Rate of abnormal uterine bleeding in women on anticoagulation for venous thromboembolism: systematic review and meta-analysis

Venous thromboembolism (VTE) disproportionately affects women of reproductive age, and abnormal uterine bleeding (AUB) associated with anticoagulation, particularly direct oral anticoagulants (DOACs), remains underreported. Suboptimal AUB management may lead to iron deficiency anemia and recurrent VTE. We aimed to compare the incidence and risk of AUB in women receiving DOACs vs low-molecular-weight heparin (LMWH)/vitamin K antagonists (VKAs) for VTE and quantify anemia and iron deficiency risks. We conducted a systematic review and meta-analysis using MEDLINE, Embase, and Cochrane databases (since inception to June 2024) for randomized trials and prospective studies. Eligible studies reported AUB in women receiving DOACs, LMWH/VKA, aspirin, or placebo. Primary outcomes were major bleeding (MB), clinically relevant nonmajor bleeding (CRNMB) from uterine sites, and unspecified AUB; secondary outcomes were iron deficiency anemia and recurrent VTE. Pooled incidence and relative risks (RRs) were calculated using random-effects models. Twenty-one studies were included (10 randomized controlled trials and 11 cohorts). AUB definitions varied: MB (n = 12), CRNMB uterine bleeding (n = 10), pictorial bleeding assessment chart (n = 2), and unspecified AUB (n = 7). The overall uterine bleeding risk did not differ between DOACs and LMWH/VKA (RR, 1.47; 95% CI, 0.93-2.33). DOACs showed no increased MB/CRNMB risk but had higher unspecified AUB (RR, 2.68; 95% CI, 1.57-4.57). Rivaroxaban showed a 2.7-fold higher AUB risk than LMWH/VKA (P < .01). Data on iron deficiency and anemia were limited. AUB risk with DOACs varies by bleeding definition. The increased risk of non-International Society on Thrombosis and Haemostasis-defined AUB, particularly with rivaroxaban, is obscured when relying on standard bleeding criteria. Improved reporting and consistent definitions are needed to better understand gender disparities in VTE treatment.