Female Hormone Therapy and Risk of Intracranial Hemorrhage From Cerebral Cavernous Malformations: A Multicenter Observational Cohort Study

Background Female hormone therapy (oral contraception in female patients of reproductive age and menopausal hormone therapy in postmenopausal patients) are not withheld from patients with cerebral cavernous malformations, although the effects of these drugs on the risk of intracranial hemorrhage are unknown. We investigated the association between female hormone therapy and intracranial hemorrhage in female patients with CCM in two large prospective, multicentre, observational cohort studies.

Methods We included consecutive patients with a CCM. We compared the association between use of female hormone therapy and the occurrence of intracranial hemorrhage due to the CCM during up to 5 years of prospective follow-up in multivariable Cox proportional hazards regression. We performed an additionally systematic review through Ovid MEDLINE and EMBASE from inception to November 2, 2021 to identify comparative studies and assess their intracranial haemorrhage incidence rate ratio according to female hormone therapy use.

Results Of 722 female patients, aged 10 years or older at time of cerebral cavernous malformation diagnosis, 137 used female hormone therapy at any point during follow-up. Female hormone therapy use (adjusted for age, mode of presentation, and CCM location) was associated with an increased risk of subsequent intracranial haemorrhage (46/137 [33·6%] versus 91/585 [15·6%], adjusted hazard ratio 1·56, 95% CI 1·09 to 2·24; p=0·015). Use of oral contraceptives in female patients aged 10-44 years adjusted for the same factors was associated with a higher risk of subsequent intracranial hemorrhage (adjusted hazard ratio 2·00, 95% CI 1·26-3·17; p=0·003). Our systematic literature search showed no studies reporting on the effect of female hormone therapy on the risk of intracranial hemorrhage during follow-up.

Discussion Female hormone therapy use is associated with a higher risk of intracranial hemorrhage from cerebral cavernous malformations. These findings raise questions about the safety of female hormone therapy in clinical practice in patients with cerebral cavernous malformation. Further studies evaluating clinical factors raising risk of thrombosis may be useful to determine which patients may be most susceptible to intracranial hemorrhage.

Classification of evidence: This study provides Class III evidence that female hormone therapy increased the risk of intracranial hemorrhage in patients with CCM.