158 Chapter 7 cycle with reasonable precision. Importantly, this study clearly demonstrates that attention should be focused on the perimenstrual window, where migraine incidence is higher compared to other phases of the menstrual cycle, and not to the ovulatory phase as often suggested by women with migraine. We know from our previous study on perimenstrual attacks that patients may find it difficult to correctly assess the relationship between phases of their menstrual cycle and attack incidence, as we convincingly showed that self-reported menstrual migraine diagnosis has extremely poor accuracy.13 Contrary to our initial hypothesis based on the estrogen-withdrawal theory, our study found no evidence of increased migraine attack incidence during the ovulatory window. Since only perimenstrual declining estrogen and not ovulatory declining estrogen seem to be linked to migraine, a possible explanation is that a sustained period of high estrogen is necessary to prime the system, making the subsequent drop more likely to trigger migraine attacks.5, 7 Another explanation for the low migraine attack incidence around ovulation may involve protective effects from progesterone or its derivative, allopregnanolone, which rise during ovulation but are low during the menstruation. Both enhance GABAergic (gamma-aminobutyric acid) activity, stimulating antinociceptive effects.22, 23 A limitation of our study might be missing e-diary data, although adherence was high (99% [IQR 96%–100%]), and imputing missing data as either migraine or non-migraine days had no impact on the results. It should be noted that menstrual migraine was diagnosed in 42% of women, a lower rate than previously reported.13 This difference is probably due to the exclusion of hormonal contraceptive users, who often experience increased migraine attack incidence during the hormone-free interval, but were excluded for the current analyses. Our previous research has demonstrated that accurately diagnosing menstrual migraine requires the use of e-diaries. Therefore, we are confident that the proportion of menstrual migraine reported in this study, and consequently our subgroup analysis, is valid. Further, this study included only female participants who self-identified as women and with a menstrual cycle, and our findings may not be generalizable to all women. This study has several strengths. We used three statistical models, each offering different advantages. The mixed-effects model accounts for individual-level variability by incorporating random effects, making it well-suited for longitudinal data and accommodating time-varying covariates. In contrast, both the case-crossover and self-controlled case series (SCCS) models effectively eliminate time-invariant confounders by using each participant as their own control, enhancing internal
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