Researchers Warn about Nonsteroidal Anti-inflammatory Drugs and Infertility

Nonsteroidal anti-inflammatory drugs (NSAIDs)—among the most commonly prescribed drugs worldwide for pain and inflammation and frequently used by women of childbearing age—may adversely affect ovulation.

NSAIDs are known to have adverse gastrointestinal, cardiovascular, and renal effects and, when used near the end of pregnancy, NSAIDs may prolong labor, result in premature closure of the fetal ductus arteriosus, and increase the risk for postpartum bleeding, Medscape Multispecialty reports. The potential for NSAIDs to impact fertility has received less attention than other complications.

NSAIDs are prostaglandin inhibitors that block cyclo-oxygenase (COX)-1 and COX-2 enzyme production. COX-2 is active in the ovaries during follicular development and inhibition of COX-2 by NSAIDs and COX-2 inhibitors (e.g., celecoxib) is thought to potentially cause reversible luteinized unruptured follicle syndrome (LUFS) in some patients, Medscape reports. This syndrome is characterized by a failure of ovulation. While clinical signs of ovulation—elevated body temperature and progesterone levels— are present, follicular rupture and ovum release do not occur. Sporadic reports of delayed ovulation and/or LUFS associated with NSAID use have appeared in the medical literature.

COX-2 inhibitors may have other adverse effects on fertility. COX-2 is thought to have a role not only in ovulation but also in fertilization, implantation, and maintenance of pregnancy. COX isoforms are important in the generation of prostaglandins that are essential for formation of proteolytic enzymes causing rupture of the egg follicles as well as prostaglandins crucial in the establishment of the placenta, according to Medscape.

Small clinical trials have demonstrated that NSAIDs and COX-2 inhibitors produce a reversible delay in follicular rupture. Unruptured follicles were more often observed in a significantly higher proportion in women using these drugs; this effect is reversible when the drug is discontinued, Medscape reports.

The most recent data were presented by Salman and colleagues at the 2015 European League Against Rheumatism (EULAR) Annual Congress. Their prospective trial randomly assigned 39 women of childbearing age with minor back pain to one of four groups:

• Diclofenac, 100 mg once daily
• Naproxen, 500 mg twice daily
• Etoricoxib (a COX-2 inhibitor not available in the United States), 90 mg once daily
• A control group that received placebo

Participants began treatment starting on day 10 of their menstrual cycles to ensure that a follicle developed in preparation for ovum release. Study medications were taken for 10 consecutive days. At baseline, progesterone levels were determined, and each woman received an ultrasound to assess the size of the dominant follicle on the affected ovary. After 10 days of treatment, these assessments were repeated. Of the women receiving NSAIDs, only 6.3 percent ovulated in the diclofenac group, 25 percent ovulated in the naproxen group, and 27.3 percent ovulated in the etoricoxib group, compared with 100 percent of the control group. All three treatment groups experienced decreases in progesterone level, and about one third of women developed functional cysts due to unruptured follicles. Ovulation returned to normal once the women discontinued NSAID or COX-2 inhibitor use, Medscape reports.

Though no large-scale, prospective controlled trial has shown a causal link between NSAID or COX-2 inhibitor use and female infertility, the investigators concluded that caution is warranted because of potential adverse effects on female fertility. They suggest that women who plan to conceive should temporarily avoid these drugs and consider substituting acetaminophen when clinically appropriate, according to Medscape.