What are the risks associated with Combined Oral Contraceptives (COCs)?

Risks Associated with Combined Oral Contraceptives (COCs)

Combined oral contraceptives carry significant cardiovascular and thrombotic risks, with venous thromboembolism being the most serious concern (approximately 4-fold increased risk), particularly in the first year of use, and arterial thrombotic events (2-fold increased risk) especially in women with additional risk factors such as smoking, hypertension, or age ≥35 years. 1, 2

Major Cardiovascular Risks

Venous Thromboembolism (VTE)

• COCs increase VTE risk 4-11 fold compared to non-users, with the highest risk occurring in the first year of use (OR: 4.17), decreasing to 2.76-fold after 4 years 3, 1, 2
• Third-generation COCs (containing desogestrel, drospirenone, or gestodene) carry approximately 2-fold higher VTE risk than second-generation formulations (levonorgestrel, norethisterone), translating to an additional 1-2 cases per 10,000 women-years 1, 4
• Risk factors that substantially elevate VTE risk include: history of estrogen-associated VTE, pregnancy-associated VTE, known thrombophilia, active cancer, and recurrent VTE 3, 5

Arterial Thrombotic Events

• COCs increase myocardial infarction risk approximately 2-fold, with risk disappearing after discontinuation 3, 2
• Stroke risk increases 2-fold overall, with ischemic stroke risk higher than hemorrhagic stroke 3, 1
• Current users show greater risk than past users, and risk does not correlate with duration of therapy 2

Risk Amplification with Comorbidities

Smoking

• Women ≥35 years who smoke ≥15 cigarettes daily have absolute contraindication to COCs 3, 5
• Smoking increases myocardial infarction risk 10-fold in COC users 2
• Stroke risk increases nearly 3-fold in COC users who smoke 2

Hypertension

• Uncontrolled hypertension (SBP ≥160 or DBP ≥100 mmHg) is an absolute contraindication 3, 5
• Moderate hypertension (SBP 140-159 or DBP 90-99 mmHg) represents a relative contraindication 3
• Women with hypertension using COCs have 3-fold increased risk of myocardial infarction and ischemic stroke, with hemorrhagic stroke risk rising 15-fold 2
• Hypertensive women on COCs show myocardial infarction odds ratios of 6-68 and ischemic stroke odds ratios of 3.1-14.5 3

Migraine

• Migraine with aura at any age is an absolute contraindication 3, 5
• Women with migraine taking COCs have 2-16 fold greater stroke risk than non-users 3

Obesity

• Women with BMI ≥30 kg/m² have increased VTE risk when using COCs, though absolute risk remains small in healthy reproductive-age women 3
• Morbidly obese women with PCOS and severe insulin resistance may have increased diabetes risk with COC use 6

Cancer Risks

Increased Cancer Risk

• Long-term COC use (≥5 years) increases cervical cancer risk among women with persistent HPV infection, including carcinoma in situ and invasive carcinoma 3
• Current breast cancer is an absolute contraindication 3, 5
• Current or recent COC users (<6 months since last use) show relative risks of 1.19-1.33 for breast cancer 1
• Longer duration of current use increases breast cancer risk, with relative risks ranging from 1.03 with <1 year** to **approximately 1.4 with >8-10 years of use 1

Decreased Cancer Risk (Protective Effects)

• COC use substantially reduces ovarian cancer risk 3, 7
• COC use substantially reduces endometrial cancer risk 3, 7
• COC use is associated with reduced colorectal cancer risk 7

Hepatic Risks

• Acute or flare of viral hepatitis is an absolute contraindication 3, 5
• Severe or decompensated cirrhosis is an absolute contraindication 3, 5
• Hepatocellular adenoma and malignant liver tumors are absolute contraindications 3, 5
• Gallbladder disease risk is increased 1

Other Serious Risks

Postpartum Period

• COC use <21 days postpartum carries increased thrombosis risk regardless of breastfeeding status, as blood coagulation normalizes by 3 weeks 3
• Breastfeeding women have theoretical concerns about milk production effects, particularly when lactation is being established 3

Metabolic Effects

• COCs can increase blood pressure, requiring measurement before initiation 5, 8
• Discontinuation of COCs in hypertensive women may improve blood pressure control 3
• Reduced glucose tolerance may occur 1

Common Adverse Effects

• Breakthrough bleeding, nausea, breast tenderness, headache 1
• Weight changes (increase or decrease) 1
• Mood changes including depression (though evidence shows COC use did not increase depressive symptoms compared to baseline) 3
• Reduced lactation when given immediately postpartum 1

Critical Clinical Pitfalls

The most dangerous error is prescribing COCs without comprehensive screening for absolute contraindications, particularly cardiovascular risk factors that compound exponentially 5, 6. Women with multiple risk factors (e.g., age ≥35 + smoking, or hypertension + migraine) face unacceptable cardiovascular risk levels even when individual factors might be Category 2 or 3 3. Blood pressure measurement is mandatory before initiation 5, 8. Routine thrombophilia screening is not indicated for all women but should be considered for those with personal or family history of VTE in relatives <50 years 4.