Choosing Oral Contraceptives With Lowest Thrombotic Risk

Peter Kovacs, MD, PhD


August 30, 2012

Hormonal Contraception and Venous Thromboembolism

Lidegaard Ø, Milsom I, Geirsson RT, Skjeldestad FE
Acta Obstet Gynecol Scand. 2012;91:769-778

Oral Contraceptive Pills

The most widely used form of contraception is the combined oral contraceptive pill. However, progestin-only pills, implants, depot medroxyprogesterone acetate (DMPA) injections, and medicated intrauterine devices are other contraceptive options, along with combined preparations available as transdermal patches and vaginal rings.

The combined pill contains 20-50 µg of ethinylestradiol and a progestin. Norethisterone was the first active progestin used in oral contraceptive pills and is classified as a first-generation progestin. Norgestrel and levonorgestrel are second-generation progestins, and desogestrel, gestodene, and norgestimate are the newer, third-generation progestins. Drospirenone is the latest progestogen component (fourth-generation) used in combined pills.

The combination pill works through multiple mechanisms: Negative feedback lowers follicle-stimulating and luteinizing hormone levels and prevents ovulation. The progestin component affects the cervical mucus, endometrium, and tubal motility and contributes significantly to the pill's contraceptive properties. The overall efficacy of the combination pill is user-dependent, but even with less-than-perfect use, it is among the most effective contraceptive options.

Risk for Venous Thromboembolism

In addition to providing effective contraception, use of the combined oral contraceptive pill is associated with multiple noncontraceptive benefits (including decreased blood loss, reduced dysmenorrhea, less cyst formation, and lower risk for ovarian/endometrial cancer). It is not, however, without adverse effects. It was recognized early on that the risk for venous thromboembolism (VTE) was increased among combination pill users.[1] This risk was attributed to its estrogen component, which affects the synthesis of clotting factors.

To mitigate this risk, the dose of the estrogen component was reduced, and later, new progestins were incorporated into the pill. Although the new progestins may be associated with a more favorable clinical profile, reports suggest a higher risk for VTE with these agents.

Many factors influence the risk for VTE. The incidence of VTE increases with age and body mass index. Family history, hematologic problems, immobilization, varicose veins, and pregnancy all affect a woman's risk for VTE. Therefore, these factors need to be controlled for when assessing the risk associated with different forms of hormonal contraception and generations of combination pills. Nonusers of hormonal contraception have a baseline risk for VTE of 1-3 per 10,000 woman-years.

A universal finding of existing research is an increased risk for VTE with the combination pill. The risk was somewhat reduced when the dose of ethinylestradiol was lowered. Most studies that compared pills from various generations found a higher risk with the third- and fourth-generation combined pills compared with the second-generation pills. Studies that failed to find a difference typically drew conclusions on the basis of a small number of VTE events.

Article Summary

This review by Lidegaard and colleagues summarizes the latest findings on VTE risk associated with hormonal contraceptives. In previous research, the investigators found the risk for VTE to be the highest (8 times the baseline risk) during the first year of contraceptive use compared with that of nonusers.[2] The risk, however, was still 3 times higher after 4 years of pill use. On the basis of findings from studies performed in different countries, the risk for VTE is 3 times higher with second-generation pills and 6-7 times higher with third- and fourth-generation pills. The absolute risk is small but cannot be ignored.

The investigators recommended the use of second-generation pills with the lowest estrogen content as the first choice of contraceptive pills. If adverse effects occur, a switch can be made to a third- or fourth-generation pill. Patients at risk for VTE should use a progestin-only pill, DMPA injections, or an intrauterine device. Older women, who have a higher risk for VTE as a result of age, also should use second-generation pills.


Under normal physiologic conditions, the mechanisms responsible for clotting and spontaneous bleeding are controlled, and the risks for both are low. However, many factors can disrupt this equilibrium. Vascular problems, inherited risk for thrombosis, immobility, obesity, and hormones, in addition to contraceptive pill use, all can influence the clotting cascade and increase the risk for VTE.

Combined oral contraceptive pills containing newer progestins are associated with a doubling of the risk for VTE compared with second-generation pills. Lidegaard and colleagues explain this finding as a differential effect on sex-hormone-binding globulin levels. Newer progestins induce much higher levels, and this affects the total estrogenicity of the pill.

However, other possible explanations exist. Newer preparations are more likely to be prescribed to new users of hormonal contraception. Most VTE occurs during the first year of use, so new users are at higher risk. Newer medications are considered safer overall, and therefore newer-generation pills may be prescribed preferentially to women who are at higher risk for VTE.

Drospirenone has antiandrogenic properties and is commonly prescribed to take advantage of this noncontraceptive benefit. Women with hyperandrogenemia (mainly polycystic ovary syndrome) are more likely to have underlying vascular problems and are at a higher baseline risk for VTE.

The message of this review is that care must be taken in the selection of a combined oral contraceptive pill and the choice has to be individualized, taking into account age, body mass index, family history, and other risk factors. The combined pill carries about the same risk for VTE as the pregnancy it is designed to prevent. Patients should be counseled about the signs of VTE to avoid more severe complications.



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