11 September 2023

Women who use non-steroidal anti-inflammatory drugs (NSAIDs) alongside hormonal contraception could be raising their risk of developing venous thromboembolism (VTE), Danish researchers have reported.

Led by a team at the University of Copenhagen, the observational study found that women using combined oral contraceptives containing third or fourth generation progestins alongside NSAIDs, such as ibuprofen, diclofenac, and naproxen, had the greatest risk, while those taking progestin-only tablets, implants and coils had a lesser risk.

Writing in The BMJ, they say while the absolute risk of developing a serious blood clot is low, even in women using high risk hormonal contraception, women should be aware of the potential risk.

The researchers examined national medical records to track first time diagnoses of VTE among two million women aged 15 to 49 years, all of whom were living in Denmark between 1996 and 2017. None had a history of blood clots, cancer, hysterectomy or fertility treatment.

Hormonal contraception was divided into high, medium and low risk, according to their association with VTE based on previous studies. High-risk hormonal contraception included combined oestrogen and progestin patches, vaginal rings, and pills containing either 50 mcg oestrogen or third or fourth generation progestins.

Medium risk contraception included all other combined oral contraceptives and the medroxyprogesterone injection, while progestin-only tablets, implants, and hormone intrauterine devices (coils) were classed as low or no risk.

NSAIDs were used by 529,704 women while using hormonal contraception, with ibuprofen being the most frequently used at 60%, followed by diclofenac (20%) and naproxen (6%).

Over an average 10-year monitoring period, 8,710 VTE events occurred, of which 2,715 were pulmonary embolisms and 5,995 deep venous thromboses.  228 (2.6%) women died within 30 days of their diagnosis.

In absolute terms, NSAID use was associated with four extra VTE events per week per 100,000 women not using hormonal contraception, 11 extra events in women using medium risk hormonal contraception, and 23 extra events in women using high risk hormonal contraception.

The association was strongest for diclofenac compared with ibuprofen and naproxen.

Although this was an observational study, the research team says it was a large study based on high quality registry data and they adjusted for a wide range of potentially influential factors.

“Using high quality, linkable, national registries, this nationwide study adds new knowledge on the risk of a potentially fatal event during concomitant use of two drug classes often prescribed to otherwise healthy women,” they write.

They add: “Women needing both hormonal contraception and regular use of NSAIDs should be advised accordingly.”


Meaidi A, Mascolo A, Sessa M, Toft-Petersen AP, Skals R, Gerds TA, Wessel Skovlund C, Morch LS, Rossi F, Capuano A, Lidegaard O, Torp-Pedersen C. (2023) “Venous thromboembolism with use of hormonal contraception and non-steroidal anti-inflammatory drugs: nationwide cohort study.” BMJ, doi: 10.1136/bmj-2022-074450

Link: https://www.bmj.com/content/382/bmj-2022-074450

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