New Study Links Some Hormonal Contraceptives to Clots

Some progesterone-only hormonal contraceptives may carry similar clot risk to certain combined pills, a new study published in JAMA Network Open found. 

A team of Dutch researchers examined the risk of developing venous thromboembolisms (VTEs) associated with different types of synthetic progesterone and estrogen, 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 estrogen 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 analyzed health data from nearly 1.4 million women in Danish national registers, who they followed for 8.4 million 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, 2691 VTEs were documented. Standardized 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 gynecology 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 including data of women with PCOS and endometriosis, both conditions which are frequently treated with hormonal contraceptives, would be valuable to clinicians. 

Yonis told Medscape Medical News that 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 personalized counseling. 

“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, including that the women included in the study were predominantly White and Dutch individuals. Women in the United States tend to have more comorbidities and also are more racially diverse. 

“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. 

The study was funded by Sygeforsikringen “Danmark.” Yonis reports receiving grant funding from TrygFonden and Laerdal outside the submitted work. Other authors report receiving personal fees and grants from Pfizer and Novo Nordisk, among others. 

Kaitlin Sullivan is a journalist living in New York.