Venous and Arterial Thrombosis during Oral Contraceptive Use: Risks and Risk Factors

Bea C. Tanis; Frits R. Rosendaal

doi:10.1055/s-2003-38334

Seminars in Vascular Medicine, Inhaltsverzeichnis

Semin Vasc Med 2003; 03(1): 069-084
DOI: 10.1055/s-2003-38334

Venous and Arterial Thrombosis during Oral Contraceptive Use: Risks and Risk Factors

Bea C. Tanis¹ , Frits R. Rosendaal^1,2

¹Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands
²Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands

Abstract

ABSTRACT

Since the introduction of oral contraceptives, their use has been associated with an increased risk of both venous and arterial thrombosis. Pulmonary embolism, myocardial infarction, and stroke are serious disorders with a considerable risk of mortality. Because worldwide over 100 million women use oral contraceptives, issues of drug safety are of great importance. The risk of venous thrombosis during low-dose oral contraceptive use is three- to sixfold increased compared with that of nonusers. The association is not only attributed to the estrogen component of the pill: the risk is twice as high for desogestrel and gestodene (third generation) containing oral contraceptives as for levonorgestrel (second generation) containing oral contraceptives. The risk of venous thrombosis is highest in the first year of use and in women with genetic or acquired risk factors for thrombosis. Both venous or arterial thrombosis are unrelated to duration of use or past use of combined oral contraceptives. The risk of myocardial infarction and stroke during low-dose oral contraceptive use is two- to fivefold increased relative to that of nonusers. The risk of arterial thrombosis induced by oral contraceptive use is more pronounced in smokers and women with hypertension, diabetes, and hypercholesterolemia. All types of thrombosis have strongly age-dependent incidences, and therefore in absolute figures the risks and effects of risk factors increase with age. The lowering of the estrogen dose in combined oral contraceptives from 50 μg to 20-30 μg in the last decade did not clearly reduce the risk of venous thrombosis, myocardial infarction, stroke, or peripheral arterial disease. For stroke and peripheral arterial disease no difference in risk was found between second and third generation oral contraceptives. For myocardial infarction study results are conflicting, and a small benefit of third- over second-generation oral contraceptives cannot be ruled out. However, this is unlikely to counterbalance the adverse effect of third generation contraceptives on venous thrombosis.

KEYWORDS

Oral contraceptives - estrogens - progestagens - venous thrombosis - arterial thrombosis - epidemiology

Volltext

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REFERENCES

1 Vandenbroucke J P, Rosing J, Bloemenkamp K W. et al . Oral contraceptives and the risk of venous thrombosis. N Engl J Med . 2001; 344 1527-1535
2 Folsom A R. Hemostatic risk factors for atherothrombotic disease: an epidemiologic view. Thromb Haemost . 2001; 86 366-373
3 Lillicrap D. The genetics of venous and arterial thromboembolism. Curr Atheroscler Rep . 2001; 3 209-215
4 Simmonds R E, Hermida J, Rezende S M, Lane D A. Haemostatic genetic risk factors in arterial thrombosis. Thromb Haemost . 2001; 86 374-385
5 Rosendaal F R. Venous thrombosis: a multicausal disease. Lancet . 1999; 353 1167-1173
6 Jordan W. Pulmonary embolism. Lancet . 1961; 2 1146-1147
7 Lorentz I. Parietal lesion and Enavid. Br Med J . 1962; 2 1191
8 Boyce J, Fawcett J W, Noall E WP. Coronary thrombosis and Conovid. Lancet . 1963; 1 111
9 Beral V. Mortality among oral-contraceptive users. Royal College of General Practitioners' Oral Contraception Study. Lancet . 1977; 2 727-731
10 Beral V. Cardiovascular-disease mortality trends and oral-contraceptive use in young women. Lancet . 1976; 2 1047-1052
11 Porter J B, Jick H, Walker A M. Mortality among oral contraceptive users. Obstet Gynecol . 1987; 70 29-32
12 Van Hooff H M, Hirasing R A, Kaptein M B. et al . The use of oral contraceptives by adolescents for contraception, menstrual cycle problems or acne. Acta Obstet Gynecol Scand . 1998; 77 898-904
13 Prandoni P, Lensing A W, Cogo A. et al . The long-term clinical course of acute deep venous thrombosis. Ann Intern Med . 1996; 125 1-7
14 Huisman M V, Büller H R, ten Cate W J. et al . Unexpected high prevalence of silent pulmonary embolism in patients with deep venous thrombosis. Chest . 1989; 95 498-502
15 Inman W H, Vessey M P. Investigation of deaths from pulmonary, coronary, and cerebral thrombosis and embolism in women of child-bearing age. Br Med J . 1968; 2 193-199
16 Parkin L, Skegg D C, Wilson M, Herbison G P, Paul C. Oral contraceptives and fatal pulmonary embolism. Lancet . 2000; 355 2133-2134
17 Records Unit and Research Advisory Service of the Royal College of General Practitioners. Oral contraception and thrombo-embolic disease. J R Coll Gen Pract . 1967; 13 267-279
18 Vessey M P, Doll R. Investigation of relation between use of oral contraceptives and thromboembolic disease. Br Med J . 1968; 2 199-205
19 Vessey M P, Doll R. Investigation of relation between use of oral contraceptives and thromboembolic disease. A further report. Br Med J . 1969; 2 651-657
20 Sartwell P E, Masi A T, Arthes F G, Greene G R, Smith H E. Thromboembolism and oral contraceptives: an epidemiologic case-control study. Am J Epidemiol . 1969; 90 365-380
21 Report from the Boston Collaborative Drug Surveillance Programme. Oral contraceptives and venous thromboembolic disease, surgically confirmed gallbladder disease, and breast tumours. Lancet . 1973; 1 1399-1404
22 Stolley P D, Tonascia J A, Tockman M S. et al . Thrombosis with low-estrogen oral contraceptives. Am J Epidemiol . 1975; 102 197-208
23 Inman W H, Vessey M P, Westerholm B, Engelund A. Thromboembolic disease and the steroidal content of oral contraceptives. A report to the Committee on Safety of Drugs. Br Med J . 1970; 2 203-209
24 Koster T, Small R A, Rosendaal F R, Helmerhorst F M. Oral contraceptives and venous thromboembolism: a quantitative discussion of the uncertainties. J Intern Med . 1995; 238 31-37
25 Rosendaal F R, Helmerhorst F M, Vandenbroucke J P. Oral contraceptives, hormone replacement therapy and thrombosis. Thromb Haemost . 2001; 86 112-123
26 Thorogood M. Oral contraceptives and myocardial infarction: new evidence leaves unanswered questions. Thromb Haemost . 1997; 78 334-338
27 Rekers H. Multicenter trial of a monophasic oral contraceptive containing ethinyl estradiol and desogestrel. Acta Obstet Gynecol Scand . 1988; 67 171-174
28 Scolding N J, Gibby O M. Fatal pulmonary embolus in a patient treated with Marvelon. J R Coll Gen Pract . 1988; 38 568
29 Fotherby K, Caldwell A D. New progestogens in oral contraception. Contraception . 1994; 49 1-32
30 Jick H, Jick S S, Gurewich V, Myers M W, Vasilakis C. Risk of idiopathic cardiovascular death and nonfatal venous thromboembolism in women using oral contraceptives with differing progestagen components. Lancet . 1995; 346 1589-1593
31 World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Effect of different progestagens in low oestrogen oral contraceptives on venous thromboembolic disease. Lancet . 1995; 346 1582-1588
32 Bloemenkamp K W, Rosendaal F R, Helmerhorst F M, Büller H R, Vandenbroucke J P. Enhancement by factor V Leiden mutation of risk of deep-vein thrombosis associated with oral contraceptives containing a third-generation progestagen. Lancet . 1995; 346 1593-1596
33 Spitzer W O, Lewis M A, Heinemann L A, Thorogood M, MacRae K D. Third generation oral contraceptives and risk of venous thromboembolic disorders: an international case-control study. Transnational Research Group on Oral Contraceptives and the Health of Young Women. BMJ . 1996; 312 83-88
34 Poulter N R. Risk of fatal pulmonary embolism with oral contraceptives. Lancet . 2000; 355 2088
35 Kemmeren J M, Algra A, Grobbee D E. Third generation oral contraceptives and risk of venous thrombosis: meta-analysis. BMJ . 2001; 323 131-134
36 Vandenbroucke J P, Helmerhorst F M, Rosendaal F R. Competing interests and controversy about third generation oral contraceptives. BMJ readers should know whose words they read. BMJ . 2000; 320 381-382
37 De Vries S C, van den Berg B P, Jong-van den Berg T L. Oral contraceptive use before and after the latest pill scare in The Netherlands. Changes in oral contraceptive use and how users change. Contraception . 1998; 57 247-249
38 Ferguson J, Jenkins M G. Effect of CSM's warning about safety of third generation oral contraceptive. General practitioners in England prescribed second generation pills instead. BMJ . 1996; 313 363
39 Farmer R D, Lawrenson R A, Thompson C R, Kennedy J G, Hambleton I R. Population-based study of risk of venous thromboembolism associated with various oral contraceptives. Lancet . 1997; 349 83-88
40 Suissa S, Blais L, Spitzer W O. et al . First-time use of newer oral contraceptives and the risk of venous thromboembolism. Contraception . 1997; 56 141-146
41 Lidegaard Ø, Edstrom B, Kreiner S. Oral contraceptives and venous thromboembolism. A case-control study. Contraception . 1998; 57 291-301
42 Farley T M, Meirik O, Marmot M G, Chang C L, Poulter N R. Oral contraceptives and risk of venous thromboembolism: impact of duration of use. Contraception . 1998; 57 61-65
43 Bloemenkamp K W, Rosendaal F R, Büller H R. et al . Risk of venous thrombosis with use of current low-dose oral contraceptives is not explained by diagnostic suspicion and referral bias. Arch Intern Med . 1999; 159 65-70
44 Farley T M, Meirik O, Collins J. Cardiovascular disease and combined oral contraceptives: reviewing the evidence and balancing the risks. Hum Reprod Update . 1999; 5 721-735
45 Herings R M, Urquhart J, Leufkens H G. Venous thromboembolism among new users of different oral contraceptives. Lancet . 1999; 354 127-128
46 Jick H, Kaye J A, Vasilakis-Scaramozza C, Jick S S. Risk of venous thromboembolism among users of third generation oral contraceptives compared with users of oral contraceptives with levonorgestrel before and after 1995; cohort and case-control analysis. BMJ . 2000; 321 1190-1195
47 Suissa S, Spitzer W O, Rainville B. et al . Recurrent use of newer oral contraceptives and the risk of venous thromboembolism. Hum Reprod . 2000; 15 817-821
48 Vandenbroucke J P, Bloemenkamp K W, Helmerhorst F M, Büller H R, Rosendaal F R. Diagnostic suspicion and referral bias in studies of venous thromboembolism and oral contraceptive use. Eur J Contracept Reprod Health Care . 2001; 6 56-57
49 World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Venous thromboembolic disease and combined oral contraceptives: results of international multicentre case-control study. Lancet . 1995; 346 1575-1582
50 Helmerhorst F M, Bloemenkamp K W, Rosendaal F R, Vandenbroucke J P. Oral contraceptives and thrombotic disease: risk of venous thromboembolism. Thromb Haemost . 1997; 78 327-333
51 Emmerich J, Rosendaal F R, Cattaneo M. et al . Combined effect of factor V Leiden and prothrombin 20210A on the risk of venous thromboembolism-pooled analysis of 8 case-control studies including 2310 cases and 3204 controls. Study Group for Pooled-Analysis in Venous Thromboembolism. Thromb Haemost . 2001; 86 809-816
52 Vandenbroucke J P, Koster T, Briët E. et al . Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Lancet . 1994; 344 1453-1457
53 Pabinger I, Schneider B. Thrombotic risk of women with hereditary antithrombin III-, protein C- and protein S-deficiency taking oral contraceptive medication. The GTH Study Group on Natural Inhibitors. Thromb Haemost . 1994; 71 548-552
54 Rosendaal F R, Koster T, Vandenbroucke J P, Reitsma P H. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance). Blood . 1995; 85 1504-1508
55 Rintelen C, Mannhalter C, Ireland H. et al . Oral contraceptives enhance the risk of clinical manifestation of venous thrombosis at a young age in females homozygous for factor V Leiden. Br J Haematol . 1996; 93 487-490
56 Martinelli I, Taioli E, Bucciarelli P, Akhavan S, Mannucci P M. Interaction between the G20210A mutation of the prothrombin gene and oral contraceptive use in deep vein thrombosis. Arterioscler Thromb Vasc Biol . 1999; 19 700-703
57 Bloemenkamp K W, Rosendaal F R, Helmerhorst F M, Vandenbroucke J P. Higher risk of venous thrombosis during early use of oral contraceptives in women with inherited clotting defects. Arch Intern Med . 2000; 160 49-52
58 Psaty B M, Smith N L, Lemaitre R N. et al . Hormone replacement therapy, prothrombotic mutations, and the risk of incident nonfatal myocardial infarction in postmenopausal women. JAMA . 2001; 285 906-913
59 Stadel B V. Oral contraceptives and cardiovascular disease (first of two parts). N Engl J Med . 1981; 305 612-618
60 Farley T M, Collins J, Schlesselman J J. Hormonal contraception and risk of cardiovascular disease. An international perspective. Contraception . 1998; 57 211-230
61 Martinelli I, Rosendaal F R, Vandenbroucke J P, Mannucci P M. Oral contraceptives are a risk factor for cerebral vein thrombosis. Thromb Haemost . 1996; 76 477-478
62 Martinelli I, Landi G, Merati G. et al . Factor V gene mutation is a risk factor for cerebral venous thrombosis. Thromb Haemost . 1996; 75 393-394
63 Martinelli I, Sacchi E, Landi G. et al . High risk of cerebral-vein thrombosis in carriers of a prothrombin-gene mutation and in users of oral contraceptives. N Engl J Med . 1998; 338 1793-1797
64 De Bruijn F S, Stam J, Koopman M M, Vandenbroucke J P. Case-control study of risk of cerebral sinus thrombosis in oral contraceptive users and in [correction of who are] carriers of hereditary prothrombotic conditions. The Cerebral Venous Sinus Thrombosis Study Group. BMJ . 1998; 316 589-592
65 De Bruijn F S, Stam J, Vandenbroucke J P. Increased risk of cerebral venous sinus thrombosis with third-generation oral contraceptives. Cerebral Venous Sinus Thrombosis Study Group. Lancet . 1998; 351 1404
66 Gombos G M, Moreno D H, Bedrossian P B. Retinal vascular occlussion induced by oral contraceptives. Ann Ophthalmol . 1975; 7 215-217
67 Edwards M, Longstaff S, Makris M. Retinal vein occlusion, the contraceptive pill and the prothrombin 20210A allele. Eye . 1999; 13 269
68 Scoditti U, Buccino G P, Pini M, Pattacini C, Mancia D. Risk of acute cerebrovascular events related to low oestrogen oral contraceptive treatment. Ital J Neurol Sci . 1998; 19 15-19
69 Capron J P, Lemay J L, Muir J F. et al . Portal vein thrombosis and fatal pulmonary thromboembolism associated with oral contraceptive treatment. J Clin Gastroenterol . 1981; 3 295-298
70 Minnema M C, Janssen H L, Niermeijer P, de Man A R. Budd-Chiari syndrome: combination of genetic defects and the use of oral contraceptives leading to hypercoagulability. J Hepatol . 2000; 33 509-512
71 Janssen H L, Meinardi J R, Vleggaar F P. et al . Factor V Leiden mutation, prothrombin gene mutation, and deficiencies in coagulation inhibitors associated with Budd-Chiari syndrome and portal vein thrombosis: results of a case-control study. Blood . 2000; 96 2364-2368
72 Fuertes-de la Haba A, Curet J O, Pelegrina I, Bangdiwala I. Thrombophlebitis among oral and nonoral contraceptive users. Obstet Gynecol . 1971; 38 259-263
73 Brandjes D P, Büller H R, Heijboer H. et al . Randomised trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis. Lancet . 1997; 349 759-762
74 Mansourati J, Da Costa A, Munier S. et al . Prevalence of factor V Leiden in patients with myocardial infarction and normal coronary angiography. Thromb Haemost . 2000; 83 822-825
75 Gagne P J, Vitti M J, Fink L M. et al . Young women with advanced aortoiliac occlusive disease: new insights. Ann Vasc Surg . 1996; 10 546-557
76 Weitz J I, Byrne J, Clagett G P. et al . Diagnosis and treatment of chronic arterial insufficiency of the lower extremities: a critical review. Circulation . 1996; 94 3026-3049
77 Van Vroonhoven J T. Intermittent claudication in premenopausal women. A correlation with the long-term use of oral contraceptives?. J Cardiovasc Surg . 1977; 18 291-295
78 Collier T M, Coopwood T B, Treadaway J P. Mesenteric thrombosis associated with oral contraceptives. Angiology . 1975; 26 518-520
79 Wilensky R J, Hubbard Jr B T. Thrombosis of the digital vessels secondary to oral contraceptives. Am J Obstet Gynecol . 1972; 113 1137-1138
80 Thorogood M, Vessey M P. An epidemiologic survey of cardiovascular disease in women taking oral contraceptives. Am J Obstet Gynecol . 1990; 163 274-281
81 Tunstall-Pedoe H, Kuulasmaa K, Amouyel P. et al . Myocardial infarction and coronary deaths in the World Health Organization MONICA Project. Registration procedures, event rates, and case-fatality rates in 38 populations from 21 countries in four continents. Circulation . 1994; 90 583-612
82 Sidney S, Siscovick D S, Petitti D B. et al . Myocardial infarction and use of low-dose oral contraceptives: a pooled analysis of 2 US studies. Circulation . 1998; 98 1058-1063
83 Dunn N R, Faragher B, Thorogood M. et al . Risk of myocardial infarction in young female smokers. Heart . 1999; 82 581-583
84 Rosenberg L, Palmer J R, Rao R S, Shapiro S. Low-dose oral contraceptive use and the risk of myocardial infarction. Arch Intern Med . 2001; 161 1065-1070
85 WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Acute myocardial infarction and combined oral contraceptives: results of an international multicentre case-control study. Lancet . 1997; 349 1202-1209
86 Lewis M A, Heinemann L A, Spitzer W O, MacRae K D, Bruppacher R. The use of oral contraceptives and the occurrence of acute myocardial infarction in young women. Results from the Transnational Study on Oral Contraceptives and the Health of Young Women. Contraception . 1997; 56 129-140
87 Tanis B C, van den Bosch A M, Kemmeren J M. et al . Oral contraceptives and the risk of myocardial infarction. N Engl J Med . 2001; 345 1787-1793
88 Dunn N R, Arscott A, Thorogood M. The relationship between use of oral contraceptives and myocardial infarction in young women with fatal outcome, compared to those who survive: results from the MICA case-control study. Contraception . 2001; 63 65-69
89 Colditz G A. Oral contraceptive use and mortality during 12 years of follow-up: the Nurses' Health Study. Ann Intern Med . 1994; 120 821-826
90 Stampfer M J, Willett W C, Colditz G A, Speizer F E, Hennekens C H. Past use of oral contraceptives and cardiovascular disease: a meta-analysis in the context of the Nurses' Health Study. Am J Obstet Gynecol . 1990; 163 285-291
91 Sidney S, Petitti D B, Quesenberry Jr P C. et al . Myocardial infarction in users of low-dose oral contraceptives. Obstet Gynecol . 1996; 88 939-944
92 Dunn N, Thorogood M, Faragher B. et al . Oral contraceptives and myocardial infarction: results of the MICA case-control study. BMJ . 1999; 318 1579-1583
93 Engel H J, Hundeshagen H, Lichtlen P. Transmural myocardial infarction in young women taking oral contraceptives. Evidence of reduced regional coronary flow in spite of normal coronary arteries. Br Heart J . 1977; 39 477-484
94 Engel H J, Engel E, Lichtlen P R. Coronary atherosclerosis and myocardial infarction in young women-role of oral contraceptives. Eur Heart J . 1983; 4 1-6
95 Njolstad I, Arnesen E, Lund-Larsen P G. Smoking, serum lipids, blood pressure, and sex differences in myocardial infarction. A 12-year follow-up of the Finnmark Study. Circulation . 1996; 93 450-456
96 Report of a WHO scientific group. Cardiovascular Disease and Steroid Hormone Contraception. Geneva: World Health Organization; 1998. WHO Technical Report Series, No 877
97 Thorvaldsen P, Asplund K, Kuulasmaa K, Rajakangas A M, Schroll M. Stroke incidence, case fatality, and mortality in the WHO MONICA project. World Health Organization Monitoring Trends and Determinants in Cardiovascular Disease. Stroke . 1995; 26 361-367
98 Petitti D B, Sidney S, Bernstein A. et al . Stroke in users of low-dose oral contraceptives. N Engl J Med . 1996; 335 8-15
99 Petitti D B, Sidney S, Quesenberry Jr P C, Bernstein A. Incidence of stroke and myocardial infarction in women of reproductive age. Stroke . 1997; 28 280-283
100 Schwartz S M, Siscovick D S, Longstreth Jr T W. et al . Use of low-dose oral contraceptives and stroke in young women. Ann Intern Med . 1997; 127 596-603
101 Collaborative group for the study of stroke in young women. Oral contraception and increased risk of cerebral ischemia or thrombosis. N Engl J Med . 1973; 288 871-878
102 Jick H, Porter J, Rothman K J. Oral contraceptives and nonfatal stroke in healthy young women. Ann Intern Med . 1978; 89 58-60
103 Petitti D B, Wingerd J, Pellegrin F, Ramcharan S. Risk of vascular disease in women. Smoking, oral contraceptives, noncontraceptive estrogens, and other factors. JAMA . 1979; 242 1150-1154
104 WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Ischaemic stroke and combined oral contraceptives: results of an international, multicentre, case-control study. Lancet . 1996; 348 498-505
105 Heinemann L A, Lewis M A, Spitzer W O. et al . Thromboembolic stroke in young women. A European case-control study on oral contraceptives. Transnational Research Group on Oral Contraceptives and the Health of Young Women. Contraception . 1998; 57 29-37
106 Lidegaard Ø, Kreiner S. Cerebral thrombosis and oral contraceptives. A case-control study. Contraception . 1998; 57 303-314
107 Poulter N R, Chang C L, Farley T M, Marmot M G, Meirik O. Effect on stroke of different progestagens in low oestrogen dose oral contraceptives. WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Lancet . 1999; 354 301-302
107a Kemmeren J M, Tanis B C, van den Bosch. et al . Risk of arterial thrombosis in relation to oral contraceptives (RATIO) study: oral contraceptives and the risk of ischemic stroke. Stroke . 2002; 33 1202-1208
108 Tzourio C, Tehindrazanarivelo A, Iglesias S. et al . Case-control study of migraine and risk of ischaemic stroke in young women. BMJ . 1995; 310 830-833
109 Carolei A, Marini C, De Matteis G. History of migraine and risk of cerebral ischaemia in young adults. The Italian National Research Council Study Group on Stroke in the Young. Lancet . 1996; 347 1503-1506
110 Collaborative Group for the Study of Stroke in Young Women. Oral contraceptives and stroke in young women. Associated risk factors. JAMA . 1975; 231 718-722
111 WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Haemorrhagic stroke, overall stroke risk, and combined oral contraceptives: results of an international, multicentre, case-control study. Lancet . 1996; 348 505-510
112 Jick S S, Myers M W, Jick H. Risk of idiopathic cerebral haemorrhage in women on oral contraceptives with differing progestagen components. Lancet . 1999; 354 302-303
113 Bellinger D A, Williams J K, Adams M R, Honore E K, Bender D E. Oral contraceptives and hormone replacement therapy do not increase the incidence of arterial thrombosis in a nonhuman primate model. Arterioscler Thromb Vasc Biol . 1998; 18 92-99
114 Van den Bosch A M, Kemmeren J M, Tanis B C. et al . The RATIO-study: oral contraceptives and the risk of peripheral arterial disease (Abst). Thromb Haemost . 2001; 86
115 Shapiro S, Slone D, Rosenberg L. et al . Oral-contraceptive use in relation to myocardial infarction. Lancet . 1979; 1 743-747
116 Stadel B V. Oral contraceptives and cardiovascular disease (second of two parts). N Engl J Med . 1981; 305 672-677
117 Meirik O. Cardiovascular safety and combined oral contraceptives. Contraception . 1998; 57 135-136
118 Mann J I, Vessey M P, Thorogood M, Doll S R. Myocardial infarction in young women with special reference to oral contraceptive practice. Br Med J . 1975; 2 241-245
119 Hannaford P. Cardiovascular events associated with different combined oral contraceptives: a review of current data. Drug Saf . 2000; 22 361-371
120 Rosendaal F R, Siscovick D S, Schwartz S M. et al . Factor V Leiden (resistance to activated protein C) increases the risk of myocardial infarction in young women. Blood . 1997; 89 2817-2821
121 Siscovick D S, Schwartz S M, Rosendaal F R, Psaty B M. Thrombosis in the young: effect of atherosclerotic risk factors on the risk of myocardial infarction associated with prothrombotic factors. Thromb Haemost . 1997; 78 7-12
122 Catto A, Carter A, Ireland H. et al . Factor V Leiden gene mutation and thrombin generation in relation to the development of acute stroke. Arterioscler Thromb Vasc Biol . 1995; 15 783-785
123 Longstreth Jr T W, Rosendaal F R, Siscovick D S. et al . Risk of stroke in young women and two prothrombotic mutations: factor V Leiden and prothrombin gene variant (G20210A). Stroke . 1998; 29 577-580
124 Task Force on Oral Contraceptives-WHO Special Programme of Research, Development and Research Training in Human Reproduction, World Health Organization. A multicentre study of coagulation and haemostatic variables during oral contraception: variations with four formulations. Br J Obstet Gynaecol . 1991; 98 1117-1128
125 Quehenberger P, Loner U, Kapiotis S. et al . Increased levels of activated factor VII and decreased plasma protein S activity and circulating thrombomodulin during use of oral contraceptives. Thromb Haemost . 1996; 76 729-734
126 Kluft C, Lansink M. Effect of oral contraceptives on haemostasis variables. Thromb Haemost . 1997; 78 315-326
127 Bloemenkamp K W, Rosendaal F R, Helmerhorst F M. et al . Hemostatic effects of oral contraceptives in women who developed deep-vein thrombosis while using oral contraceptives. Thromb Haemost . 1998; 80 382-387
128 Speroff L, DeCherney A. Evaluation of a new generation of oral contraceptives. The Advisory Board for the New Progestins. Obstet Gynecol . 1993; 81 1034-1047
129 Dahlbäck B, Carlsson M, Svensson P J. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C. Proc Natl Acad Sci U S A . 1993; 90 1004-1008
130 Koster T, Rosendaal F R, De Ronde H. et al . Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study. Lancet . 1993; 342 1503-1506
131 Bertina R M, Koeleman B P, Koster T. et al . Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature . 1994; 369 64-67
132 Østerud B, Robertsen R, Asvang G B, Thijssen F. Resistance to activated protein C is reduced in women using oral contraceptives. Blood Coagul Fibrinolysis . 1994; 5 853-854
133 Olivieri O, Friso S, Manzato F. et al . Resistance to activated protein C in healthy women taking oral contraceptives. Br J Haematol . 1995; 91 465-470
134 Bokarewa M I, Falk G, Sten-Linder M. et al . Thrombotic risk factors and oral contraception. J Lab Clin Med . 1995; 126 294-298
135 Hellgren M, Svensson P J, Dahlback B. Resistance to activated protein C as a basis for venous thromboembolism associated with pregnancy and oral contraceptives. Am J Obstet Gynecol . 1995; 173 210-213
136 Hirsch D R, Mikkola K M, Marks P W. et al . Pulmonary embolism and deep venous thrombosis during pregnancy or oral contraceptive use: prevalence of factor V Leiden. Am Heart J . 1996; 131 1145-1148
137 Bennet L, Odeberg H. Resistance to activated protein C, highly prevalent amongst users of oral contraceptives with venous thromboembolism. J Intern Med . 1998; 244 27-32
138 Rosing J, Tans G, Nicolaes G A. et al . Oral contraceptives and venous thrombosis: different sensitivities to activated protein C in women using second- and third-generation oral contraceptives. Br J Haematol . 1997; 97 233-238
139 Vandenbroucke J P, Helmerhorst F M, Bloemenkamp K W, Rosendaal F R. Third-generation oral contraceptive and deep venous thrombosis: from epidemiologic controversy to new insight in coagulation. Am J Obstet Gynecol . 1997; 177 887-891
140 Winkler U H. Effects on hemostatic variables of desogestrel containing oral contraceptives. Am J Obstet Gynecol . 1998; 179 S51-S61
141 Rosing J, Middeldorp S, Curvers J. et al . Low-dose oral contraceptives and acquired resistance to activated protein C: a randomised cross-over study. Lancet . 1999; 354 2036-2040
142 Rosing J, Tans G. Effects of oral contraceptives on hemostasis and thrombosis. Am J Obstet Gynecol . 1999; 180 S375-S382
143 Tans G, Curvers J, Middeldorp S. et al . A randomized cross-over study on the effects of levonorgestrel- and desogestrel-containing oral contraceptives on the coagulation pathways. Thromb Haemost . 2000; 84 15-21
144 Henkens C M, Bom V J, Seinen A J, van der Meer J. Sensitivity to activated protein C; influence of oral contraceptives and sex. Thromb Haemost . 1995; 73 402-404
145 Curvers J, Thomassen M C, Nicolaes G A. et al . Acquired APC resistance and oral contraceptives: differences between two functional tests. Br J Haematol . 1999; 105 88-94
146 De Visser C M, Rosendaal F R, Bertina R M. A reduced sensitivity for activated protein C in the absence of factor V Leiden increases the risk of venous thrombosis. Blood . 1999; 93 1271-1276
147 Mackie I J, Piegsa K, Furs S A. et al . Protein S levels are lower in women receiving desogestrel-containing combined oral contraceptives (COCs) than in women receiving levonorgestrel-containing COCs at steady state and on cross-over. Br J Haematol . 2001; 113 898-904
148 Pabinger I, Schneider B. Thrombotic risk in hereditary antithrombin III, protein C, or protein S deficiency. A cooperative, retrospective study. Gesellschaft fur Throm. Arterioscler Thromb Vasc Biol . 1996; 16 742-748
149 Kjaer A, Lebech A M, Borggaard B. et al . Lipid metabolism and coagulation of two contraceptives: correlation to serum concentrations of levonorgestrel and gestodene. Contraception . 1989; 40 665-673
150 Refn H, Kjaer A, Lebech A M. et al . Metabolic changes during treatment with two different progestogens. Am J Obstet Gynecol . 1990; 163 374-377
151 Van Tilburg H N, Rosendaal F R, Bertina R M. Thrombin activatable fibrinolysis inhibitor and the risk for deep vein thrombosis. Blood . 2000; 95 2855-2859
152 Meijers J C, Middeldorp S, Tekelenburg W. et al . Increased fibrinolytic activity during use of oral contraceptives is counteracted by an enhanced factor XI-independent down regulation of fibrinolysis: a randomized cross-over study of two low-dose oral contraceptives. Thromb Haemost . 2000; 84 9-14
153 Ernst E. Oral contraceptives, fibrinogen and cardiovascular risk. Atherosclerosis . 1992; 93 1-5
154 Godsland I F, Crook D, Simpson R. et al . The effects of different formulations of oral contraceptive agents on lipid and carbohydrate metabolism. N Engl J Med . 1990; 323 1375-1381
155 Crook D, Godsland I. Safety evaluation of modern oral contraceptives. Effects on lipoprotein and carbohydrate metabolism. Contraception . 1998; 57 189-201
156 Gevers Leuven A J, Dersjant-Roorda M C, Helmerhorst F M. et al . Effects of oral contraceptives on lipid metabolism. Am J Obstet Gynecol . 1990; 163 1410-1413
157 Godsland I F, Crook D, Worthington M. et al . Effects of a low-estrogen, desogestrel-containing oral contraceptive on lipid and carbohydrate metabolism. Contraception . 1993; 48 217-227
158 Lobo R A, Skinner J B, Lippman J S, Cirillo S J. Plasma lipids and desogestrel and ethinyl estradiol: a meta-analysis. Fertil Steril . 1996; 65 1100-1109
159 Young R L, DelConte A. Effects of low-dose monophasic levonorgestrel with ethinyl estradiol preparation on serum lipid levels: a twenty-four month clinical trial. Am J Obstet Gynecol . 1999; 181 59-62
160 Kemmeren J M, Algra A, Grobbee D E. Effect of second and third generation oral contraceptives on lipid metabolism in the absence or presence of the factor V Leiden mutation. J Intern Med . 2001; 250 441-448
161 World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception.Cardiovascular disease and use of oral and injectable progestogen-only contraceptives and combined injectable contraceptives. Results of an international, multicenter, case-control study. Contraception . 1998; 57 315-324
162 Vasilakis C, Jick H, Mar Melero-Montes M. Risk of idiopathic venous thromboembolism in users of progestagens alone. Lancet . 1999; 354 1610-1611
163 Poulter N R, Chang C L, Farley T M, Meirik O. Risk of cardiovascular diseases associated with oral progestagen preparations with therapeutic indications. Lancet . 1999; 354 1610
164 Vandenbroucke J P, van der Meer J F, Helmerhorst F M, Rosendaal F R. Factor V Leiden: should we screen oral contraceptive users and pregnant women?. BMJ . 1996; 313 1127-1130
165 Rosendaal F R. Oral contraceptives and screening for factor V Leiden. Thromb Haemost . 1996; 75 524-525
166 Schambeck C M, Schwender S, Haubitz I. et al . Selective screening for the factor V Leiden mutation: is it advisable prior to the prescription of oral contraceptives?. Thromb Haemost . 1997; 78 1480-1483
167 Cosmi B, Legnani C, Bernardi F, Coccheri S, Palareti G. Value of family history in identifying women at risk of venous thromboembolism during oral contraception: observational study. BMJ . 2001; 322 1024-1025
168 Vandenbroucke J P, van der Meer J M F, Helmerhorst F M, Rosendaal F R. Family history and risk of venous thromboembolism with oral contraception. Family history is important tool. BMJ . 2001; 323 752
169 Middeldorp S, Henkens C M, Koopman M M. et al . The incidence of venous thromboembolism in family members of patients with factor V Leiden mutation and venous thrombosis. Ann Intern Med . 1998; 128 15-20
170 Simioni P, Sanson B J, Prandoni P. et al . Incidence of venous thromboembolism in families with inherited thrombophilia. Thromb Haemost . 1999; 81 198-202
171 Middeldorp S, Meinardi J R, Koopman M M. et al . A prospective study of asymptomatic carriers of the factor V Leiden mutation to determine the incidence of venous thromboembolism. Ann Intern Med . 2001; 135 322-327
172 Palareti G, Legnani C, Frascaro M. et al . Screening for activated protein C resistance before oral contraceptive treatment: a pilot study. Contraception . 1999; 59 293-299
173 Ridker P M, Miletich J P, Hennekens C H, Buring J E. Ethnic distribution of factor V Leiden in 4047 men and women. Implications for venous thromboembolism screening. JAMA . 1997; 277 1305-1307
174 Rosendaal F R, Doggen C J, Zivelin A. et al . Geographic distribution of the 20210 G to A prothrombin variant. Thromb Haemost . 1998; 79 706-708
175 Green D. Genetic hypercoagulability: screening should be an informed choice. Blood . 2001; 98 20
176 Mannucci P M. Genetic hypercoagulability: prevention suggests testing family members. Blood . 2001; 98 21-22
177 Tormene D, Simioni P, Sartori M T, Girolami A. Heterozygous carrier of G20210A prothrombin mutation used oral contraceptive treatment for 23 years without thrombotic events, and developed cerebral venous thrombosis 1 month after resumption of the medication at the age of 50. Blood Coagul Fibrinolysis . 2001; 12 161-162
178 Rosendaal F R. Thrombosis in the young: epidemiology and risk factors. A focus on venous thrombosis. Thromb Haemost . 1997; 78 1-6
179 Jick H, Jick S, Myers M W, Vasilakis C. Risk of acute myocardial infarction and low-dose combined oral contraceptives. Lancet . 1996; 347 627-628