Nonoral Hormonal Contraception Linked With Increased Risk for Venous Thrombosis

CLINICAL CONTEXT

Several studies have evaluated the risk for venous thrombosis, including deep vein thrombosis and pulmonary embolism, in women using oral contraceptive pills. However, few data are available regarding the risk for venous thrombosis in users of nonoral hormonal contraceptives.

To prevent pregnancy, nonoral hormonal contraceptives continuously release hormones into the body. The objective of this study by Lidegaard and colleagues was to determine the risk for venous thrombosis in current users of nonoral hormonal contraception.

STUDY SYNOPSIS AND PERSPECTIVE

Women who use transdermal patches or vaginal rings for contraception may be at significantly increased risk for venous thromboembolism compared with women who do not use hormonal contraception, according to a national registry-based Danish study published online May 10 in the BMJ.

Women using transdermal patches had a relative risk (RR) of 7.9 (95% confidence interval [CI], 3.5 - 17.7) for deep vein thrombosis and pulmonary embolism compared with women not using hormonal contraception after adjusting for age, calendar year, and education. Similarly, women using vaginal rings had an RR of 6.5 (95% CI, 4.7 - 8.9) compared with nonusers. In contrast, women taking oral hormonal contraceptives had a 3.2-fold increase (95% CI, 2.7 - 3.8) relative to women not using hormonal contraception.

The incidence for venous thrombosis was 2.1 events/10,000 woman-years in nonusers, 9.7 events/10,000 woman-years for those using contraceptive patches, 7.8 events/10,000 woman-years for those using the vaginal ring, and 6.2 events/10,000 woman-years for those using oral hormonal contraception.

Given the increased RR for women using nonoral versus oral hormonal contraception, Øjvind Lidegaard, MD, from the University of Copenhagen, Denmark, and colleagues conclude that women should switch to oral contraception to reduce their risk for deep vein thrombosis and pulmonary embolism.

Melissa Gilliam, MD, MPH, from the Department of Obstetrics and Gynecology at the University of Chicago, Illinois, suggests a more balanced approach: "I think it is important to put these things in perspective and include a thorough discussion of health benefits, cancer prevention, and general safety of these methods," Dr. Gilliam said to Medscape Medical News.

"I generally prescribe second-generation progestin birth control pills because they are cheapest. In addition, I always counsel my patients about the risk of blood clots and that it might be slightly higher with some methods rather than others, and I give them the numbers so they can see they are overall low...but I also explain that the risk of clot is still higher with pregnancy, so if after counseling about all methods they really feel as if the patch and the ring are their best options, they are still at lower risk of a clot than if they were to become pregnant," Dr. Gilliam added, noting the importance of considering other options.

"I find in my young population, the biggest issue is adherence, so I try to counsel them for long-acting methods like the [intrauterine device], as it is not thrombogenic and most likely to prevent pregnancy," Dr. Gilliam said.

Indeed, the authors found that women using the levonorgestrel intrauterine device demonstrated a significant decrease in risk for venous thrombosis, even relative to those not using hormonal contraception at all.

More Than 1.5 Million Women Studied for 10 Years

For the study, the researchers obtained data from 4 Danish national registries for 1,626,158 thrombosis-free nonpregnant women aged 15 to 49 years from January 2001 to December 31, 2010.

During 9,429,128 woman-years of follow-up, 5287 cases of venous thrombosis were recorded, 3434 of which were confirmed, for an adjusted incidence rate of 2.1/10,000 woman-years.

The increased risk associated with nonoral hormonal contraceptives may be explained by the 3- and 5-fold increase in sex hormone–binding globulin and the 3.75-fold increase in activated protein C sensitivity among vaginal ring users, the authors note.

Moreover, the authors note that the results are supported by pharmacokinetic studies showing 60% higher levels of estrogen among women using the patches compared with the corresponding oral contraceptive.

Progestogen-only subcutaneous implants showed a trend for increased risk for thrombosis (RR, 1.4; 95% CI, 0.6 - 3.4) compared with women not using hormonal contraception, and a nonsignificant decline in risk (RR, 0.4; 95% CI, 0.2 - 1.1) compared with those using levonorgestrel-containing contraceptives.

"The modest non-significant 40% increased relative risk of venous thrombosis in women using subcutaneous implants is not surprising," the authors write, noting that other types of progestogen-only contraceptives do not confer increased risk.

This was confirmed among women using the levonorgestrel intrauterine device, which decreased the risk for venous thrombosis by 40% relative to nonusers of hormonal contraceptives and by 80% for those taking combination pills, respectively (RR, 0.6; 95% CI, 0.4 - 0.8; RR, 0.2; 95% CI, 0.1 - 0.3, respectively).

The protective influence of progestin-only contraception may depend on dose, the authors suggest.

Study limitations include a lack of data regarding body mass index (adiposity is a well-documented risk factor for venous thrombosis) and information on smoking status, a weak factor among young women.

"[W]e have no reason to believe in preferential prescribing of specific types of hormonal contraception among smokers," the authors explain. "In Denmark the correlation between smoking and length of education is strong. Thus, controlling for years of schooling and length of education may have captured most confounding (if any) influenced by smoking."

Should Women Switch to Combination Oral Contraceptives?

The clinical implications of these findings can be expressed as the number of women who should switch from the transdermal patch or vaginal ring to combination oral contraceptives containing levonorgestrel to avoid an event of venous thromboembolism.

If the incidence rates of venous thromboembolism in women using combination oral contraceptives containing levonorgestrel, the vaginal ring, and contraceptive patch are 6, 11, and 14 per 10,000 exposure years, respectively, 2000 women using the ring and 1250 using the patch would have to switch to oral contraceptives to prevent a single event during the course of 1 year.

"[W]omen are generally advised to use combined oral contraceptives with levonorgestrel or norgestimate, rather than to use transdermal patches or vaginal rings," the authors conclude.

"This is an important study...larger sample size is very helpful in considering the overall implications and generalizability of the results," Lisa Kane Low, PhD, CNM, FACNM, director of midwifery education from the University of Michigan School of Nursing, Ann Arbor, told Medscape Medical News in an interview, noting the importance of keeping perspective on the overall low risk for venous thrombosis while balancing the seriousness and implications of such an event.

"Women's healthcare providers will need to incorporate this new evidence of comparative risk of contraceptive methods into their counseling as they work with women to select the optimal contraceptive method for their individual situation," Dr. Low concluded, noting that the risks associated with oral hormonal contraceptives are better known than that of newer, nonoral methods.

The study was supported by the Gynaecological Clinic, Juliane Marie Center, Rigshospitalet. Dr. Lidegaard has disclosed receiving speech honorariums from Bayer Pharma Denmark, MSD Denmark, and Theramex during the last 3 years; he also has served as an expert witness in a US legal case. One coauthor has had congress expenses paid by pharmaceutical companies twice during the last 3 years. Dr. Gilliam and Dr. Low have disclosed no relevant financial relationships.