Etiology
Review: Combined oral contraceptives are associated with venous thrombosis
Stegeman BH, de Bastos M, Rosendaal FR, et al. Different combined oral contraceptives and the risk of venous thrombosis: systematic review and network meta-analysis. BMJ. 2013;347:f5298.
Clinical impact ratings: F ★★★★★✩✩ H ★★★★★✩✩ Questions
Source of funding: No external funding.
Are combined oral contraceptives associated with venous thrombosis in healthy women? Does the association differ with progestogen generation?
For correspondence: Dr. O.M. Dekkers, Leiden University Medical Center, Leiden, The Netherlands. E-mail [email protected]. ■
Commentary
Review scope Included studies compared use of combined oral contraceptives with nonuse (never use or previous use) or use of another combined oral contraceptive in healthy women. Studies of women who used hormone replacement therapy or nonoral or progestogen-only contraceptives, or who had recurrent venous thrombosis, were excluded. Outcome was venous thrombosis (deep venous thrombosis and pulmonary embolism).
Review methods MEDLINE, EMBASE/Excerpta Medica, Web of Science, Cochrane Library, CINAHL, Academic Search Premier, ScienceDirect, and reference lists of key articles (Apr 2013) were searched for studies with ≥ 10 events. 26 observational studies, including 14 case–control studies, 9 cohort studies, and 3 nested case–control studies published in 25 articles met the inclusion criteria; no randomized controlled trials were included. 5 studies objectively confirmed venous thrombosis in all patients; 14 studies objectively confirmed venous thrombosis in some patients or subjectively confirmed venous thrombosis.
Main results Meta-analysis of 15 studies that included a nonuse group showed that use of oral contraceptives was associated with increased risk for venous thrombosis (Table). Network meta-analysis, which included indirect comparisons, showed that each generation of progestogen was associated with an increased risk for venous thrombosis compared with nonuse, that no generation differed from the previous generation (Table), and that third-generation progestogens did not differ from first-generation progestogens (relative risk 1.2, 95% CI 0.8 to 1.9). Network meta-analysis of 10 combined oral contraceptive types showed that each type increased risk for venous thrombosis compared with nonuse.
Conclusion Combined oral contraceptives, regardless of type or progestogen generation, are associated with venous thrombosis in healthy women. Association between use of combined oral contraceptives and venous thrombosis* Oral contraceptives
Relative risk (95% CI) compared with nonusers
Relative risk (CI) compared with previous generation of progestogen
All combined oral contraceptives
3.5% (2.9 to 4.3)
Not applicable
First-generation progestogen
3.2% (2.0 to 5.1)
Not applicable
Second-generation progestogen
2.8% (2.0 to 4.1)
0.9% (0.6 to 1.4)
Third-generation progestogen
3.8% (2.7 to 5.4)
1.3% (1.0 to 1.8)
*CI defined in Glossary.
JC12
© 2013 American College of Physicians
Network meta-analysis is an instructive and valuable way to compare the effects of the many different doses and formulations of the estrogen and progesterone components of oral contraceptives that heretofore have only been indirectly suggested. While ethinyl estradiol is consistent among estrogen formulations, several generations of progestins have made direct comparisons of oral contraceptives challenging for clinicians wishing to customize the effects and minimize potential harms. The network meta-analysis by Stegeman and colleagues confirms that combined oral contraceptives are associated with an increased risk for venous thrombosis. However, the lower the dose of ethinyl estradiol, the lower the risk for venous thromboembolism (VTE) (1). At the same time, the progestin component has its own associated/additional risk for VTE that is present regardless of format (intrauterine devices, implants, or injections as stand-alone methods of contraception; pills as combined contraceptives). The risk for death from pregnancy must remain in conversations about risk for VTE due to contraception. The risk for death due to childbirth, excluding HIV/AIDS, starts at 7 per 100 000 women in those 15 to 19 years of age and increases to 28 per 100 000 in women 40 to 44 years of age (2, 3). The risk for VTE from combined oral contraception is real (NNH = 900) but less than the increased risk for death from pregnancy for those < 35 years of age, even when considering third-generation progestins. The take-home message for clinicians when counseling for family planning does not differ from the committee opinion of the American College of Obstetricians and Gynecologists (4). It is to disclose the reduction in risk for death by using contraceptives to prevent pregnancy, and within the options that are behaviorally appropriate for the woman, to minimize her risk for VTE during her desired period of infertility. Diane M. Harper, MD, MPH, MS Lauren E.S. Wilfling, DO, MBA Christopher F. Blanner, MD University of Louisville School of Medicine Louisville, Kentucky, USA References 1. Dickey RP. Managing Contraceptive Pill Patients. 8th ed. Fort Collins, CO: EMIS; 1994. 2. Ory HW. Mortality associated with fertility and fertility control: 1983. Fam Plann Perspect. 1983;15:57-63. 3. Wilmoth J. The lifetime risk of maternal mortality: concept and measurement. Bull World Health Organ. 2009;87:256-62. 4. Committee on Gynecologic Practice. ACOG Committee Opinion Number 540: Risk of venous thromboembolism among users of drospirenone-containing oral contraceptive pills. Obstet Gynecol. 2012;120:1239-42.
17 December 2013 | ACP Journal Club | Volume 159 • Number 12
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/929454/ by a University of California San Diego User on 05/19/2017
Review: Combined oral contraceptives are associated with venous thrombosis
Stegeman BH, de Bastos M, Rosendaal FR, et al. Different combined oral contraceptives and the risk of venous thrombosis: systematic review and network meta-analysis. BMJ. 2013;347:f5298.
Clinical impact ratings: F ★★★★★✩✩ H ★★★★★✩✩ Questions
Source of funding: No external funding.
Are combined oral contraceptives associated with venous thrombosis in healthy women? Does the association differ with progestogen generation?
For correspondence: Dr. O.M. Dekkers, Leiden University Medical Center, Leiden, The Netherlands. E-mail [email protected]. ■
Commentary
Review scope Included studies compared use of combined oral contraceptives with nonuse (never use or previous use) or use of another combined oral contraceptive in healthy women. Studies of women who used hormone replacement therapy or nonoral or progestogen-only contraceptives, or who had recurrent venous thrombosis, were excluded. Outcome was venous thrombosis (deep venous thrombosis and pulmonary embolism).
Review methods MEDLINE, EMBASE/Excerpta Medica, Web of Science, Cochrane Library, CINAHL, Academic Search Premier, ScienceDirect, and reference lists of key articles (Apr 2013) were searched for studies with ≥ 10 events. 26 observational studies, including 14 case–control studies, 9 cohort studies, and 3 nested case–control studies published in 25 articles met the inclusion criteria; no randomized controlled trials were included. 5 studies objectively confirmed venous thrombosis in all patients; 14 studies objectively confirmed venous thrombosis in some patients or subjectively confirmed venous thrombosis.
Main results Meta-analysis of 15 studies that included a nonuse group showed that use of oral contraceptives was associated with increased risk for venous thrombosis (Table). Network meta-analysis, which included indirect comparisons, showed that each generation of progestogen was associated with an increased risk for venous thrombosis compared with nonuse, that no generation differed from the previous generation (Table), and that third-generation progestogens did not differ from first-generation progestogens (relative risk 1.2, 95% CI 0.8 to 1.9). Network meta-analysis of 10 combined oral contraceptive types showed that each type increased risk for venous thrombosis compared with nonuse.
Conclusion Combined oral contraceptives, regardless of type or progestogen generation, are associated with venous thrombosis in healthy women. Association between use of combined oral contraceptives and venous thrombosis* Oral contraceptives
Relative risk (95% CI) compared with nonusers
Relative risk (CI) compared with previous generation of progestogen
All combined oral contraceptives
3.5% (2.9 to 4.3)
Not applicable
First-generation progestogen
3.2% (2.0 to 5.1)
Not applicable
Second-generation progestogen
2.8% (2.0 to 4.1)
0.9% (0.6 to 1.4)
Third-generation progestogen
3.8% (2.7 to 5.4)
1.3% (1.0 to 1.8)
*CI defined in Glossary.
JC12
© 2013 American College of Physicians
Network meta-analysis is an instructive and valuable way to compare the effects of the many different doses and formulations of the estrogen and progesterone components of oral contraceptives that heretofore have only been indirectly suggested. While ethinyl estradiol is consistent among estrogen formulations, several generations of progestins have made direct comparisons of oral contraceptives challenging for clinicians wishing to customize the effects and minimize potential harms. The network meta-analysis by Stegeman and colleagues confirms that combined oral contraceptives are associated with an increased risk for venous thrombosis. However, the lower the dose of ethinyl estradiol, the lower the risk for venous thromboembolism (VTE) (1). At the same time, the progestin component has its own associated/additional risk for VTE that is present regardless of format (intrauterine devices, implants, or injections as stand-alone methods of contraception; pills as combined contraceptives). The risk for death from pregnancy must remain in conversations about risk for VTE due to contraception. The risk for death due to childbirth, excluding HIV/AIDS, starts at 7 per 100 000 women in those 15 to 19 years of age and increases to 28 per 100 000 in women 40 to 44 years of age (2, 3). The risk for VTE from combined oral contraception is real (NNH = 900) but less than the increased risk for death from pregnancy for those < 35 years of age, even when considering third-generation progestins. The take-home message for clinicians when counseling for family planning does not differ from the committee opinion of the American College of Obstetricians and Gynecologists (4). It is to disclose the reduction in risk for death by using contraceptives to prevent pregnancy, and within the options that are behaviorally appropriate for the woman, to minimize her risk for VTE during her desired period of infertility. Diane M. Harper, MD, MPH, MS Lauren E.S. Wilfling, DO, MBA Christopher F. Blanner, MD University of Louisville School of Medicine Louisville, Kentucky, USA References 1. Dickey RP. Managing Contraceptive Pill Patients. 8th ed. Fort Collins, CO: EMIS; 1994. 2. Ory HW. Mortality associated with fertility and fertility control: 1983. Fam Plann Perspect. 1983;15:57-63. 3. Wilmoth J. The lifetime risk of maternal mortality: concept and measurement. Bull World Health Organ. 2009;87:256-62. 4. Committee on Gynecologic Practice. ACOG Committee Opinion Number 540: Risk of venous thromboembolism among users of drospirenone-containing oral contraceptive pills. Obstet Gynecol. 2012;120:1239-42.
17 December 2013 | ACP Journal Club | Volume 159 • Number 12
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/929454/ by a University of California San Diego User on 05/19/2017
