The popular anti-inflammatory drugs ibuprofen and naproxen could contribute to the risk of miscarriage when taken early in pregnancy, researchers report online September 6 in the Canadian Medical Association Journal.

Other research has indicated that the common painkillers collectively known as NSAIDs, or non-steroidal anti-inflammatory drugs, can impart some danger to a fetus. Pill bottles caution pregnant women to consult their doctors before taking the drugs, and specifically to avoid NSAIDs during the final three months of gestation. The new study bolsters evidence that would extend that caution to the first trimester.

“Women who are thinking about getting pregnant and have stopped using contraception — or just someone in reproductive age — should be a little careful,” says epidemiologist De-Kun Li of Kaiser Permanente Northern California Division of Research in Oakland, who wasn’t involved in the study.  

In Quebec province, where the study was done, NSAIDs are typically obtained by prescription, with the exception of ibuprofen (Advil, Motrin, Nuprin), which is also available over the counter. University of Montreal epidemiologist Anick Bérard and her colleagues checked prescriptions filled by 4,700 women who had miscarriages and about 47,000 other pregnant women who didn’t.

During the first 20 weeks of pregnancy, 7.5 percent of those who miscarried had filled an NSAID prescription beforehand, compared with only 2.6 percent the women who hadn’t miscarried.

Use of NSAIDs was associated with a 2.4-fold increase in risk of miscarriage. The researchers checked for use of ibuprofen, naproxen (Aleve), celecoxib (Celebrex), rofecoxib (Vioxx) and diclofenac, which has many trade names. They didn’t include aspirin, an NSAID, in the measurements, or acetaminophen (Tylenol), which isn’t an NSAID.

The new study is the third and largest observational study linking NSAID exposure to miscarriage. In 2001, Danish researchers detected a similar NSAID risk. And in 2003, Li and his colleagues found that NSAIDs such as ibuprofen and naproxen seemed to impart a greater miscarriage risk than aspirin (SN: 8/23/03, p. 115).

In the United States, ibuprofen and naproxen are widely available without a prescription. “As a rule, people think over-the-counter medications are less toxic than prescription meds, but many times it’s not true,” Bérard says.

NSAIDs have broad effects because they inhibit two enzymes, a process that slows the synthesis of chemical messengers called prostaglandins. These messengers are instrumental in inflammation and are among the compounds that induce fever. The ability to limit these effects, coupled with effective marketing, has placed NSAIDs among the best-selling drugs in the world.

But prostaglandins also play a role in reproduction, and studies in animals have shown that a lack of prostaglandins can lead to defective embryo implantation in the uterus.

In its pregnancy handbook, the American College of Obstetricians and Gynecologists counsels women to generally avoid aspirin and other NSAIDs. But advice from other sources on the first-trimester risks has been mixed, in part because scientists must rely on animal tests of the drugs. A trial testing the risks of NSAIDs versus no NSAIDs in pregnant women won’t happen, Li says, because it would be unethical to dole out drugs that could potentially harm a fetus.

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