Hormonal contraception and stroke …

Stroke & Vascular Disorders

Updated 12.03.2025
Released 12.16.2003
Expires For CME 12.03.2028

Hormonal contraception and stroke

Authors: Kristin Miller MD, Sarah Wyckoff MD

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Editor: Steven R Levine MD

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Hormonal contraception and stroke

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Introduction

Overview

According to the Centers for Disease Control and Prevention's 2022–2023 National Survey of Family Growth, 11% of women aged 15 to 49 use oral contraception and 10.5% of women aged 15 to 49 use an intrauterine device or contraceptive implant. The association between hormonal contraception and venous thrombosis and thromboembolism is well established, but the relationship between hormonal contraception and arterial complications is more complicated. Overall, hormonal contraception appears to increase the relative risk of ischemic stroke modestly. Although the risk of ischemic stroke secondary to hormonal contraception on a population level remains low, this risk is accentuated in women with migraine with aura and in women who smoke.

Key points

	• Most physicians recommend discontinuation of hormonal contraception after ischemic stroke, particularly estrogen-containing contraception.
	• Women with migraine with aura who take hormonal contraception have an increased risk of ischemic stroke (six times more likely) compared to women without migraine who do not take hormonal contraception.
	• In women with specific stroke risk factors, such as smoking, migraine with aura, or hypertension, shared decision making is recommended to determine the best contraception choice to balance the risk of stroke from contraception and with pregnancy.
	• In women with specific stroke risk factors, such as smoking, migraine with aura, or hypertension who are considering contraception, progestin-only contraception or nonhormonal contraception is reasonable.
	• Notably, despite an increased risk of ischemic stroke with hormonal contraception, the risk is still lower than the risk of ischemic stroke associated with pregnancy.

Historical note and terminology

The first oral contraceptive pill was approved by the United States Food and Drug Administration in 1960. Soon thereafter, reports began to emerge in the literature of healthy women on oral contraceptives developing cerebrovascular “instances” and “disturbances” (54; 71). A 1973 case-control study of women aged 15 to 44 in academic hospitals in 12 cities in the United States found that 29% of 429 women with stroke were active users of oral contraception compared to approximately 14% of 843 women without stroke (12).

In 1996, the World Health Organization (WHO) Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception, a case-control study across 17 countries that included 2649 women (697 with ischemic stroke), found that the risk of ischemic stroke was significantly higher in current users of oral contraception compared to nonusers (64).

In 2000, the first meta-analysis of studies that examined the risk between oral contraceptive use and ischemic stroke was published (21). Across the 16 studies included, the relative risk of stroke in contraceptive users was notably higher than in nonusers (RR 2.75; 95% CI: 2.23–3.38). However, the authors concluded that the absolute risk increase attributable to oral contraceptives was likely low given the low incidence of stroke among the relevant age group. Importantly, the dose of estrogen has decreased in most oral contraceptives since the era of the included studies.

In 2001, the American Heart Association (AHA) endorsed a low risk of stroke with low-dose oral contraceptives in women without additional risk factors but noted that oral contraceptives should be avoided in women with additional risk factors, such as smoking or a previous personal history of thromboembolism (23). This recommendation was reiterated in the 2006 and 2011 editions of the guidelines. In 2014, the first specific guidelines for the prevention of stroke in women were published and included a class 3 recommendation that oral contraceptives may be harmful in women with additional risk factors, such as smoking or prior thromboembolic events (09). The 2024 AHA guidelines for the primary prevention of stroke dedicated a section to hormonal contraception and included two class 1 recommendations: (1) that lower doses of ethinyl estradiol are recommended to minimize potential increases in stroke risk in individuals considering combined hormonal contraception and that (2) in individuals with specific stroke risk factors (such as age greater than 35 years, tobacco use, hypertension, and migraine with aura), shared decision making is recommended to determine the best contraceptive choice to balance the risk of stroke from contraception and the risk of stroke with pregnancy (08). Additionally, the guidelines offered a class 2a recommendation that in individuals with the stroke risk factors previously described, progestin-only contraception or non-hormonal contraception is reasonable to prevent the increased stroke risk associated with estrogen-containing contraception.

Hormonal contraception is a widely used and effective form of birth control. Despite an increased risk of stroke with hormonal contraception, the risk of stroke is still lower than the risk associated with pregnancy and childbirth. This article will review data on the association between stroke and hormonal contraception. Most studies reviewed include combined oral contraceptives, which are combined formulations of estrogen and progesterone. Doses of estrogen and forms of progestin vary depending on the generation of oral contraceptive and the specific formulation. Many of these studies also include some information on transdermal, injectable, and implantable hormonal contraception. These methods of delivery are also discussed, although to a lesser extent given the paucity of high-quality data.

Clinical manifestations

Presentation and course

	• Patients with ischemic stroke associated with hormonal contraception present identically to patients with ischemic stroke not associated with hormonal contraception.
	• Hormonal contraception has been associated with two less common stroke syndromes: cerebral venous thrombosis and reversible cerebral vasoconstriction syndrome. Both syndromes tend to present with headache.

Ischemic stroke and intracranial hemorrhage. Patients with ischemic stroke or transient ischemic attack typically present with acute-onset, focal neurologic symptoms, such as weakness, numbness, aphasia, dysarthria, vision loss, or gait disturbance. The goal of acute ischemic stroke treatment is to preserve the ischemic penumbra, whether it be allowing for permissive hypertension, treating with intravenous thrombolysis, or endovascular thrombectomy. A Ukranian case control study using data from 2017 to 2024 of 45 women aged 19 to 35 years old showed oral contraception use was associated with a higher neurologic deficit using the National Institutes of Health Stroke Scale (NIHSS), though there was a high likelihood of confounders and lack of adjustment for these (61). Patients with intracranial hemorrhage typically present with focal neurologic signs, as is the case for ischemic stroke. Patients with intracranial hemorrhage may also have a depressed level of consciousness or other symptoms related to increased intracranial pressure. Some patients fully recover after ischemic stroke or intracranial hemorrhage, but others are left with substantial disability or death.

Cerebral venous thrombosis. Symptoms of cerebral venous thrombosis may present acutely or subacutely. Patients often report headache. Venous infarction, hemorrhage, and seizures can occur, presumably due to impaired venous drainage. In severe cases, intracranial pressure increases. Cerebral venous thrombosis is treated with urgent systemic anticoagulation, even in the setting of associated intracranial hemorrhage. Catheter thrombolysis or venous thrombectomy can be considered in patients with clinical and radiographic deterioration despite anticoagulation, although no strong evidence supports a role for these interventions.

Reversible cerebral vasoconstriction syndrome. Classically, patients with reversible cerebral vasoconstriction syndrome present with a severe, acute-onset (“thunderclap”) headache. Patients can also demonstrate focal neurologic symptoms related to acute ischemic stroke, subarachnoid hemorrhage, or intracerebral hemorrhage.

Prognosis and complications

Ischemic stroke associated with hormonal contraception. A 2021 retrospective analysis of 179 female patients in Switzerland aged 18 to 50 with acute ischemic stroke from 2003 to 2015 found that patients on systemic hormonal contraception compared to nonusers had a more favorable 12-month outcome, defined as an mRS of 2 or less (13). Contraceptive users had a lower risk of stroke or transient ischemic attack recurrence at 12 months (OR 0.04; 95% CI: 0.00–0.55). All patients in the contraceptive group discontinued hormonal contraception in the first 12 months after the index stroke.

A more favorable outcome among women with ischemic stroke associated with hormonal contraception is not surprising because these patients tend to be younger and healthier than women with stroke who do not use contraception. Furthermore, women with stroke associated with hormonal contraception have an easily modifiable risk factor (withdrawal of hormonal contraception or transition to a potential lower risk progestin-only alternative), whereas women with stroke not associated with hormonal contraception may have less easily modified risk factors (hereditary hypercoagulable states, vascular risk factors, etc).

Intracerebral hemorrhage associated with hormonal contraception. Data on the prognosis of patients with intracerebral hemorrhage associated with hormonal contraception are lacking. In general, the 30-day mortality rate after intracerebral hemorrhage can range from 30% to 50% and is largely affected by clinical features and underlying etiology, but this rate is difficult to extrapolate to patients with intracerebral hemorrhage associated with hormonal contraception. Patients with intracerebral hemorrhage associated with hormonal contraception tend to be younger and healthier and, thus, have a better prognosis (65).

Cerebral venous thrombosis associated with hormonal contraception. In a single-center study of 24 patients with cerebral venous thrombosis between 1992 and 2002, oral contraceptive use was the presumed etiology in four patients (05). All patients were treated with heparin followed by oral anticoagulation. Of the four patients with oral contraceptive use, one reported a new severe headache, one reported cognitive dysfunction, and two were normal at hospital discharge.

In a prospectively maintained database of patients with cerebral venous thrombosis (all causes) between 1998 and 2001, mortality at the end of the median follow-up period of 16 months was 8.3%, and excellent outcome, defined as an mRS of 1 or less, was seen in 79.1% of patients and increased to 86.6% with an mRS of 2 or less (18). In this cohort, hormone replacement therapy was noted in 4.3% of the cohort and oral contraceptives in 54.3% of patients younger than 50 years of age.

In a retrospective single-center cohort study of 139 female patients with cerebral venous thrombosis presenting between 2018 and 2021, oral contraceptive use was associated with a lower rate of in-hospital mortality (adjusted OR: 11.732, p = 0.004) and favorable 3-month follow-up outcome defined as an mRS of 2 or less (adjusted OR: 4.423; 95% CI: 0.423–46.248) (63). Of note, 57 patients (accounting for 77% of oral contraceptive users in the study) had no other identified cause for cerebral venous thrombosis except oral contraception, despite comprehensive screening for infection, hematological, and rheumatological conditions.

Reversible cerebral vasoconstriction syndrome associated with hormonal contraception. Due to the low reported incidence of reversible cerebral vasoconstriction syndrome, data on the prognosis of reversible cerebral vasoconstriction syndrome associated with hormonal contraception are lacking. In one study analyzing the reversible cerebral vasoconstriction syndrome registries of two academic hospitals, approximately 97% of patients were functionally independent based on Barthel Index scores at a median follow-up time of 78 months (28). The time course for improvement or resolution of differing symptoms associated with reversible cerebral vasoconstriction syndrome is variable.

Biological basis

	• The precise mechanism by which oral contraception promotes coagulability remains unknown.
	• Loss of homeostasis in coagulation factors is thought to lead to a thrombophilic state that can cause arterial and venous thrombus formation in the setting of oral contraceptive use.

The precise effects of hormonal contraception on various components of the coagulation cascade are unknown. Much research has found an effect of hormonal contraception on thrombogenic agents (eg, fibrinogen, prothrombin, and coagulation factors) and endogenous antithrombotic factors (eg, protein C, protein S, and antithrombin).

The effects on the coagulation cascade are more pronounced in third-generation hormonal contraceptives as compared to second-generation, which use differing formulations of progesterone (38; 56; 62; 43). These effects include an increase in fibrinogen, prothrombin, and factors VII, VIII, and X (38). There is also a decrease in protein S and antithrombin, both of which regulate the coagulation cascade via inhibition (56; 29; 31), and in the tissue factor pathway inhibitor (24; 14; 62; 43). Of note, hormonal replacement therapy has also been shown to affect similar components of the coagulation cascade in a dose-dependent manner (48).

Protein C, an antithrombotic factor in the coagulation cascade, is a potentially relevant site of action of hormonal contraception. In a mouse model and in clinical studies, both free tissue factor pathway inhibitor and protein S decrease in response to hormonal therapy (26; 62; 57). There has, however, been one case-control study that did not find an association between tissue factor pathway inhibitor and protein S levels with stroke (46).

A small study analyzing the immunohistochemistry of thrombi retrieved during mechanical thrombectomy for arterial ischemic stroke in five patients with high estrogen states (one postpartum, one undergoing hormone replacement therapy, and three using oral contraceptives) found thrombin-activatable fibrinolysis inhibitor (TAFI) expression, a driver of thrombosis, was significantly higher (25.6 ± 11.9% versus 9.3 ± 9.0%, p = 0.043*) compared to aged-matched male controls (02). It is thought that TAFI expression may prevent tissue plasminogen activator (tPA)-induced activation of plasminogen. Prior studies have reported tPA concentration needs to be increased up to 9-fold to achieve the same clot lysis times when TAFI levels are maximal (47).

A linear relationship between the levels of sex hormone binding globulin (SHBG) during the use of oral contraceptive and the risk of venous thrombosis has been suggested (40). However, a study of postmenopausal women in the Woman’s Health Initiative (WHI) found an inverse relationship between the level of SHBG and ischemic stroke (36).

Although not well understood, estrogen appears to have a stronger effect on coagulation factors and hypercoagulability than progesterone. There are some investigations in cell and rate models that suggest progesterone may play a neuroprotective role, though this has been studied after cerebral ischemia has already occurred (55; 70).

Etiology and pathogenesis

The precise mechanism by which oral contraception promotes coagulability remains unknown.

In normal hemostasis, injury to the vascular endothelium results in a cascade of interactions between coagulation factors and components of the exposed vascular endothelium. This cascade results in the aggregation of platelets locally around the region of vascular injury. Fibrin fibrils stabilize this aggregation with a fibrin mesh, which forms a thrombus, which, in turn, can prevent blood from flowing distally (66). In some cases, the thrombus will embolize, moving distally. The embolus may subsequently get lodged within a smaller portion of the circulatory system, block flow distally, and lead to ischemia of the affected tissue.

A change in the plasma levels of hemostatic agents, including coagulation factors, inhibitors, and fibrinolytic factors, has been associated with increases in stroke risk (52; 51; 37). The effects on hemostasis following an increase in thrombogenic agents and a decrease in antithrombotic agents result in a hypercoagulable state, which, in turn, leads to an increased risk of thrombosis in the large and small vessels throughout the body.

In the setting of a hypercoagulable state, cerebral ischemic injury can result from the formation of in situ thrombus in the cerebral arteries, leading to ischemic stroke, or from emboli from arterial thrombus elsewhere. Venous emboli may also form in the cerebral veins, leading to cerebral venous thrombosis, or in the extremity or pelvic veins allowing for the potential for paradoxical emboli to the brain if an intracardiac shunt is present.

Any amount of ischemia results in cytotoxicity within brain parenchyma and causes focal neurologic deficits based on the region in which brain parenchyma sustained injury. Clinical symptoms are based on both the size and location of ischemia.

Epidemiology

	• Combined hormonal contraception is associated with an increased risk of ischemic stroke.
	• Estrogen appears to drive this increased risk of stroke in a dose-dependent manner, with higher doses of estrogen being associated with higher rates of stroke.
	• The use of progesterone-only contraception has not been associated with an increased risk of ischemic stroke.
	• Combination oral contraception is associated with intracranial hemorrhage, cerebral venous thrombosis, and reversible cerebral vasoconstriction syndrome in some studies, though these data are not as robust.

Risk of ischemic stroke

Combined estrogen and progesterone formulations. In 1996, the World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception published the results of its case-control study, which examined the risk of ischemic stroke in association with current use of combined hormonal birth control in 697 cases and in 1962 age-matched controls (64). The risk of ischemic stroke in contraceptive users compared to nonusers was higher in Europe (aOR: 2.99; 95% CI: 1.65–5.40), developing countries (aOR: 2.93; 95% CI: 2.15–4.00), Asia (aOR: 3.55; 95% CI: 2.13–5.92), and Latin America (aOR: 2.76; 95% CI: 1.86–4.11).

Many but not all cohort and case-control studies have found an association between combined hormonal contraception and ischemic stroke. A 2015 Cochrane review identified 24 studies that assessed the risk of ischemic stroke in users of combined oral contraception versus nonusers (45). Combined oral contraceptive users showed an increased risk of stroke (RR: 1.7; 95% CI: 1.5–1.9) compared to nonusers. However, significant heterogeneity was found among studies.

A 2012 cohort study of Danish women aged 15 to 48 years presenting between 1995 and 2009 investigated the risk of thrombotic stroke in women according to contraception type, estrogen dose, progestin type, and route of administration (35). The study was massive, with a cohort size of 1,626,158 women with 14,251,063 person-years of observation. Thrombotic stroke was observed in 3311 (0.20%) women. Oral contraceptives containing 20 µg, 30 to 40 µg, and 50 µg of ethinyl estradiol were associated with a relative risk of thrombotic stroke of 1.60 (95% CI: 1.37–1.87), 1.75 (95% CI: 1.61–1.92), and 1.97 (95% CI: 1.45–2.66) respectively, though the linear trend was not significant (p=0.24). In the United States, a population-based cross-sectional study of the National Inpatient Sample for women aged 15 to 50 between 2015 and 2020 reported a greater incidence of arterial ischemic stroke in oral contraceptive pill users compared to non–oral contraceptive pill users (2.8% vs. 0.4%; OR: 7.50; 95% CI: 7.43–7.58; P < 0.001) that persisted in a subgroup analysis of hospitalizations without stroke risk factors following adjustment for age and race and ethnicity (15).

Registry data provides insight into how contraceptive choices and preferences have changed over the past 15 years to include differing dosages of estrogen-containing pills. A large 2025 prospective cohort study of 2,025,691 Danish women aged 15 to 49 years between 1996 to 2021 across 22,209,697 person-years of observation evaluated the risk of ischemic stroke in users and non-users of hormonal contraception (69). Combined oral contraception was associated with an increased adjusted incidence rate ratio for ischemic stroke (2.0; 95% CI: 1.9 - 2.2). Stratified by estrogen dose, the use of combined oral contraceptives containing 20 µg and 30 to 40 µg of ethinyl estradiol were associated with increased adjusted incidence rate ratios for ischemic stroke of 1.9 (95% CI: 1.7–2.2) and 2.0 (95% CI: 1.9–2.2), respectively, when compared with no use of hormonal contraception and adjustment for progestin type.

Another 2025 large retrospective cohort study of 1,711,757 Danish women aged 18 to 49 years between 2004 and 2021 across 14,697,788 person-years of observation similarly investigated the incidence rate ratio of ischemic stroke in users of combined hormonal contraceptives compared to non-users (32). Similar to previous studies, the use of combined oral contraceptives was associated with overall increased adjusted incidence rate ratios of ischemic stroke compared to non-users (1.77; 95% CI: 1.62–1.93), and there was no significant difference when comparing users of combined oral contraceptives with 20 µg or less ethinyl estradiol versus 30 to 40 µg ethinyl estradiol. Given low sample size, the study was unable to comment on risk associated with combined oral contraceptives containing 50 µg of ethinyl estradiol. Interestingly, compared to second-generation combined oral contraceptive users (levonorgestrel/norgestimate), the adjusted incidence rate ratio of ischemic stroke for third-generation users (desogestrel/gestodene) did not differ significantly (1.14, 95% CI: 0.97–1.35), whereas it was decreased by 30% (0.70, 95% CI: 0.50–0.98) for fourth-generation users (drospirenone), indicating possibly lower ischemic stroke risk with newer formulations.

Although the 2025 Danish cohort studies did not find a significant increase in ischemic stroke risk with higher ethinyl estradiol doses in oral hormonal contraception users or longer duration of use in all combined hormonal contraception users, other studies did show increased risk (32; 69). A case-control analysis from a large United States tertiary care center found that in 203,853 combination hormonal contraception users (including pills, patches, and vaginal rings) aged 18 to 55 from 2010 to 2019, the ischemic stroke risk was higher with 30 or more micrograms of ethynyl estradiol compared to less than 30 micrograms (OR: 1.52; 95% CI: 1.02–2.26) (02). In a 2019 meta-analysis, an increased risk of ischemic stroke was associated with every 10 µg increase in estrogen dose in oral hormonal contraceptives (OR :1.20; 95% CI: 1.17–1.22) (34). The investigators also found that duration of exposure may also increase stroke risk (OR for every 5-year increment in duration of contraception 1.24; 95% CI: 1.03–1.49).

A 2016 systematic review identified two studies that reported the risk of arterial events among combined hormonal patch users compared to combined oral contraceptive users (59). Neither study found a difference in the risk of ischemic stroke between the patch and oral contraceptive users. The aforementioned 2025 Danish prospective cohort study echoed these results (69). In both 2025 Danish cohort studies, the use of combined hormonal vaginal rings was associated with an increased adjusted incidence rate ratio of ischemic stroke compared to non-use (aIRR: 1.79; 95% CI: 1.11–2.89 and aIRR 2.4; 95% CI: 1.5–3.7) that was not significantly different from the risk associated with use of oral combined oral contraception (32; 69).

There are multiple studies that suggest other risk factors may compound the risk of stroke while on oral contraception. In the 2002 Risk of Arterial Thrombosis in Relation to Oral Contraceptives (RATIO) study, the risk of stroke was higher in women on oral contraception who were obese (OR 4.6; 95% CI: 2.4–8.9) compared to women who were not (OR 2.2; 95% CI: 1.5–3.0) (30).

In the 1996 WHO study, the odds ratio of ischemic stroke for smokers compared to nonsmokers was 7.20 (95% CI: 3.23–16.1) among contraceptive users in Europe (64). For smokers versus nonsmokers in developing countries, the odds ratio was 4.83 (95% CI: 2.76–8.43). Similarly, for women on oral contraceptives in the RATIO study, the risk of stroke was higher in women who smoked (OR 4.4; 95% CI: 2.7–7.3) compared to women who did not smoke (OR 2.8%; 95% CI:1.5–5.0).

Progesterone-only formulations. A 2018 systematic review found six studies (five case-control and one cohort) that examined the risk of stroke in women taking progesterone-only contraception (22). On meta-analysis, the use of progesterone-only contraception was not associated with an increased risk of stroke (adjusted pooled RR 1.02; 95% CI: 0.72–1.33). Similarly, in the 2012 Danish cohort study, progestin-only contraceptives, including the levonorgestrel-releasing IUD, were not associated with thrombotic stroke, regardless of route of administration (35). In a retrospective 2024 Danish cohort study of women aged 18 to 49 years between 2004 and 2021, investigators found a lower adjusted incidence rate of ischemic stroke in nonpregnant women using the levonorgestrel-releasing IUD compared to nonusers of hormonal contraception (0.78; 95% CI: 0.70–0.88), as well as compared to users of non IUD hormonal contraception (0.64; 95% CI: 0.56–0.72) (33). This was consistent with findings from the 2025 prospective Danish cohort study of data between 1996 to 2021 (adjusted IRR: 1.0; 95% CI: 1.0–1.3) (69). However, the 2025 Danish study notably found an increased adjusted incidence rate of ischemic stroke in users of progestin-only oral contraceptives (aIRR: 1.6; 95% CI: 1.3–2.0), subcutaneous progestin-only implants (aIRR: 2.1; 95% CI: 1.2–3.8), and the progestin-only injection (aIRR: 1.8; 95% CI: 0.8–4.4) compared to non-users, though the findings were not significant for the progestin-only injection. These new data indicate that perhaps there may be increased ischemic stroke risk with systemic progestin-only products.

Risk of intracranial hemorrhage

A 2018 meta-analysis sought to estimate the risk of hemorrhagic stroke associated with the current use of oral contraceptives (67). Five cohort studies and 10 case-control studies including 4271 patients with hemorrhagic stroke were included in the analysis. An increased risk of hemorrhagic stroke (subarachnoid hemorrhage and intracerebral hemorrhage) was found for contraceptive users (summary OR: 1.39; 95% CI: 1.05–1.83). When each type of hemorrhage was examined individually, contraceptive users were at an increased risk of subarachnoid hemorrhage (OR: 1.60; 95% CI: 1.21–2.12) but not intracerebral hemorrhage (summary OR: 0.92; 95% CI: 0.33–2.54). However, it should be noted that ten studies evaluated subarachnoid hemorrhage, whereas only four evaluated intracerebral hemorrhage. A 2025 meta-analysis of five studies also estimated the risk of subarachnoid stroke associated with the current use of oral contraceptives and found no statistically significant association (03). A subsequently published cohort study of 769 female patients with subarachnoid hemorrhage and 225,700 female controls from the United Kingdom Biobank similarly found no association between the use of oral contraception and subarachnoid hemorrhage (adjusted HR: 0.96; 95% CI: 0.81–1.15) (10).

The retrospective 2024 Danish cohort study of women aged 18 to 49 years between 2004 to 2021 found no significant impact of levonorgestrel-releasing IUD use on the adjusted incidence rate of intracerebral hemorrhage compared to non-users of hormonal contraception (0.94; 95% CI: 0.69–1.28) (33).

Risk of cerebral venous thrombosis

Because it is well-established that hormonal contraception is associated with venous thrombosis, it is not surprising that hormonal contraception is associated with cerebral venous thrombosis. A 2015 meta-analysis identified nine case-controlled studies published between 1996 and 2005 that investigated the association between oral contraception and cerebral venous thrombosis (04). Across the studies, the pooled odds ratio for developing cerebral venous thrombosis for contraceptive users compared to nonusers was 7.59 (95% CI: 3.82–15.09). However, heterogeneity among the nine included studies was high (I2 = 72.1%). Current guidelines recommend screening for contraceptive use in the initial clinical assessment of women with cerebral venous thrombosis (09).

Risk of reversible cerebral vasoconstriction syndrome

Case reports have reported an association between estrogen withdrawal and reversible cerebral vasoconstriction syndrome (39; 68). In one report, a woman developed reversible cerebral vasoconstriction syndrome 1 month after starting a combination oral contraceptive pill (53). Because reversible cerebral vasoconstriction syndrome can present with ischemic stroke, subarachnoid hemorrhage, and intracerebral hemorrhage, some of the patients included in the aforementioned studies may have had this diagnosis.

Diagnostic workup

• Diagnosis of stroke relies on the clinical presentation and can be confirmed with imaging techniques ranging from noncontrast head CT to specialized MR imaging.

Beyond imaging techniques to confirm the diagnosis of ischemic stroke, intracranial hemorrhage, cerebral venous thrombosis, or reversible cerebral vasoconstriction syndrome, diagnostic work-up to suggest or establish the etiology as related to hormonal contraception relies on a thorough evaluation of other potential cardiac and vascular etiologies. This work-up will typically entail vessel imaging with a CT angiogram, MR angiogram, or carotid dopplers; cardiac imaging with a transthoracic echocardiogram; and cardiac rhythm monitoring and may include hypercoagulable serologic studies to evaluate for an underlying inherited or acquired thrombophilia apart from the use of hormonal contraception.

Ischemic stroke. A non-contrast head CT is required to diagnose ischemic stroke, as intracranial hemorrhage must be ruled out. If a head CT is negative for hemorrhage, a patient’s history and examination may be sufficient to confer a diagnosis of ischemic stroke. If the diagnosis is uncertain, or if clarifying the location and the extent of the infarct is important, an MRI brain may be pursued.

Intracranial hemorrhage. A non-contrast head CT is a sensitive, specific, and quick test for intracranial hemorrhage.

Cerebral venous thrombosis. Cerebral venous thrombosis can sometimes be suggested based on characteristic findings on a non-contrast head CT. Often a dedicated CT venogram or an MRI brain or MR venogram is required to confirm the diagnosis.

Reversible cerebral vasoconstriction syndrome. MRI or CT scanning is used to determine whether reversible cerebral vasoconstriction syndrome has caused an associated intracranial hemorrhage (intraparenchymal hemorrhage or subarachnoid hemorrhage) or ischemic stroke. In addition, vessel imaging with a CT angiogram, MR angiogram, or conventional angiogram should be performed to evaluate for focal narrowing of the intracranial vessels. Vessel changes can be dynamic in reversible cerebral vasoconstriction syndrome, so repeat vessel imaging may be needed to secure the diagnosis.

Management

	• Discontinuation of estrogen-containing hormonal contraception is generally recommended following a stroke or cerebral venous thrombosis.
	• Acute management of stroke, whether ischemic or hemorrhagic, in the setting of hormonal contraception use is no different than that not associated with hormonal contraception.

Although high-quality evidence is lacking, most providers recommend discontinuation of estrogen-containing hormonal contraception in women who have had an ischemic stroke. There are multiple studies that suggest a lower increased risk of stroke with progesterone-only contraception (35; 22; 33), though there are others that may still suggest a higher risk of stroke with certain progesterone-only contraception (69). Research is ongoing to identify effective nonhormonal contraception alternatives that may have a lower stroke risk (01).

In the 2014 AHA Guidelines for Prevention of Stroke in Women, blood pressure measurement prior to initiating hormonal contraception was recommended (09). This recommendation was based on results from the WHO Study and the Transnational Study (58). In the WHO study, women on oral contraception who had their blood pressure checked prior to initiating contraception had lower odds of ischemic stroke than did women on oral contraception who did not have their blood pressure checked (OR: 3.90; 95% CI: 1.83–8.33 versus OR: 2.26; 95% CI: 1.12–4.55) (64). Similarly, in a population of 220 women with ischemic stroke and 775 controls in the Transnational Study, women who had their blood pressure checked had lower odds of thromboembolic stroke compared to women who had not (25). The authors suspected that blood pressure checks served as a surrogate for better healthcare or health behavior. In two Danish studies, stroke incidence was lower than in non-Danish studies, and this was hypothesized to be related to the fact that the majority of Danish women have their blood pressure checked before obtaining prescriptions for contraceptives (42; 35).

However, this recommendation was not carried forward in the 2024 AHA Guidelines on Primary Prevention of Stroke (08). These recommendations suggest lower doses of ethinyl estradiol to minimize potential increased stroke risk as well as consideration of specific stroke risk factors and shared decision-making to determine the best contraceptive choice.

Outcomes

The natural history of stroke may be more favorable for patients with contraceptive-associated stroke as these patients tend to be healthier and younger than typical stroke patients. There is no evidence to suggest a difference in treatment effect for patients with contraceptive-associated stroke compared to those with stroke from other causes.

Special considerations

Pregnancy

Although patients who are currently pregnant do not receive exogenous hormonal contraceptives, there continues to be a risk of stroke associated with pregnancy, especially in the third trimester and the postpartum period (27). In patients with a history of cerebral venous thrombosis regardless of the association with hormonal contraception, prophylaxis with low molecular weight heparin is suggested during the pregnancy and immediate postpartum period (49; 09; 17; 19). Postpartum angiopathy, a form of reversible cerebral vasoconstriction syndrome associated with pregnancy and a postpartum state, has been described; there is no evidence for a high risk of recurrence with future pregnancies, although data are limited (44).

Migraine

Migraine headache is one of the most common neurologic diseases and is known to disproportionately affect women. Migraine with aura independently increases the risk of ischemic stroke (16; 60). An association between hormonal contraception and stroke in women with headache was first identified in the 1960s, raising concern about the safety of oral contraception in women with migraine (20). Over time, many case-control and cohort studies have sought to quantify this risk.

In 2000, the International Headache Society Task Force on Combined Oral Contraceptives & Hormone Replacement Therapy noted no contraindication to the use of oral contraception in women with migraine who did not have migraine aura or additional risk factors, such as age over 35 years, ischemic heart disease, hypertension, smoking, or diabetes mellitus (07). A potentially increased risk of ischemic stroke in women with migraine with aura who are using oral contraception was noted.

A 2017 study using a nationwide healthcare claims database investigated the association among combined hormonal contraceptive use, migraine with aura versus without, and ischemic stroke (11). Among females aged 15 to 49 between 2006 and 2012, 1884 women with a first-ever ischemic stroke were identified and age-matched to four controls (n=7536). Among women on combined hormonal contraceptives, the risk of ischemic stroke was almost two times higher in women with migraine without aura compared to women without migraine (OR: 1.77; 95% CI: 1.09–2.88). For women with migraine with aura, the odds were greater than six (OR: 6.08; 95% CI: 3.07–12.05). Per the current guidelines, smoking cessation should be strongly recommended for women with migraine headaches with aura (09).

A 2018 systematic review and meta-analysis evaluated 15 studies of women with migraine on hormonal contraception that reported stroke risk (50). The risk of stroke in migraine patients who used any dose of estrogen was higher than nonusers, with odds ranging from 1.08 to 16.9. The dose of estrogen was reported in seven of the studies. The authors found limited evidence regarding the effect of estrogen dosing on stroke risk.

In 2020, a systematic review of observational studies that included 12,256 women with migraine on low-dose combination hormonal contraception suggested increased odds of ischemic stroke in contraception users than in nonusers (41). Due to significant heterogeneity, a meta-analysis was not performed.

A case-control analysis sought to clarify how migraine history may impact stroke risk (06). Of 203,853 combination hormonal contraception users in the study (127 with ischemic stroke), stroke risk was twice as high in women with a history of migraine (OR: 2.00; 95% CI: 1.27–3.17).

References

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Authors

Kristin Miller MD

Dr. Miller of Northwestern University received consulting fees from iSchemaView, Inc.
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Sarah Wyckoff MD

Dr. Wyckoff of Columbia University Medical School owns stock in Pfizer Inc. and Viatris Inc.
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Editor

Steven R Levine MD

Dr. Levine of the SUNY Health Science Center at Brooklyn has no relevant financial relationships to disclose.
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Former Authors

Ann Helms MD MS
Steven J Kittner MD MPH
Olukemi Ajayi MD
Michael J Schneck MD
Murray Flaster MD PhD
Marisa McGinley DO
Sarkis Morales-Vidal MD
Jose Biller MD
Janaki Girish Patel MD
Mollie McDermott MD MS

Patient Profile

Age range of presentation: Stroke associated with contraceptive use

Typical: 15 to 49 years

Atypical: N/A
Sex preponderance: Stroke associated with contraceptive use

Male: 0%

Female: 100%
Heredity: No hereditary factors
Population groups selectively affected: Women are selectively affected.
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-10: Ischemic stroke: I63

Intracerebral hemorrhage: I619

Intracranial hemorrhage: I629

Migraine with aura: G43.1
ICD-11: Cerebral ischaemic stroke of unknown cause: 8B11.5

Intracerebral haemorrhage: 8B00

Intracranial haemorrhage, unspecified: 8B0Z

Migraine with aura, unspecified: 8A80.1Z

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Hormonal contraception and stroke

Associated Disorders

CADASIL
Sickle cell disease
Factor V Leiden

Differential Diagnosis

Migraine
Seizure
Hypoglycemia
Hyperglycemia

Also Relevant

Cerebral venous thrombosis
Hypercoagulable states and cerebrovascular disease
Ischemic stroke
Pregnancy and stroke
Reversible cerebral vasoconstriction syndromes
- Stroke in young adults

	• Routine screening for thrombophilia in all women who initiate oral contraceptives is not recommended.
	• Among women who have had a transient ischemic attack or stroke, discontinuation of hormonal contraception is reasonable.

Hormonal contraception and stroke

Cite this article

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Risk of ischemic stroke

Risk of intracranial hemorrhage

Risk of cerebral venous thrombosis

Risk of reversible cerebral vasoconstriction syndrome

Prevention

Differential diagnosis

Confusing conditions

Associated or underlying disorders

Diagnostic workup

Management

Outcomes

Special considerations

Pregnancy

Migraine

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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