As CHR has developed special expertise in the management of diminished ovarian reserve (DOR), whether due to premature ovarian aging (POA) in younger women, or physiological aging of older women above age 40 years, we are seeing an ever increasing number of women with DOR requesting care. It is not surprising, therefore, that the resulting shift in patient population has led to a much more clnically challenging patient population. As we begin the second half of 2009, we decided to formally quantitate these changes for the first time.

Changing Ages: Older Women?

As Figure 1 nicely demonstrates, as recently as 2005/6, the average age of CHR patients reaching egg retrieval in an IVF cycle was ca. 36 years. Although it already represented a higher average age than other IVF centers reported at the time, by 2007/8, our average patient age had climbed even further to about 37.5 years. As of the first five months of 2009, the mean age of our IVF patients reached an incredible age of ca. 39.5 years.

Figure 2 shows more detail. Between 2005 and 2009, we noted a complete reversal of age distribution: in 2005, women under age 38 represented a large majority of patients, while by 2008, women above 39 years had come to represent the majority. In other words, CHR has been witnessing a very rapid “graying” of its patient population, likely to be unprecedented in any other IVF centers in the world.

Are We Seeing More DOR?

Since women of identical ages can have greatly varying levels of ovarian reserve (OR), age alone is not enough to understand the changing OR in our patient population. We, therefore, asked whether the levels of anti-Müllerian hormone (AMH), reflective of OR, changed in the same period.

Figure 3 clearly demonstrates that this, indeed, also has been the case. While AMH levels in women above age 36 remained the same or only minimally declined between 2006 and 2008, they very significantly declined in the youngest patient population at age 31 - 35 years.

All of this, of course, means that CHR’s population not only has been aging (i.e., “graying”) to a significant degree, but even young patients, seeking care at CHR, have dramatically changed recently, with an ever increasing number of them presenting with significant degrees of DOR and, therefore, POA. Demographics, thus, very clearly demonstrate a rather remarkable change in CHR’s patient population over the last few years, reflected by dramatically increasing ages and significantly declining OR. CHR’s patient population, therefore, is unmatched in poor prognostic indicators, which makes CHR’s pregnancy outcomes that much more noteworthy!

Comparing Patients among IVF Centers

Age and OR, of course, are the principal parameters, reflective and predictive of pregnancy chances. An IVF program’s overall performance will thus always depend on its patient population. We, approximately three years ago, demonstrated this fact when another well-known IVF center in the tri-state area allowed us to compare OR parameters between our patient population and theirs.

In those years, AMH was not yet widely used. Therefore, comparisons relied on follicle stimulating hormone (FSH) levels to assess OR. As Figure 4 well demonstrates, even then, CHR’s patient population demonstrated significantly higher FSH levels, reflecting much poorer OR.

What makes these findings, however, extra-remarkable is the fact that they predate the most recent increases in patient age and declines in OR in our younger patients, thus strongly suggesting that, if this same kind of comparisons were to be made today, the clinical difference in patient populations between CHR and other IVF centers would be even more pronounced than just a few years ago.

Outcome data

Because patient populations differ dramatically between individual IVF centers, it is difficult to compare pregnancy outcome data. Indeed, both publishers of annual IVF outcome data, the Centers for Disease Control (CDC) and the American Society for Assisted Reproduction (SART), very clearly point out this fact in their annual reports. Yet, it is understandable that patients still compare pregnancy outcome data between IVF centers since they really have no other way of judging the performance of IVF programs.

However, as the here presented CHR data very clearly demonstrate, when IVF pregnancy data are compared between centers, an educated consumer also tries to take into account the patient population that a given center treats. Our data, for example, very clearly demonstrate that women between ages 31 and 35 years changed dramatically between 2006 and 2008 (Figure 3). This would suggest that, as their OR on average declined, they became more “difficult” patients to treat and, therefore, their pregnancy chances should theoretically decline.

For similar reasons, CHR’s patients between ages 31 and 35 are likely to have poorer OR than women of identical ages at practically all other IVF centers in the country, if not the world, because we treat proportionally more women with DOR at those ages than virtually anybody else.

Moreover, it is telling that the statistical data in the CDC/SART annual center reports end with female age 42 years. This cut-off is obviously a reflection of the practice patterns at the vast majority of IVF centers, where women over 42 years are mostly refused treatment. In contrast, at CHR, we now routinely treat patients up to age 48 and our oldest IVF pregnancy, so far, has been established in a woman at age 46 years and 10 months.

This, of course, means that when we report pregnancy rates “above age 40,” they mean something very different from the pregnancy rates for the same age bracket at other centers, which rarely, if ever, treat women above age 42 years, unless they agree to egg donation.

To understand the implications of varying patient population is, therefore, of crucial importance when comparing the efficacy of IVF programs. We can state with considerable certainty, as reflected in the here reported demographic patient data, that no other IVF center in the world is likely to deal with as difficult a patient population as CHR. Given this adversity, it is remarkable that we have not only maintained our excellent pregnancy rates, but, in many aspects, continued to improve upon them.

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With the belief that extending fertility into the future is a logical extension of CHR’s fertility-related services, CHR has established the Fertility Preservation Center (FPC). As we have noted in previous issues of VOICE, young women now have measures to determine if they have elevated risks of POA (for instance, through the CGG repeat counts on the FMR1 gene). If such an elevated risk is revealed, women can now guard against the possibility of premature loss of fertility at our center.

Beyond the normal and abnormal aging process of the ovaries, fertility can be compromised in many ways, including from treatments for cancer and as a result of autoimmune diseases, such as lupus. Because FPC’s Medical Director, Norbert Gleicher, MD, is an expert in infertility and autoimmunity, FPC is in a unique position to help patients with such conditions, who wish to take pro-active steps to preserve thier fertility into the future.

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Recognizing the growing demand for the most advanced infertility treatments, as well as for treatments unavailable outside of the Untied States, CHR has steadily expanded our outreach to those patients beyond the U.S. border. Recently, we have extended our effort even further, devoting an entire section of our website to various conditions and treatments explained in detail in eight different languages, ranging from French, Chinese to Russian. The response has been astounding: we receive daily torrents of inquiries from all over the world.

Interestingly, this global endeavor has confirmed one of our long-term views on government regulations in medicine. On many occasions, we have warned of the dangers of excessive government interference in infertility medicine. Especially in Europe, various governing bodies are involved in the regulations of often miniscule details of infertility treatments, including the number of embryos to be transferred, the no-compensation policy for egg donors, and the ban on preimplantation genetic diagnosis, to name a few. These stringent regulations have created a population of patients who are frustrated by the artificial barrier placed between them and the best treatment possible.

Reflecting this frustrated patient population overseas, a large part of inquiries we receive concerns one of these treatment options that are either simply unavailable in their native country, or are so severely restricted as to be impractical. An example of the former is a French couple with three boys who longed to have a girl. “Unless we can be sure that our next child will be a girl, we will not try to have another child, although it breaks our hearts that we may never have a girl,” they wrote. As for the latter, the large number of inquiries on egg donation testifies to the reality that there is a genuine desire to at least carry the baby, even if it is not genetically related to the mother. This need is not met in most other industrialized countries, because of the severe shortage of egg donors (who are often not allowed to be compensated for her time and effort, and sometimes not guaranteed future anonymity).

To serve these international patients better, CHR is in the midst of expanding our network of “international representatives” who coordinate patient care under our supervision. The first to join our network is Peter Hermann, MD, who practices medicine in Spain. He has visited CHR many times in the past, and is familiar with our treatment protocols, which puts him in the perfect position to coordinate the patient care in Spain. In the coming months, CHR is planning to expand this global network of physicians so that international patients can receive optimal care while minimizing the strain of international trips.

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DHEA utilization around the world is rapidly increasing. Our colleague, Ed Ryan in Toronto, Canada, who generally is treating a somewhat younger patient population than we here at CHR, submitted a number of abstracts to ASRM and the Canadian Fertility Society, in which he reports outstanding pregnancy rates after DHEA supplementation, both in association with IUIs and with IVF.

Greek colleagues, who were the first to report pregnancy success in a small series of women with outright premature ovarian failure (POF), in a recent letter in Fertility and Sterility reported on continuous success in these patients (Mammas and Mammas, Fertil Steril doi:10.1016/j.fertnstert. 2008.12.108).

In our own ongoing DHEA research, we are making progress in slowly understanding who will most benefit from DHEA supplementation. In a study recently completed, and submitted for publication, we were able to confirm once again that DHEA works well with premature ovarian aging (POA) under age 38 and with physiological ovarian aging above age 38 years. Keeping everything else the same, the beneficial effect appears, however, particularly large with POA and this is further explained by the observation that pregnancy success apparently directly correlates with the ability of DHEA to objectively improve ovarian reserve (OR).

We have recently repeatedly noted in these pages that OR is now increasingly evaluated via anti-Müllerian hormone (AMH) rather than follicle stimulating hormone (FSH). Utilizing AMH, we now were able to demonstrate that an increase in AMH levels following DHEA supplementation, suggesting objective improvement in OR, was statistically highly predictive of pregnancy success. Inversely, if AMH did not improve, pregnancy was much less likely.

Improvements in OR, of course, are much more likely in younger women with POA than in older women with physiological DOR. Therefore, the higher pregnancy success with POA should not surprise.

These data are the first step in predicting who will and will not benefit from DHEA supplementation. Much work remains still to be done, but we are convinced that in the not too distant future we will be able to be more selective in deciding whom to recommend DHEA supplementation among infertility patients.

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Dear Dr. Barad,

How do you thank the people who gave you a miracle?

Words cannot express the thanks I feel for you helping us to achieve my dream of becoming a mother. Our baby, Madison Alexis, was born January 2, 2009. She is perfect and we owe it all to you.

Thank you for always taking the time to answer my emails. Your calm but confident ways were very comforting & reassuring to me. I felt that I was receiving the best possible care with you as my doctor. You came highly recommended to me, and will be highly recommended by me. I appreciate your sensitivity to all of my needs. It was a great experience to deal with doctors and staff who are kind, helpful, knowledgeable and professional. Additionally, it was nice to deal with people who knew who I was each time I came into the office. You are a very special group of people whom we’ll never forget.

With all of our thanks, and much love.
Kathy & Madison

Would you like your CHR experience featured in a future edition of The Voice? An ongoing open call has been established for all CHR patients interested in sharing their experience, or simply featuring pictures of their bundles of joy. If you are interested in submitting your experience or pictures, please e-mail us.

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