Letnar, G., Andersen, K. K., & Olsen, T. S. (2025). Ischemic Stroke in Users of Combined Hormonal Contraceptives: A Danish Registry Study. Stroke, 56(2), 276-284. https://doi.org/10.1161/STROKEAHA.124.049252
Letnar G, Andersen KK, Olsen TS. Ischemic Stroke in Users of Combined Hormonal Contraceptives: A Danish Registry Study. Stroke. 2025;56(2):276-284. doi:10.1161/STROKEAHA.124.049252
Letnar, Gašper, et al. "Ischemic Stroke in Users of Combined Hormonal Contraceptives: A Danish Registry Study." Stroke, vol. 56, no. 2, 2025, pp. 276-284.
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The combined hormonal contraceptive (CHC) with ethinylestradiol and progestins is the most widely used contraceptive method among young women and is used by millions worldwide. However, uncertainties exist about the risk of ischemic stroke associated with the use of CHCs with low-dose ethinylestradiol (<50-µg ethinylestradiol) and with the newest fourth-generation progestins that have only been sparsely investigated for the risk of ischemic stroke.
Methods
In this cohort study based on Danish registries covering the entire Danish female population aged 18 to 49 years from 2004 to 2021, we investigated incidence rate ratios (IRRs) of ischemic stroke using CHCs compared with nonuse of hormonal contraceptives. Analyses focused on comparing CHCs based on ethinylestradiol content (30-40versus ≤20-μg ethinylestradiol), progestin generation (second, third, and fourth) in CHCs, and route of administration (monophasic versus sequential). Poisson regression models adjusting for age, education, ethnicity, calendar year, and medication used for risk factors were utilized.
Results
In total, 1 711 757 nonpregnant women contributed 14 697 788 person-years to the investigation. For users of CHCs containing <50-µg ethinylestradiol, the adjusted IRR was increased by 1.77 (95% CI, 1.62-1.93) compared with nonusers of hormonal contraceptives. IRR did not differ between CHCs with 30to 40and ≤20-µg ethinylestradiol. Adjusted incidence rate difference between CHC users and nonusers of hormonal contraceptives ranged from 1 in 100 000 women per year in 18 to 24 years of age to 24 in 100 000 women per year in ≥45 years of age. Incidence rate in users of fourth-generation CHCs was 30% lower than that of second-generation CHCs adjusted IRR (0.70 [95% CI, 0.50-0.98]). IRR for users of third-generation CHCs did not differ significantly from that of second-generation users adjusted IRR (1.14 [95% CI, 0.97-1.35]).
Conclusions
Use of CHCs was associated with a 1.77 higher IRR of ischemic stroke. IRR did not relate to ethinylestradiol content in users of CHCs with <50-µg ethinylestradiol. IRR was 30% lower in users of fourth-generation than in users of second-generation CHCs.
To clarify the association between fertility treatment and the risk for cancer in children. Meta-analysis. None. Twenty-five cohort and case-control studies involving children born after fertility treatment as the exposure of interest and cancer as the outcome. None. Medline was searched through September 2012 to identify relevant studies. The study-specific estimates for each cancer outcome were combined into a pooled relative risk (RR) with 95% confidence interval (CI) by a meta-analytic approach. We found that children born after fertility treatment were at increased risk for all cancers (RR = 1.33; 95% CI, 1.08-1.63) and for hematological cancers (RR = 1.59; 95% CI, 1.32-1.91), central nervous system/neural cancers (RR = 1.88; 95% CI, 1.02-3.46), and other solid cancers (RR = 2.19; 95% CI, 1.26-3.80). For specific cancer types, we found increased risks for leukemias (RR = 1.65; 95% CI, 1.35-2.01), neuroblastomas (RR = 4.04; 95% CI, 1.24-13.18), and retinoblastomas (RR = 1.62; 95% CI, 1.12-2.35) associated with fertility treatment. The results of the largest meta-analysis on this topic to date indicate an association between fertility treatment and cancer in offspring. However, our results do not rule out that factors related to underlying subfertility, rather than the procedure itself, are the most important predisposing factors for childhood cancer.
Yonis H et al., 2025·BMJ·Free full text on PubMed Central
To evaluate the association between contemporary hormonal contraceptive use and the risk of incident ischaemic stroke and myocardial infarction.
Real-world, nationwide, prospective cohort study.
Denmark, by use of national registries. All women aged 15-49 years residing in Denmark between 1996 and 2021, with no history of arterial or venous thrombosis, antipsychotics use, cancer, thrombophilia, liver disease, kidney disease, polycystic ovary syndrome, endometriosis, infertility treatment, hormone therapy use, oophorectomy, and hysterectomy. First time diagnosis of ischaemic stroke or myocardial infarction at discharge. Among 2 025 691 women followed up for 22 209 697 person years, 4730 ischaemic strokes and 2072 myocardial infarctions occurred. Standardised ischaemic stroke rate per 100 000 person years were 18 (95% confidence interval 18 to 19) for no use, 39 (36 to 42) for combined oral contraception, 33 (25 to 44) for progestin-only pills, and 23 (17 to 29) for intrauterine device. Standardised myocardial infarction rate per 100 000 person years were 8 (8 to 9) for no use, 18 (16 to 20) for combined oral contraception, 13 (8 to 19) for progestin-only pills, and 11 (7 to 16) for intrauterine device. Compared with no use, current use of combined oral contraception was associated with an adjusted rate ratio of 2.0 (1.9 to 2.2) for ischaemic stroke and 2.0 (1.7 to 2.2) for myocardial infarction. These corresponded to standardised rate differences of 21 (18 to 24) extra ischaemic strokes and 10 (7 to 12) extra myocardial infarctions per 100 000 person years. Compared with no use, current use of progestin-only pills was associated with an adjusted rate ratio of 1.6 (95% CI 1.3 to 2.0) for ischaemic stroke and 1.5 (1.1 to 2.1) for myocardial infarction, equating to 15 (6 to 24) extra ischaemic strokes and four (-1 to 9) extra myocardial infarctions per 100 000 person years. Increased arterial thrombotic risk was also observed with use of the combined vaginal ring (adjusted incidence rate ratio of 2.4 (1.5 to 3.7) for ischaemic stroke and 3.8 (2.0 to 7.3) for myocardial infarction), patch (3.4 (1.3 to 9.1) and no myocardial infarctions), and progestin-only implant (2.1 (1.2 to 3.8) and ≤3 myocardial infarctions), whereas no increased risk was observed with progestin-only intrauterine device (1.1 (1.0 to 1.3) for ischaemic stroke and 1.1 (0.9 to 1.3) for myocardial infarction). Use of contemporary oestrogen-progestin and progestin-only contraceptives was associated with an increased risk of ischaemic stroke and, in some cases, myocardial infarction except for the levonorgestrel-releasing intrauterine device, which was not associated with either. 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.
Although several studies have assessed the risk of venous thromboembolism with newer hormonal contraception, few have examined thrombotic stroke and myocardial infarction, and results have been conflicting. In this 15-year Danish historical cohort study, we followed nonpregnant women, 15 to 49 years old, with no history of cardiovascular disease or cancer. Data on use of hormonal contraception, clinical end points, and potential confounders were obtained from four national registries. A total of 1,626,158 women contributed 14,251,063 person-years of observation, during which 3311 thrombotic strokes (21.4 per 100,000 person-years) and 1725 myocardial infarctions (10.1 per 100,000 person-years) occurred. As compared with nonuse, current use of oral contraceptives that included ethinyl estradiol at a dose of 30 to 40 μg was associated with the following relative risks (and 95% confidence intervals) for thrombotic stroke and myocardial infarction, according to progestin type: norethindrone, 2.2 (1.5 to 3.2) and 2.3 (1.3 to 3.9); levonorgestrel, 1.7 (1.4 to 2.0) and 2.0 (1.6 to 2.5); norgestimate, 1.5 (1.2 to 1.9) and 1.3 (0.9 to 1.9); desogestrel, 2.2 (1.8 to 2.7) and 2.1 (1.5 to 2.8); gestodene, 1.8 (1.6 to 2.0) and 1.9 (1.6 to 2.3); and drospirenone, 1.6 (1.2 to 2.2) and 1.7 (1.0 to 2.6), respectively. With ethinyl estradiol at a dose of 20 μg, the corresponding relative risks according to progestin type were as follows: desogestrel, 1.5 (1.3 to 1.9) and 1.6 (1.1 to 2.1); gestodene, 1.7 (1.4 to 2.1) and 1.2 (0.8 to 1.9); and drospirenone, 0.9 (0.2 to 3.5) and 0.0. For transdermal patches, the corresponding relative risks were 3.2 (0.8 to 12.6) and 0.0, and for a vaginal ring, 2.5 (1.4 to 4.4) and 2.1 (0.7 to 6.5). Although the absolute risks of thrombotic stroke and myocardial infarction associated with the use of hormonal contraception were low, the risk was increased by a factor of 0.9 to 1.7 with oral contraceptives that included ethinyl estradiol at a dose of 20 μg and by a factor of 1.3 to 2.3 with those that included ethinyl estradiol at a dose of 30 to 40 μg, with relatively small differences in risk according to progestin type. (Funded by the Danish Heart Association.).
Lidegaard Ø et al., 2011·BMJ·Free full text on PubMed Central
To assess the risk of venous thromboembolism from use of combined oral contraceptives according to progestogen type and oestrogen dose.
National historical registry based cohort study.
Four registries in Denmark. Non-pregnant Danish women aged 15-49 with no history of thrombotic disease and followed from January 2001 to December 2009. Relative and absolute risks of first time venous thromboembolism. Within 8,010,290 women years of observation, 4307 first ever venous thromboembolic events were recorded and 4246 included, among which 2847 (67%) events were confirmed as certain. Compared with non-users of hormonal contraception, the relative risk of confirmed venous thromboembolism in users of oral contraceptives containing 30-40 µg ethinylestradiol with levonorgestrel was 2.9 (95% confidence interval 2.2 to 3.8), with desogestrel was 6.6 (5.6 to 7.8), with gestodene was 6.2 (5.6 to 7.0), and with drospirenone was 6.4 (5.4 to 7.5). With users of oral contraceptives with levonorgestrel as reference and after adjusting for length of use, the rate ratio of confirmed venous thromboembolism for users of oral contraceptives with desogestrel was 2.2 (1.7 to 3.0), with gestodene was 2.1 (1.6 to 2.8), and with drospirenone was 2.1 (1.6 to 2.8). The risk of confirmed venous thromboembolism was not increased with use of progestogen only pills or hormone releasing intrauterine devices. If oral contraceptives with desogestrel, gestodene, or drospirenone are anticipated to increase the risk of venous thromboembolism sixfold and those with levonorgestrel threefold, and the absolute risk of venous thromboembolism in current users of the former group is on average 10 per 10,000 women years, then 2000 women would need to shift from using oral contraceptives with desogestrel, gestodene, or drospirenone to those with levonorgestrel to prevent one event of venous thromboembolism in one year. After adjustment for length of use, users of oral contraceptives with desogestrel, gestodene, or drospirenone were at least at twice the risk of venous thromboembolism compared with users of oral contraceptives with levonorgestrel.
3 cases of stroke in young women of childbearing age are presented to show the severity of illness and mortality in women using oral contraceptives. All 3 patients smoked more than 15 cigarettes a day. The mortality rate from cerebrovascular disease in OC users has been estimated as 4.7 times that of nonusers. The risk of developing a thrombotic stroke is 9.5 times greater than a control group's. Cerebral infarction has a relatively low mortality rate in young women, 9%, but a nonfatal stroke can have a devastating effect on the patient and her family. While there were no deaths among the 3 cases, each was left with a varying degree of neurological deficit while still in the peak of a normal life span. The possibility of synergistic potentiation of OC-associated cerebral thrombosis by cigarette use is uncertain but studies have noted some correlation between the 2. It is not clear that reduction in estrogen dosage has reduced the risk of cardiac or cerebral disease. The first patient developed extreme symptoms after a heavy drinking session, thereby raising the question of alcohol as a precipitating factor.
Klaus Kaae Andersen, Gasper Letnar, Tom Skyhøj Olsen
K Andersen, G Letnar, Thomas Olsen, T Olsen
PMID 39648905 39648905 DOI 10.1161/STROKEAHA.124.049252 10.1161/STROKEAHA.124.049252 Letnar et al. 2024, Letnar 2024
Cite this article
Letnar, G., Andersen, K. K., & Olsen, T. S. (2025). Ischemic Stroke in Users of Combined Hormonal Contraceptives: A Danish Registry Study. Stroke, 56(2), 276-284. https://doi.org/10.1161/STROKEAHA.124.049252
Letnar G, Andersen KK, Olsen TS. Ischemic Stroke in Users of Combined Hormonal Contraceptives: A Danish Registry Study. Stroke. 2025;56(2):276-284. doi:10.1161/STROKEAHA.124.049252
Letnar, Gašper, et al. "Ischemic Stroke in Users of Combined Hormonal Contraceptives: A Danish Registry Study." Stroke, vol. 56, no. 2, 2025, pp. 276-284.
