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Research

Venous thromboembolism with use of hormonal contraception and non-steroidal anti-inflammatory drugs: nationwide cohort study

BMJ 2023; 382 doi: https://doi.org/10.1136/bmj-2022-074450 (Published 06 September 2023) Cite this as: BMJ 2023;382:e074450

Linked Editorial

NSAIDs, hormonal contraception, and venous thromboembolism

Linked Opinion

Filling in the gaps in our understanding of hormonal contraception
  1. Amani Meaidi, physician, postdoctoral researcher1 2,
  2. Annamaria Mascolo, pharmacovigilance officer3 4,
  3. Maurizio Sessa, associate professor5,
  4. Anne Pernille Toft-Petersen, physician6,
  5. Regitze Skals, statistician7,
  6. Thomas Alexander Gerds, professor8,
  7. Charlotte Wessel Skovlund, postdoctoral researcher9,
  8. Lina Steinrud Morch, senior researcher9,
  9. Francesco Rossi, professor3 4,
  10. Annalisa Capuano, professor3 4,
  11. Oejvind Lidegaard, professor1 2,
  12. Christian Torp-Pedersen, professor8 10 11
  1. 1Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
  2. 2Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
  3. 3Department of Experimental Medicine, Section of Pharmacology “L. Donatelli,” University of Campania ‘L. Vanvitelli’, Naples, Italy
  4. 4Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology, Naples, Italy
  5. 5Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
  6. 6Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
  7. 7Unit of Clinical Biostatistics, Aalborg University Hospital, Aalborg, Denmark
  8. 8Department of Public Health, Section of Biostatistics, University of Copenhagen, Copenhagen, Denmark
  9. 9Cancer Surveillance and Pharmacoepidemiology, The Danish Cancer Society Research Center, Copenhagen, Denmark
  10. 10Department of Cardiology, Nordsjaellands Hospital, Hilleroed, Denmark
  11. 11Department of Clinical Epidemiology and Cardiology, Aalborg University Hospital, Aalborg, Denmark
  1. Correspondence to: A Meaid amani-meaidi{at}live.dk
  • Accepted 1 August 2023

Abstract

Objective To study the influence of concomitant use of hormonal contraception and non-steroidal anti-inflammatory drugs (NSAIDs) on the risk of venous thromboembolism.

Design Nationwide cohort study.

Setting Denmark through national registries.

Participants All 15-49 year old women living in Denmark between 1996 and 2017 with no medical history of any venous or arterial thrombotic event, cancer, thrombophilia, hysterectomy, bilateral oophorectomy, sterilisation, or infertility treatment (n=2 029 065).

Main outcome measure A first time discharge diagnosis of lower limb deep venous thrombosis or pulmonary embolism.

Results Among 2.0 million women followed for 21.0 million person years, 8710 venous thromboembolic events occurred. Compared with non-use of NSAIDs, use of NSAIDs was associated with an adjusted incidence rate ratio of venous thromboembolism of 7.2 (95% confidence interval 6.0 to 8.5) in women not using hormonal contraception, 11.0 (9.6 to 12.6) in women using high risk hormonal contraception, 7.9 (5.9 to 10.6) in those using medium risk hormonal contraception, and 4.5 (2.6 to 8.1) in users of low/no risk hormonal contraception. The corresponding numbers of extra venous thromboembolic events per 100 000 women over the first week of NSAID treatment compared with non-use of NSAIDs were 4 (3 to 5) in women not using hormonal contraception, 23 (19 to 27) in women using high risk hormonal contraception, 11 (7 to 15) in those using medium risk hormonal contraception, and 3 (0 to 5) in users of low/no risk hormonal contraception.

Conclusions NSAID use was positively associated with the development of venous thromboembolism in women of reproductive age. The number of extra venous thromboembolic events with NSAID use compared with non-use was significantly larger with concomitant use of high/medium risk hormonal contraception compared with concomitant use of low/no risk hormonal contraception. Women needing both hormonal contraception and regular use of NSAIDs should be advised accordingly.

Footnotes

  • Contributors: CTP initiated the study. AM designed the study, with contributions from all co-authors. AM conducted the data management. AM did the analyses, with contribution from RKS and TAG. All authors, led by AM, were involved in data interpretation and the writing of the manuscript. AM is the guarantor. The corresponding author attests that all listed authors meet the authorship criteria and that no others meeting the criteria have been omitted.

  • Funding: The study was supported by the Danish Heart Foundation. The Danish Heart Foundation did not contribute to any part of study conduct or publication.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at https://www.icmje.org/disclosure-of-interest/ and declare: support from the Danish Heart Foundation, which funded AM’s salary, including this study; LSM has received grants from the health insurance organisation “Denmark,” the Danish Cancer Society’s Scientific Committee, and Novo Nordisk for research unrelated to the present study; CTP has received grants from Novo Nordisk and Bayer outside the current study; no other relationships or activities that could appear to have influenced the submitted work.

  • The lead author affirms that the 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 originally planned (and, if relevant, registered) have been explained.

  • Dissemination to participants and related patient and public communities: We plan to disseminate results to relevant medical societies in the form of press releases from the authors’ departments.

  • Provenance and peer review: Not commissioned; externally peer reviewed.

Data availability statement

Raw data used to conduct this study are accessible only through approval from the Danish Data Protection Agency and the Danish Health Data Board. Although anonymised, the data were available at an individual level, making data sharing restricted by the General Data Protection Regulation of EU law.

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