine. This study aimed to test the hypothesis that single nucleotide polymorphisms (SNPs) robustly associated with migraine are individually or collectively associated with menstrual migraine (MM). Methods Genotyping of migraine susceptibility SNPs was conducted using the Agena MassARRAY platform on DNA samples from 235 women diagnosed with menstrual migraine as per International Classification for Headache Disorders II (ICHD-II) criteria and 140 controls. Alternative genotyping methods including restriction fragment length polymorphism, pyrosequencing and Sanger sequencing were used for validation. Statistical analysis was performed using PLINK and SPSS. Results Genotypes of 34 SNPs were obtained and investigated for their potential association with menstrual migraine. Of these SNPs, rs2506142 located near the neuropilin 1 gene (NRP1), was found to be significantly associated with menstrual migraine (p = 0.003). Genomic risk scores were calculated for all 34 SNPs as well as a subset of 7 SNPs that were nearing individual significance. Overall, this analysis suggested these SNPs to be weakly predictive of MM, but of no prognostic or diagnostic value. Conclusions Our results suggest that NRP1 may be important in the etiology of MM. It also suggests some genetic commonality between common migraine subtypes (MA and MO) and MM. The identification of associated SNPs may be the starting point to a better understanding of how genetic factors may contribute to the menstrual migraine sub-type.

Abstract Several data indicate that migraine, especially migraine with aura, is associated with an increased risk of ischemic stroke and other vascular events. Of concern is whether the risk of ischemic stroke in migraineurs is magnified by the use of hormonal contraceptives. As migraine prevalence is high in women of reproductive age, it is common to face the issue of migraine and hormonal contraceptive use in clinical practice. In this document, we systematically reviewed data about the association between migraine, ischemic stroke and hormonal contraceptive use. Thereafter a consensus procedure among international experts was done to develop statements to support clinical decision making, in terms of cardiovascular safety, for prescription of hormonal contraceptives to women with migraine. Overall, quality of current evidence regarding the risk of ischemic stroke in migraineurs associated with the use of hormonal contraceptives is low. Available data suggest that combined hormonal contraceptive may further increase the risk of ischemic stroke in those who have migraine, specifically migraine with aura. Thus, our current statements privilege safety and provide several suggestions to try to avoid possible risks. As the quality of available data is poor further research is needed on this topic to increase safe use of hormonal contraceptives in women with migraine.

Following the publication of this article [1], the authors noticed that they incorrectly reported the Absolute risk of ischemic stroke in women aged 20 to 44 years in relation to the use of hormonal contraception and migraine status due to a miscalculation. They apologize for this misreported result.