Low dose oestrogen combined oral contraception and risk of pulmonary embolism, stroke, and myocardial infarction in five million French women: cohort study
BMJ 2016; 353 doi: https://doi.org/10.1136/bmj.i2002 (Published 10 May 2016) Cite this as: BMJ 2016;353:i2002
- Alain Weill, epidemiologist1,
- Marie Dalichampt, statistician1,
- Fanny Raguideau, epidemiologist2,
- Philippe Ricordeau, head1,
- Pierre-Olivier Blotière, statistician1,
- Jérémie Rudant, epidemiologist1,
- François Alla, professor of public health1,
- Mahmoud Zureik, scientific director2
- 1Department of Studies in Public Health, French National Health Insurance, 75986 Paris Cedex 20, France
- 2French National Agency for Medicines and Health Products Safety, Saint-Denis, France
- Correspondence to: A Weill alain.weill{at}cnamts.fr
- Accepted 22 March 2016
Abstract
Objective To assess the risk of pulmonary embolism, ischaemic stroke, and myocardial infarction associated with combined oral contraceptives according to dose of oestrogen (ethinylestradiol) and progestogen.
Design Observational cohort study.
Setting Data from the French national health insurance database linked with data from the French national hospital discharge database.
Participants 4 945 088 women aged 15-49 years, living in France, with at least one reimbursement for oral contraceptives and no previous hospital admission for cancer, pulmonary embolism, ischaemic stroke, or myocardial infarction, between July 2010 and September 2012.
Main outcome measures Relative and absolute risks of first pulmonary embolism, ischaemic stroke, and myocardial infarction.
Results The cohort generated 5 443 916 women years of oral contraceptive use, and 3253 events were observed: 1800 pulmonary embolisms (33 per 100 000 women years), 1046 ischaemic strokes (19 per 100 000 women years), and 407 myocardial infarctions (7 per 100 000 women years). After adjustment for progestogen and risk factors, the relative risks for women using low dose oestrogen (20 µg v 30-40 µg) were 0.75 (95% confidence interval 0.67 to 0.85) for pulmonary embolism, 0.82 (0.70 to 0.96) for ischaemic stroke, and 0.56 (0.39 to 0.79) for myocardial infarction. After adjustment for oestrogen dose and risk factors, desogestrel and gestodene were associated with statistically significantly higher relative risks for pulmonary embolism (2.16, 1.93 to 2.41 and 1.63, 1.34 to 1.97, respectively) compared with levonorgestrel. Levonorgestrel combined with 20 µg oestrogen was associated with a statistically significantly lower risk than levonorgestrel with 30-40 µg oestrogen for each of the three serious adverse events.
Conclusions For the same dose of oestrogen, desogestrel and gestodene were associated with statistically significantly higher risks of pulmonary embolism but not arterial thromboembolism compared with levonorgestrel. For the same type of progestogen, an oestrogen dose of 20 µg versus 30-40 µg was associated with lower risks of pulmonary embolism, ischaemic stroke, and myocardial infarction.
Footnotes
We thank Anthony Saul for English revision of the manuscript.
Contributors: This study was conducted at the official request of the French Ministry of Health. MZ, PR, FA, and AW had the idea for the study. AW and MZ conceived the study design. AW planned the study and drafted the manuscript. MD performed data management. MD and PB did the statistical analyses. AW and MZ were responsible for management of the project and oversaw the study. All authors contributed to the interpretation of the data, revised the manuscript, and approved the final manuscript. AW and MD are the guarantors.
Funding: This research was funded by the French National Health Insurance Fund (CNAMTS) and the French National Agency for Medicines and Health Products Safety (ANSM). AW, MD, PB, JR, PR, and FA are employees of the French National Health Insurance Fund, MZ and FR of the French National Agency for Medicines and Health Products Safety. The present paper represents the opinions of the authors and does not necessarily reflect the position of their employers.
Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.
Ethical approval: This study was approved by the French data protection agency Commission Nationale de l'Informatique et des Libertés (regulatory decision DE-2011-078).
Data sharing: No additional data available.
Transparency: The lead author affirms that this manuscript is an honest, accurate and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.
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