NSAIDs With Hormonal Birth Control Tied to Blood Clot Risk

Popular pain relievers — such as ibuprofen, diclofenac, and naproxen — have been historically linked by research to a heightened risk of developing a venous thromboembolism (VTE), a blood clot that forms deep in a vein per the CDC. Some of these blockages can form in the leg, thigh, pelvis, or arm, possibly leading to serious illness, disability, and in some cases, death.

Research has also found that taking birth control that contains estrogen and a progestin increases the risk for blood clots. Estrogen is a sex hormone that plays a major role in the female reproductive system, and progestin, a synthetic form of progesterone, is the hormone that plays a role in the menstrual cycle.

A large study published this month in the The BMJ journal adds to the body evidence concerning these blood clot risks. The research revealed that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with an increased likelihood of blood clots in women of childbearing age.

“Studying around two million reproductive-aged women, we found that this risk was even higher in women using combined hormonal contraception [containing estrogen and progestin] than in women using progestin-only formulations or no hormonal contraception — potentially suggestive of a drug interaction between combined hormonal contraceptives and NSAIDs,” says lead author Amani Meaidi, MD, a postdoctoral researcher at the University of Copenhagen in Denmark.

While Risks May Be Higher, Incidents Are Still Low

Although hormonal birth control were linked with a higher likelihood of deep vein thrombosis and pulmonary embolism, Anne-Marie Amies Oelschlager, MD, an ob-gyn based in Seattle who serves as chair of the American College of Obstetricians and Gynecologists (ACOG) Clinical Consensus Committee on Gynecology, underscores that the rates of these events were low overall.

“NSAIDs like ibuprofen and naproxen are effective for painful periods and have a low risk of clotting for the vast majority of people,” says Dr. Oelschlager, who was not involved in the study.

In study participants not using hormonal contraception, NSAID use was associated with four extra VTE events per week per 100,000. NSAIDs were linked to 11 extra events in women using medium-risk hormonal contraception, and 23 extra events in women using high-risk hormonal contraception.

Considering Alternatives to Higher-Estrogen Birth Control and NSAIDs

High-risk contraceptives included combined estrogen and progestin patches, vaginal rings, and pills containing 50 micrograms of estrogen.

Dr. Meaidi and her team suggest that women can lower risk by choosing medium-risk or low- or no-risk birth control formulations.

Medium-risk contraception was defined as all other combined oral contraceptives (which contain less than 50 micrograms estrogen) and the medroxyprogesterone injection. Medroxyprogesterone (Depo-Proverra) is given every three months and does not contain estrogen.

Low- or no-risk options were progestin-only tablets, implants, and hormone intrauterine devices (coils).

Women may also want to discuss alternatives to NSAIDs with their doctor.

“Heat, exercise, and distraction are effective for menstrual pain,” says Oelschlager. “Acetaminophen is another pain reliever that appears to have a lower clotting risk and may be an option for those who wish to avoid ibuprofen, naproxen, or diclofenac.”

Results Based on a Large Study Population

For this scientific paper, researchers reviewed national medical records of 2,029,065 women ages 15 to 49 living in Denmark between 1996 and 2017 with no history of blood clots, cancer, hysterectomy, or fertility treatment.

Among that population, over half a million (529,704) were using NSAIDs while on hormone birth control. Ibuprofen (Advil, Midol, or Motrin) was the most frequently used NSAID (60 percent). About 20 percent used diclofenac (Voltaren, Zipsor, Zorvolex, or Cataflam) and 6 percent used naproxen (Aleve).

Meaidi notes that on average most NSAID users filled a one-week NSAID treatment order two times during 10 years of follow-up, indicating NSAID use was for short-term, temporary pain.

Over an average 10-year monitoring period, 8,710 venous thromboembolic events occurred. Of these, 2,715 were pulmonary embolisms (PEs; obstructions in the blood vessels that send blood to the lungs) and 5,995 were deep venous thromboses (DVTs).

A total of 228 (2.6 percent) women died within 30 days of their diagnosis.

A Bigger Threat From Diclofenac?

Compared with ibuprofen and naproxen, diclofenac was associated with the greatest risk—a twofold increased likelihood of thrombosis compared with women taking ibuprofen or naproxen.

Diclofenac is a stronger NSAID than ibuprofen and naproxen and has been associated with a higher cardiovascular disease risk compared with other NSAIDs. A prior study in The BMJ found diclofenac to be linked with a 50 percent increased risk of cardiac arrest, while ibuprofen was linked with a 31 percent greater risk.

“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,” wrote Morten Schmidt, MD, at Aarhus University Hospital in Denmark, in a linked editorial.

Dr. Schmidt added that healthcare authorities and regulators should include these research findings in their safety assessment of available over-the-counter diclofenac, and women using hormone birth control and their clinicians should consider alternatives to NSAIDs for analgesics (painkillers).

Why These Treatments May Be Increasing Blood Clot Risk

While the study findings suggest that these painkillers may be related to blood clot risk in women using hormone birth control, they do not show that they cause blood clots or that the medications interacted to heighten the risk.

Meaidi speculates, however, that the outcomes may be related to effects on the body’s coagulation (blood clotting) system.

“NSAIDs are known to increase blood platelet aggregation, which normally is associated with arterial thrombosis — heart attack and stroke,” she explains. “Oral contraceptives activate the coagulation system. How the two drug classes may intensify the coagulation system in a way that intensifies the risk of thrombosis is not known, however.”

Further research is needed to investigate the potential mechanism of the interaction between the two drug classes, according to Meaidi.

The authors recognize several limitations with the study. It was based on observations from previously recorded medical data versus results from directly following a controlled group. It was also missing information about smoking and obesity, which they say may have affected their results.

Overall, Oelschlager suggests that hormone birth control and NSAIDs are still considered safe for women who are young and healthy, and can be used together if needed.

“If you have risk factors for DVT or PE — like a clotting disorder, family history of clotting disorders, obesity, tobacco use, heart failure, autoimmune conditions, or a recent surgery, injury, or pregnancy, I would advise you to discuss lower-risk contraceptive options with your doctor,” she says.