A population-based self-controlled case series study from four countries in Europe suggests the commonly used painkillers may have been unfairly blamed for raising the risk of blood clots in women using hormonal contraceptives.
Non-steroidal anti-inflammatory drugs may not be solely responsible for the increased risk of venous thromboembolisms in women taking hormonal contraceptives, new research has shown.
The study, which used data from more than three million women across four European countries, concluded that the underlying health conditions that necessitated the use of NSAIDs also contributed to the increased VTE risk.
“We observed increased venous thromboembolism risk not only during NSAID use but also in the period before initiation, on the day of initiation, and after exposure,” said the researchers. “A similar pattern was observed with paracetamol, a prespecified negative control exposure not expected to increase venous thromboembolism risk.”
“These findings suggest that the observed association between NSAID use and venous thromboembolism is unlikely to be causal and is more consistent with residual or unmeasured confounding.”
The findings were published in The Lancet Obstetrics, Gynaecology, & Women’s Health.
Data regarding the use of hormonal contraceptives and NSAIDs were sourced from four locations: the Danish Data Health Registries (January 2014 to November 2024), the Norwegian Linked Health Registry (January 2018 to December 2023), the Information System for the Development of Research in Primary Care in Spain (January 2014 to June 2023), and the Clinical Practice Research Datalink in the UK (January 2014 to June 2024). The Danish data came from dispensation records, while data for the remaining three countries were based on prescription records.
The researchers focused on women aged 15-49 years who used hormonal contraceptives with no history of venous or arterial thromboembolism, cancer (excluding non-melanoma skin cancer), thrombophilia, hysterectomy, bilateral oophorectomy, sterilisation, or infertility treatment prior to using the hormonal contraceptives. Women who used NSAIDs in the 90 days before starting hormonal contraceptives were excluded, as were women with less than 365 days of data available before starting hormonal contraceptives.
Hormonal contraceptives were classified into one of three groups based on their known VTE risk: low (oral contraceptives, implants, or intrauterine devices that only used progestogen), medium (medroxyprogesterone injections or combined hormonal contraceptive formulations containing <50µg of ethinyl oestradiol or oestradiol), or high (transdermal patches, vaginal rings, or oral tables containing ≥50µg of ethinyl oestradiol).
The women were “followed” from the start of a contraceptive episode or study period (whichever occurred later) until they stopped using hormonal contraceptives, they switched to a different contraceptive risk group, they turned 50, or they fell pregnant.
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The rate of VTE in women exposed to hormonal contraceptives was estimated at six different timepoints based on concomitant NSAID exposure: baseline (only exposed to hormonal contraceptives), pre-exposure to NSAIDs (the two weeks before using NSAIDs while taking hormonal contraceptives), NSAID initiation (the first day of concurrent hormonal contraceptives and NSAID use), the main risk period (the first seven days of taking both hormonal contraceptives and NSAIDs), the extended risk period (the remaining time where hormonal contraceptives and NSAIDs were used simultaneously), and post-exposure to NSAIDs (the 30 days after stopping NSAIDs while hormonal contraceptives were still being used).
No country had high-risk hormonal contraceptives as the most commonly used contraceptive technique. Low-risk hormonal contraceptives were most common in Denmark (636,348 of 1,441,931, 44.1%), Norway (448,284 of 876,932, 51.1%), and the UK (460,703 of 1,002,435, 46.0%), while medium-risk contraceptives were most widely used in Spain (204,658 of 384,413, 53.2%).
Regardless of the hormonal contraceptive risk category, the proportion of women who used a prescribed NSAID while taking hormonal contraceptives sat between 20% and 50% across Denmark (28.8% for low-risk contraceptive users, 23.8% for medium-risk users, and 20.0% for high-risk users), Norway (27.5%, 25.8%, and 29.0%), and Spain (39.2%, 46.7%, and 30.2%). The proportions in the UK were lower; 16.7% for low-risk, 11.7% for medium-risk, and 9.6% for high-risk.
The real-world rate of VTE while using NSAIDs and hormonal contraceptives was less than 0.1% for all risk groups across the four countries, except for high-risk users in Norway:
- UK: 0.04% for low-risk, 0.02% for medium-risk, and 0.02% for high-risk
- Denmark: 0.07% for low-risk, 0.04% for medium-risk, and 0.04% for high-risk
- Norway: 0.04% for low-risk, 0.08% for medium-risk, and 0.14% for high-risk
- Spain: 0.03% for low-risk, 0.06% for medium-risk, and 0.05% for high-risk
After adjusting for age, seasonality, and potential indications for NSAID use, there was a consistent pattern in VTE risk across all countries and hormonal contraceptive risk categories: the incident rate ratios were raised before NSAID use commenced, peaked on the day concomitant use started, and then decreased over time.
