Abstract
Methods
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.
Results
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).
Compared with nonuse, VTE rate ratios were 4.6 (95% CI, 4.2-5.0) for combined pills, 4.5 (95% CI, 3.1-6.5) for vaginal rings, 5.0 (95% CI, 2.1-12.0) for patches, 1.8 (95% CI, 1.4-2.3) for progestin-only pills, 1.0 (95% CI, 0.8-1.1) for IUDs, 2.4 (95% CI, 1.4-4.0) for implants, and 5.7 (95% CI, 3.5-9.3) for injections (Table).
Corresponding additional VTEs per 10 000 person-years were 8.0 (95% CI, 7.2 to 8.7) for combined pills vs nonuse, 6.0 (95% CI, 2.1 to 9.8) for vaginal rings, 6.1 (95% CI, −3.6 to 15.8) for patches, 1.6 (95% CI, 0.7 to 2.6) for progestin-only pills, 0.1 (95% CI, −0.3 to 0.6) for IUDs, 1.4 (95% CI, −0.7 to 3.5) for implants, and 9.9 (95% CI, 0.5 to 19.3) for injections (Table).
VTE excess per 10 000 person-years varied by combined pill formulation (Table), from 3.0 (95% CI, −1.8 to 7.7) for 20-µg estrogen pills with levonorgestrel to 14.2 (95% CI, 9.2 to 19.3) for combined pills containing third-generation progestins. Pills with bioidentical estradiol also showed increased VTE rates.
Associations persisted when exclusively considering confirmed VTE diagnoses.
BMI and smoking data were available for 347 654 females (2 159 859 person-years, 771 VTEs). Family history was available for 1 067 866 females (6 759 035 person-years, 2483 VTEs). Associations remained consistent after adjusting for BMI, smoking, and family history (Table).
Discussion
The study showed VTE risk variation across hormonal contraceptives with highest rates for combined pills, especially those containing third-generation progestins, and no significant difference in risk for IUDs relative to no use. For patches and implants, the increased VTE risk was uncertain due to limited data.
Study limitations included that residual confounding may have remained despite extensive control, and that external generalizability may have been limited by the study population’s homogeneity and health profile.
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.
Results
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).
Compared with nonuse, VTE rate ratios were 4.6 (95% CI, 4.2-5.0) for combined pills, 4.5 (95% CI, 3.1-6.5) for vaginal rings, 5.0 (95% CI, 2.1-12.0) for patches, 1.8 (95% CI, 1.4-2.3) for progestin-only pills, 1.0 (95% CI, 0.8-1.1) for IUDs, 2.4 (95% CI, 1.4-4.0) for implants, and 5.7 (95% CI, 3.5-9.3) for injections (Table).
Corresponding additional VTEs per 10 000 person-years were 8.0 (95% CI, 7.2 to 8.7) for combined pills vs nonuse, 6.0 (95% CI, 2.1 to 9.8) for vaginal rings, 6.1 (95% CI, −3.6 to 15.8) for patches, 1.6 (95% CI, 0.7 to 2.6) for progestin-only pills, 0.1 (95% CI, −0.3 to 0.6) for IUDs, 1.4 (95% CI, −0.7 to 3.5) for implants, and 9.9 (95% CI, 0.5 to 19.3) for injections (Table).
VTE excess per 10 000 person-years varied by combined pill formulation (Table), from 3.0 (95% CI, −1.8 to 7.7) for 20-µg estrogen pills with levonorgestrel to 14.2 (95% CI, 9.2 to 19.3) for combined pills containing third-generation progestins. Pills with bioidentical estradiol also showed increased VTE rates.
Associations persisted when exclusively considering confirmed VTE diagnoses.
BMI and smoking data were available for 347 654 females (2 159 859 person-years, 771 VTEs). Family history was available for 1 067 866 females (6 759 035 person-years, 2483 VTEs). Associations remained consistent after adjusting for BMI, smoking, and family history (Table).
Discussion
The study showed VTE risk variation across hormonal contraceptives with highest rates for combined pills, especially those containing third-generation progestins, and no significant difference in risk for IUDs relative to no use. For patches and implants, the increased VTE risk was uncertain due to limited data.
Study limitations included that residual confounding may have remained despite extensive control, and that external generalizability may have been limited by the study population’s homogeneity and health profile.
| Original language | English |
|---|---|
| Journal | JAMA |
| Number of pages | 3 |
| ISSN | 0098-7484 |
| DOIs | |
| Publication status | E-pub ahead of print - 2025 |