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Keywords:

  • epidemiology;
  • oral contraception;
  • postmenopausal hormone therapy;
  • venous thrombosis

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Funding
  8. Disclosure of Conflict of Interest
  9. References

Roach REJ, Lijfering WM, Helmerhorst FM, Cannegieter SC, Rosendaal FR, van Hylckama Vlieg A. The risk of venous thrombosis in women over 50 years old using oral contraception or postmenopausal hormone therapy. J Thromb Haemost 2013; 11: 124–31.

Summary.  Background: Oral contraception (OC) and postmenopausal hormone therapy (HT) can be used to alleviate menopausal symptoms. However, the risk of venous thrombosis (VT) associated with OC use in women over 50 years old has never been assessed and the two preparations have not been directly compared. Objectives: To determine and compare the risk of VT associated with OC and HT use. Methods: From a large case–control study, 2550 women aged over 50 years old, 1082 patients with a first VT and 1468 controls, were included. Odds ratios (ORs) and 95% confidence intervals for VT were calculated for OC-users (164 patients and 54 controls) and HT-users (88 patients and 102 controls) compared with non-hormone users (823 patients and 1304 controls). Results: OC-users had a 6.3-fold (4.6–9.8) increased risk of VT. This ranged from 5.4 (3.3–8.9) for preparations containing levonorgestrel to 10.2 (4.8–21.7) for desogestrel. The VT-risk associated with oral HT use was 4.0 (1.8–8.2) for conjugated equine estrogen combined with medroxyprogesterone acetate and 3.9 (1.5–10.7) for micronized estradiol combined with norethisterone acetate. Non-oral HT did not increase the risk of VT: OR 1.1 (0.6–1.8). Relative risk estimates were further increased in hormone users with factor V Leiden, prothrombin G20210A or blood group non-O and hormone users with a family history of VT. Conclusions: In this study, non-oral HT seemed to be the safest hormonal preparation in women over 50 years old. OC use increased the VT risk the most, especially in women with inherited thrombophilia or a family history of VT.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Funding
  8. Disclosure of Conflict of Interest
  9. References

Venous thrombosis is a disease that occurs in 1–2 per 1000 people per year [1]. An established risk factor for venous thrombosis is the use of exogenously administered female hormones (oral contraception and postmenopausal hormone therapy) [2–11]. Women under the age of 50 using oral contraception have a 4- to 5-fold higher risk of venous thrombosis than non-hormone users in the same age group [2,4,10]. However, to our knowledge, there are no data available on the risk of venous thrombosis in women over 50 years old taking oral contraception. An estimation of this risk is important as over 5% of women in this age group still use oral contraception, either because they have not yet reached the menopause or to prevent menopausal symptoms [12], but these benefits cannot currently be balanced against the venous thrombotic risk.

In women over 50 years old, research on female hormone use has focused on postmenopausal hormone therapy, which is associated with a 3-fold increased risk of venous thrombosis compared with non-hormone use [5,6,8]. As in oral contraception, the route of administration and the hormonal content of postmenopausal hormone therapy affect the risk of venous thrombosis to a different extent [7,13,14]. However, previous studies on the risk of venous thrombosis in women using oral combined postmenopausal hormone therapy (containing both an estrogen and a progestagen) have only studied conjugated equine estrogen and esterified estrogen in combination with medroxyprogesterone acetate [15,16]. To our knowledge, the risk associated with micronized estradiol combined with norethisterone acetate, which is a common choice of postmenopausal hormone therapy in the Netherlands, has not previously been estimated. Furthermore, although oral contraception and postmenopausal hormone therapy have often been studied separately, a direct comparison of their thrombotic risks in postmenopausal women is lacking. This complicates the decision of whether to continue oral contraception until after the menopause or to switch to postmenopausal hormone therapy to alleviate menopausal symptoms. In this report, we aimed to seek clarification of the above-mentioned points.

Materials and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Funding
  8. Disclosure of Conflict of Interest
  9. References

Study design

This study was performed using data from the MEGA study, a large case–control study on risk factors for venous thrombosis. Details of this study have been described previously [17]. Briefly, between March 1999 and September 2004, 4956 consecutive patients aged 18–70 years with a first episode of deep venous thrombosis or pulmonary embolism were included from six anticoagulation clinics in the Netherlands. Detailed diagnostic information was obtained from hospital discharge reports and general practitioners. Deep vein thrombosis was objectively confirmed using Doppler ultrasonography. Pulmonary embolism was confirmed by a ventilation perfusion lung scan, spiral computed tomography or angiogram. In a case–control study it is important that the control group reflects the exposure frequency in the source population of the cases [18,19]. In our study, partners of the cases, as well as random digit dialing (RDD) controls from the same neighborhood as the cases, were included. In total, 3297 partners and 3000 RDD controls participated. Both patients and controls had to be between 18 and 70 years old. Exclusion criteria were severe psychiatric problems and the inability to speak Dutch. The study was approved by the Medical Ethics Committee of the Leiden University Medical Center, Leiden, the Netherlands. All participants gave written informed consent.

For the current analyses, only women over 50 years old were included. A total of 2550 women were eligible: 1082 patients, 900 partner controls and 568 random digit dialing controls. Partner controls were defined as the female partners of male patients with venous thrombosis. As the prevalence of oral contraception and postmenopausal hormone therapy use was the same in partner controls and RDD controls (oral contraception 4% and 5% and postmenopausal hormone therapy 7% and 6%, respectively), the two control groups were pooled into a single control group of 1468 individuals.

Data collection

Participants completed a detailed questionnaire on risk factors for venous thrombosis. Items covered in the questionnaire included oral contraception use and postmenopausal hormone therapy use in the year before the index date. The index date was defined as the date of diagnosis of venous thrombosis for patients and their partners and the date of completing the questionnaire for the random control subjects. To ensure that each hormonal preparation was classified correctly, all participants were asked to select the brand name and dose of the hormonal preparation they used from two comprehensive lists: one for oral contraception and one for postmenopausal hormone therapy. Furthermore, at least 3 months after discontinuation of anticoagulation, or during anticoagulant therapy in patients who continued this for over 1 year, patients and controls visited the anticoagulation clinic for an interview and a blood sample to obtain DNA. During the interview, details on current oral contraception or postmenopausal hormone therapy use were verified. Exact information on the hormonal content of each preparation was subsequently obtained for each brand name using the Dutch online drug index. The blood samples were used to assess common genetic risk factors, as has been described previously [20,21].

Statistical analysis

In women over 50 years old, we assessed the relative risks of venous thrombosis in oral contraception users and postmenopausal hormone therapy users compared with a single control group of non-hormone users (previous and never hormone users combined). Women were classified as current users if they were using hormones at or in the month before the index date. One woman used both oral contraception (as a contraceptive method) and postmenopausal hormone therapy (to treat recurrent urinary tract infections) and was included in both analyses. Odds ratios (ORs) were calculated by unconditional logistic regression, and 95% confidence intervals (95% CIs) were derived from the model. Patients with deep vein thrombosis and patients with pulmonary embolism (with or without deep vein thrombosis) were combined in most analyses but also analyzed separately. Furthermore, to ensure that the results were not distorted by malignancy, an important risk factor for venous thrombosis [20], the main analyses were repeated after exclusion of women with active malignancy or malignancy diagnosed in the 5 years before the index date. All risk estimates were adjusted for age, body mass index (BMI), smoking status and family history of venous thrombosis. BMI (weight (kg)/(height (m)2)) was calculated using weight and height as stated by the participants in the questionnaire. A positive family history was defined as having at least one parent or sibling with a history of venous thrombosis [17].

To confirm that our results for oral contraception use reflect the risk of venous thrombosis in postmenopausal women using this preparation (rather than in women using it as a form of contraception), we performed a sensitivity analysis in postmenopausal women alone. Unfortunately, we did not have accurate medical information on individual menopausal status. Therefore, in this analysis, the menopause was defined at 58 years, by which age the vast majority (99%) of women are postmenopausal [22].

As the risk of venous thrombosis can differ according to the route of hormone administration [7,11,13], orally and non-orally administered hormonal contraception and postmenopausal hormone therapy were analyzed separately. Hormones administered by intrauterine devices, injections, subcutaneous implants, transdermal gels and skin patches were classified as non-oral hormones.

Varying doses and types of estrogen and progestagen have been found to affect the risk of venous thrombosis differently [2,7,10,15]. Therefore, oral contraception was divided according to progestagen type into preparations containing levonorgestrel, desogestrel, gestodene or lynestrenol, which were analyzed separately. These preparations were subsequently compared with levonorgestrel as a reference group, as previous research has shown that this is associated with the lowest risk of venous thrombosis in younger women [2]. Other types of progestagens could not be included in these analyses as numbers were too small (in total, 11 cases and four controls). As progestagens can be combined with different doses of estrogen, we performed a similar analysis after restriction to the most commonly used doses of ethinylestradiol. For levonorgestrel, gestodene and desogestrel this was 30 μg and for lynestrenol 37.5 μg of ethinylestradiol. Oral postmenopausal hormone therapy users were divided into unopposed estrogen users, all except two of whom used micronized estradiol, and combined postmenopausal hormone therapy users. Combined postmenopausal hormone therapy was further divided into 0.625 mg of conjugated equine estrogen with medroxyprogesterone acetate and micronized estradiol with norethisterone acetate. Micronized estradiol with norethisterone acetate is prescribed with two different doses of estradiol (1 mg, which is comparable to 0.625 mg conjugated equine estrogen [23], or 2 mg) in the Netherlands, which were analyzed separately in a sub-analysis. These two preparations were compared with non-hormone use and with preparations containing conjugated equine estrogen combined with medroxyprogesterone acetate as a reference group. Women using postmenopausal hormone therapy containing only a progestagen (n = 15 patients and n = 19 controls) were excluded from all analyses, as progestagen alone is not prescribed for the treatment of menopausal symptoms but to treat other gynecological disorders [24].

Based on both experimental and observational findings, it has been argued that the effect of hormones on the risk of venous thrombosis decreases with an increasing duration of use [2,6,7,9,10,25]. To study this phenomenon we viewed < 2, 2–5 years and more than 5 years of consecutive hormone use compared with non-hormone use separately. In addition, we compared 2–5 years and more than 5 years of use with < 2 years of use as a reference group.

Finally, as the risk of venous thrombosis has been found to be especially high in hormone users with genetic thrombophilia [3,7,26–30], we studied the combined effect of factor V Leiden, prothrombin G20210A or blood group non-O with oral contraception or postmenopausal hormone therapy on the risk of venous thrombosis. As a woman’s genetic status is generally unknown when hormones are prescribed, we repeated the same analysis with family history of venous thrombosis, which is easily obtained in clinical practice. All statistical analyses were performed with SPSS for Windows, release 17.0 (SPSS Inc, Chicago, IL, USA).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Funding
  8. Disclosure of Conflict of Interest
  9. References

A total of 2550 women aged over 50 years old, 1082 patients and 1468 controls, were included in this study. Their characteristics are summarized in Table 1. The mean age at enrollment was 59 years (range, 50–70) in both patients and controls. Five hundred and fifty-three patients (54%) had been diagnosed with deep vein thrombosis and 475 (46%) with pulmonary embolism. Oral contraception was used by 164 patients (16%) and 54 controls (4%). Postmenopausal hormone therapy was used by 88 patients (8%) and 102 controls (7%). Among controls, women using oral contraception and women using postmenopausal hormone therapy were 6 and 5 years younger, respectively, than non-hormone users. The majority (98%) of patients with active malignancy did not use a hormonal preparation.

Table 1.   Clinical characteristics
 Female patientsFemale control subjects
OverallOC usersHT usersNo hormone useOverallOC usersHT usersNo hormone users
  1. DVT, deep vein thrombosis; PE, pulmonary embolism; OC, oral contraception; HT, postmenopausal hormone therapy; VT, venous thrombosis. Continuous variables denoted as mean (range), categorical variables as number (%). Data were missing for some patients in some subgroups.

Total1082 (100)164 (16)88 (8)823 (76)1468 (100)62 (4)102 (7)1304 (89)
Age in years59 (50–70)53 (50–63)57 (50–70)61 (50–70)59 (50–70)53 (50–69)58 (50–70)59 (50–70)
Venous thrombosis
 DVT only, n (%)552 (54)107 (65)50 (60)397 (51)    
 PE +- DVT, n (%)475 (46)60 (35)34 (40)381 (49)    
Venous thrombotic risk factors
 Normal weight, n (%)343 (38)69 (42)39 (47)243 (36)598 (44)33 (56)48 (50)517 (43)
 Overweight, n (%)347 (38)55 (36)29 (35)264 (39)525 (39)19 (32)39 (41)467 (39)
 Obesity, n (%)221 (24)34 (22)15 (18)172 (25)236 (17)7 (12)9(9)220 (18)
 Non-smoking, n (%)382 (40)65 (40)27 (33)292 (41)649 (46)24 (40)41 (41)584 (47)
 Previous smoking, n (%)320 (33)57 (35)27 (33)236 (33)415 (30)16 (27)32 (32)367 (30)
 Current smoking, n (%)258 (27)42 (25)28 (33)188 (26)334 (24)21 (34)27 (27)286 (23)
 No family history of VT545 (65)93 (65)38 (56)415 (66)904 (75)43 (82)61 (69)800 (75)
 1 family member with VT237 (28)37 (26)20 (29)180 (28)264 (22)6 (12)24 (27)234 (22)
 ≥ 2 family members with VT60 (7)13 (10)10 (15)37 (6)36 (3)3 (6)3(3)30 (3)
 Malignancy175 (16)2(1)2(2)171 (21)46 (3)1 (2)3(3)42 (3)
Genetic thrombophilia
 Factor V Leiden110 (12)25 (16)18 (22)67 (10)50 (3)1 (2)4(5)45 (4)
 Prothrombin G20210A50 (6)11 (7)4(5)35 (5)37 (3)2 (4)2(2)33 (3)
 Blood group non-O605 (68)118 (76)60 (73)428 (65)656 (55)23 (51)50 (58)583 (54)

Overall, after adjustment for age, BMI, smoking status and family history of venous thrombosis, the relative risk of venous thrombosis associated with oral contraception use was 6.3 (95% CI, 4.6–9.8) compared with non-hormone use (Table 2). This risk differed according to progestagen type and ranged from 5.4 (95% CI, 3.3–8.9) for preparations containing levonorgestrel to 10.2 (95% CI, 4.8–21.7) for preparations containing desogestrel. Using levonorgestrel as a reference category, preparations containing gestodene, desogestrel and lynestrenol were all associated with increased risks of venous thrombosis: ORs 1.9 (95% CI, 0.5–6.8), 1.8 (95% CI, 0.8–4.4) and 1.6 (95% CI, 0.4–7.1), respectively. Restricting the analysis to progestagens combined with the most commonly used doses of ethinylestradiol did not change these risk estimates. Excluding women with active malignancy slightly increased the risk estimate, OR 7.9 (95% CI, 5.5–11.5), as most women with active malignancy were in the non-hormone-using reference group.

Table 2.   Risk of venous thrombosis in hormone users compared with non-hormone-users
 PatientsControlsOR (95%CI)*OR (95%CI)
  1. OR, odds ratio; HT, postmenopausal hormone therapy. Data were missing for some participants in some subgroups. *Adjusted for age. Adjusted for age, BMI, smoking and family history of venous thrombosis.

Oral contraception
 No hormone use823 (76)1304 (89)ReferenceReference
 Overall164 (14)53 (4)5.8 (4.1–8.1)6.3 (4.6–9.8)
  Levonorgestrel79 (7)36 (2)4.6 (3.0–6.9)5.4 (3.3–8.9)
  Gestodene17 (2)4(0)9.1 (3.0–27.3)9.3 (3.0–29.0)
  Desogestrel48 (4)11 (1)9.2 (4.7–18.1)10.2 (4.8–21.7)
  Lynestrenol10 (1)4(0)5.1 (1.6–16.3)7.0 (1.9–26.4)
Women > 58 years old
 No hormone use552 (90)817 (94)ReferenceReference
 Oral contraception use11 (2)4 (0.5)5.8 (1.8–18.7)5.9 (1.5–23.5)
Postmenopausal hormone therapy
 No hormone use823 (76)1304 (89)ReferenceReference
 Oral HT62 (6)54 (4)1.6 (1.1–2.3)1.7 (1.1–2.5)
  Estrogen alone19 (2)31 (2)1.0 (0.6–1.8)0.6 (0.3–1.2)
  CEE/MPA16 (1)8(1)3.5 (1.8–6.6)4.0 (1.8–8.2)
  E2/NETA27 (2)15(1)3.6 (1.5–8.6)3.9 (1.5–10.7)
 Non-oral HT26 (2)48 (3)0.9 (0.6–1.5)1.1 (0.6–1.8)
Women > 58 years old
 No hormone use552 (90)817 (94)ReferenceReference
 Oral HT29 (5)25 (3)1.9 (1.2–3.4)1.4 (0.7–2.5)
 Non-oral HT16 (3)26 (3)1.0 (0.5–1.8)1.3 (0.6–2.6)

Three types of non-oral hormonal contraception were used by our study participants: injectable depot-medroxyprogesterone acetate (n = 8 patients and n = 1 control), the levonorgestrel-releasing intrauterine device (n = 1 patient and n = 6 controls) and the contraceptive vaginal Nuvaring (n = 1 control). As these patient-control ratios are very different, pooling the three types of non-oral hormonal contraception would yield uninformative results. The numbers were also too small to obtain reliable risk estimates for each type separately. However, the patient-control ratios indicate that injectable depot-medroxyprogesterone acetate is associated with an increased risk of venous thrombosis, whereas the levonorgestrel-releasing intrauterine device is not.

Overall, postmenopausal hormone therapy was associated with a 1.4-fold (95% CI, 1.0–2.0) increased risk of venous thrombosis. This risk estimate did not change after exclusion of women with active malignancy, OR 1.6 (95% CI, 1.1–2.5). The highest risk was associated with oral combined preparations of postmenopausal hormone therapy. There did not seem to be a difference between the risk associated with 0.625 mg conjugated equine estrogen combined with medroxyprogesterone acetate, OR 4.0 (95% CI, 1.8–8.2), and the risk associated with micronized estradiol combined with norethisterone acetate, OR 3.9 (95% CI, 1.5–10.7). However, the dose of micronized estradiol in combined preparations with norethisterone acetate was positively associated with the risk of venous thrombosis. Daily administration of 1 mg micronized estradiol (which is comparable to 0.625 mg of conjugated equine estrogen) [23] was associated with a 2.2-fold (95% CI, 0.3–16.4) increased risk, whereas daily administration of 2 mg micronized estradiol was associated with a 4.5-fold (95% CI, 0.8–25.1) increased risk. When these preparations were compared with preparations containing conjugated equine estrogen combined with medroxyprogesterone acetate as a reference group, the risk of venous thrombosis was OR 0.9 (95% CI, 0.1–5.8) for 1 mg of micronized estradiol combined with norethisterone acetate and 1.5 (95% CI, 0.1–14.5) for 2 mg of micronized estradiol combined with norethisterone acetate. Compared with non-hormone-users, oral estrogen alone did not increase the risk of venous thrombosis, OR 0.6 (95% CI, 0.3–1.2).

All women (n = 74) using a non-oral form of postmenopausal hormone therapy used transdermal patches containing micronized estradiol. This was the safest hormonal preparation in women over 50 years old, OR 1.1 (95% CI, 0.6–1.8). Results did not change after exclusion of women with active malignancy, OR 1.0 (95% CI, 0.6–1.7). Seven women (n = 2 cases and n = 5 controls) used transdermal patches that also contained norethisterone acetate.

Restricting the main analyses to postmenopausal women alone (aged over 58 years, n = 610 cases and n = 874 controls) did not change the risk estimates. Both oral contraception and postmenopausal hormone therapy were associated with a higher relative risk of deep vein thrombosis than of pulmonary embolism. Oral contraception users had a 7.5-fold (95% CI, 5.1–11.1) increased risk of deep vein thrombosis and a 5.3-fold (95% CI, 3.4–8.2) increased risk of pulmonary embolism. For oral postmenopausal hormone therapy these results were 1.8 (95% CI, 1.2–2.9) and 1.5 (95% CI, 0.9–2.5) and for non-oral postmenopausal hormone therapy they were 1.6 (95% CI, 0.9–3.0) and 0.8 (95% CI, 0.3–1.9), respectively.

When the duration of postmenopausal hormone therapy use was taken into account (Table 3), women using oral postmenopausal hormone therapy for < 2 years had the highest risk of venous thrombosis, OR 3.2 (95% CI, 1.5–7.1). This risk decreased over time and was no longer increased in women who had used postmenopausal hormone therapy for over 5 years, OR 0.9 (95% CI, 0.4–2.0). Using 0–2 years of use as a reference group, the risk of venous thrombosis was 0.7 (95% CI, 0.2–2.7) after 2–5 years and 0.2 (95% CI, 0.0–1.0) after 5 or more years. For non-oral postmenopausal hormone therapy, the risk of venous thrombosis was 0.4 after 0–2 years of use (95% CI, 0.1–1.7), 1.0 (0.3–3.4) after 2–5 years and 1.4 (95% CI, 0.7–2.9) after 5 or more years. Using 0–2 years of use as a reference group, these risks were 2.2 (95% CI, 0.4–12.0) after 2–5 years and 2.8 (95% CI, 0.9–14.3) after 5 or more years of non-oral postmenopausal hormone therapy use.

Table 3.   The duration of HT use and the risk of venous thrombosis
 Patients, n (%)Controls, n (%)OR* (95% CI)OR (95% CI)
  1. OR, odds ratio; HT, postmenopausal hormone therapy. Data were missing for some participants in some subgroups. *Adjusted for age. Adjusted for age, BMI, smoking and family history of venous thrombosis.

Oral HT
 No hormone use823 (76)1304 (89)ReferenceReference
 0–2 years of use24 (2)12 (2)3.6 (1.8–7.3)3.2 (1.5–7.1)
 2–5 years of use15(2)15 (2)1.9 (0.9–4.0)2.2 (0.9–5.6)
 > 5 years of use12 (3)17 (3)1.1 (0.5–2.4)0.9 (0.4–2.0)
Non-oral HT
 No hormone use823 (76)1304 (89)ReferenceReference
 0–2 years of use3 (2)13 (2)0.4 (0.1–1.4)0.4 (0.1–1.7)
 2–5 years of use5 (2)9 (2)1.0 (0.3–3.0)1.0 (0.3–3.4)
 > 5 years of use17 (3)21 (3)1.3 (0.7–2.6)1.4 (0.7–2.9)

It was not possible to divide oral contraception according to the same durations of use, as only seven women had been using oral contraception for < 5 years. Nevertheless, in contrast to the findings on postmenopausal hormone therapy, our results show that women using oral contraception for more than 5 years still had a strongly increased risk of venous thrombosis, OR 6.3 (95% CI, 4.6–9.8).

In a final analysis we viewed the combined effect of genetic thrombophilia or a family history of venous thrombosis with the use of oral contraception or postmenopausal hormone therapy (Table 4). The relative risk of venous thrombosis was especially high in women using oral contraception with one or more thrombophilic defects, with an OR of 16.3 (95% CI, 9.2–28.9). The risk of venous thrombosis in postmenopausal hormone therapy users with genetic thrombophilia was also higher than the overall risk in postmenopausal hormone therapy users, OR 2.9 (95% CI, 1.9–4.6). When the same analysis was performed using family history as a proxy for genetic thrombophilia, the results were very similar: 14.2 (95% CI, 6.7–30.0) for oral contraception use and 2.4 (95% CI, 1.4–4.1) for postmenopausal hormone therapy.

Table 4.   Genetic thrombophilia, hormone use and the risk of venous thrombosis
 Cases (n = 898)Controls (n = 1201)OR* (95% CI)OR (95% CI)
  1. FVL, factor V Leiden; FII, prothrombin G20210A; OC, oral contraception; HT, postmenopausal hormone therapy; VT, venous thrombosis. Data were missing for some participants in some subgroups. *Adjusted for age. Adjusted for age, smoking and BMI.

FVL/FII/blood group non-O
 No hormone use, no thrombophilia211 (23)455 (38)Reference 
 No hormone use, thrombophilia450 (50)614 (51)1.6 (1.3–1.9)1.6 (1.3–2.0)
 OC use, no thrombophilia27 (3)20 (2)3.7 (1.9–6.9)3.5 (1.7–7.1)
 OC use, thrombophilia128 (14)25 (2)13.9 (8.4–23.0)16.3 (9.2–28.9)
 HT use, no thrombophilia13 (1)35 (3)0.8 (0.4–1.6)0.8 (0.4–1.7)
 HT use, thrombophilia69 (8)52 (4)3.1 (2.0–4.6)2.9 (1.9–4.6)
Family history of VT
 No hormone use, no family history416 (50)800 (67)ReferenceReference
 No hormone use, family history217 (26)264 (22)1.6 (1.3–2.0)1.5 (1.2–1.9)
 OC use, no family history88 (11)36 (3)6.3 (4.1–9.7)6.5 (4.2–10.1)
 OC use, family history48 (6)9 (1)14.2 (6.8–29.8)14.2 (6.7–30.0)
 HT use, no family history38 (5)61 (5)1.3 (0.8–1.9)1.3 (0.9–2.1)
 HT use, family history30 (4)27 (2)2.3 (1.3–3.9)2.4 (1.4–4.1)

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Funding
  8. Disclosure of Conflict of Interest
  9. References

In our study of hormone users over 50 years old, oral contraception use was associated with the highest risk of venous thrombosis compared with non-hormone-use, especially when containing desogestrel or gestodene as progestagen (a 9- to 10-fold increased risk). Non-oral postmenopausal hormone therapy patches were the safest hormonal preparation with regard to the risk of venous thrombosis.

Although many women over 50 years old use oral contraception (over one-third of all hormone users in our control group), to our knowledge, this is the first study to assess the risk of venous thrombosis in oral contraception users in this age group. The relative risks associated with both oral contraception and non-oral hormonal contraception were similar to or higher than those previously estimated in younger women [2,10]. However, as the incidence of venous thrombosis increases exponentially with age [1], the absolute risk increase in women over 50 years old is much higher than the risk in younger oral contraception users. In previous research, the incidence rate of venous thrombosis in women aged 50–70 years (the ages included in our study) was 1.4 (95% CI, 1.2–1.7) per 1000 person years [1]. Thus, a 6.3-fold increased risk indicates that 9 per 1000 women over 50 years old using oral contraception develop venous thrombosis each year. For oral and non-oral postmenopausal hormone therapy these numbers are much lower: 2.4 and 1.6 per 1000 women per year, respectively. It is therefore of significant clinical importance to discourage women over 50 years old from using oral contraception for the treatment of menopausal symptoms: there are much safer alternatives. If contraception is deemed necessary and a hormonal form is preferred, oral contraception containing levonorgestrel is the least harmful option.

Overall, the results of our analysis in women using postmenopausal hormone therapy are in line with previous research [5,7,9,13–15,31]. Previous studies on combined postmenopausal hormone therapy have all focused on combinations containing conjugated equine estrogens or esterified estrogens [6,9,15]. However, in the Netherlands, combined postmenopausal hormone therapy often contains micronized estradiol with norethisterone acetate. Indeed, 33% of combined oral postmenopausal hormone therapy users in the MEGA control group used this type of postmenopausal hormone therapy at inclusion. Our results show that, when used with comparable doses of estrogen, estradiol combined with norethisterone acetate was associated with a lower risk of venous thrombosis than conjugated equine estrogen combined with medroxyprogesterone acetate. However, numbers were small and further research is needed to confirm these findings. Previous research has also shown that oral hormone administration is associated with a higher risk of venous thrombosis than non-oral hormone administration [13,14,31]. In our study, we confirmed these findings. Oral hormone administration is known to induce activated protein C (APC) resistance, whereas non-oral hormone administration does so to a lesser extent, in all likelihood because of the absence of a first pass metabolism in the liver [32]. Furthermore, APC resistance is thought to reduce fibrinolysis, making clots less likely to embolize [33,34]. This could explain why, in both oral contraception and postmenopausal hormone therapy users, the overall risk of deep vein thrombosis was higher than the risk of pulmonary embolism. Although numbers of non-oral contraception users in our study were small, the results are in line with previous research in younger women [11].

The strength of our study is that oral contraception users and postmenopausal hormone therapy users were compared with a single control group of non-hormone-users. This enabled us to not only calculate the risk of venous thrombosis associated with both oral contraception and postmenopausal hormone therapy, but also to compare the risk estimates on a relative scale. Another strength is the large study design. Data were collected in the same manner for all participants and all venous thrombotic events were objectively diagnosed. A limitation of our study is that the information on hormone use was self-reported. Although measures were taken to ensure complete reporting, it is possible that some women did not report their hormone use correctly. However, it is unlikely that this would have occurred at a different rate in the patient than in the control group (non-differential misclassification). Therefore, if such misclassification occurred, our results would be an underestimation of the true risk estimates. Another potential limitation is that we do not have reliable medical data on the postmenopausal status of the women. However, there is no reason to assume that the risk of side-effects of using oral contraception depends on the indication for use. In addition, as over 99% of European women are postmenopausal by the age of 58 years [22], and the analysis of these women yielded virtually identical results as the overall analyses, we believe that our results give an accurate estimate of the venous thrombotic risks of postmenopausal women using oral contraception or postmenopausal hormone therapy. Furthermore, as numbers in some subgroups were small, some risks could not be estimated and others resulted in wide confidence intervals. Therefore, although in line with the results of previous studies, these findings should be viewed with caution. Unfortunately for the same reason it was not possible to quantify the effect of treatment duration or the combined effect of hormone use and thrombophilia for all hormonal preparations separately. However, the mechanism through which hormone use increases the risk of venous thrombosis in the first years of use and in combination with genetic thrombophilia is most likely the same for all hormonal preparations.

In summary, we have reported a detailed epidemiological analysis of the risk of first venous thrombosis in female hormone users over 50 years old. These women have the highest risk of venous thrombosis when using oral contraception, especially if they had genetic thrombophilia or a positive family history of venous thrombosis. Non-oral postmenopausal hormone therapy patches were not associated with an increased venous thrombotic risk in women over 50 years old.

Funding

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Funding
  8. Disclosure of Conflict of Interest
  9. References

This research was supported by the Netherlands Heart Foundation (NHS 98.113), the Dutch Cancer Foundation (RUL 99/1992) and the Netherlands Organization for Scientific Research (912-03-033| 2003). A. van Hylckama Vlieg is supported by a transatlantic fellowship from the Leducq Foundation, Paris, France. W. M. Lijfering is a Postdoctoral Researcher of the Netherlands Heart Foundation (2011T012). The funding organizations had no role in the study design, data collection and analysis, decision to publish, or preparation, review or approval of the manuscript.

Disclosure of Conflict of Interest

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Funding
  8. Disclosure of Conflict of Interest
  9. References

The authors state that they have no conflict of interest.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Funding
  8. Disclosure of Conflict of Interest
  9. References
  • 1
    Naess IA, Christiansen SC, Romundstad P, Cannegieter SC, Rosendaal FR, Hammerstrom J. Incidence and mortality of venous thrombosis: a population-based study. J Thromb Haemost 2007; 5: 6929.
  • 2
    van Hylckama Vlieg A, Helmerhorst FM, Vandenbroucke JP, Doggen CJ, Rosendaal FR. The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case-control study. BMJ 2009; 339: b2921.
  • 3
    Vandenbroucke JP, Koster T, Briet E, Reitsma PH, Bertina RM, Rosendaal FR. Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Lancet 1994; 344: 14537.
  • 4
    Venous thromboembolic disease and combined oral contraceptives: results of international multicentre case-control study. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Lancet 1995; 346: 157582.
  • 5
    Daly E, Vessey MP, Hawkins MM, Carson JL, Gough P, Marsh S. Risk of venous thromboembolism in users of hormone replacement therapy. Lancet 1996; 348: 97780.
  • 6
    Grady D, Wenger NK, Herrington D, Khan S, Furberg C, Hunninghake D, Vittinghoff E, Hulley S. Postmenopausal hormone therapy increases risk for venous thromboembolic disease. The Heart and Estrogen/progestin Replacement Study. Ann Intern Med 2000; 132: 68996.
  • 7
    Canonico M, Plu-Bureau G, Lowe GD, Scarabin PY. Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis. BMJ 2008; 336: 122731.
  • 8
    Canonico M, Fournier A, Carcaillon L, Olie V, Plu-Bureau G, Oger E, Mesrine S, Boutron-Ruault MC, Clavel-Chapelon F, Scarabin PY. Postmenopausal hormone therapy and risk of idiopathic venous thromboembolism: results from the E3N cohort study. Arterioscler Thromb Vasc Biol 2010; 30: 3405.
  • 9
    Cushman M, Kuller LH, Prentice R, Rodabough RJ, Psaty BM, Stafford RS, Sidney S, Rosendaal FR. Estrogen plus progestin and risk of venous thrombosis. JAMA 2004; 292: 157380.
  • 10
    Lidegaard O, Nielsen LH, Skovlund CW, Skjeldestad FE, Lokkegaard E. Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001–9. BMJ 2011; 343: d6423.
  • 11
    van Hylckama Vlieg A, Helmerhorst FM, Rosendaal FR. The risk of deep venous thrombosis associated with injectable depot-medroxyprogesterone acetate contraceptives or a levonorgestrel intrauterine device. Arterioscler Thromb Vasc Biol 2010; 30: 2297300.
  • 12
    Hardman SM, Gebbie AE. Hormonal contraceptive regimens in the perimenopause. Maturitas 2009; 63: 20412.
  • 13
    Canonico M, Oger E, Plu-Bureau G, Conard J, Meyer G, Levesque H, Trillot N, Barrellier MT, Wahl D, Emmerich J, Scarabin PY. Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the ESTHER study. Circulation 2007; 115: 8405.
  • 14
    Douketis JD, Julian JA, Kearon C, Anderson DR, Crowther MA, Bates SM, Barone M, Piovella F, Turpie AG, Middeldorp S, van NP, Prandoni P, Wells PS, Kovacs MJ, MacGillavry MR, Costantini L, Ginsberg JS. Does the type of hormone replacement therapy influence the risk of deep vein thrombosis? A prospective case-control study. J Thromb Haemost 2005; 3: 9438.
  • 15
    Smith NL, Heckbert SR, Lemaitre RN, Reiner AP, Lumley T, Weiss NS, Larson EB, Rosendaal FR, Psaty BM. Esterified estrogens and conjugated equine estrogens and the risk of venous thrombosis. JAMA 2004; 292: 15817.
  • 16
    Dentali F, Douketis JD, Gianni M, Lim W, Crowther MA. Meta-analysis: anticoagulant prophylaxis to prevent symptomatic venous thromboembolism in hospitalized medical patients. Ann Intern Med 2007; 146: 27888.
  • 17
    Bezemer ID, van der Meer FJ, Eikenboom JC, Rosendaal FR, Doggen CJ. The value of family history as a risk indicator for venous thrombosis. Arch Intern Med 2009; 169: 6105.
  • 18
    Rothman KJ. Types of epidemiologic study. Epidemiology: An Introduction. New York: Oxford University Press, 2002; 7387.
  • 19
    Miettinen OS. The “case-control” study: valid selection of subjects. J Chronic Dis 1985; 38: 5438.
  • 20
    Blom JW, Doggen CJ, Osanto S, Rosendaal FR. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA 2005; 293: 71522.
  • 21
    Bezemer ID, Bare LA, Doggen CJ, Arellano AR, Tong C, Rowland CM, Catanese J, Young BA, Reitsma PH, Devlin JJ, Rosendaal FR. Gene variants associated with deep vein thrombosis. JAMA 2008; 299: 130614.
  • 22
    Jacobsen BK, Heuch I, Kvale G. Age at natural menopause and all-cause mortality: a 37-year follow-up of 19,731 Norwegian women. Am J Epidemiol 2003; 157: 9239.
  • 23
    Mashchak CA, Lobo RA, Dozono-Takano R, Eggena P, Nakamura RM, Brenner PF, Mishell DR Jr. Comparison of pharmacodynamic properties of various estrogen formulations. Am J Obstet Gynecol 1982; 144: 5118.
  • 24
    Thigpen JT, Brady MF, Alvarez RD, Adelson MD, Homesley HD, Manetta A, Soper JT, Given FT. Oral medroxyprogesterone acetate in the treatment of advanced or recurrent endometrial carcinoma: a dose-response study by the Gynecologic Oncology Group. J Clin Oncol 1999; 17: 173644.
  • 25
    Miller J, Chan BK, Nelson HD. Postmenopausal estrogen replacement and risk for venous thromboembolism: a systematic review and meta-analysis for the U.S. Preventive Services Task Force. Ann Intern Med 2002; 136: 68090.
  • 26
    Rosendaal FR, Vessey M, Rumley A, Daly E, Woodward M, Helmerhorst FM, Lowe GD. Hormonal replacement therapy, prothrombotic mutations and the risk of venous thrombosis. Br J Haematol 2002; 116: 8514.
  • 27
    Guimaraes DA, dos Santos MS, Gomes KB, van der Bom JG, Rios DR, Cardoso J, Franco RM, Teixeira GS, Dusse LM, Carvalho M, Fernandes AP. Interaction between oral estrogen plus progestogen therapy and ABO blood groups on coagulation activation in postmenopausal women. Menopause 2012; 19: 33945.
  • 28
    Herrington DM, Vittinghoff E, Howard TD, Major DA, Owen J, Reboussin DM, Bowden D, Bittner V, Simon JA, Grady D, Hulley SB. Factor V Leiden, hormone replacement therapy, and risk of venous thromboembolic events in women with coronary disease. Arterioscler Thromb Vasc Biol 2002; 22: 10127.
  • 29
    Straczek C, Oger E, Yon de Jonage- Canonico MB, Plu-Bureau G, Conard J, Meyer G, Alhenc-Gelas M, Levesque H, Trillot N, Barrellier MT, Wahl D, Emmerich J, Scarabin PY. Prothrombotic mutations, hormone therapy, and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration. Circulation 2005; 112: 3495500.
  • 30
    Smith NL, Heckbert SR, Lemaitre RN, Reiner AP, Lumley T, Rosendaal FR, Psaty BM. Conjugated equine estrogen, esterified estrogen, prothrombotic variants, and the risk of venous thrombosis in postmenopausal women. Arterioscler Thromb Vasc Biol 2006; 26: 280712.
  • 31
    Canonico M, Oger E, Conard J, Meyer G, Levesque H, Trillot N, Barrellier MT, Wahl D, Emmerich J, Scarabin PY. Obesity and risk of venous thromboembolism among postmenopausal women: differential impact of hormone therapy by route of estrogen administration. The ESTHER Study. J Thromb Haemost 2006; 4: 125965.
  • 32
    Tchaikovski SN, Rosing J. Mechanisms of estrogen-induced venous thromboembolism. Thromb Res 2010; 126: 511.
  • 33
    Bajzar L, Kalafatis M, Simioni P, Tracy PB. An antifibrinolytic mechanism describing the prothrombotic effect associated with factor V Leiden. J Biol Chem 1996; 271: 2294952.
  • 34
    Parker AC, Mundada LV, Schmaier AH, Fay WP. Factor V Leiden inhibits fibrinolysis in vivo. Circulation 2004; 110: 35948.