CHR Update November 2010

It just seems like yesterday that we suffered in sweltering heat. This month we already celebrate Thanksgiving, with the Holiday Season quickly to follow. Change is so rapid these days, it seems!

Change is, however, nowhere quicker than in medicine, where, based on newly generated research, best available evidence (i.e., our best available knowledge level) is in constant flux. This month’s CHR UPDATE is, therefore, mostly dedicated to two important IVF-related issues, where reappraisals are called for.

Low intensity IVF

In recent years a new concept of IVF has entered world-wide practice, initially mostly led by colleagues from Asia and Europe, but more recently also aggressively pursued by fertility centers in this country. Proponents of so-called low intensity IVF (LI-IVF) argue that IVF, as it is currently practiced, is neither clinically nor economically the most efficient way to treat infertile women and, on top, also is excessively cumbersome to patients, while exposing them unnecessarily to excessive amounts of medications.

Since everybody in medicine, of course, wants to be clinically as effective as possible, at the lowest possible costs and with the least medication usage, the concept sounds highly attractive. It, therefore, should not surprise that physicians and patients alike fell in love with this new approach, and that LI-IVF programs sprouted all over the world, under such acronyms as minimal stimulation IVF, natural cycle IVF, modified natural cycle IVF, controlled natural cycle IVF, patient friendly IVF and (in NYC) mini-IVF.

There is only one problem with this wonderful, new concept of LI-IVF: It was never experimentally proven to do any of the things it promised to do. Indeed, much to the contrary: a small number of published studies actually raise serious questions about claims of clinical- and cost-effectiveness, especially in women with diminished ovarian reserve (DOR), where LI-IVF was principally proposed.

For example, a widely touted approach toward LI-IVF, coming out of Japan’s and likely the world’s largest IVF program, reported the center’s anecdotal experience in one single publication (Teramato and Kato., Reprod Biomed Online 2007;15:134-148). We call this anecdotal because the authors in this report broke most rules of study design, which renders their data practically uninterpretable. This is actually quite a pity since their study of ca. 43,000 cycles represents, likely, the largest single-center IVF report ever published. A properly selected study population, undoubtedly, could have been selected from amongst this huge cycle volume.

This study, constantly cited in support of LI-IVF, reported that only 11.1% of cycles resulted in live births. By U.S. standards, this live birth rate represents a rather dismal outcome for an unselected patient population. How such an approach, therefore, could be considered clinically effective – and cost-effective – is rather puzzling.

The same group also published a single study in support of so-called natural cycle IVF, where the authors propose this approach based on "as many" as only three established pregnancies and transfer of only one embryo in every 16 cycle attempts (Matsuura et al., J Assist Reprod Genet 2008;15:163-7). This, once again, quite clearly does not represent an acceptable outcome in a U.S. practice!

While investigators are often blinded by their enthusiasm to shortcomings in their own work, it is puzzling how outside observers can accept such obviously inadequate data sets as motivation to pursue changes in well-established IVF practice with well-defined and satisfactory outcomes. This trend is especially difficult to understand, coming only a short time after the disastrous premature introduction of preimplantation genetic diagnosis (PGS) into routine IVF.

UPDATE readers will recall that CHR investigators were, likely, the first to warn about PGS (for details, please review prior UPDATEs), making the point that a good theoretical concept does not always become good clinical practice. Quite frequently, indeed, when properly investigated, great theoretical concepts prove not to work in clinical practice. This should not surprise: if investigators could only rely on their hunches and ideas, nobody would ever have to conduct clinical trials!

As already stated above, LI-IVF, of course, does represent a highly attractive theoretical concept. However, as with PGS before, early reported data were anything but reassuring.

Because in the past we, here at CHR, had one hell of a time convincing colleagues of the shortcoming of PGS, this time we decided on a different approach: When patients started pressuring CHR physicians for a LI-IVF program, CHR, indeed, started to offer such a program, though with the caveat that it be administered like a clinical trial.

We gave the program the name the EcoIVF™ Program, but kept it completely separate from our traditional IVF program. Like during the early days of IVF, patients interested in this program were advised by informed consent that we could not make representations about clinical effectiveness (pregnancy rates) and cost-effectiveness, and promised that we would follow results of this program longitudinally and, intermittently, publish those, as they became available. Readers of these pages have, indeed, on prior occasions seen updates on our EcoIVF™ experience.

Though still small, our EcoIVF™ numbers are now large enough to reach important statistical conclusions, which we also just summarized for publication. And these conclusions demonstrate quite convincingly that LI-IVF needs substantial additional investigations before (if ever) it should be offered to infertility patients in uncontrolled fashion, as unfortunately is often the case now.

It is important to note that, when CHR introduced EcoIVF™, we did so only in limited fashion by restricting this procedure to young women with normal ovarian reserve. Older patients (above age 38) and younger women with premature ovarian aging (POA) were excluded. The reasons were obvious: if we wanted to determine whether EcoIVF™ was effective clinically (in terms of pregnancy rates) and economically (in terms of cost), we, first, wanted to investigate patients with the best prognosis. If the procedure was found to be effective in such good-prognosis patients, we could ethically go on and test the procedure in less favorable patients. Should the procedure, however, turn out to be ineffective in even the best-prognosis patients, it would appear unethical to even pursue investigations in less favorable patients.

We compared a first group of such good-prognosis patients undergoing EcoIVF™ with matched control patients undergoing standard IVF. Through this comparison, we now found that EcoIVF™, in comparison to regular IVF, in young women with normal ovarian reserve, significantly reduces pregnancy chances, both in fresh cycles and cumulatively (with frozen embryo transfer cycles). We expected a lower pregnancy chance cumulatively, because LI-IVF is always expected to produce fewer eggs and embryos. However, we, at least in initial fresh IVF cycles, expected comparable pregnancy chances in EcoIVF™ to those in regular IVF. Mild ovarian stimulation (like above noted Japanese study, we used clomiphene citrate, augmented by low dose gonadotropins in EcoIVF™), thus, also appears to reduce fresh cycle pregnancy chances.

Considering the 11.1% live birth rate reported by our Japanese colleagues, this low pregnancy rate in EcoIVF™ should not have come as a total surprise, but this finding was, nevertheless, disappointing, even though our pregnancy rate with EcoIVF™ was significantly higher than the rate reported by our Japanese colleagues. It, however, did not come even close to the excellent pregnancy rate we have achieved in this young, and prognostically very favorable patient population with standard IVF.

We, however, were even more surprised in the evaluation of costs. Cost evaluations per cycle, of course, make little sense in such circumstances because a cycle of LI-IVF, of course, always will be less costly than a regular IVF cycle. The correct economic question to ask is, however, which treatment achieves a pregnancy/live birth at lower cost, not which cycle is less costly.

And when costs were investigated in this way, because of much higher pregnancy chances with regular IVF, there were no significant cost differences between the two approaches when it comes to cost per live birth.

EcoIVF™ is, of course, not synonymous with every form of LI-IVF. It, however, is very likely quite representative of the most successful, and most widely practiced forms of LI-IVF. Our EcoIVF™ data, therefore, once again, in analogy with the previously mentioned PGS experience, should be considered a warning about the uncontrolled introduction of LI-IVF into daily IVF practice.

Our data strongly suggest that, even in best prognosis patients, LI-IVF, likely, reduces fresh and cumulative pregnancy chances and, therefore, increases the time required for conception. Worst of all, it does so without generating economic benefits in return!

Since these data were produced in best-prognosis patients, it is quite likely that in poorer-prognosis patients these findings may be even more pronounced. In women with diminished ovarian reserve (DOR), whether due to age or POA, we, therefore, now expect even larger differences in pregnancy outcomes and, therefore, likely, even a cost disadvantage of LI-IVF in comparison to regular IVF (though this, as of this point, is just another untested assumption).

Paradoxically, many authorities, including previously noted Japanese colleagues, promote LI-IVF in women with DOR. Based on our data, we, more than ever, consider such an approach unethical, if offered outside of controlled research settings with appropriate informed consents.

Like our field’s previous experience with PGS, LI-IVF, thus, appears to represent a well-intentioned new IVF concept that reduces pregnancy chances for infertile women without offering adequately defined compensatory benefits. Therefore, LI-IVF should not be used and/or recommended to patients, outside of clinical trials, and without appropriate experimental informed consents.

CHR has since appropriately modified all Eco-IVF™-related information on its website, as well as the informed consent under which the procedure is offered. Because cost-effectiveness data are not yet absolutely clear at present, we will continue to offer this procedure as an "experimental" procedure, with intermittent outcome evaluations, to young women with normal ovarian reserve if patients still wish to pursue such an option after receiving full informed consent, based on best available medical evidence of the moment. CHR, however, will also continue our existing policy of not offering EcoIVF™ to women with DOR. Stay tuned for the next update on the subject!

Egg versus embryo donation?

With an increasing number of single women pursuing pregnancy, we are constantly being asked whether they should try embryo donation or individual sperm and egg donations, to create their own embryos. Not less frequently, a similar question comes up for couples, though in such cases, the "partner factor" also comes into play: is giving the male partner an opportunity to be the genetic father an advantage, or disadvantage, for a given couple?

While this question is not what we want to address here, the basic choice between embryo donation and separate egg and semen donations (or partner sperm) requires some technical clarifications. We are concentrating on technical issues here, because we cannot, and do not wish to, comment on personal preferences, religious beliefs and other motivations that may lead to one or the other choice. Our purpose here is simply to compare what objectively lends itself to comparisons: the outcomes.

So, let’s start with embryos: They are the embryos produced in the course of infertility treatments and, therefore, derive from couples who themselves suffer from infertility. These embryos generally come from eggs of women older than egg donors, who are usually in their 20s. Moreover, one can further assume that ovarian problems will be much more frequent amongst infertility patients than egg donors. Thus, there can be little doubt that egg quality (and embryo quality) with egg donation will be substantially higher.

Donor embryos are usually those embryos an infertile couple has left over after conceiving on their own. In other words, it is very likely that a couple’s best-looking (likely also their best-quality) embryos were used first. Donated embryos, therefore, represent a couple’s "second choice" embryos. Statistically, this, likely, means that donated embryos are embryos with lower pregnancy chances than the couple’s "first choice" embryos that led to their own pregnancy.

Finally, donated embryos are always frozen (cryopreserved), while donor eggs, and the embryos that come from donor eggs, at least in the initial embryo transfer, are always fresh. Fresh embryos, of course, always have a slightly better pregnancy chance than cryopreserved/thawed embryos.

Adding up all of the above technical advantages of donor eggs over donor embryos, it will not surprise that egg donation will give patients much higher pregnancy chances per cycle than embryo donation.

Two additional advantages of egg donation need to be considered: At least at CHR, egg donation gives patients the option of selecting donor characteristics quite in detail. Embryo donation, in contrast, rarely offers the option of selection beyond basic race/ethnicity. Since CHR, likely, offers the largest and most diverse egg donor pool anywhere in the world, in most cases, our patients have excellent options to "match" their donor in looks and characteristics with the recipient.

And, while one embryo donation cycle, of course, is significantly less costly than one egg donation cycle, like in the earlier discussion of low intensity IVF (LI-IVF), the question is not the costs per cycle but the total costs incurred before the patients have a baby at home. Looking at costs from such a vantage point, egg donation, once again, probably represents the better option.

In summary, while there may be social, psychological, religious and other personal reasons for choosing embryo donation over egg donation, an objective analysis, solely concentrating on technical outcome and cost, finds little in favor of embryo donation and overwhelmingly favors egg donation. We thought you should know!

Here is Octomom again!

We here at CHR, of course, were not surprised at all when Octomom was proven to have (knowingly or unknowingly) misrepresented the number of embryos transferred into her uterus by her genius physician. According to various press releases, she initially had claimed that 6 embryos had been transferred, when in reality 12 (!!!) were replaced.

Drs. Gleicher and Barad very quickly recognized and pointed out that it was very unlikely that 6 embryos represented the truth and probably nothing but the truth, because the statistical improbability against 6 embryos leading to 8 offspring was simply too large (Gleicher and Barad. Further comments on the Suleman case. Expert Rev Obstet Gynecol 2010;5:501-2). We, of course, also noted this fact in these pages in our previous UPDATEs.

The Suleman case, thus, exactly turned out to be what we from the very beginning suspected: a simply bizarrely managed case, by an obviously completely misguided physician, lacking any reasonable clinical judgment! One cannot reach any other conclusions, because replacement of 12 embryos in a woman in her mid-30s, with prior successful IVF pregnancies, can only be seen as an absolutely "crazy" act. We didn’t do that even in the earliest days of IVF!

Whether the patient, by pressuring the physician, played a role in this decision no longer really matters, because the degree by which this physician stepped outside of reasonable minimal standards of care is just too extreme!

What all of this demonstrates is that we were absolutely correct in making the point that this case has nothing to teach us. It is simply too far outside of reasonableness to be taken seriously as a teaching experience.

What we learned from all of this

If there is a common thread in the three items discussed in this month’s UPDATE, then it is that, in the end, common sense prevails. This is the important lesson patients and physicians always have to remember as they confront ever-increasing volumes of information, often contradictory and based on absolutely no objective evidence.


– The CHR

Norbert Gleicher, MD, leads CHR’s clinical and research efforts as Medical Director and Chief Scientist. A world-renowned reproductive endocrinologist, Dr. Gleicher has published hundreds of peer-reviewed papers and lectured globally while keeping an active clinical career focused on ovarian aging, immunological issues and other difficult cases of infertility.