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Thomson
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).
There is no clear advantage in prescribing
COCs with higher VTE risk containing desogestrel
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