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Use of common painkillers alongside hormonal contraception linked to heightened risk of blood clots
Absolute risk remains low but women should be advised accordingly, say researchers
Women who use non-steroidal anti-inflammatory painkillers alongside hormonal contraception appear to be at a small increased risk of blood clots known as venous thromboembolism (VTE), finds a large Danish study published by The BMJ today.
The risk was greater in women using combined oral contraceptives containing third or fourth generation progestins, but smaller in women using progestin-only tablets, implants and coils, alongside the non-steroidal anti-inflammatory drugs (NSAIDs) ibuprofen, diclofenac, and naproxen.
The researchers stress that the absolute risk of developing a serious blood clot is low, even in women using high risk hormonal contraception. But given the widespread use of both hormonal contraception and NSAIDs, they say women should be advised of this potential drug interaction accordingly.
NSAIDs have previously been linked to blood clots, but little is known about whether using NSAIDs influences the risk of venous thromboembolism in otherwise healthy women using hormonal contraception.
To address this, researchers used national medical records to track first time diagnoses of venous thromboembolism among 2 million women aged 15 to 49 years living in Denmark between 1996 and 2017 with no 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.
A range of potentially influential factors such as age, education level, pregnancy history, prior surgery, high blood pressure and diabetes, were also taken into account.
In the study, NSAIDs were used by 529,704 women while using hormonal contraception. Ibuprofen was the most frequently used NSAID (60%), followed by diclofenac (20%) and naproxen (6%).
Over an average 10-year monitoring period, 8,710 venous thromboembolic events occurred (2,715 pulmonary embolisms and 5,995 deep venous thromboses), and 228 (2.6%) women died within 30 days of their diagnosis.
In absolute terms, NSAID use was associated with four extra venous thromboembolic 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.
Among individual NSAIDs, the association was strongest for diclofenac compared with ibuprofen and naproxen.
This is an observational study, so can’t establish cause, and the researchers highlight several limitations, such as missing information about smoking and obesity, which they say may have affected their results.
Nevertheless, this was a large study based on high quality registry data and the researchers were able to adjust for a wide range of potentially influential factors. What’s more, the associations persisted after further analysis, suggesting that they are robust.
As such, the researchers conclude: “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 add: “Women needing both hormonal contraception and regular use of NSAIDs should be advised accordingly.”
These data raise important concerns about using NSAIDs, particularly diclofenac, and high risk hormonal contraception concomitantly, writes Morten Schmidt at Aarhus University Hospital, in a linked editorial.
He suggests that healthcare authorities and regulators should include these findings in their safety assessment of available over-the-counter diclofenac, and women using hormonal contraception and their clinicians should consider alternatives to NSAIDs for analgesia.
“If treatment with NSAIDs is needed, agents other than diclofenac seem preferable, along with lower risk hormonal contraceptives such as progestin only tablets, implants, or intrauterine devices,” he concludes.
Expert Reaction
These comments have been collated by the Science Media Centre to provide a variety of expert perspectives on this issue. Feel free to use these quotes in your stories. Views expressed are the personal opinions of the experts named. They do not represent the views of the SMC or any other organisation unless specifically stated.
Associate Professor Ashraf Ghanem is a researcher in organic chemistry from the Biomedical Science Program in the School of Science at The University of Canberra
As is the case in all drugs, there will be always beneficial effects alongside potential risks affecting people differently. Hormonal contraceptive drugs contain hormones like estrogen and progestin that inhibit ovulation (the release of an egg from an ovary). It is well known that estrogen and progestogens have been linked to increased risks of blood clots as they increase the level of clotting factors.
Furthermore, some of the non-steroidal anti-inflammatory drugs, also known as NSAIDs such as ibuprofen, diclofenac and naproxen can also increase the risk of blood clot or venous thromboembolism (VTE).
Consequently, the risk of VTEs has been always there and such caution has been always described with the administration of the pills or the use of the aforementioned NSAIDs. The current Danish study published by The BMJ today is claiming small increased risk of blood clots in women who use non-steroidal anti-inflammatory painkillers alongside hormonal contraception than those who are using separately. They claim that the risk remains low. There is no evidence of drug interaction between the two elements and this itself put the study at risk.
Furthermore, crucial info about smoking and obesity is missing or hasn’t been addressed putting lots of doubts about the real cause of blood clot or VTE. For example, in recent Danish study, researchers found that among nearly 19,000 Danish adults followed for 20 years, those who were obese or heavy smokers had an increased risk of developing VTE Compared with non-smokers, those who smoked 25 cigarettes a day or more had a 52 percent greater risk.
This study found higher rates of blood clots among women who took three commonly used type of painkillers – ibuprofen, naproxen and diclofenac – while also taking birth control pills. This effect was strongest among women who were taking birth control pills already associated with higher blood clotting risks. These higher-risk pills are mainly not PBS-funded; they include brands such as Marvelon, Minulet, Yaz and Yasmin and Diane-35, as well as patches and vaginal rings.
This was a small increase in risk. On average, 1 in 4400 women experienced a blood clot who wouldn’t have otherwise if they used these painkillers together with higher-risk birth control. Around one third of the clots were in the lungs (“pulmonary embolisms”), which are potentially fatal.
The take-home message from this study is to avoid combined use of these painkillers and specific types of birth control if possible. It also adds to existing evidence that lower risk types of birth control that are equally effective to higher-risk options should be a first choice, with higher risk products reserved for those not tolerating first-choice options. And among painkillers, these three products, and especially diclofenac should be avoided while using many commonly-used types of birth control.
Dr Ian Musgrave is a Senior Lecturer in the Faculty of Medicine, School of Medicine Sciences, within the Discipline of Pharmacology at the University of Adelaide.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are are the most commonly used class of drugs in the world and a widely used for pain control and treatment of inflammation. NSAIDs are often linked to an increased risk of bleeding as they affect blood-clotting mechanisms, and low dose aspirin is used to reduce the risk of blood clots. Paradoxically, high dose NSAIDs have been linked to clotting events like deep vein thrombosis.
Hormonal contraction is also linked to an increased incidence of blood clots, and this large, nation-wide Danish study investigated whether use of NSAIDs could interact with hormonal contraception. 2.0 million women aged between 15-49 year old were followed for 22 years looking for the clotting events in the legs (deep vein thrombosis) or lung clots (pulmonary embolism). The divided the women into high risk, medium risk and low risk groups due to their use of hormonal contraception.
The way the study was reported can give rise to unwarranted concern. The conclusion “NSAID use was positively associated with the development of venous thromboembolism in women of reproductive age.” Was only true for the high risk group, the medium group risk was the same as the women on no hormonal contraception and for the low risk group the risk may even be less. The risk of clotting events in women in the high-risk hormonal group who used NSAIDs was around 1.5 times that of women who used NSAIDs but did not use hormonal contraceptives.
The strengths of the study is the large nation-wide coverage, linked to extensive medical databases so NSAID use could be effectively monitored, and avoids the bias of people trying to recall how much of a medication they used. However, only 0.4% of the population had a clotting event, and the small numbers affect the robustness of the result. Nonetheless this study provides good evidence that women on hormonal contraception who are at high risk of clotting events have an increased risk when on NSAIDs, and prescribing should pain relief in these women should recognise this risk. What was not clear from this study is how long you need to be taking NSAIDs before the risk was increased (that is, will a single NAIDS tablet for pain relief be a risk or do you need to be on them for a lengthy period). Regardless, women should consult their medical practitioner before making any changes to their pain medication.
