A team of researchers has suggested that some progesterone-only hormonal contraceptives may carry similar clot risk to certain combined pills, according to theirstudy.
The Danish scientists had examined the risk of developing venous thromboembolisms (VTEs) associated with different types of synthetic progesterone and oestrogen, such as norgestimate, levonorgestrel and desogestrel, as well as contraceptive methods, such as vaginal rings, pills and patches.
Combined hormonal pills, specifically desogestrel, and the progesterone-only medroxyprogesterone (Depo-Provera) injection were shown to have the highest risk for clots.
“What’s new here are the updated risk estimates for newer formulations, such as low-dose oestrogen pills, vaginal rings, and implants, that haven’t been as thoroughly studied in large population-based cohorts,” said Harman Gailan Hassan Yonis, MD, a professor at Aalborg University Hospital in Denmark, who led the research.
Yonis and his team analysed health data from nearly 1.4m women in Danish national registers, whom they followed for 8.4m person-years.
None of the women included had a history of thrombosis, cancer, liver or kidney disease, infertility treatment, hormone therapy, polycystic ovary syndrome (PCOS), or endometriosis, among other conditions.
The researchers adjusted for age, education, and chronic conditions like hypertension, diabetes, and multiple sclerosis.
In total, 2 691 VTEs were documented. Standardised VTE rates per 10 000 person-years were 2.0 (1.9-2.1) for women who had never used hormonal birth control. VTE rates were as high as 10 (9.2-10.9) for combined pills and 11.9 (4.4-25.6) for injections. The lowest rate was 2.1 (1.7-2.6) for intrauterine devices.
Combined hormonal pill desogestrel carried the highest adjusted incidence rate ratio (IRR), at 7.9 (6.0-10.3), followed by gestodene, also a combined pill, at 6.7 (5.6-7.9).
The injection medroxyprogesterone was found to have the highest adjusted IRR among the progesterone-only methods, at 5.7 (3.5-9.3), which was similar to the risk posed by two types of combined pills: Cyproterone acetate and drospirenone.
“We’ve known from some prior research that our higher forms of progesterone were associated with clots. The fact that it was as high as some combination pills is new information,” said Alexandria Wells, MD, a clinical assistant professor of obstetrics and gynaecology at Stony Brook Medicine in New York.
Wells pointed out that other factors within the patient population may have played a role in the higher VTE risk for injections. For example, clinicians commonly prescribe progesterone-only options, including medroxyprogesterone, to patients who have a higher risk for clotting.
The higher risk could be attributed to a population with more risk for clots, Wells said. Or the drug may be causing a higher risk.
Wells said that including data of women with PCOS and endometriosis, both conditions which are frequently treated with hormonal contraceptives, would be valuable to clinicians.
Yonis toldMedscape Medical Newsthat these women were omitted because they are often on other hormonal treatments that could increase clot risk independent of contraceptives.
Chronic inflammation and metabolic syndrome are also common in people with PCOS, both of which increase a person’s risk for blood clots.
While the study alone is unlikely to change prescribing guidelines immediately, Yonis and Wells said clinicians can use the results to drive personalised counselling.
“It will help you to point the patients in the right direction. Birth control is still very safe, but if a patient is particularly concerned about clots, this can help you tailor your counseling more,” Wells said.
Yonis noted several limitations of the study –published in JAMA Network Open – including that the women included in the research were predominantly white and European.
“While the biological mechanisms underlying the risk for venous blood clots are likely similar across ethnic groups, the absolute risk might differ due to varying genetic, environmental, and lifestyle factors,” Yonis said.
Study details
Contemporary Hormonal Contraception and Risk of Venous Thromboembolism
Harman Gailan Hassan Yonis, Lina Steinrud Mørch, Ellen Løkkegaard, et al.
Published in JAMA Network Open on 10 February 2025
Hormonal contraception is a recognised risk factor for venous thromboembolism (VTE),with the risk influenced by oestrogen dose and progestin type. However, VTE risk with newer formulations containing low-dose oestrogen, novel progestins, and bioidentical oestrogen requires further investigation. This study examined VTE risk across contemporary hormonal contraceptives.
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. 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.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, including pills with oestrogen and progestin (combined pills), vaginal rings, patches, progestin-only pills, intrauterine devices (IUDs), implants, and injections. 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.
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 standardised 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.
Results
Among 1 397 235 females followed up for 8 455 601 person-years, 2691 VTEs occurred.
Standardised 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.
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.
VTE excess per 10 000 person-years varied by combined pill formulation, from 3.0 (95% CI, −1.8 to 7.7) for 20-µg oestrogen 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.
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.
Medscape article –New Study Links Some Hormonal Contraceptives to Clots (Open access)
See more from MedicalBrief archives:
Blood clot risk rises with Pill/painkiller combo – Danish study
Contraception with fewer hormones still effective –Philippines modelling study
Link confirmed between the Pill and clot risk
