A comprehensive Danish cohort study of more than two million women revealed that most contemporary hormonal contraceptives, except for levonorgestrel-releasing intrauterine devices, are associated with elevated risks of ischemic stroke and myocardial infarction.

The study, published in BMJ, analyzed more than 22 million person-years of follow-up data, during which 4,730 ischemic strokes and 2,072 myocardial infarctions occurred. The research found that current use of combined oral contraceptives was associated with an adjusted rate ratio of 2.0 (95% CI = 1.9–2.2) for ischemic stroke and 2.0 (95% CI = 1.7–2.2) for myocardial infarction compared with no use.

"Although absolute risks were low, clinicians should include the potential risk of arterial thrombosis in their assessment of the benefits and risks when prescribing a hormonal contraceptive method," the researchers, led by Harman Yonis of the Department of Cardiology at Nordsjaellands Hospital in Hilleroed, Denmark, wrote.

The highest risk estimates were observed with nonoral combined hormonal contraceptives. The vaginal ring showed an adjusted incidence rate ratio of 2.4 (95% CI = 1.5–3.7) for ischaemic stroke and 3.8 (95% CI = 2.0–7.3) for myocardial infarction. The combined hormonal patch demonstrated an adjusted ischemic stroke rate ratio of 3.4 (95% CI = 1.3–9.1).

Notably, progestin-only pills were also associated with increased risk, showing an adjusted rate ratio of 1.6 (95% CI = 1.3-2.0) for ischemic stroke and 1.5 (95% CI = 1.1-2.1) for myocardial infarction.

In absolute terms, these relative risks translated to approximately one extra ischemic stroke for every 4,760 women using combined oral contraceptives annually and one extra myocardial infarction for every 10,000 women per year of use compared with nonusers.

The study utilized comprehensive Danish national registries to track all women aged 15 to 49 years residing in Denmark between 1996 and 2021, excluding those with pre-existing conditions that might confound results. The researchers adjusted for multiple variables including age, calendar time, educational level, hypertension, diabetes, hypercholesterolemia, and atrial fibrillation or flutter. Importantly, the associations persisted even after additional adjustments for smoking and body mass index in a subpopulation analysis.

Duration of use did not appear to influence risk. Indeed, elevated risk remained stable over time for combined oral contraceptives. This finding contrasts with previous research, including a UK Biobank study that found the highest risks occurred during the first year of use. The levonorgestrel-releasing intrauterine device was the only method that showed no increased arterial thrombotic risk, with adjusted rate ratios of 1.1 (95% CI = 1.0–1.3) for ischemic stroke and 1.1 (95% CI = 0.9–1.3) for myocardial infarction.

The findings have particular significance given that at least 248 million women worldwide use hormonal contraception, according to WHO estimates cited in the study. However, the researchers noted that the study's external generalizability may be limited by the Danish population's homogeneity.

Full disclosures can be found in the study.