The Contraceptive Ring and Relative Risk for VTE

My name is Anne-Marie Amies Oelschlager. I'm Associate Professor of Obstetrics and Gynecology at the University of Washington School of Medicine in Seattle, Washington. I'm also the Director of Pediatric and Adolescent Gynecology at Seattle Children's Hospital.

Today I'm going to talk about 2 recent studies. One was published recently in the British Medical Journal^[1]; the other was presented recently at the 60th Annual Clinical Meeting of the American Congress of Obstetricians and Gynecologists.^[2] Both of these studies looked at the relative risk or increased risk for venous thromboembolism (VTE) associated with combination hormonal contraceptives. The fact that combination oral contraceptives can increase the risk for VTE has been well studied and well documented.

For most women, the risk for thromboembolism is very low in the reproductive years. The things that we know increase the risk for thromboembolism include:

A strong family history of thromboembolism;
Obesity;
Smoking;
Increasing age;
Use of combination oral contraceptive pills containing estrogen; and
Pregnancy.

These 2 studies address the question of whether the transvaginal ring may increase the risk for VTE.

The first study enrolled Danish women between ages 15 and 49 years and was conducted between 2001 and 2010.^[1] Using a national registry, [Lidegaard and colleagues] were able to identify all women who had been prescribed hormonal contraceptives during that time. The authors also collected information on women admitted to the hospital with a history of thromboembolism as their diagnosis. They corroborated this admission history with a prescription of anticoagulation therapy for 4 weeks after discharge from the hospital.

When the investigators looked at the data, they found that the overall risk for thromboembolism in the entire population was 5287 over 9 million women-years studied. So, the overall rate of VTE was 5.6 per 10,000 women-years. When they looked at women using no form of hormonal contraception, they found that the risk for VTE was 2.1 per 10,000 women-years. When women were using combination oral contraceptive pills, including ethinylestradiol and progestins, they found that the overall risk was 6.2 per 10,000 women-years, and the incidence increased to 9.7 with the patch and 7.8 with the ring. Therefore, the risk for VTE in patch or ring users was even higher than that for oral contraceptive pill users.

Given that the study is a general population study, the limitations include no information about obesity, family history, or smoking status. Overall, the study indicates that an increased risk -- a relative risk -- for VTE is associated with using the NuvaRing® (contraceptive ring) over combination oral contraceptive pills, and that this risk is slightly less than [that associated with] using the patch. Even using oral contraceptive pills was found to have a higher risk [for VTE] than using [a contraceptive implant] or the levonorgestrel-releasing intrauterine system.

The second study was presented at the [60th Annual Clinical Meeting of the] American Congress of Obstetricians and Gynecologists by Dr. Heinemann [of ZEG - Berlin Center for Epidemiology and Health Research].^[2] This prospective cohort study recruited 33,000 women to compare adverse events between women using the contraceptive ring and those taking combination oral contraceptive pills. Thirty-four VTE events occurred during the 4 years of follow-up. The investigators found that the risk for VTE was 8.8 per 10,000 women-years in the contraceptive ring group and 9.9 per 10,000 women-years in the combination oral contraceptive pill group. They surveyed the study participants and excluded all long-term users and women who had a prior history of deep venous thrombosis before entering the study. The VTEs were confirmed by going back and directly contacting the study participants and corroborating with their physicians' information.

Putting this in perspective, the question is, what do we do with this information? One study showed an increase in risk; one study showed no increase in risk. I think there is biological plausibility that the contraceptive ring may increase the risk for VTE. We know that the serum concentrations [of sex hormone binding globulin] associated with the transvaginal route are higher than with combination oral contraceptive pills.^[3] The interesting thing to [note in regard to] the Danish study is that not only was a definite reduction in risk for VTE observed in women using the levonorgestrel-releasing intrauterine system in comparison with women using oral contraceptive pills, but this risk also was decreased in comparison with women using no form of hormonal contraception.

In our patients, especially those who have an increased risk for VTE -- they're older, they may be smokers, they may be obese -- we should always consider lower-risk alternatives if at all possible, the lowest-risk options being the levonorgestrel-releasing intrauterine system or a contraceptive implant, followed by levonorgestrel-containing oral contraceptive pills. For patients who really want to use combination oral contraceptive pills containing third-generation progestins, or for those who would prefer a transdermal or transvaginal route, they should be counseled that [these contraceptive methods may carry] an increased risk for VTE in comparison with other methods.

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