Is there a link between NSAID and Infertility?

Diclofenac Tablets

NSAIDs are the most commonly prescribed class of drugs worldwide and frequently consumed by patients of all age groups including women of child bearing age.

In USA most of them are freely available over the counter! According to the American College of Preventive Medicine (ACPM) report they are the second most commonly sold medications second to cough/cold and allergy remedies.

ACPM reported that over 430 million pack units of these medications were sold in the US during 2009.

The Medical world is well aware of the gastrointestinal, cardiovascular and nephrotoxicity of these class of drugs. It is also known that the potential cause of prolongation of labor, premature closure of the fetal ductus arteriosus, and increased risk for postpartum hemorrhage is due to near term use of NSAIDs.

It is the potential of these drugs to effect ovulation, conception and hormone levels in women of reproductive age that is catching attention recently.

Sporadic case series of reversible ovulatory failure associated with the development of luteinized unruptured follicles in women with inflammatory arthritis taking non-steroidal anti-inflammatory drugs appeared in medical literature as back as 1996.

Small prospective RCTs 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 of women using these agents, and this effect is reversible upon drug discontinuation.

The most recent study was presented as a poster in this year’s European League Against Rheumatism (EULAR) Annual Congress by Salman S et al. In this small trial of 39 randomly selected women who visited the Rheumatology consultation clinic, the investigators divided them into 3 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 fourth group served as controls, who received no treatment (control volunteers).

The treatment was started on Day 10^th  of the menstrual cycle and it was given for 10 days A baseline blood sample was taken from each patients for hormonal analysis (progesterone level) together with an ultra sonsography to assess the mean diameter of the dominant follicle.

The tests were repeated after 10 days of treatment.

It was seen that out of the women receiving NSAIDs, 6.3% ovulated in the diclofenac group, 25% ovulated in the naproxen group, and 27.3% ovulated in the etoricoxib group, compared with 100% 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, which disappeared by the next cycle.
Ovulation returned to normal once the women discontinued NSAID or COX-2 inhibitor use.

The investigators advocated the use of NSAID or COX-2 inhibitor with caution in those women who wants to conceive.

To summarize, these small  studies and case reports  have demonstrated an association between NSAIDs, COX-2 inhibitors and  LUFS, delayed ovulation, or ovulation failure, although no causation is demonstrated between infertility and use of these drugs.

This findings calls for more large scale and robust studies in the future to establish a link as  NSAIDs and COX-2 inhibitors are commonly prescribed and  also abused by women of childbearing age as they are freely available OTC.

Physicians should be aware of these potential adverse effects, particularly in women being treated for infertility.

For now it seems wise to proceed with caution when using them in women with fertility concerns and substitute them with acetaminophen. 

References:

1. http://ard.bmj.com/content/74/Suppl_2/117.3
2. Matyas RA, Mumford SL, Schliep KC, et al. Effects of over-the-counter analgesic use on reproductive hormones and ovulation in healthy, premenopausal women. Hum Reprod. 2015;30:1714-1723.
3. Akil M, Amos RS, Stewart P. Infertility may sometimes be associated with NSAID consumption. Br J Rheumatol. 1996;35:76-78.
4. http://www.medscape.com/viewarticle/856186
5. Salman S, Sherif B, Al-Zohyri A. Effects of some non steroidal anti-inflammatory drugs on ovulation in women with mild musculoskeletal pain. Ann Rheum Dis. 2015;74(Suppl 2):117-118.

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