How genetic variables impact oral contraceptive use and VTE risk


A comprehensive study delved into the interplay of polygenic and hereditary factors in venous thromboembolism risk among oral contraceptive users, shedding light on potential genetic markers for refined risk assessment and counseling.

How genetic variables impact oral contraceptive use and VTE risk | Image Credit: © dalaprod - © dalaprod -

How genetic variables impact oral contraceptive use and VTE risk | Image Credit: © dalaprod - © dalaprod -

The risk of venous thromboembolism (VTE) is increased by oral contraceptive (OC) use because of polygenic effects as well as hereditary effects, according to a recent study published in the American Journal of Obstetrics & Gynecology.


  1. The study confirms previous findings that oral contraceptive (OC) users face a heightened risk of venous thromboembolism (VTE), a serious cardiovascular condition.
  2. VTE risk isn't solely attributable to genetic factors, with only 6% of VTE's heritability explained by genetic variants. Polygenic risk scores (PRSs) are suggested for better analysis.
  3. While PRS didn't significantly differ between OC users and non-users, it did identify high-risk groups, suggesting its potential efficacy in refining risk assessment.
  4. Factor V Leiden and prothrombin factor 2 variants were associated with increased VTE risk, especially among OC users, underscoring the importance of genetic screening.
  5. The study highlights a significant increase in VTE risk during the first 2 years of OC use, emphasizing the importance of considering temporal factors in risk assessment and counseling.

VTE, a leading cause of cardiovascular death worldwide, is impacted by a variety of acquired and inherited factors. Data has indicated OC users are at an increased risk of thrombotic events, with VTE risk increased by the excess estrogenicity of OCs.

The risk of VTE is increased 3-fold to 5-fold among women who use OCs, but genetic variants explain only 6% of VTE’s heritability. As VTE is a polygenic disorder, its genetic liability can be analyzed using polygenic risk scores (PRSs). However, clinical characteristics and a family history of VTE are currently used for risk assessment in contraceptive counseling.

Investigators conducted a population-based cohort study to evaluate the efficacy of PRS for identifying women with a high risk of developing VTE. Participants were aged 37 to 72 years and were recruited from assessment centers between 2006 and 2010.

Touch-screen and nurse-administered questionnaires and physical examinations were used to obtain baseline data. VTE was the primary outcome of the analysis, measured as a binary outcome based on patients’ relation to OC exposure.

Exclusion criteria included missing OC use data, no covariate data, not being genotyped, and not being White European. Participants were followed from birth until VTE diagnosis, end-of-study follow-up, bilateral oophorectomy or hysterectomy, or beginning of menopause. The cohort was stratified based on PRS.

OC use data included ever taken OC pill, age started OC pill, and age when an OC pill was last used. Hospital admission data and cause of death register were evaluated to determine the first occurrence of VTE in patients. Participants were genotyped using the UKB Axiom array (ThermoFisher Scientific, Santa Clara, CA) and the UK BiLEVE array.

There were 244,420 women included in the final analysis, 10,856 of whom experienced a first ever VTE event during the follow-up period. Initiation of OC use during the follow-up was reported by 193,371 participants. While more women in the never-user group had a VTE episode, this is likely because this population was older during recruitment.

Factor V Leiden (FVL) and prothrombin factor 2 (PTM) variant carrying was reported by 8682 and 4119 OC users, respectively. The frequency of FVL among OC users was 4.48% vs 2.13% for PTM. For never-users, these rates were 4.51% and 2.20%, respectively. PRS did not significantly differ between users and never users of OCs.

When categorizing risk groups, 24,291 women were in the highest PRS for VTE group, 10,985 in the FVL carriers group, and 5244 in the PTM carriers group. The incidence rate of VTE was significantly higher in all high genetic risk groups vs their respective reference groups, with carrier status increasing the area under the curve (AUC) by approximately 1% and high risk PRS increasing the AUC by 3.5%.

During the first 2 years of OC use, the hazard ratio for VTE development was 3.09. An association was not found between OC use and VTE risk for the remaining years. When stratified based on PRS decile, women in the first decile had a significantly increased risk during the first 2 years of OC use vs those in the tenth decile.

These results indicated genetic variants may account for risks not considered when evaluating traditional clinical and genetic factors. Investigators recommended further studies in other population to confirm this data.


Lo Faro V, Johansson T, Johansson A. The risk of venous thromboembolism in oral contraceptive users: the role of genetic factors—a prospective cohort study of 240,000 women in the UK Biobank. Am J Obstet Gynecol. 2024;230:360.e1-13. doi:10.1016/j.ajog.2023.09.012

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