VTE Risk with Annovera
Annovera (segesterone acetate and ethinyl estradiol vaginal ring) increases the risk of venous thromboembolism (VTE) by 3-4 fold compared to non-users, with an estimated rate of 3-12 cases per 10,000 woman-years, similar to other combined hormonal contraceptives. 1
Understanding the Risk Magnitude
The FDA label for Annovera clearly states that females are at increased risk for VTE when using this product 1. To contextualize this risk:
- Non-users of hormonal contraception: 1-5 VTE cases per 10,000 woman-years
- Combined hormonal contraceptive users (including Annovera): 3-12 cases per 10,000 woman-years
- Pregnancy: 5-20 cases per 10,000 woman-years
- Postpartum period (within 12 weeks): 40-65 cases per 10,000 woman-years 1
Route of Administration Matters
Combined contraceptives delivered by non-oral routes (patches, vaginal rings) increase the risk of thromboembolism by a factor of 3-4 2. This is a critical consideration, as vaginal rings like Annovera carry similar VTE risk to third-generation oral contraceptives containing desogestrel or gestodene 3, 4.
The French Society of Endocrinology guidelines emphasize that non-oral combined hormonal contraceptives (vaginal rings and patches) affect clotting parameters similarly to oral administration, significantly modifying circulating antithrombin and protein S levels, resistance to activated protein C, and increasing plasma SHBG concentrations 2.
Specific Contraindications for Annovera
Annovera is absolutely contraindicated in women with:
- Current or history of deep vein thrombosis or pulmonary embolism
- Inherited or acquired hypercoagulopathies
- Age >35 years who smoke (smoking dramatically increases cardiovascular risk)
- Personal history of VTE
- Inherited thrombophilia (risk multiplied by 5-16 fold) 1
High-Risk Periods and Populations
The risk of VTE is highest during the first year of use and when restarting hormonal contraception after a break of 4 weeks or longer 1.
Critical timing considerations:
- Start Annovera no earlier than 4 weeks postpartum in non-breastfeeding women
- Discontinue at least 4 weeks before major surgery and through 2 weeks after
- Discontinue during prolonged immobilization 1
BMI Limitations
Annovera has not been adequately studied in women with BMI >29 kg/m² because this subpopulation was excluded from clinical trials after VTEs were reported in women with BMI >29 kg/m² 1. Higher body weight is associated with lower systemic exposure to both segesterone acetate and ethinyl estradiol, potentially affecting both efficacy and risk profile 1.
Additional Risk Factors That Amplify VTE Risk
The following factors significantly increase VTE risk when combined with Annovera use:
- Age >40 years (particularly beyond 40)
- Obesity
- Family history of VTE
- Post-partum status
- Recent surgery
- Immobilization or long journeys
- Smoking 2
Comparative Risk with Other Contraceptives
Research comparing the etonogestrel-containing vaginal ring (NuvaRing) to combined oral contraceptives found similar VTE rates (8.3 vs 9.2 per 10,000 woman-years, with adjusted HR 0.8,95% CI 0.5-1.5) 5. While this study evaluated a different vaginal ring formulation, it supports that vaginal rings carry VTE risk comparable to combined oral contraceptives.
Clinical Management Approach
Before prescribing Annovera:
- Evaluate past medical history and family history of thrombotic or thromboembolic disorders
- Assess for inherited or acquired hypercoagulopathy
- Screen for all contraindications listed above
- Verify BMI is ≤29 kg/m²
- Confirm patient is not a smoker if age >35 years 1
During use:
- Stop immediately if arterial or deep venous thrombotic event occurs
- Discontinue if unexplained vision loss, proptosis, diplopia, papilledema, or retinal vascular lesions develop (evaluate for retinal vein thrombosis)
- Consider discontinuation 4 weeks before planned major surgery 1
The VTE risk with Annovera, while real and clinically significant, remains lower than the VTE risk associated with pregnancy itself, which is an important consideration when counseling patients about contraceptive options.