What are the risks and percentages of developing blood clots (Deep Vein Thrombosis (DVT) or Pulmonary Embolism (PE)) with Hormone Replacement Therapy (HRT)?

Blood Clot Risk with Hormone Replacement Therapy

HRT approximately doubles to triples your risk of developing blood clots (venous thromboembolism), with the absolute risk increasing from about 2 per 1,000 women to 4-7 per 1,000 women per year, and this risk is highest during the first year of use.

Overall Risk Magnitude

Combined estrogen-progestin HRT increases venous thromboembolism risk with a relative risk of 2.14 (95% CI 1.64-2.81), meaning users have more than double the risk compared to non-users 1. The Women's Health Initiative confirmed this with a relative hazard of 2.11 (95% CI 1.26-3.55) 1, 2.

In absolute terms from FDA-approved conjugated estrogens data 3:

• Combined HRT (estrogen + progestin): Risk increases from 17 per 10,000 women-years to 35 per 10,000 women-years
• Deep vein thrombosis specifically: from 13 to 26 per 10,000 women-years
• Pulmonary embolism specifically: from 8 to 18 per 10,000 women-years

Estrogen-only HRT also increases risk but with somewhat lower magnitude 3:

• Overall VTE risk: from 22 per 10,000 to 30 per 10,000 women-years
• After 7 years of use: from 16 per 1,000 to 16-28 per 1,000 4

Critical Timing Considerations

The risk is dramatically elevated during the first year of HRT use, with a relative risk of 3.49 (95% CI 2.33-5.59) in the initial 12 months 1. This represents a 3.5-fold increase compared to baseline, making the first year the highest-risk period 2.

The risk persists throughout continued use but is most pronounced early 3. After discontinuation, the risk returns to baseline levels similar to never-users 5.

Route of Administration Matters

Oral estrogens carry the thrombotic risk described above, while transdermal estrogens may be safer 5, 6. Transdermal preparations in healthy women without background thrombotic risk are not associated with increased thrombosis risk 6. This difference relates to first-pass hepatic metabolism with oral formulations that affects clotting factors 5.

High-Risk Populations Requiring Extra Caution

Women with the following conditions face substantially higher absolute risks and should generally avoid HRT 2, 7:

• Factor V Leiden or prothrombin 20210A mutation: These prothrombotic genetic variants significantly amplify HRT's thrombotic risk 2, 8
• Antiphospholipid antibodies: The American College of Rheumatology strongly recommends against combined estrogen-progestin in these patients 2, 7
• Obesity: Further enhances thrombotic risk beyond HRT alone 5, 8
• History of previous venous thromboembolism: Baseline risk is already elevated 5
• Cardiovascular disease: In women with established heart disease, combined HRT increased VTE risk from 3 per 1,000 to 3-29 per 1,000 at 1 year 4
• Immobilization or recent surgery: HRT should be discontinued 4-6 weeks before major surgery when feasible 3

Age-Specific Considerations

Women aged 50-59 years (within 10 years of menopause) have lower absolute risks than older women 3, 4. In this younger subgroup taking combined HRT, the absolute VTE risk remained less than 1 in 500, though still statistically increased 4.

Women over 65 years have higher baseline thrombotic risk, making the absolute risk increase with HRT more clinically significant 3.

Progestogen Type Considerations

Limited data suggest norpregnane derivatives might be more thrombogenic than other progestogens 5. Injectable depot medroxyprogesterone acetate (DMPA) carries a relative risk of 2.67 (95% CI 1.29-5.53) for VTE, higher than other progestin-only contraceptives 7.

Clinical Decision Algorithm

For women considering HRT:

1. Screen for absolute contraindications 2, 7, 3:

   • Active or recent (within 1 year) venous thromboembolism
   • Known thrombophilia (Factor V Leiden, prothrombin mutation, antiphospholipid antibodies)
   • Severe obesity
   • Immobilization or upcoming major surgery within 4-6 weeks

2. If no absolute contraindications exist and menopausal symptoms are severe 4, 6:

   • Prefer transdermal estrogen over oral formulations to minimize thrombotic risk 5, 6
   • Use the lowest effective dose for the shortest duration needed 4
   • Recognize the first year carries 3.5-fold increased risk 1

3. Counsel on absolute risk 3:

   • For combined oral HRT: expect approximately 18 additional VTE events per 10,000 women per year
   • For estrogen-only oral HRT: expect approximately 8 additional VTE events per 10,000 women per year
   • Risk of fatal pulmonary embolism remains low but real

4. Discontinue immediately if 3:

   • Leg pain, swelling, warmth (DVT symptoms)
   • Sudden chest pain, shortness of breath (PE symptoms)
   • Planned surgery or prolonged immobilization anticipated

Common Pitfalls to Avoid

Do not assume all HRT formulations carry equal thrombotic risk - transdermal preparations appear safer than oral 5, 6. Do not continue HRT through periods of immobilization or perioperative periods - discontinue 4-6 weeks before elective surgery when possible 3. Do not prescribe HRT for cardiovascular disease prevention - it increases rather than decreases thrombotic events 1, 3. Do not overlook the dramatically elevated first-year risk - this is when vigilance must be highest 1.