BACKGROUND: Millions of women worldwide use exogenous hormones as oral contraceptives or hormone replacement therapy. Still, time-dependent and long-term consequences of exogenous hormones on stroke risk remains unclear.

METHODS: We examined the association between self-reported oral contraceptive and hormone replacement therapy use and stroke risk in 257 194 women from the UK Biobank, born between 1939 and 1970. Outcomes included any type of stroke, ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage. Exposures were analyzed as time-varying variables in Cox regression models.

RESULTS: During first year of oral contraceptive use, an increased event rate of any stroke was observed (hazard ratio [HR], 2.49 [95% CI, 1.44-4.30]), while the hazards were found to be comparable during remaining years of use (HR, 1.00 [95% CI, 0.86-1.14]), compared with nonusers. Similarly, first year of hormone replacement therapy use was associated with higher hazard rates of any stroke (HR, 2.12 [95% CI, 1.66-2.70]), as well as cause-specific stroke, including ischemic stroke (HR, 1.93 [95% CI, 1.05-3.57]) and subarachnoid hemorrhage (HR, 2.17 [95% CI, 1.25-3.78]), which remained increased for any stroke during remaining years of use (HR, 1.18 [95% CI, 1.05-1.31]), and after discontinuation (HR, 1.16 [95% CI, 1.02-1.32]).

CONCLUSIONS: Oral contraceptive use and hormone replacement therapy were associated with an increased risk of stroke, especially during the first year of use, possibly due to immediate changes in hemostatic balance. This study provides new insights on the effects of hormone exposure on stroke risk and provide evidence of not only an overall risk but also a pronounced effects seen in the beginning of treatment.

AIM: Research on the effect of oral contraceptive (OC) use on the risk of depression shows inconsistent findings, especially in adult OC users. One possible reason for this inconsistency is the omission of women who discontinue OCs due to adverse mood effects, leading to healthy user bias. To address this issue, we aim to estimate the risk of depression that is associated with the initiation of OCs as well as the effect of OC use on lifetime risk of depression.

METHODS: This is a population-based cohort study based on data from 264,557 women from the UK Biobank. Incidence of depression was addressed via interviews, inpatient hospital or primary care data. The hazard ratio (HR) between OC use and incident depression was estimated by multivariable Cox regression with OC use as a time-varying exposure. To validate causality, we examined familial confounding in 7,354 sibling pairs.

RESULTS: We observed that the first 2 years of OC use were associated with a higher rate of depression compared to never users (HR = 1.71, 95% confidence interval [CI]: 1.55-1.88). Although the risk was not as pronounced beyond the first 2 years, ever OC use was still associated with an increased lifetime risk of depression (HR = 1.05, 95% CI: 1.01-1.09). Previous OC use were associated with a higher rate of depression compared to never users, with adolescent OC users driving the increased hazard (HR = 1.18, 95% CI: 1.12-1.25). No significant association were observed among adult OC users who had previously used OCs (HR = 1.00, 95% CI: 0.95-1.04). Notably, the sibling analysis provided further evidence for a causal effect of OC use on the risk of depression.

CONCLUSIONS: Our findings suggest that the use of OCs, particularly during the first 2 years, increases the risk of depression. Additionally, OC use during adolescence might increase the risk of depression later in life. Our results are consistent with a causal relationship between OC use and depression, as supported by the sibling analysis. This study highlights the importance of considering the healthy user bias as well as family-level confounding in studies of OC use and mental health outcomes. Physicians and patients should be aware of this potential risk when considering OCs, and individualized risk-benefit assessments should be conducted.

BACKGROUND: More than 150 million women worldwide use oral contraceptives. Women with inherited thrombophilia and carriers of certain thrombophilia gene variants, such as factor V Leiden and the prothrombin, are at an increased risk for venous thromboembolism, especially when combined with oral contraceptive use. Venous thromboembolism is a complex disorder involving many genetic risk factors, and recently, polygenic risk scores have been proposed to capture a significant proportion of the genetic risk of venous thromboembolism.

OBJECTIVE: The aim of this study was to estimate the risk for developing venous thromboembolism when initiating oral contraceptive use (first 2 years) and during continued use among women with a high genetic liability.

STUDY DESIGN: We used a prospective study design in which 244,420 participants from the UK Biobank were followed from birth. The effect of oral contraceptive use during the first 2 years and in the remaining years of oral contraceptive use on the risk of developing venous thromboembolism was estimated using a Cox regression with a time-dependent exposure variable. Women were stratified according to their polygenic risk scores and whether they were carriers of factor V Leiden and/or prothrombin variants.

RESULTS: When genetic risk was not considered, an increased risk for venous thromboembolism was observed during the first 2 years of oral contraceptive use (hazard ratio, 3.09; 95% confidence interval, 3.00-3.20) but not during continued use (hazard ratio, 0.92; 95% confidence interval, 0.80-1.05). However, when genetic risk was considered, women in the highest polygenic risk score category had a more pronounced risk of developing a venous thromboembolism during the first 2 years of oral contraceptive use (hazard ratio, 6.35; 95% confidence interval, 4.98-8.09), and a high risk was also observed among factor V Leiden (hazard ratio, 5.73; 95% confidence interval, 5.31-6.17) and prothrombin variant carriers (hazard ratio, 5.23; 95% confidence interval, 4.67 - 5.87). A high polygenic risk score in combination with being a factor V Leiden and prothrombin variant carrier conferred the highest risk for developing a venous thromboembolism during the first 2 years of oral contraceptive use (hazard ratio, 14.8; 95% confidence interval, 9.28-23.6). Women with a high genetic liability also had an increased risk during continued use but it was less pronounced, and the highest risk was conferred to carriers of both factor V Leiden and the prothrombin variant (hazard ratio, 4.93; 95% confidence interval, 3.16-7.7).

CONCLUSION: Evaluating polygenic risk can identify additional venous thromboembolism risk that is not captured in the commonly investigated genes for inherited thrombophilia. Our results indicate that oral contraceptive use is associated with an increased risk for developing a venous thromboembolism, particularly among women with a high genetic predisposition, and that oral contraceptive use dramatically increases the risk thereof short after initiation of use, which decreases with continued use. This suggests that the polygenic risk score could be used to identify women who are at high risk for developing a venous thromboembolism and advise them on alternative methods of contraception.

Objective To assess the effect of contemporary menopausal hormone therapy on the risk of cardiovascular disease according to the route of administration and combination of hormones.

Design Nationwide register based emulated target trial.

Setting Swedish national registries.

Participants 919 614 women aged 50-58 between 2007 and 2020 without hormone therapy use in the previous two years, identified from the Swedish population.

Interventions 138 nested trials were designed, starting each month from July 2007 until December 2018. Using the prescription registry data for that specific month, women who had not used hormone therapy in the previous two years were assigned to one of eight treatment groups: oral combined continuous, oral combined sequential, oral unopposed oestrogen, oral oestrogen with local progestin, tibolone, transdermal combined, transdermal unopposed oestrogen, or non-initiators of menopausal hormone therapy.

Main outcome measures Hazard ratios with 95% confidence intervals were estimated for venous thromboembolism, as well as for ischaemic heart disease, cerebral infarction, and myocardial infarction separately and as a composite cardiovascular disease outcome. Treatment effects were estimated by contrasting initiators and non-initiators in observational analogues to “intention-to-treat” analyses and continuous users versus never users in “per protocol” analyses.

Results A total of 77 512 women were initiators of any menopausal hormone therapy and 842 102 women were non-initiators. 24 089 women had an event recorded during the follow-up: 10 360 (43.0%) had an ischaemic heart disease event, 4098 (17.0%) had a cerebral infarction event, 4312 (17.9%) had a myocardial infarction event, and 9196 (38.2%) had a venous thromboembolic event. In intention-to-treat analyses, tibolone was associated with an increased risk of cardiovascular disease (hazard ratio 1.52, 95% confidence interval 1.11 to 2.08) compared with non-initiators. Initiators of tibolone or oral oestrogen-progestin therapy had a higher risk of ischaemic heart disease (1.46 (1.00 to 2.14) and 1.21 (1.00 to 1.46), respectively). A higher risk of venous thromboembolism was observed for oral continuous oestrogen-progestin therapy (1.61, 1.35 to 1.92), sequential therapy (2.00, 1.61 to 2.49), and oestrogen-only therapy (1.57, 1.02 to 2.44). Additional results in per protocol analyses showed that use of tibolone was associated with a higher risk of cerebral infarction (1.97, 1.02 to 3.78) and myocardial infarction (1.94, 1.01 to 3.73).

Conclusions Use of oral oestrogen-progestin therapy was associated with an increased risk of heart disease and venous thromboembolism, whereas the use of tibolone was associated with an increased risk of ischaemic heart disease, cerebral infarction, and myocardial infarction but not venous thromboembolism. These findings highlight the diverse effects of different hormone combinations and administration methods on the risk of cardiovascular disease.