Abstract
Objective: To investigate whether users of oral contraceptives who are carriers of a hereditary prothrombotic condition (factor V Leiden mutation, protein C, S, or antithrombin deficiency) have an increased risk of cerebral sinus thrombosis.
Design: Comparison of a prospective series of cases of cerebral sinus thrombosis with population data.
Setting: Neurological teaching hospitals from different regions in the Netherlands (cases) and a representative sample of the non-institutionalised Dutch population (controls).
Subjects: 40 women aged 18-54 years with cerebral sinus thrombosis (cases) and 2248 women aged 18-49 years (controls).
Main outcome measure: Current use of oral contraceptives at the time of the thrombosis (cases) or at the time of the questionnaire (controls). Prevalences of a hereditary prothrombotic condition in patients and in the population with odds ratios.
Results: 34 of 40 (85%) women with cerebral sinus thrombosis used oral contraceptives, versus 1007 of 2248 (45%) of the control women; the age adjusted odds ratio was 13 (95% confidence interval 5 to 37). Seven of 36 patients (19%) had a prothrombotic deficiency, versus 7% expected in the population; this corresponds to a threefold to fourfold increase in risk. In women who used oral contraceptives and also carried a prothrombotic defect, the odds ratio for cerebral sinus thrombosis was about 30 relative to women who had neither risk factor.
Conclusion: The use of oral contraceptives and being a carrier of a hereditary prothrombotic condition increase the risk of and interact in a multiplicative way in the development of cerebral sinus thrombosis.
Key messages
The use of oral contraceptives is associated with an increased risk of cerebral venous sinus thrombosis
This risk of cerebral venous sinus thrombosis in women who use oral contraceptives is larger if there is an additional hereditary prothombotic factor (protein C, S, or antithrombin deficiency, factor V Leiden mutation)
The association between oral contraceptives, thrombophilia, and deep vein thrombosis is also valid for cerebral sinus thrombosis
Women do not need to stop using oral contraceptives as the absolute risk of cerebral sinus thrombosis is very small
Full Text
The Full Text of this article is available as a PDF (502.7 KB).
Table.
Use of oral contraceptives and prothrombotic disorders in cases (women with cerebral venous sinus thrombosis aged 18-54 years, puerperium excluded) and use of oral contraceptives in controls
| Age (years) | Cases
|
Proportion (%) of controls taking contraceptives | ||
|---|---|---|---|---|
| Proportion (%) taking contraceptives | No with factor V Leiden | No with C, S, or antithrombin deficiency | ||
| 18-19 | 3/3 (100) | 1 | 0 | 60/107 (56) |
| 20-24 | 7/7 (100) | 0 | 0 | 271/336 (81) |
| 25-29 | 4/4 (100) | 1 | 1 | 255/400 (64) |
| 30-34 | 7/7 (100) | 2 | 0 | 176/392 (45) |
| 35-39 | 5/6 (83) | 0 | 1 | 105/342 (31) |
| 40-44 | 3/5 (60) | 0 | 0 | 79/336 (24) |
| 45-49 | 4/5 (80) | 0 | 0 | 61/335 (18) |
| 50-54 | 1/3 (33) | 1 | 0 | No data |
| Total | 34/40 (85) | 5* | 2† | 1007/2248 (45) |
Data missing for four women.
Data missing for three women.
Acknowledgments
The Cerebral Venous Sinus Thrombosis Study Group comprised S F T M de Bruijn, J Stam, A W A Lensing, J G P Tijssen, P M Bossuyt, L J Kappelle, J Van Gijn, D W J Dippel, P J Koudstaal, J J Van Hilten, R A C Roos, J L A Eekhof, J J Van der Sande, H L Hamburger, J Lodder, C C Tijssen, F W Bertelsman, J C Koetsier, P Sandercock, P Humphrey, G N Mallo, P Verlooy, H K Van Walbeek, J W Snoek, and C L Franke.
We thank M Budde for help in collecting patient data and blood samples; C Hooykaas, H van der Heide, and G C G Verweij for kindly providing control data; and M Vermeulen, H R Büller, and W A van Gool for their useful comments.
Footnotes
Funding: The treatment trial was partly funded by Sanofi Winthrop.
Conflict of interest: None.
References
- 1.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. [PubMed] [Google Scholar]
- 2.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;344:1453–1457. doi: 10.1016/s0140-6736(94)90286-0. [DOI] [PubMed] [Google Scholar]
- 3.Bousser M, Chiras J, Bories J, Castaigne P. Cerebral venous thrombosis: a review of 38 cases. Stroke. 1985;16:199–213. doi: 10.1161/01.str.16.2.199. [DOI] [PubMed] [Google Scholar]
- 4.Deschiens MA, Conard J, Horellou MH, Ameri A, Preter M, Chedru F, et al. Coagulation studies, factor V Leiden, and anticardiolipin antibodies in 40 cases of cerebral venous thrombosis. Stroke. 1996;27:1724–1730. doi: 10.1161/01.str.27.10.1724. [DOI] [PubMed] [Google Scholar]
- 5.Peters M, Breederveld C, Kahle LH, ten Cate JW. Rapid microanalysis of coagulation parameters by automated chromogenic substrate methods, application in neonatal patients. Thromb Res. 1982;28:773–781. doi: 10.1016/0049-3848(82)90103-7. [DOI] [PubMed] [Google Scholar]
- 6.Boyer C, Rothschild C, Wolf M, Amiral J, Meyer D, Larrieru M. A new method of estimation of protein C by ELISA. Thromb Res. 1984;36:579–589. doi: 10.1016/0049-3848(84)90197-x. [DOI] [PubMed] [Google Scholar]
- 7.Deutz-Terlouw PP, Ballering L, Wijngaarden vA, Bertina RM. Two ELISAs for measurement of protein S, and their use in the laboratory diagnosis of protein S deficiency. Clin Chim Acta 1989;186:321. [DOI] [PubMed]
- 8.Dahlback B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C. Proc Natl Acad Sci USA. 1993;90:1004–1008. doi: 10.1073/pnas.90.3.1004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Voorberg J, Roelse J, Koopman R. Association of idiopathic venous thromboembolism with single point mutation at Arg 506 of factor V. Lancet. 1994;343:1535–1536. doi: 10.1016/s0140-6736(94)92939-4. [DOI] [PubMed] [Google Scholar]
- 10.CBS; Nederlands Instituut voor onderzoek van de Eerstelijnsgezondheidszorg; Inspectie voor de Gezondheidszorg. Enkele vormen van geboortenregeling. In: Centraal Bureau voor de Statistiek. Statistisch jaarboek 1996. The Hague: SDU, 1996:502.
- 11.Statistics Netherlands. Netherlands health interview survey 1981-1995. The Hague: SDU, 1996.
- 12.Rothman KJ. Modern epidemiology. Boston: Little, Brown; 1986. [Google Scholar]
- 13.Ridker PM, Miletich JP, Hennekkens CH, Buring JE. Ethnic distribution of factor V Leiden in 4047 men and women. Implications for venous thromboembolism screening. JAMA. 1997;277:1305–1307. [PubMed] [Google Scholar]
- 14.Hach-Wunderle V, Scharrer I. Pravalenz des hereditaren Mangels an Antithrombin III, Protein C und Protein S. Deutschen Medischen Wochenschrift. 1993;118:187–190. doi: 10.1055/s-2008-1059317. [DOI] [PubMed] [Google Scholar]
- 15.Tait RC, Walker ID, Reitsma PH, Islam SI, McCall F, Poort SR, et al. Prevalence of protein C deficiency in the healthy population. Thromb Haemost. 1995;73:87–93. [PubMed] [Google Scholar]
- 16.Kalbag RM, Woolf AL. Cerebral venous thrombosis. London: Oxford University Press; 1967. [Google Scholar]
- 17.Realini JP, Goldzieher JW. Oral contraceptives and cardiovascular disease: a critique of the epidemiologic studies. Am J Obstet Gynecol. 1985;152:729–798. doi: 10.1016/s0002-9378(85)80001-6. [DOI] [PubMed] [Google Scholar]
- 18.Dormont D, Anxionnat C, Evrard S, Louaille C, Chiras J, Marsault C. MRI in cerebral venous thrombosis. J Neuroradiol. 1994;21:81–99. [PubMed] [Google Scholar]
- 19.Buchanan LTCDS, Brazinsky MAJJH. Dural sinus and cerebral venous thrombosis incidence in young women receiving oral contraceptives. Arch Neurol 1970;22:440-4. [DOI] [PubMed]
- 20.Martinelli I, Landi G, Merati G, Cella R, Tosetto A, Mannucci PM. Factor V gene mutation is a risk factor for cerebral venous thrombosis. Thromb Haemost. 1996;75:393–394. [PubMed] [Google Scholar]
- 21.Martinelli I, Rosendaal FR, Vandenbroucke JP, Mannucci PM. Oral contraceptives are a risk factor for cerebral vein thrombosis [letter] Thromb Haemost. 1996;76:477–478. [PubMed] [Google Scholar]
- 22.Rosing J, Tans G, Nicolaes GA, Thomassen MC, van Oerle R, van der Ploeg PM, 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. doi: 10.1046/j.1365-2141.1997.192707.x. [DOI] [PubMed] [Google Scholar]
- 23.Zuber M, Toulon P, Marnet L, Mas J. Factor V Leiden mutation in cerebral venous thrombosis. Stroke. 1996;27:1721–1723. doi: 10.1161/01.str.27.10.1721. [DOI] [PubMed] [Google Scholar]
- 24.Krayenbühl HA. Cerebral venous and sinus thrombosis. Clin Neurosurg. 1966;14:1–24. [PubMed] [Google Scholar]