Which progestins have the lowest risk of venous thromboembolism (VTE)?

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Progestins with Lowest Thrombosis Risk

For women concerned about VTE risk, levonorgestrel-based contraceptives (particularly the levonorgestrel IUD and low-dose progestin-only pills with levonorgestrel or norethindrone) have the lowest thrombotic risk and show no significant increase in VTE compared to non-users 1, 2.

Progestin-Only Methods: The Safest Options

Minimal to No VTE Risk:

  • Levonorgestrel IUD: No excess VTE risk demonstrated; does not affect hemostatic parameters 1, 2
  • Low-dose progestin-only pills:
    • Levonorgestrel 30 mcg: No excess risk (OR 0.59,95% CI 0.33-1.03) 1, 2
    • Norethindrone 350 mcg: No excess risk 1
    • Desogestrel 75 mcg: No excess risk 1
  • Etonogestrel implant: No significant VTE association 3

Higher VTE Risk - Avoid These:

  • Depot medroxyprogesterone acetate (DMPA): Significantly increased risk (aOR 2.37,99% CI 1.95-2.88) 3; WHO study showed concerning trend (OR 2.19) 1
  • Oral medroxyprogesterone acetate: Elevated risk (aOR 1.98,99% CI 1.41-2.80) 3
  • Norethindrone acetate (high-dose): Increased risk (aOR 3.00,99% CI 1.96-4.59) 3

Combined Hormonal Contraceptives: Progestin Hierarchy

When combined with ethinyl estradiol, levonorgestrel serves as the reference standard with the lowest VTE risk among combined methods 4, 2.

Relative VTE Risk by Progestin (compared to levonorgestrel-containing COCs):

  • Levonorgestrel: Reference (lowest risk)
  • Norethindrone: Similar risk (RR 0.98,95% CI 0.71-1.37) 2
  • Norgestimate: Slightly higher (RR 1.19,95% CI 0.96-1.47) 2; notably has peripheral anti-androgenic activity and lowest VTE risk among third-generation progestins 5
  • Desogestrel: Higher risk (RR 1.82,95% CI 1.49-2.22) 2
  • Gestodene: Higher risk (RR 1.86,95% CI 1.59-2.18) 2
  • Drospirenone: Higher risk (RR 1.64,95% CI 1.27-2.10) 2
  • Cyproterone acetate: Higher risk (RR 1.88,95% CI 1.47-2.42) 2

Clinical Algorithm for Selection

Step 1: Assess VTE Risk Factors

  • Personal history of VTE
  • Inherited thrombophilia
  • Age >40 years
  • Obesity
  • Smoking
  • Immobilization/surgery
  • Postpartum status

Step 2: Choose Based on Risk Profile

For women WITH VTE risk factors or history:

  • First choice: Levonorgestrel IUD (no increased VTE risk)
  • Second choice: Low-dose progestin-only pills (levonorgestrel 30 mcg or norethindrone 350 mcg)
  • Third choice: Etonogestrel implant
  • Avoid: All combined hormonal contraceptives, DMPA, high-dose oral progestins

For women WITHOUT VTE risk factors needing combined contraception:

  • First choice: Levonorgestrel-containing COCs (lowest dose estrogen possible, preferably ≤30 mcg)
  • Second choice: Norethindrone-containing COCs
  • Third choice: Norgestimate-containing COCs (if anti-androgenic effects desired)
  • Avoid: Desogestrel, gestodene, drospirenone, cyproterone acetate combinations

Critical Caveats

Duration matters: VTE risk is highest in the first year of combined hormonal contraceptive use (RR 4.17 in <1 year vs 2.76 in >4 years) 2. This elevated early risk persists regardless of progestin type.

Dose-dependent effects: Lower estrogen doses reduce VTE risk across all progestin types 1, 2. The 50 mcg ethinyl estradiol formulations carry significantly higher risk (RR 2.2) compared to 30 mcg formulations 1.

Route of administration: Transdermal patches and vaginal rings increase VTE risk 3-4 fold compared to oral routes, even with similar hormonal content 1.

Progestin-only methods are not all equal: While low-dose progestin-only pills and LNG-IUDs are safe, DMPA carries meaningful VTE risk due to its high systemic progestin dose and unique pharmacological properties 1, 3.

References

4
Research

A systematic review and meta-analysis of venous thrombosis risk among users of combined oral contraception.

International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics, 2018

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