Andrey Nailor, M.D.·Published 8 June 2010·9 min read
Key points
Venous thromboembolism (VTE) is a common disorder, and oral contraceptives (OC) are well-known risk factors associated with venous thromboembolism(VTE)(2,15,44,49).
The individual risk of VTE varies as a result of a complex interaction between congenital and transient or permanent acquired risk factors.
Risk factors can be either intrinsic as age, overweight, previous VTE, thrombophilia or related to surgical procedures, and/ or to medical disorders such as neoplastic diseases (61,62).
Retrospective family cohort studies revealed the absolute risk of venous thromboembolism in women with single or multiple thrombophilic defects taking hormonal contraceptives (64,65,66).
Venous thromboembolism (VTE) is a common disorder, and oral contraceptives (OC) are well-known risk factors associated with venous thromboembolism(VTE)(2,15,44,49).
The individual risk of VTE varies as a result of a complex interaction between congenital and transient or permanent acquired risk factors.
Risk factors can be either intrinsic as age, overweight, previous VTE, thrombophilia or related to surgical procedures, and/ or to medical disorders such as neoplastic diseases (61,62).
Inherited thrombophilia is a very important risk factor of venous thromboembolism (VTE) however, there are only few studies on the risk of VTE in women with inherited thrombophilia who use oral contraceptives (63,64). {embed="ref/stat-menu-obgyn1"}
Retrospective family cohort studies revealed the absolute risk of venous thromboembolism in women with single or multiple thrombophilic defects taking hormonal contraceptives (64,65,66).
Because of the high prevalence of the carriers of the G20E10A mutation of the prothrombin gene (PT20210A) (6.5%) and the carriers of the factor V Leiden mutation (FVL) (2%) (a hereditary disorder in which activated factor V is inactivated by activated protein C) in the Spanish population, a retrospective family cohort study of 325 women, belonging to 97 families with inherited thrombophilia, was performed to determine the risk of VTE associated with hormonal contraceptives (HCs) intake.
The results of this study showed for carriers of the PT20210A mutation, the risk of VTE in HC users was 3-fold higher than that in non-carriers.
Carriers of FVL (FactorV Leiden) mutation taking HCs showed an OR of 1.4, indicating a tendency to increase the risk of VTE (67).
Genetic screening for these mutations should be considered in potential OC users belonging to families with thrombophilia (68). Women with hereditary deficiencies of protein S, protein C or antithrombin are at high risk of VTE when taking hormonal contraceptives, particularly if other thrombophilic defects are present (69,70,71).
Generally, they have VTE at a younger age, and sometimes this event may be dramatic but the overall risk is not increased by HCs (72,73,74,75).
In addition, rare cases of thromboembolism in young women caused from the increase of coagulation factor VIII were reported (76,77).
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A retrospective study compared the venous impact of chlormadinone acetate, at antigonadotropic doses, versus no hormonal treatment in 204 women at high risk of venous thromboembolism. During follow-up (mean of 33 months) nine episodes of VTE were observed: three in women receiving CMA and six in untreated women.
Written and revised by
Andrey Nailor, M.D.
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Using the Cox model to adjust for confounding variables such as age, thrombophilia and body mass index, the relative risk of VTE associated with the use of CMA was not significant [relative risk:RR 0.8 (78). Therefore, which is the risk of VTE in normal women taking hormonal contraceptives?
The risk of venous thromboembolism seems primarily dependent on the dose of ethinylestradiol; although the potential contribution of the new progestins in reducing vascular risks is of great importance (2,15,44,49).
Unfortunately, the major disadvantage of third generation HCs, according to most authors, is the increased risk of vascular effects. (22,55,79). These events seem more pronounced during the first year of use (5,48 ). {embed="ref/stat-menu-obgyn1"}
In 1995, an important study reported that desogestrel and gestodene could increase the risk of venous thromboembolism and showed an antagonist effect of LNG on the EE-induced rise of factor VII activity and on the EE-induced reduction of total and free protein S (26,36,42).
In addition, the effects of a combined oral contraceptive containing 20mcg EE and 75mcg gestodene (GSD) on hemostatic parameters were investigated. Results showed no significant changes in fibrinogen,protein C, AT III or D-dimer during COC use.
While the increase in platelet count, decrease in protein S level, prothrombin activity and activated partial thromboplastin time, and the prolongation of thrombin time were significant (80).
Furthermore, the thrombotic risk with the use of particular third-generation oral contraceptives was elevated among carriers of the factor V Leiden mutation.
This disorder is a common risk factor for venous thrombosis,which is associated with a 3 to 7-fold increased risk in heterozygous individuals (61,62,81,82). A plausible logical mechanism for the thrombotic effects of second and third-generation oral contraceptives is still lacking.
Rosing reported that oral contraceptive use leads to acquired activated protein C (APC) resistance and women using third-generation HCs are more resistant to the anticoagulant action of APC than users of second-generation HCs (83,84).
The difference could be explained by differential effects of progestagens on plasma sensitivity to activated protein C (APC). A study assessed the effect of APC on endogenous thrombin potential (ETP) in the plasma of healthy women using either, combined HC or progestagen-only OC,and in non-users. Carriers of factor V Leiden were excluded.
Compared with non-users, there was no significant change in APC resistance in women using progestagen-only HC (chlormadinone acetate). Women who used combined HC were less sensitive to APC than non-users (P <0.001) and the difference was significantly more pronounced in women using third-generation HC than in those who used second-generation OC containing levonorgestrel (P < 0.05).
Compared with HC containing levonorgestrel, the use of norethisterone-containing HC was associated with an increased resistance to APC (P < 0.05). Women who used cyproterone-containing HC (n = 10) were less sensitive to APC than those using third-generation HC (P <0.05) or second-generation HC containing levonorgestrel (P < 0.05) (78,85).
Few data are available on involvement of progestins in the coagulation patho-mechanisms. It is, therefore,likely that the vascular effects of progestins are mediated through progestin receptors as well as through down-regulation of estradiol receptors [54,56,59]. Estrogen and progestin receptors are localized in endothelial and smooth muscle cells of the vessel wall, but there are differences in the response of vein and arteries to sex-steroids (49). {pagebreak}
In fact, in the veins progestins may increase the capacitance resulting in a decrease blood flow[48,49]. Modification in hemostasis parameters seems to depend to type and dose of progestogen, the presence of estrogen compound and the duration of use[57,85,86].
The risk of combined formulation could be a consequence of vascular action of progestins. In fact, it seems that some progestins may up-regulate thrombin receptor expression while, other progestins did not.[59].
Definitive conclusions about the significance of these findings have not yet achieved. In this light, the prudent choice of hormonal regimen could be recommended. {embed="ref/stat-menu-obgyn1"}
Using progestins with minimal vascular toxicity may lead to relative safety of estrogen-progestin preparations for pre-menopausal women, also HHT-affected[58].
Desogestrel is less androgenic than previous generations of synthetic progestins. Consequently, when the dose of EE in HC was reduced, the potency of progestagens was increased.
Moreover, progestagens with no or reduced androgenic activity were preferred for use in HC with respect to lipid and carbohydrate metabolism (87).
A beneficial effect of these progestins on the coagulation factors is less apparent. It has been suggested that with a reduced androgenic effect of the progestins, the activity of ethinylestradiol is more sensible, since the estrogens are the source of disturbance in coagulation factors.
The third generation of progestins does not appear to represent an advance in reducing arterial accidents, whereas the reduction from 50 to 30 mcg of ethinylestradiol did in reducing venous pathology.
Moreover, the crude rate of VTE per 10.000 woman years was 4.10 in current users : 3.10 in users of second-generation HCs,and 4.96 in users of third- generation HCs. Among users of third generation progestagens, the risk of VTE was higher in users of desogestrel (DSG) with 20 mcg EE than in users of gestodene or desogestrel with 30 mcg EE. The odds-ratio for VTE was estimated 3.49 in the first case and 1.18 for the others. (86,87).
The risk of VTE in users of desogestrel-containing HCs is significantly elevated compared to that of LNG –containing HCs. While, the risk of VTE in users of norgestimate-containing HCs was similar to that of users of LNG-containing HCs. (88,89).
Unexpected idiopathic cardiovascular death rates among 303.470 women who were current HCs, users were 4.3/100.000 for LNG,1.5/100.000 for desogestrel (DSG) and 4.8/100.000 for gestodene. When compared with LNG the relative risk adjusted for age and calendar period was 0.4 for DSG and 1.4 for gestodene HCs (86,87).
The studies carried out on women with and without family history of thrombosis and /or carrier of the factor V Leiden mutation treated with DSG-containing HCs reported the same risk of deep–vein-thrombosis (DVT).
This risk resulted higher of 2.2-fold when compared with LNG-containing HCs with the same amount of EE and it was highest in the youngest age categories (82,90,91,92). {pagebreak}
The increased fibrinolytic activity during HCs use appears to be induced by the estrogen component and may be the result of an enhanced down-regulation of fibrinolysis (26,51,82,90).
Compared to second generation, the use of third generation oral contraceptives has been associated with an increased risk of venous thrombosis, especially in women with the factor V Leiden mutation (87,91).
These HCs induce a decrease in factor V, whereas the levels of all other coagulant factors increased. {embed="ref/stat-menu-obgyn1"}
Several studies demonstrate that many progestins markedly potentiate the vascular procoagulant effects of thrombin by increasing the availability of membrane thrombin receptors in the smooth muscle and this effect seems linked to their glucocorticoid-like-activity (59).
When the women used POP (progestin-only pill), a differential effect from DSG and LNG was only found for factor IX.
While, in women at high risk of VTE (previous documented history of deep vein thrombosis or pulmonary embolism, carriers of a congenital or acquired thrombophilia or history of a severe/fatal venous thrombosis in a first-degree family member) chlormadinone acetare (17a hydroxyprogesterone derivative) only, used at antigonadotropic doses during 18-20 cycles, was not associated with a significant increase in the risk of VTE (78).
In carriers of the factor V Leiden mutation, DSG- containing oral contraceptives induce more pronunced changes in factor V and in factor VII compared with LNG. Comparing DSG and LNG only,exclusively for factor V a differential effect was found.
It appears that DSG-containing oral contraceptives have a more pronunced effect on the coagulation system than LNG-containing oral contraceptives which may explained by a less effective compensation of the thrombotic effect of ethinylestradiol by desogestrel (51,61,87,91,92).
When compared to COCs containing LNG or norethisterone, these containing desogestrel or gestodene present a two-fold greater risk of VTE.
For COCs containing cyproterone acetate, the risk is four-fold greater, while there are no or insufficient data for those containing norgestimate, chlormadinone acetate or drospirenone (86,88,91,92).
Deep venous thrombosis with pulmonary embolus is a rare complication of oral contraceptives, which generally occurs in adult women and becomes more common with increasing age (87,90).
Nevertheless, these complication are believed to be less common with low-dose oral contraceptives than with high doses, a case of thromboembolism with a life-threatening pulmonary embolism in an adolescent on low dose triphasic oral contraceptives has been reported (73).
In the development of these thrombotic events, secondary hypercoagulable states may have an important relief. However, these are complex clinical conditions associated with an increased risk of thrombosis in which the exact patho physiology is still poorly understood (94).
With regard to the contraceptive patch, the available data suggest that the risk of VTE is similar to that observed with COCs. In the last years, several studies found a relatively moderate risk of non fatal venous thromboembolism in the contraceptive patch (ethinylestradiol/ norelgestromin) users. Despite this, the contraceptive patch may be an appropriate option for many women. {pagebreak}
Nevertheless, some studies reported that the increase in activated protein resistance is greater with the patch than with either triphasic and monophasic COCs. (95). There are no sufficient data concerning vaginal rings.
In conclusion, epidemiological studies have indicated a risk 2-fold increased of nonfatal VTE with use of HCs containing desogestrel or gestodene compared with LNG. {embed="ref/stat-menu-obgyn1"}
Therefore, these studies not provide evidence for a cause-and-effect relationship between HCs- containing desogestrel or gestodene and VTE.
Enhancement by thrombophilic diseases, especially with factor V Leiden mutation of risk of deep-vein-thrombosis associated with oral contraceptives containing a third –generation progestagen has been reported (62,66,82,90, 92). Until now, no sufficient and adequate data about the new formulations as patch, vaginal ring and combined hormonal contraceptives containing progestins with antiandrogenic properties were obtained.
-- Rosa Sabatini and Giuseppe Loverro Dept. Obstetrics and Gynecology, General Hospital Policlinico-University of Bari, Italy -- {embed="ref/65"}
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