Which Hormonal Contraceptives Pose a Lower Thrombosis Risk?

Peter Kovacs, MD, PhD


December 28, 2016

Hormonal Contraception and Thrombosis

Sitruk-Ware R
Fertil Steril. 2016;106:1289-1294


Almost one half of all pregnancies are unplanned,[1] making it important for patients to know about effective forms of contraception. Combined hormonal contraceptive preparations (pill, patch, vaginal ring) are not as effective as intrauterine devices or tubal ligation, but offer more protection than barrier or calendar methods.[2] Among the many hormonal preparations, the contraceptive pill is used most often.

Oral contraceptives are not without side effects, however. An increased risk for cardiovascular disease and venous thromboembolism (VTE) in women taking oral contraceptives has been noted.[3,4]

This paper reviewed the risk for thrombosis with hormonal conceptive methods.


The baseline risk for VTE is 1-2 per 10,000 reproductive-aged women. Epidemiologic studies have shown an increase in VTE risk of about fourfold among users of oral contraceptives, but this still remains less than the risk for VTE of 20 in 10,000 during pregnancy.

The estrogen component of the oral contraceptive pill, in a dose-dependent manner, is the primary cause for the increased risk. The progestin component has undergone changes over the years, and in more recent preparations, less androgenic or antiandrogenic progestins are used.

In observational studies, when combined hormonal contraceptives containing third- or fourth-generation progestins (norelgestromin, etonogestrel, drospirenone) were compared with levonorgestrel-containing preparations, an increased risk for thrombosis was found. This included oral, vaginal, and transdermal products. Prospective cohort studies, however, did not find an increased risk with newer progestins compared with products containing a second-generation progestin. This suggests that observational studies were unable to control for all known risk factors.

The estrogen component of the pill (ethinyl estradiol) is primarily responsible for the increased risk through modulating the hepatic synthesis of clotting factors. Newer estrogens (estradiol valerate or 17-beta estradiol) have no or only minimal effect on liver metabolism. The progestin alone has no impact on the clotting cascade. Androgenic progestins, however, attenuate the effect of estrogen. Less androgenic, newer formulas have less impact on the estrogen-induced effects in the liver.


There are important messages in this paper. Medicine is taking an individualized approach, and contraception has to be individualized too. Risk factors for VTE, including obesity, age, family/personal history, diabetes, and hypertension, have to be assessed. Patients at high risk should use a method (tubal ligation, intrauterine device, progestin only) that will not augment the overall risk. In addition, there are combined oral contraceptives with varying estrogen doses and different progestins.

Second-generation progestins that are more androgenic seem to better counteract the procoagulant effect of ethinyl estradiol. There are, however, new estrogen components (17-beta estradiol and estradiol valerate) that have been successfully used in combined oral contraceptives and have no or minimal procoagulant effects.[5]

In the future, combined hormonal contraceptives with components that resemble the natural hormone and are delivered by an alternate, nonoral route should be tested. The currently available products, however, still have a favorable VTE profile compared with pregnancy and therefore should be offered to patients who need effective contraception.


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