Abstract
INTRODUCTION: Infertility represents a global health concern and assisted reproductive technologies expose an increasing number of women and men to intensive hormonal interventions. At the same time, migraine and other headache disorders are highly prevalent in the reproductive age group and hormonal fluctuations are well-established headache triggers. The impact of fertility treatments on headache remains unclear and guidance for clinical management is lacking. METHODS: This systematic review followed PRISMA guidelines and was pre-registered in PROSPERO. PubMed and Embase were searched up to 1(st) of August 2025 using predefined strategies combining “migraine” or “headache” with fertility-related terms. Original human studies reporting on common fertility treatments and headache were included. Data were synthesized qualitatively due to heterogeneity in design and outcomes. In parallel, headache-related adverse events were extracted from Food and Drug Administration or, alternatively, European Medicines Agency drug labeling for fertility medications. RESULTS: The search retrieved 3,305 unique records, of which 196 full-text articles were assessed and 104 met inclusion criteria. Across studies of selective estrogen receptor modulators, aromatase inhibitors, gonadotropins, analogous of gonadotropin-releasing hormone, and luteal phase support with progesterone or estrogen, headache was frequently reported, with rates ranging from rare (<1%) to nearly 50%, depending on agent and protocol. Reporting was typically nonspecific, with almost no information on headache type, severity, or temporal relation to treatment phases. Case reports and a retrospective case–control study linked headache to treatment-related complications such as ovarian hyperstimulation syndrome (OHSS) and cerebrovascular events, with migraine history associated with a markedly increased risk for OHSS. CONCLUSION: Headache is a common but undercharacterized adverse event across fertility treatments. Given the potential contribution of hormonal, vascular, and psychosocial mechanisms, systematic assessment of headache, careful evaluation of patients with migraine or vascular risk factors, and standardized reporting in future trials are essential to inform individualized and safer reproductive care. CLINICAL TRIAL NUMBER: Not applicable.