Up to 30% of reproductive-aged women seek medical attention for heavy menstrual bleeding (HMB). Estrogen-containing contraceptives and antifibrinolytics are first-line treatments. Despite evidence for these agents for HMB and for antifibrinolytics in other high-estrogen states (eg, postpartum), many antifibrinolytic monographs warn against use with concurrent estrogen-containing contraception given theoretical thromboembolic risk.

This study aimed to systematically evaluate the literature that explores the combined effect of pharmacologic or high physiologic estrogen and antifibrinolytic agents on thromboembolic risk in women of reproductive age when used for heavy menstrual or postpartum bleeding.

A systematic literature search was performed of records until April 2023. Publications written in English describing risk or reported cases of thromboembolism in reproductive-age women prescribed antifibrinolytics with estrogen-containing contraceptives or with a physiologic estrogenic state were included.

We identified 4302 publications; 55 publications with 199 228 participants were included. Two case reports and one case series described thromboembolism with concomitant estrogen-containing contraceptives and antifibrinolytic use. Four of 5 patients in the case series had other thrombotic risk factors. Fifty-two publications investigated antifibrinolytic use postpartum. Four RCTs of postpartum antifibrinolytic use assessed thromboembolism as a secondary outcome, none of which reported increased risk with antifibrinolytics. One case report suggested possible thrombotic risk wherein the patient had other provoking risk factors.

We found no strong evidence that intermittent antifibrinolytic use in physiologic estrogenic states is associated with increased reported cases or risk of thromboembolic events. Prospective studies are warranted to assess the thrombotic risk of combined estrogen-containing contraceptives and antifibrinolytics.