116 Chapter 5 E-diary study, preferably including a baseline period of several months before conception to accurately estimate migraine aura frequency before pregnancy and breastfeeding. The follow-up period should ideally cover the entire pregnancy and postpartum period, which may be challenging in regards to timing and compliance. The effect of continuous hormonal contraception on frequency of migraine attacks with and without aura is currently being assessed in a randomized clinical trial (ClinicalTrials.gov: NCT04007874). The current study also has strengths. Women were recruited through our research website (www.whatstudy.nl/en/) and social media channels, making them more representative of the general population. We consider the cohort to be well defined. Instead of self-reports, diagnoses were made by a researcher with headache expertise (IEV, BWHvdA, DSvC) during a clinical interview based on the ICHD-3 criteria, in consultation with a headache specialist (GMT) if necessary. We used a previously validated E-diary to reliably determine the relation between migraine attacks with and without aura and menstruation.3, 13, 34 A large group of women was followed with a median follow-up time of 150 days to obtain a reliable measure of migraine attack frequency at the time of the perimenstrual window. Migraine attacks were defined using an algorithm within our E-diary which is based on the ICHD-3 criteria, rather than self-reports. Compliance to the E-diary showed to be very high, which is promising for future studies attempting to unravel the exact pathophysiological role of sex hormones in migraine. In conclusion, the perimenstrual window is associated with increased susceptibility solely to migraine attacks without aura, both in women diagnosed with MO as in those with MA. Both women with MO and MA can thus be diagnosed with menstrual migraine, but only the attacks without aura should be counted for a menstrual migraine diagnosis. Migraine auras may be provoked by high estradiol levels, but the present study found no clear evidence of an increased risk of migraine auras during high estradiol levels of a natural menstrual cycle. Possibly, unlike during pregnancy, estradiol levels during a natural menstrual cycle may not reach the threshold for inducing migraine auras.9 Clearly, further research including hormone measurements in blood samples from different timepoints of the menstrual cycle will have to reveal the exact effects of sex hormone levels both on the trigeminovascular system and susceptibility to CSD.
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