Hormonal contraception is a recognized risk factor for venous thromboembolism (VTE),1,2 with the risk influenced by estrogen dose and progestin type. However, VTE risk with newer formulations containing low-dose estrogen, novel progestins, and bioidentical estrogen requires further investigation. This study examined VTE risk across contemporary hormonal contraceptives.
Using Danish national registers, we conducted a nationwide cohort study including all females aged 15 to 49 years without a history of thrombosis, cancer, thrombophilia, liver or kidney disease, infertility treatment, hormone therapy, oophorectomy, hysterectomy, polycystic ovary syndrome, and endometriosis (eTable 1 in Supplement 1). Females were followed up from January 1, 2011, or their 15th birthday until July 1, 2021, emigration, death, or an exclusionary event.
Outcome was a first diagnosis of lower limb deep venous thrombosis or pulmonary embolism (eTable 1 in Supplement 1).3 In a sensitivity analysis, we exclusively included VTE diagnoses confirmed by relevant imaging or subsequent anticoagulant prescription redemption.
Hormonal contraception use was determined through redeemed prescriptions,4 including pills with estrogen and progestin (combined pills), vaginal rings, patches, progestin-only pills, intrauterine devices (IUDs), implants, and injections. eTable 2 in Supplement 1 lists all hormonal contraceptives available during the study. Exposure time was calculated from purchased daily doses for short-acting contraceptives and estimated for long-acting methods as 1 year less than the maximum approved duration.
Females were temporarily censored during pregnancy and surgery.
Information on age, calendar year, education, cardiovascular comorbidities, and chronic inflammatory disorders was available for all females. Body mass index (BMI) and smoking were known for some parous females, while family history was available for females with parents in Denmark (eTable 1 in Supplement 1).
Poisson regression provided VTE rate ratios adjusted for age, calendar time, education, hypertension, diabetes, hypercholesterolemia, atrial fibrillation/flutter, systemic connective disorders, inflammatory polyarthropathies, inflammatory bowel diseases, and multiple sclerosis. Absolute rates and rate differences were standardized according to the distribution of these factors in the entire cohort.
We used R software version 4.2.1 (The R Foundation). Statistical significance was defined as a 2-sided 95% CI that did not cross the null. This study was reported using the Strengthening the Reporting of Observational Studies in Epidemiology guidelines.
The Danish Health Data Board and Data Protection Agency granted approval. Informed consent was not required because the data were anonymized.
Among 1 397 235 females followed up for 8 455 601 person-years, 2691 VTEs occurred. eTable 3 in Supplement 1 shows the cohort characteristics.
Standardized VTE rates per 10 000 person-years were 2.0 (95% CI, 1.9-2.1) for nonuse, 10.0 (95% CI, 9.2-10.9) for combined pills, 8.0 (95% CI, 4.6-12.8) for vaginal rings, 8.1 (95% CI, 1.5-25.1) for patches, 3.6 (95% CI, 2.8-4.7) for progestin-only pills, 2.1 (95% CI, 1.7-2.6) for IUDs, 3.4 (95% CI, 1.7-6.3) for implants, and 11.9 (95% CI, 4.4-25.6) for injections (Table).