Combined Oral Contraceptives and Risk of Venous Thromboembolism

Summary

Obesity and estrogen-containing contraceptives are well-known independent cardiovascular risk factors. However, a significant number of obese women continue to receive prescriptions for estrogen-containing hormonal products for contraception. We have conducted a narrative review to discuss the most recent evidence, ongoing research and controversial issues on the synergistic effect of obesity and contraceptive use, in terms of cardiovascular risk. There is compelling evidence of an interaction between obesity and contraception in increasing cardiovascular risk. Women who are both obese and use combined oral contraceptives (COCs) have a greater risk (between 12 and 24 times) of developing venous thromboembolism than non-obese non-COC users. The data discussed here offer new insights to increase clinicians’ awareness of cardiovascular risk in the clinical management of obese women. The synergistic effect of obesity and COCs on the risk of deep vein thrombosis should be taken into account when prescribing hormonal contraceptives. Progestin-only products are a safer alternative to COCs in patients who are overweight or obese. Obese women taking contraceptives should be viewed as an “at risk” population and, as such, should receive advice to change their lifestyle, avoiding other cardiovascular risk factors, as a form of primary prevention. This indication should be extended to young women, since data show that COCs should be avoided in obese women of any age.

Comments

Obese women who use oral contraceptives containing estrogen and progestin have a 24-fold increased risk of venous thromboembolism (VTE) compared with nonobese women who do not use the medications, according to a review article published in ESC Heart Failure , a journal. of the European Society of Cardiology (ESC).1

Study author Professor Giuseppe Rosano from IRCCS San Raffaele Pisana, Rome, Italy, said: “It is well established that both obesity and estrogen-containing contraceptives are risk factors for VTE. Despite this, obese women continue to receive these medications. Scientific evidence indicates that obesity and combined oral contraceptives have a synergistic effect on the risk of VTE and this should be considered in prescribing decisions. “Progestogen-only products, including pills, intrauterine devices or implants, are a safer alternative to the combined pill in overweight women.”

This review article highlights the latest evidence on the independent effects of obesity and contraceptives, and their synergistic effects, on VTE risk and provides clinical recommendations. VTE refers to a blood clot in a vein and includes two life-threatening conditions: deep vein thrombosis and pulmonary embolism.

The World Health Organization estimates that the global prevalence of obesity nearly tripled between 1975 and 2016, with 15% of adult women obese. The risk of VTE increases progressively with body mass index (BMI), and in obese women it is more than twice that of non-obese women. Obesity has the most substantial impact on women with VTE under the age of 40, who have a five-fold increased risk compared to nonobese women. Professor Rosano noted: “The particularly high risk in obese women under 40 is important, as it is at this age that many seek contraception.”

Combined oral contraceptives are associated with an increased likelihood of VTE, with users having a three- to seven-fold increased likelihood of VTE compared to non-users. In contrast, progestin-only products are not associated with an increased risk of VTE.

The combination of overweight/obesity and the use of combined oral contraceptives increases the likelihood of blood clots in women of reproductive age. For example, a large population-based study found that overweight and obesity were associated with a 1.7- and 2.4-fold increased risk of VTE, respectively. However, in combination pill users, the risk of VTE was 12 times higher in overweight women and 24 times higher in obese women, compared with normal weight non-users.

Professor Rosano said: "Obese women taking contraceptives are vulnerable to VTE and should take steps to limit their other predisposing factors to cardiovascular disease, for example by stopping smoking and increasing their levels of physical activity."

In summary , in women who combine obesity and COC use, literature data indicate that cardiovascular risks, primarily VTE risks, are increased 12- to 24-fold compared to non-obese non-COC users. The synergistic effect of obesity and COCs on the risk of DVT should be taken into account when prescribing hormonal contraceptives. Progestin-only products ( POPs) are a safer alternative to COCs in patients who are overweight or obese.

Conclusions and recommendations

The risk of VTE and PE increases progressively with BMI, and in obese women it is more than double that in non-obese subjects. Overweight/obesity has the most substantial impact in women under 40 years of age when the RR is 5 times higher than in non-obese subjects. Hypercoagulability, hypofibrinolysis, and a proinflammatory state appear to be the underlying mechanisms involved in the increased risk of thromboembolic events in obese women.
Women of reproductive age who have had bariatric surgery should avoid pregnancy for 12 to 24 months due to their weight loss. A possible decrease in the effectiveness of contraceptive products due to surgical procedures has been postulated in this group. However, the United Kingdom Medical Eligibility Criteria (UKMEC) grants grade 1 (a condition for which there is no restriction on the use of the method) to POPs in women with a history of bariatric surgery with BMI ≥ 35 kg/m2, while AHCs are not recommended.
The RRs of VTE comparing COC users with non-users are between 3 and 7 times higher in COC users vs. non-users. 13, 14 On the contrary, COCs, such as low-dose norethisterone pills, desogestrel alone pills or releasing IUD of hormones are not associated with an increased risk of VTE while the drospirenone pill alone did not report any cases of VTE or ASD along with its clinical development program. There is limited evidence that injectable DMPA may increase the risk of VTE.
Furthermore, thrombophilic states may have an impact on embolic events in obese women on contraception, although data on this specific population are not available to our knowledge. Family history of VTE, thrombophilia, age, and obesity should be taken into account when prescribing hormonal contraceptives.
It should be noted that the absolute risks of thrombotic stroke and myocardial infarction associated with COC use are low , although they appear to depend on the dose of ethinyl estradiol.
In the case of the use of COCs in obese women, the thromboembolic risk is enhanced, mainly of VTE, which ranges between 12 and 24 times when compared to the risk in non-obese non-COC users.
Given that VTE risks tend to be associated in the same subject and that overweight/obesity may be associated with smoking, high blood pressure, and age, it is crucial to evaluate the consolidated thrombotic risk resulting from the presence of each VTE risk if is present in the group.
The recommendation is to exercise caution with the use of COCs in overweight and obese patients, choosing the safest alternatives when prescribing hormonal contraceptives due to the increasing global prevalence of obesity.
Currently, obesity in combination with a sedentary lifestyle deserves special consideration when prescribing hormonal contraceptives due to the excessive risk of VTE.
Recommendations from the WHO, the Center for Disease Control (CDC) and the United Kingdom Medical Eligibility Criteria (UKMEC) provide grade 1 (a condition for which there is no restriction on the use of the method) to all POPs. , including pills, IUDs or implants for women with BMI ≥ 30 kg/m2. Additionally, WHO, CDC and UKMEC provide grade 2 recommendations for progestin-only pills and progestin-only implants when there are multiple risk factors for cardiovascular disease, smoking, diabetes, hypertension, obesity and dyslipidemias.
Progestin-only products (POPs) should be considered a safer alternative to COCs in obese women and in women who have multiple thromboembolic risks and seek hormonal contraception.

Combined Oral Contraceptives and Risk of Venous Thromboembolism

Combined birth control pill linked to increased risk of blood clots in obese women.