Does the mini pill (progestin-only pill) norethindrone (generic name) increase the risk of Deep Vein Thrombosis (DVT) compared to Combined Oral Contraceptives (COCs)?

Mini Pill (Norethindrone) Has Lower DVT Risk Compared to Combined Oral Contraceptives

Progestin-only pills (POPs) like norethindrone do not increase the risk of deep vein thrombosis (DVT), while combined oral contraceptives (COCs) are associated with a 2-6 fold increased risk of venous thromboembolism. 1

Risk Comparison Between Mini Pills and COCs

Mini Pills (Progestin-Only Pills)

• POPs containing norethindrone are not associated with elevated blood pressure or increased risk of thrombosis 1
• The U.S. Medical Eligibility Criteria for Contraceptive Use classifies POPs as Category 2 (benefits generally outweigh risks) for women with a history of DVT/PE, compared to Category 3 or 4 (risks generally outweigh benefits or unacceptable health risk) for COCs 1
• Even for women with higher risk factors for recurrent DVT/PE, POPs remain Category 2, while COCs are Category 4 (contraindicated) 1

Combined Oral Contraceptives

• COCs containing ethinyl estradiol are associated with a 2-6 fold increase in VTE risk over baseline 2
• The estrogen component in COCs creates a procoagulant environment with decreases in antithrombin III and protein S levels 2
• Risk varies based on the type of progestin used in combination with estrogen:
  • DRSP/EE (drospirenone/ethinyl estradiol) shows higher DVT risk compared to NET/EE (norethindrone/ethinyl estradiol) 3
  • Age further increases this risk, particularly in women over 40 years 3

Mechanism of DVT Risk Difference

The difference in thrombotic risk between mini pills and COCs is primarily due to:

1. Absence of estrogen: The estrogen component in COCs is primarily responsible for the increased thrombotic risk 1
2. Progestin type and dose: POPs contain lower doses of progestin compared to COCs 1
3. RAAS effects: Estrogen in COCs activates the renin-angiotensin-aldosterone system, which can contribute to thrombotic risk 1

Risk Stratification for Contraceptive Users

For women considering contraception options with history of or risk factors for DVT:

• Lowest risk: Progestin-only pills (norethindrone) 1
• Moderate risk: COCs containing norethindrone/ethinyl estradiol 3
• Highest risk: COCs containing newer generation progestins (especially drospirenone) with ethinyl estradiol 3

Important Considerations and Caveats

• Family history alone is insufficient to identify all women at risk of VTE before starting contraceptives - only about 16% of women who developed VTE while on COCs had a positive family history 4
• Risk factors for DVT/VTE are additive - women with multiple risk factors (obesity, smoking, immobility, inherited thrombophilia) have substantially higher risk 2
• Women over 50 using oral contraception have a 6.3-fold increased risk of venous thrombosis compared to non-hormone users, while non-oral hormone therapy showed no increased risk (OR 1.1) 5

Clinical Decision Algorithm

1. Assess baseline VTE risk:

   • Personal or family history of VTE
   • Known thrombophilia
   • Age (especially >40 years)
   • Obesity, smoking status
   • Immobility or recent surgery

2. Contraceptive recommendation based on risk:

   • Low risk (no risk factors): Either mini pill or COC acceptable
   • Moderate risk (1 risk factor): Consider mini pill (norethindrone) as first choice
   • High risk (≥2 risk factors or history of DVT): Mini pill strongly preferred; COCs contraindicated

3. Monitoring:

   • Watch for signs of DVT (unilateral leg swelling, pain, warmth)
   • Discontinue immediately if DVT is suspected

The evidence clearly demonstrates that progestin-only pills like norethindrone have a significantly lower risk of DVT compared to combined oral contraceptives, making them a safer option for women concerned about thrombotic risk.