Sex-specific management of migraine a systematic review and consensus statement from the European Headache Federation (EHF)

Abstract Background Migraine burden is over twice as high among females than males. Although sex differences are recognized in migraine, robust sex-specific guidance for management remains limited. Objective To systematically review and synthesize current evidence on sex-related clinical differences in migraine, including treatment outcomes and reproductive management, and to provide evidence-based or expert consensus recommendations where high-quality data are lacking. Methods A systematic literature review using the PICO framework addressed 24 sex-specific questions across three domains: (1) biological sex differences across the lifespan, (2) sex-specific variations in treatment outcomes, and (3) fertility and reproduction-related management. To address anticipated evidence gaps, a structured Delphi consensus process complemented the review. The protocol was registered in PROSPERO (CRD420251058438). Results Thirty-seven studies informed 10 evidence summaries. Acute and preventive anti-CGRP therapies seem to show similar efficacy between sexes. For menstrual-related migraine attacks (MM), triptans and lasmiditan are effective, with frovatriptan being recommended for short-term prevention; long-term prevention include topiramate and anti-CGRP mAbs. In pregnancy triptans, greater occipital nerve (GON) blocks, and onabotulinumtoxinA are safe, with GON blocks showing potential efficacy. During breastfeeding, triptans appear to be safe. Anti-CGRP mAbs are equally effective in pre and postmenopausal women. Expert consensus emphasizes the influence of hormonal transitions on migraine expression across sexes and supports the use of acetaminophen, antiemetics, magnesium, NSAIDs, steroids, beta-blockers, amitriptyline, and calcium channel blockers as generally safe in WOCBP and during pregnancy, although some agents have trimester-specific limitations. Efficacy was noted for acetaminophen, sumatriptan, antiemetics, magnesium, propranolol, amitriptyline, and onabotulinumtoxinA. During breastfeeding, acetaminophen, NSAIDs, domperidone, prochlorperazine, magnesium, caffeine, beta-blockers, tricyclics, onabotulinumtoxinA, and GON blocks were considered safe. Conclusions Evidence is limited, but sex (likely mediated by sex hormones) influence the clinical course of migraine, and likely treatment response. Limitations include absence of sex-specific analyses in older trials, underrepresentation of men, and scarce reproductive safety data. Integrating sex-based analyses and broadening trial inclusion and more reproductive safety evidence are essential for personalized, equitable migraine care.