NEWS FROM REPRODUCTIVE PARTNERS

Antagon - A New and Simpler Alternative to Lupron
by David R. Meldrum, M. D.

GnRH agonists have been routinely used for IVF cycles since they prevent ovulation before egg retrieval, improve the ovarian response, and increase the success rate approximately two-fold over IVF cycles without use of a GnRH agonist. These benefits are produced by suppression of luteinizing hormone (LH). Leuprolide acetate (Lupron) has been the most common GnRH agonist used for IVF, although Synarel (a form given by nasal spray) has been tried with similar success. Lupron is given by injections under the skin, sometimes overlapping with an oral contraceptive, but often given starting about one week after ovulation.

For a GnRH agonist to suppress luteinizing hormone, it must first stimulate the release of gonadotropins (FSH and LH). This can complicate the IVF cycle by causing a cyst to form and by requiring extra time for LH and the estrogen level to be suppressed. Generally about 3 weeks of treatment is required but individual patients may require longer treatment. 

A new medication, Antagon (a GnRH antagonist) which suppresses LH within hours will soon be available. Therefore, it can be used only during the latter period of egg maturation when it is important to avoid excessive LH levels and when LH could rise enough to cause release of the eggs. It is usually used for only 3 to 5 days. Injection discomfort is similar or less than Lupron. Its most important advantage is in avoiding menopausal symptoms that occur with use of GnRH agonist after suppression and before estrogen rises with ovarian stimulation. In some women these can be severe with headache, moodiness or problems with recent memory. Such side effects could be more important with certain occupations (for example lapses in memory could be very disturbing for a trial lawyer or for someone giving lectures).

Large trials in Europe and North America have compared Antagon to GnRH agonist. A slightly lower egg yield and success rate (about 5%) was noted. However, Antagon was compared to GnRH agonist protocols that have been refined for over 10 years and with which the investigators were very familiar. It actually seems remarkable that the results with Antagon came so close with a first pass at defining an optimal protocol.

I have been involved in research on GnRH analogs for almost 20 years and Reproductive Partners was involved in the North America Antagon study. Based on the results I have advised using an oral contraceptive in the preceding cycle to improve egg yield and to allow flexibility in scheduling the egg retrieval. Since the LH levels were quite low on Antagon, and low LH levels could reduce egg quality, we are recommending that women on Antagon should take 1 or 2 ampules of hMG (Pergonal, Humegon or Repronex), that contains LH. These modifications should bring the Antagon results to levels very close or equal to Lupron. At Reproductive Partners we will be involved in studies to examine both of these variables over the next year or two, but I would feel confident that patients who wish to use Antagon would not significantly influence their results.

The large trials described above excluded poor responders. Since poor responders can have improved results by avoiding suppression with a GnRH agonist, they may do particularly well on Antagon. We will be doing a controlled study comparing Antagon with the mini-Lupron flare, which is currently the protocol of choice for poor responders.

In summary, Antagon should provide the same benefits as the GnRH agonist with fewer injections and no menopausal side effects, thus further simplifying ovarian stimulation for IVF. 

(NOTE: Although the FDA has approved Antagon for release, its introduction to the marketplace has been delayed by a patent dispute.)

Need for Folic Acid is an Important
Part of Preconceptual Counseling

A recent survey indicates that only 7% of women are aware that folic acid should be taken prior to conception. This is despite a seven-year old recommendation by the Public Health Service and the Institute of Medicine that all women of childbearing age should consume 400 micrograms of folic acid daily to reduce the chance of having a baby with a neural tube defect (MMWR, 1999;48:325-327). 

The sad result of the failure of women and their doctors to pay attention to this message is that the potential to prevent more than 2000 cases of neural tube defects a year (out of an estimated 4000 a year) has not been realized. In order to overcome this deficiency the government last year mandated that cereal and grain products be fortified with folic acid. However, even with this measure getting enough folic acid from the diet is extremely difficult. In addition, folic acid is effective only if taken in the first few weeks of pregnancy. So taking a folic acid supplement or a multivitamin containing 0.4 milligrams of folic acid has been recommended for all women of reproductive age. 

However this is better than the situation in 1995 when only 2% were aware that folic acid should be taken before pregnancy. The bottom line is that the percentage of women taking a vitamin supplement containing folic acid on a daily basis has increased from 28% to 32% between those years but is still far from the goal.

At Reproductive Partners we have prepared an information sheet on preconceptual recommendations which deals with the folic acid issue and many others to consider. 

Rise in Multiple Births Reported
By Government Agency

If you haven't noticed, there seems to be a dramatic increase in the numbers of families with twins, triplets and even more. This observation was borne out by the National Center for Health Statistics which, according to a recent report, noted that more than 104,000 sets of twins were born in 1997, a 52 percent increase in twins over the past two decades. There were more than 6700 births of triplets or more in 1997, a fourfold increase since 1980.

The increase is particularly striking in older women. There were more twins born to women in their late 40s in 1997 than in all the 1980s. The agency attributes the trend to the popularity of fertility drugs combined with the trend for women to wait longer to have children.

It is well known that multiple births pose additional risks to the babies and mothers as well. Complications such as prematurity, low birth weight, vision and hearing impairments, developmental delay as well as maternal anemia and high blood pressure are more likely to occur.

At Reproductive Partners we strive to prevent high level multiple pregnancies by limiting the number of embryos we transfer in IVF procedures, studying and employing the blastocyst transfer in couples at high risk for multiples and using fertility drugs conservatively to try to limit the number of eggs developed. Careful and prudent techniques can reduce, but not eliminate, the risk of multiple pregnancy.