Purpose of reviewTo inform about the risk of venous thromboembolism (VTE) of different hormonal contraceptives in differentpatient groups.
Recent findingsCombined oral contraceptives (COCs) differ significantly regarding VTE risk depending on amount ofestrogen and type of progestogen: COCs containing desogestrol, gestoden or drospirenone incombination with ethinylestradiol (so called third-generation or fourth-generation COCs) are associatedwith a higher VTE risk than COCs with ethinylestradiol and levonorgestrel or norethisterone (so calledsecond-generation COCs). The VTE risk for transdermal COCs like vaginal ring (NuvaRing) or patch (Evra)is as high as for COCs of third or fourth generation. Progestogen-only contraceptive methods do notincrease VTE risk significantly. New kinds of COC without ethinylestradiol but with estradiol valerat orestradiol showed a much lower degree of coagulation activation than ‘classical’ COC containingethinylestradiol.
SummarySecond-generation COCs should be the first choice when prescribing hormonal contraception.
In patients with a history of VTE and/or a known thrombophilic defect, COCs are contraindicated, butprogestogen-only contraceptives can be safely used in this patient group. Whether newer COCs withestradiol valerate or estradiol have a lower VTE risk remains to be elucidated.
Keywordscombined oral contraceptives, estradiovalerat, progestogen-only contraceptive, thrombophilia,venous thromboembolism health problem in the European Union (EU), with over one million VTE events and around 220 000 Many risk factors beside contraception contribute VTE-related deaths per annum (Cohen et al. to VTE in women of reproductive age and they are Hormonal contraception methods of first choice are combined oral contraceptives (COCs). Theadvantage is the contraceptive safety, its easy (1) less than 40 years: annual risk 1 in 10 000 use and a beneficial effect on acne and hyper- (most likely underestimated, high rate of menorrhagia or dysmenorrhagia. About 60% of all women between 16–30 years in industrialized countries like EU use COCs, which usually contain (3) more than 80 years: annual risk 1 in 100 ethinylestradiol and a progestogen (german guide-line Women of reproductive age, who usecontraceptive methods with ethinylestradiol, are at a six to eight times higher risk for VTE than nonusers depending on the kind of contraceptive used. VTE is often clinically silent, and therefore is often undiagnosed especially in younger women Curr Opin Obstet Gynecol 2012, 24:235–240 1040-872X ß 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins Nonusers of COCs have an incidence of VTE  COCs differ significantly regarding VTE risk depending of about five to 10 in 100 000. Overall hazard ratio on amount of estrogen and type of progestogen.
for thromboembolism and COC use in all women  COCs of the third and fourth generation have a is 2–6 but much higher in thrombophilic remarkably higher VTE risk than COCs of the second women and depending on whether the patient generation; therefore, COCs of the second generation has a single or combined thrombophilic defect should be prescribed as the first choice. COCs are contraindicated in patients with a history of VTE [andshould also be restricted in patients with known The risk of VTE is the highest in the first year of thrombophilia, especially in patients with a hereditary use of COCs and higher in first-time users of deficiency of anticoagulants (protein C, protein S and The risk of VTE turns out to be lower after 1 year of use, but remains higher than in nonusers.
 Progestogen-only contraceptives can safely be used in patients with history of VTE/thrombophilia.
Eight to 12 weeks after cessation of COCs, the VTE risk turns to normal. Therefore, it is  New COCs with estradiol valerat or estradiol instead not recommended to stop COCs before planned of ethinylestradiol may have a lower risk of VTE than surgery. Instead COC users should receive a pharmacological thromboprophylaxis after surgery (4) obesity: three-fold VTE risk for BMI greater (6) genetic thrombophilia, for example, factor V (7) immobility: surgery, trauma, prolonged travel The VTE risk of COCs is highly dependent on the content of estrogen and the type of progestogen Table 1. Risk of venous thrombosis in different thrombophilias with and without use of combined oral Prothrombin G20210A mutation, heterozygous Prothrombin G20210A mutation heterozygous and factor V Leiden mutation heterozygous Antiphospholipid antibodies (lupus anticoagulants, anticardiolipin antibodies, antib 2-glycoprotein I AT, antithrombin; OR, odds ratio. Adapted from Thrombotic risks of oral contraceptives Rott (1) levonorgestrel or noresthisterone are called Table 2. Effects an haemostatic balance for combined oral contraceptive and progestogen-only (2) gestoden or desogestrel are called COC of dienogest are called antiandrogenic COC, see The use of COC containing levonorgestrel is associated with an almost four-fold increased risk [odds ratio (OR) 3 and 6] relative to nonusers, whereas the risk of VTE compared with nonuserswas increased 5.6-fold for gestodene, 7.3-fold for BP, blood pressure; COC, combined oral contraceptive.
desogestrel, 6.8-fold for cyproterone acetate and6.3-fold for drospirenone Antiandrogenic COCs have a four-fold risk for VTE compared with levonorgestrel-containing used in COCs, and therefore significantly differs COCs. These COCs, therefore, seem to have the Ethinylestradiol and progestogens have totally A crossover study showed that the fibrinolytic different effects on hemostasis. Ethinylestradiol acts potential is decreased in users of COCs, but as a hemostatic activator: procoagulants increase more pronounced in users of desogestrel-containing and anticoagulants, especially protein S, decrease COCs compared with levonorgestrel-containing COCs Furthermore, the increase in activity of Intake of progestogens alone in contrast leads to some coagulation factors is higher in desogestrel- an increase in protein S and fibrinolytic potency, see containing COCs compared with levonorgestrel- Table 3. Classification of combined oral contraceptive COC, combined oral contraceptive; EE, ethinylestradiol; IUS, intrauterine system.
1040-872X ß 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins One new COC contains estradiol valerat instead confidence interval (CI) 0.76–3.99] and for women of ethinylestradiol and dienogest. A study showed a using progestogen-only injectables (OR 2.19, 95% less pronounced effect on hemostatic activation CI 0.66–7.26). Although limited by small numbers, markers like D-dimer and prothrombin fragment the data suggest that there is little or no increase in and only a minimal impact on metabolic parameters risk of VTE associated with use of oral or injectable like HDL-cholesterol compared with COCs contain- study, injectable depot medroxyprogesterone acetate The second new COC contains estradiol instead (MPA) contraceptives were associated with a 3.6-fold of ethinylestradiol. Estradiol has been used in (95% CI, 1.8-fold–7.1-fold) increased risk of venous hormonal replacement therapy for many years thrombosis compared with nonusers of hormonal and is known as an estrogen with a much lower contraceptives Thus, whether injectable depot VTE risk than ethinylestradiol. It is combined with MPA contraceptives might be associated with a small the progestogen nomegestrol. This combination increase of thrombotic risk is still a matter of debate.
has less influence on hemostasis, as well as lipids There now exists a new subcutaneous injectable and carbohydrate metabolism compared with COCs depot MPA contraceptive with only two-thirds of with ethinylestradiol and levonorgestrel the dose of the intramuscular form. It is still not clear It is not known whether these changes of estro- whether this lower dose of MPA decreases the risk gen type lead to real changes in thrombotic risk.
of VTE. Also, no data regarding VTE risk exist fornorethisterone enantat (Noristerat), another inject-able POC.
A postmarketing study evaluated the safety of levonorgestrel-only implants in developing The transdermal contraceptive patch and the vagi- countries It included 7977 women with over nal contraceptive ring both contain ethinylestradiol 95% completing 5 years of follow-up. Only one and progestogen. There is some evidence that the levonorgestrel-only implant user developed a DVT thrombotic risk while using ethinylestradiol is not and no increase in mortality was identified. No data dependent on the route of administration. Even were identified regarding the etonorgestrel-only transvaginal and transdermal use of ethinylestradiol implant (Implanon). Further evidence supporting leads to an activation of the homeostatic system no increased risk of VTE with POC is provided by and to a thrombotic risk similar to COCs a 1999 case–control study (adjusted RR 1.3, 95% CI Both transdermal contraceptive methods, therefore, are contraindicated in patients with a history of VTE There seems to be no increased risk of VTE for the levonorgestrel-releasing intrauterine system(Mirena) Although COCs containing desogestrel have been found to have an increased risk of VTE com- pared with those containing levonorgestrel or nor- ethisterone, the desogestrel-only pill cerazette has There is no evidence for activation of the homeo- not been associated with an increased risk. However, static system by progestogen-only contraceptive data are limited. A randomized, controlled, double- blind trial of desogestrel-only and levonorgestrel- Few studies have been large enough to quantify only pills did not identify any clinically significant the risk of VTE associated with the use of progestogen-only contraception. A hospital-based, Preparations approved for emergency contra- case–control study by WHO in Africa, Asia, Europe ception (so-called postcoital pills) are not associated and Latin America evaluated the risks of cardio- with an increase in VTE: 750 mg levonorgestrel vascular disease with the use of oral and injectable (Levogynon) or 30 mg ulipristal acetate (ellaone).
POC. A total of 1137 women with VTE and 9997 Both preparations are not associated with an control patients were recruited. Cases and controls increase in VTE, and therefore can be used safely were matched for age, BMI and live births. Cases were more likely to have other cardiovascularrisk factors (hypertension, diabetes or rheumaticheart disease) or to be smokers. No significant increase in OR for VTE was identified with the use of any progestogen-only method. The OR High-dose progestogens for therapeutic indications for progestogen-only pill users was 1.74 [95% like menorrhagia appear to be associated with an Thrombotic risks of oral contraceptives Rott Table 4. WHO medical eligibility criteria for contraceptive use 2008 1, a condition for which there is no restriction for the use of the contraceptive method; 2, a condition where the advantages of using the method generallyoutweigh the theoretical or proven risks; 3, a condition where the theoretical or proven risks usually outweigh the advantage of using the method; 4, a conditionwhich represents an unacceptable health risk if the contraceptive method is used. COC, combined oral contraceptive. Adapted from increased risk of VTE (adjusted RR 5.3, 95% CI 1.5– contraceptive methods with ethinylestradiol is 18.7). Reanalysis of data from the WHO Collabora- contraindicated. On the other hand, there is an even tive Study also showed an increase in VTE risk higher risk for VTE in pregnancy and the post- with therapeutic progestogens (OR 5.92, 95% CI partum period. For this reason, an adequate alterna- 1.16–30.1), but small numbers have resulted in wide tive contraception must be offered to these patients.
contraception generally in adolescents with throm-bophilia. Estrogen-free, progestogen-only contra- ception methods are safe regarding VTE risk.
The following contraceptives, therefore, can be used in thrombophilic adolescents (see also The VTE risk in pregnancy and the postpartum period progestogen-only pills, like Cerazette , 28 mini is much higher than during use of any COC. The overall VTE risk in women with no thrombophilicdefect, a single or combined defect is 0.73 (0.30– (1) intrauterine copper device or intrauterine 1.51), 1.97 (0.94–3.63) and 7.65 (3.08–15.76) per 100 person-years. The risk is highest in the post- partum period with a hazard ratio of 16.0 (8.0–32.2) per 100 person-years. Even the a priori absolute risk (4) MPA injectables [lower dose should be preferred of VTE during pregnancy-postpartum in women without any thrombophilic defect is higher than Several different COCs exist that differ significantly regarding the VTE risk but show no difference COCs with levonorgestrel or noretisterone (so called second-generation COCs) should be first choice as recommended in the national guidelines for contraception in the Netherlands, Belgium, Papers of particular interest, published within the annual period of review, have Denmark, Norway and the UK. Other European countries lack such guidelines, but they are urgently Additional references related to this topic can also be found in the CurrentWorld Literature section in this issue (pp. 267–268).
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