Letnar Gasper, Andersen Klaus Kaae, Olsen Tom Skyhøj
Omicron ApS, Copenhagen, Telefonvej 8d 2860 Søborg, Denmark (G.L., K.K.A.).
Department of Neurology, Bispebjerg University Hospital, Bispebjerg bakke 23, Copenhagen, Denmark (T.S.O.).
Stroke. 2025 Feb;56(2):276-284. doi: 10.1161/STROKEAHA.124.049252. Epub 2024 Dec 9.
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.
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 (30-40- versus ≤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.
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 30- to 40- and ≤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]).
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.
含乙炔雌二醇和孕激素的复方激素避孕药（CHC）是年轻女性中使用最广泛的避孕方法，全球有数百万人使用。然而，对于使用低剂量乙炔雌二醇（<50μg乙炔雌二醇）的CHC以及最新的第四代孕激素（对其缺血性中风风险研究较少）与缺血性中风风险之间的关系仍存在不确定性。
在这项基于丹麦登记处的队列研究中，涵盖了2004年至2021年丹麦18至49岁的全体女性人口，我们调查了使用CHC与未使用激素避孕药相比缺血性中风的发病率比（IRR）。分析重点是比较基于乙炔雌二醇含量（30 - 40μg与≤20μg乙炔雌二醇）、CHC中孕激素代数（第二代、第三代和第四代）以及给药途径（单相与序贯）的CHC。使用了针对年龄、教育程度、种族、日历年份和用于风险因素的药物进行调整的泊松回归模型。
总共1711757名未怀孕女性为该研究贡献了14697788人年的数据。对于使用含<50μg乙炔雌二醇的CHC的女性，与未使用激素避孕药的女性相比，调整后的IRR增加了1.77（95%CI，1.62 - 1.93）。含30 - 40μg和≤20μg乙炔雌二醇的CHC之间的IRR没有差异。CHC使用者与未使用激素避孕药的使用者之间调整后的发病率差异范围从18至24岁女性每年每100000人中有1例到≥45岁女性每年每100000人中有24例。第四代CHC使用者的发病率比第二代CHC使用者调整后的IRR低30%（0.70 [95%CI，0.50 - 0.98]）。第三代CHC使用者的IRR与第二代使用者调整后的IRR没有显著差异（1.14 [95%CI，0.97 - 1.35]）。
使用CHC与缺血性中风的IRR高1.77相关。对于使用含<50μg乙炔雌二醇的CHC的女性，IRR与乙炔雌二醇含量无关。第四代CHC使用者的IRR比第二代CHC使用者低30%。
