Thrombotic Outcomes Following Hormonal Treatment of Heavy Menstrual Bleeding in Pediatric Patients Taking Anticoagulation

Introduction: Anticoagulant-associated heavy menstrual bleeding (HMB) is a common and under recognized complication in women who are being treated for venous thromboembolism (VTE), leading to complications such as anemia and decreased quality of life. The appropriate management of HMB in this population is complex and often requires hormonal therapy which may significantly increase the risk for VTE. Additionally, combined oral contraceptives may need to be used to control heavy menstrual bleeding despite contributing to the overall risk for VTE. Due to limited adult and pediatric data, there are currently no expert consensus guidelines for the treatment of anticoagulant-associated HMB. We describe a single institutional experience and thrombotic outcomes following hormonal therapy for anticoagulation-associated HMB in adolescents.

Methods: A retrospective cohort of pediatric females ages 9-21 years treated at Children's Healthcare of Atlanta were identified between January 2016 and July 2019. Patients were identified using common ICD codes for both HMB and anticoagulation/thrombosis. Patient demographic information, clinical characteristics, and thrombotic outcomes were abstracted from review of the electronic medical record. Patients receiving anti-platelet therapy with clopidogrel were included due to the reported similarity of bleeding complications compared to anticoagulants. Summary statistics were performed and Student's t test, Fisher's exact test, and Chi square test were used for statistical analysis (SAS v9.4, 2012, Cary, NC, USA). A p value <0.05 was considered statistically significant.

Results: The cohort was comprised of 17 adolescent females with confirmed anticoagulation-associated HMB. Among the cohort, 59% identified as White, 35% Black, and 6% Asian. Body Mass Index was normal in 41%, while 24% were obese and 35% were underweight. Indications for anticoagulation included VTE (n=11), pulmonary embolism (n=6), May-Thurner Syndrome with placement of iliac vein stent (n=3), and other vascular anomalies with confirmed stenosis/thrombosis (n=2). The most common risk factor for thrombosis was initiation of combined hormone oral contraceptives within 3 months of the event that led to initiation of anticoagulation (35%). Anticoagulant medications used included lovenox (n=13), clopidogrel (n=3), and lovenox/aspirin (n=1). The median age at initiation of hormonal therapy for HMB was 17.3 years (min-max, 12.6-18.3 years), with a median time between starting anticoagulation and initiation of hormonal therapy of 11 days (min-max, 0-529 days). Medications used to treat HMB included medroxyprogesterone (n=9), norethindrone (n=6), norethindrone-ethinyl estradiol (n=1), and etonogestrel implant (n=1). After initiating hormonal therapy, amenorrhea or menstrual suppression was reported in all but one individual (n=16/17). Following initiation of hormonal therapy with medroxyprogesterone, only one adolescent experienced a new VTE event. This adolescent had the additional risk factors of May-Thurner anatomy, heterozygous FV Leiden and prothrombin gene mutations, and antiphospholipid antibody syndrome. The median length of follow-up from initiation of hormonal therapy was 325 days (min-max, 43-932 days). Statistical differences between groups were not feasible due to small sample size and few outcome events.

Conclusions: The proper treatment of anticoagulation-associated HMB using hormonal therapy in the pediatric population is unclear, but our data suggest that treatment with hormonal therapy reduces anticoagulation-associated HMB while adding minimal risk for VTE. The only VTE event that occurred in our cohort was in the setting of multiple strong risk factors for VTE. Larger pediatric studies are required in order to confirm these findings.