Use of combined oral contraceptives and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases

BMJ. 2015 May 26:350:h2135. doi: 10.1136/bmj.h2135.


Objective: To investigate the association between use of combined oral contraceptives and risk of venous thromboembolism, taking the type of progestogen into account.

Design: Two nested case-control studies.

Setting: General practices in the United Kingdom contributing to the Clinical Practice Research Datalink (CPRD; 618 practices) and QResearch primary care database (722 practices).

Participants: Women aged 15-49 years with a first diagnosis of venous thromboembolism in 2001-13, each matched with up to five controls by age, practice, and calendar year.

Main outcome measures: Odds ratios for incident venous thromboembolism and use of combined oral contraceptives in the previous year, adjusted for smoking status, alcohol consumption, ethnic group, body mass index, comorbidities, and other contraceptive drugs. Results were combined across the two datasets.

Results: 5062 cases of venous thromboembolism from CPRD and 5500 from QResearch were analysed. Current exposure to any combined oral contraceptive was associated with an increased risk of venous thromboembolism (adjusted odds ratio 2.97, 95% confidence interval 2.78 to 3.17) compared with no exposure in the previous year. Corresponding risks associated with current exposure to desogestrel (4.28, 3.66 to 5.01), gestodene (3.64, 3.00 to 4.43), drospirenone (4.12, 3.43 to 4.96), and cyproterone (4.27, 3.57 to 5.11) were significantly higher than those for second generation contraceptives levonorgestrel (2.38, 2.18 to 2.59) and norethisterone (2.56, 2.15 to 3.06), and for norgestimate (2.53, 2.17 to 2.96). The number of extra cases of venous thromboembolism per year per 10,000 treated women was lowest for levonorgestrel (6, 95% confidence interval 5 to 7) and norgestimate (6, 5 to 8), and highest for desogestrel (14, 11 to 17) and cyproterone (14, 11 to 17).

Conclusions: In these population based, case-control studies using two large primary care databases, risks of venous thromboembolism associated with combined oral contraceptives were, with the exception of norgestimate, higher for newer drug preparations than for second generation drugs.

MeSH terms

  • Adolescent
  • Adult
  • Case-Control Studies
  • Contraceptives, Oral, Combined / adverse effects*
  • Databases, Factual
  • Denmark / epidemiology
  • Female
  • Humans
  • Middle Aged
  • Odds Ratio
  • Practice Patterns, Physicians' / statistics & numerical data*
  • Risk Factors
  • State Medicine / statistics & numerical data
  • United Kingdom / epidemiology
  • Venous Thromboembolism / chemically induced
  • Venous Thromboembolism / epidemiology*
  • Venous Thromboembolism / etiology


  • Contraceptives, Oral, Combined