A recent investigation examined whether stress-related psychiatric disorders modify the association between combined hormonal contraceptive use and cardiovascular or thrombotic risk in women.
Cardiovascular disease remains the leading cause of death among women, and psychosocial stress is increasingly recognised as an important contributor to cardiovascular risk. Depression, anxiety and post-traumatic stress disorder (PTSD) are highly prevalent in women and have each been linked to adverse cardiovascular outcomes. At the same time, millions of women use hormonal contraceptives, which alter endogenous sex hormone levels and have demonstrated mixed associations with vascular and thrombotic risk. Despite these overlapping risk domains, little research has explored how psychiatric stress disorders and hormonal contraception interact to influence cardiovascular health.
Study authors aimed to determine whether stress-related diagnoses moderate associations between contraceptive use and major adverse cardiovascular events (MACE) or deep-vein thrombosis (DVT). The investigators used electronic health record data from the Mass General Brigham Biobank. Eligible participants were women aged 18–55 years who consented to inclusion in the biobank before September 2020 and maintained active consent through 2025. Lifetime histories of depression, anxiety and PTSD were identified. Hormonal contraceptive exposure was defined using RxNorm prescription codes and limited to combined oestrogen–progestin methods; women using progestin-only methods were excluded.
Outcomes were incident MACE (including myocardial infarction, unstable angina, heart failure, coronary or peripheral revascularisation, stroke and transient ischaemic attack) and DVT. To ensure temporality, psychiatric diagnoses and contraceptive use had to occur before consent, while outcomes had to occur after consent. Covariates included demographic characteristics and established clinical risk factors such as smoking, hypertension, hyperlipidaemia, diabetes, cancer, obesity and thrombophilia.
The final sample comprised 31,824 women with a mean age of 38.5 years. Over one-third (37.6%) had a history of combined hormonal contraceptive use. Stress-related disorders were common: 28.5% had depression, 11.1% anxiety and 6.3% PTSD. MACE occurred in 1.5% of the cohort and DVT in 0.9%. Third- and second-generation contraceptives were the most frequently used formulations. These baseline figures demonstrate both the high prevalence of psychiatric morbidity and the relatively low absolute rates of hard cardiovascular outcomes in this largely premenopausal population.
Results were mixed and largely contrary to the initial hypothesis that stress disorders would amplify cardiovascular or thrombotic risk associated with contraceptive use. Depression and anxiety did not significantly moderate associations between contraceptive use and either MACE or DVT after adjustment. In both groups, contraceptive use showed no harmful cardiovascular signal, and in some models appeared associated with lower odds of MACE. Thus, there was insufficient evidence that depression or anxiety meaningfully altered the cardiovascular safety profile of combined hormonal contraceptives.
In contrast, PTSD demonstrated a significant moderating effect for MACE but not for DVT. Among women without PTSD, contraceptive use was associated with approximately 31% lower odds of MACE, suggesting a potential protective association. However, this protective relationship did not extend to women with PTSD. In those with PTSD, the odds ratio for MACE was greater than 1, indicating a possible increase in risk, although this finding did not reach statistical significance. This divergence implies that PTSD may uniquely alter the cardiovascular implications of hormonal contraceptive exposure.
Exploratory analyses further examined whether contraceptive generation influenced outcomes, given prior evidence that earlier, higher-oestrogen formulations may increase thrombotic risk. Restricting the sample to women who used only one generation, the investigators found no significant generation-specific moderation by depression, anxiety or PTSD for either MACE or DVT.
The authors discussed several potential explanations for the distinctive PTSD finding. PTSD is characterised by persistent sympathetic activation, heightened physiological reactivity and impaired fear learning, mechanisms more strongly linked to cardiovascular dysregulation than the behavioural or affective features typical of depression and anxiety. Hormonal contraceptives may interact with these autonomic or inflammatory pathways differently in women with PTSD, potentially offsetting any protective cardiovascular effects observed in other groups. However, unmeasured confounders, including trauma type or social determinants, may also contribute.
In conclusion, combined hormonal contraceptive use was generally associated with lower or neutral cardiovascular risk in women with depression or anxiety, but these potential benefits did not extend to women with PTSD. The findings suggest that PTSD may represent a distinct context in which contraceptive use relates differently to cardiovascular health. The authors call for further research to clarify how hormonal contraception and PTSD interact to influence cardiovascular risk and to inform tailored clinical care for women with stress-related disorders.
Source: JAMA
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