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Anti-Inflammatory Drug May Boost Implant Success

A non-steroidal anti-inflammatory drug (NSAID) may be the key to boost the success of embryo implantation in in-vitro fertilization procedures, say doctors in a new, international study.1

Yet the findings contradict those of other studies which warn of the risks of NSAID use for women attempting to have children.

The drug is known as piroxicam (peer-OX-ih-kam), and marketed as Feldene by Pfizer. It's prescribed as a therapy for both osteoarthritis and rheumatoid arthritis.2

How NSAIDs Work
NSAIDs are available to consumers over-the-counter or by prescription. Examples of over-the-counter NSAIDs include aspirin and ibuprofen. They're used to relieve mild to moderate pain accompanied by inflammation and swelling. NSAIDs do this by blocking the action of an enzyme in the body known as cyclooxygenase (sye-kloh-OX-eh-jen-aze), or COX. The enzyme makes hormone-like substances called prostaglandins that are involved in the development of inflammation and pain.3

"During the past 20 years, numerous studies have been made to improve the implantation process," wrote Bo Sun Joo, PhD, with the Center for Reproductive Medicine and Infertility at Good Moon-Hwa Hospital in Busan, Korea and her colleagues in the October issue of the journal Fertility and Sterility. "Most of their attempts have been focused on the induction and selection of the best quality embryos, and the improvement of uterus receptivity."

In Sync
In order for an embryo to implant in the uterus properly to begin a pregnancy, several molecular events occur that prepare the uterus to receive the embryo. If the uterus isn't receptive to an embryo, implantation will fail.4

While improvements in controlled ovarian hyperstimulation, fertilization and the way embryos are kept in culture in IVF have been made in recent years, "little development has increased the uterus receptivity" to the embryo just prior to implantation, the Korean researchers pointed out.

Previous research5 has found that the more a uterus contracts just before implantation, the less likely a successful implantation will occur, said the Korean investigators. Doctors have suggested that multiple contractions may force the embryo out of the uterine cavity.5

Since it's known that prostaglandins boost uterine contractions, and since NSAIDs block the production of prostaglandins, the investigators wanted to find out if this might be the link in the use of piroxicam in this way prior to embryo transfer.

Does This NSAID Help Boost Implantation?
Their study involved nearly 200 consecutive IVF cycles involving fresh embryos, and 78 cycles involving previously frozen embryos performed at the Korean researchers' hospital over a 2-year period. A cycle begins with the patient's evaluation, and ends with a successful implantation. Only women who underwent IVF due to a tubal factor, male infertility factor, unexplained reasons, or because of endometriosis were included.

All women were selected at random in the blinded study to receive 10 milligrams (mg) of piroxicam or placebo approximately 1 to 2 hours before embryo transfer. A placebo is a nontherapeutic intervention used as a comparison to the therapeutic drug being tested. Patients are given either intervention, and then the effects of the drug and placebo are compared.

On average, four embryos were transferred to the uterus for pregnancy in both groups. There were no significant differences in embryo quality between the two groups, the doctors reported.

IVF Outcomes Measured
In cycles using fresh embryos, the odds of a successful implantation were about 18% for women who took piroxicam before embryo transfer, compared to just 8.6% for those given a placebo. The pregnancy rate was about 47% in the women given the NSAID prior to transfer, compared to 28% for those who took a placebo beforehand.

"When the pregnancy rates were compared according to the causes of infertility, piroxicam treatment increased [the rates] about twice as much in patients with tubal, male infertility, or endometriosis factors compared to the control group," wrote Joo and her team. "However, no beneficial effect of piroxicam was found in unexplained infertile patients." (About 44 percent of the women taking the NSAID eventually became pregnant, compared to about 39 percent of those taking placebo.)

In cycles using previously frozen embryos, the implantation and pregnancy rates were 9.4% and 25.6%, respectively, in the group taking the NSAID. That compares to 2.3% and 7.7%, respectively, for those given a placebo, the study team reported.

The researchers also found that those women under age 40 generally did better than those over 40 years of age.

NSAID Caveat
The positive findings contradict warnings from other doctors, however, about the potential risks of using COX inhibitors (a subcategory of NSAIDs like piroxicam) for women attempting to become pregnant.6 In an editorial earlier this year, Robert Norman, MD, and Ruijin Wu, MD, wrote that blocking the action of prostaglandins in the body can disrupt the development of the uterine lining as it gears up to receive the embryo. That's because this development is similar to inflammation, which is what COX inhibitors block.

Still, in an interview last March with Priority Healthcare, Norman acknowledged that "we don't have a lot of information about this topic, and I guess we should not scare people too much."

In their editorial, Norman and Wu cited previous animal studies involving mice bred without a gene that causes COX activity as having lower ovulation, fertilization and implantation rates.

A Possible Miscarriage Risk?
In a 2003 study,7 doctors at Kaiser Permanente in California concluded that taking aspirin or NSAIDs prior to conception can increase the likelihood of a miscarriage. They interviewed 1063 women about their medication history prior to conception, and found that using NSAIDs boosted the chances of a miscarriage by 80%. The researchers theorized that these drugs somehow lead to abnormal implantation that predisposes an embryo to miscarriage. They cited animal studies that have found that prostaglandins are essential for healthy implantation. However, piroxicam use was not included in the study.

Despite these other studies, the Korean investigators point out that "there are no reports concerning any adverse effects from one dose (10 mg) of piroxicam during the preimplantation period. Our present study does not show any increase in spontaneous abortion [miscarriage], as well as malformation after piroxicam treatment compared to the control group in IVF."

As previously mentioned, the beneficial effect of piroxicam in this case may be directly related to its ability to reduce uterus contractions prior to implantation. "In this respect, the one-time oral treatment with piroxicam on the day of embryo transfer seems to increase the implantation of [the embryo] by calming uterine contraction rather than inhibiting embryo development …" wrote Joo and her colleagues. Further research to confirm that is needed, they said.

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