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

Venous thromboembolism (VTE) disproportionately affects reproductive-age women, and abnormal uterine bleeding (AUB) associated with anticoagulation, particularly direct oral anticoagulants (DOACs), remains under-reported. Suboptimal AUB management may lead to iron deficiency anemia (IDA) and recurrent VTE. To compare the incidence and risk of AUB in women receiving DOACs versus low molecular weight heparin/vitamin K antagonists (LMWH/VKA) for VTE, and quantify anemia and iron deficiency risks. We conducted a systematic review and meta-analysis using MEDLINE, Embase, and Cochrane databases (inception-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 non-major bleeding (CRNMB) from uterine sites, and unspecified AUB; secondary outcomes were IDA and recurrent VTE. Pooled incidence and relative risks (RR) were calculated using random-effects models. Twenty-one studies were included (10 RCTs, 11 cohorts). AUB definitions varied: MB (n=12), CRNMB uterine bleeding (n=10), pictorial bleeding assessment chart (n=2), unspecified AUB (n=7). 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 vs LMWH/VKA (p<0.01). Data on iron deficiency and anemia were limited. AUB risk with DOACs varies by bleeding definition. The increased risk of non-ISTH-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.