CHR VOICE: May 2015

The deadline for abstract submissions to the Annual Meeting of the American Society for Reproductive Medicine (ASRM) was this year May 5. Like in years before, the weeks leading up to this deadline are among the busiest at CHR since a variety of data analyses, updates and interpretations had to be completed in preparation for abstract submissions.

While going to print with this issue of the VOICE, we are not certain yet about the final number of CHR’s abstract submissions this year; but, like last year, expect to come in at around 20. This number will, once again, place CHR in submission numbers into the top 1% of submitting fertility centers. The meeting this year will take place in Baltimore, Maryland, October 17-21, which by then, hopefully, will have recovered from the current upheaval.

 

More Thoughts on Crossing the Germline

In last month’s VOICE we commented extensively on discussions among scientists on whether human experimentations should be conducted that involve “crossing the germline.” As then explained, this term means making changes in an early-stage embryo that affect that embryo’s genetic make up (its “genome”). These changes are distributed throughout all of that embryo’s cells (i.e., the whole human being if the embryo implants and live birth occurs) and will result in this human passing on this genetic change to offspring and future generations.

As we reported last month, a few prominent scientists had called for a moratorium on all human experimentations involving such genetic manipulations, including research that would avoid transfer of so-treated embryos and, therefore, never would lead to pregnancies and births. In our opinion to significant degrees representing scientific and commercial self-interests, these investigators argued that such a complete moratorium on all human experimentation was required to prevent potential “rogue” scientists from applying these powerful new techniques of “genetic editing” prematurely, while their safety had not yet been established.

© Zephyris/Richard Wheeler/Wikimedia Commons ©Zephyris/Richard Wheeler/Wikimedia Commons

 

Experiments avoiding embryo transfers, however, of course would never have the potential of creating safety issues to either mother or offspring since offspring would never be created. In confirmation of how much these concerns were, indeed, driven by self-interests, they in their opinion piece were open about their fears that premature utilization of gene editing techniques “crossing of the germline, “could cause the complete shut down of all such research” (Lanphier et al., Nature 2015;519:410-411).

Like many other scientists and scientific organizations, including in a recent formal public statement the ASRM, we, here at CHR, objected to such a universal moratorium on all human research and consider the idea regressive and illogic. Instead, we argued in favor of responsible human research, which, at this stage, and until further research assured safety of utilized techniques, would not result in human pregnancies and deliveries.

Proponents of such limited human research, in our opinion correctly, argue that certain experimentations on human embryos (either donated for such purposes by patients or specifically created for such research purposes, as currently under the law allowed in some states) would, likely, succeed in developing safe techniques to correct genetic defects in embryos – in itself a highly desirable goal in medicine.

Safety of such treatments could be established with high degrees of certainty by testing stem cell lines established from such embryos. Serious investigators, of course, would consider clinical applications of “genetic editing” only once safety has been established with high degrees of certainty. Moreover human IVF (i.e., transfer of so treated embryos in the uterus) using such techniques would be considered only after appropriate approval by Institutional Review Boards (IRBs).

Since we published our comments last month, a second wave of highly critical articles of “crossing the germline” appeared in the media after Chinese investigators reported a rather unsuccessful attempt of “editing” the genetic germline of human embryos (Liang et al; Protein Cell 2015 http://dx.doi.org/10.1007/s13238-015-0153-5). Even highly experienced and very knowledgeable medical writers, like Gina Kolata from The New York Times, reached all the wrong conclusions: Instead of concluding that this Chinese study reaffirmed the strong need for improved techniques to successfully “edit the human germline,” Kolata (The New York Times, April 24, 2015, A3) and others took the Chinese experience as evidence that critics of “germline editing” had been correct in their warnings of impending doom.

They, of course, are not correct: many times before, naysayers had warned that irresponsible investigators would prematurely and irresponsibly apply new scientific techniques and technologies to patients in reproductive medicine unless specifically prohibited from doing so. As the Chinese investigators in this case, however, again very well demonstrated, reproductive scientists are usually fully aware what is and is not ethically appropriate. They used genetically abnormal embryos in their experiments and, of course, did not transfer them into patients. In addition, does anybody really believe that unethical rogue investigators would feel bound by a voluntary moratorium?

In summary, CHR reaffirms its strong belief that human experimentation with “germline editing” is timely, clinically potentially very important and ethical, as long as so “treated” embryos are not transferred until safety of such treatments has been established with high probability.

How this controversy affected CHR’s research efforts

We also reported last month on a new research affiliation with colleagues at The Salk Institute in La Jolla, California, who had developed a highly reliable method for “germline editing” in a mouse model, which they described in a groundbreaking paper that appeared last month in the prestigious science journal Cell (Reddy et al., Cell 2015; http://dx.doi.org/10.1016/j.cell.2015.03.051). In expectation of appearance of this paper and the reliability of described techniques in the mouse, it appeared logical to investigate the same techniques also in human embryos.

CHR, therefore, was delighted to collaborate with our colleagues on such a project when asked after CHR’s Medical Director and Chief Scientist, Norbert Gleicher, MD, visited Salk and reached agreement on a study protocol.

Our colleagues at Salk submitted the project in March to their institution’s IRB, where it quickly passed through the approval process without comments. On April 23 it was scheduled for approval by CHR’s IRB. A few days before that date, our Salk colleagues, however, informed us that the administration of the Salk Institute had informed them that they would not be permitted to initiate the project. CHR, therefore, withdrew the project from consideration by CHR’s IRB.

We were deeply saddened and disappointed by the decision of the Salk Institute’s administration. Considering the reputation for groundbreaking research this institution has earned over decades, CHR was nothing but puzzled by this totally unexpected decision, which we, quite frankly, do not consider commensurate with the institute’s reputation. It, indeed, smacks of censorship and political correctness rather than freedom of scientific expression, for which the Salk Institute has stood since its founding.

CHR, therefore, hopes that, after further considerations and study of the pros and cons of this decision, our colleagues at the Salk Institute will be permitted to expand their groundbreaking research from mice into the human experience. Not to permit them to do so in carefully controlled fashion, does not serve mankind, which, after all, is what the Salk Institute was founded for. Should Salk’s administration change their mind, CHR will be there to help if asked again. In the meantime, CHR is exploring the option of conducting this research with colleagues from other research centers.

Treating mitochondrial genetic diseases

As a first step in planning the collaboration with our colleagues from the Salk Institute, we considered to investigate whether the “gene editing” techniques they so successfully applied in mice were also usable in humans with so-called mitochondrial genetic diseases. This is a small number of genetic diseases usually caused by a single gene defect in the so-called mitochondrial genome (genetic material associated with mitochondria in the cytoplasm of cells rather than the nucleus, where most genetic material is concentrated).

We discussed these diseases last month in the VOICE, though mostly in conjunction with so-called “three-parent IVF,” which also offers a potential cure for mitochondrial diseases, inherited from mothers to offspring. Assuming that the by Salk investigators developed “gene editing” techniques can be equally successfully applied to human as mouse embryos, these techniques would be simpler and likely more reliable in eliminating mitochondrial diseases in offspring than “three-parent IVF.” They also would not result in offspring with genetic material from three parents since only diseased mitochondrial genes would be replaced, and no cytoplasm transfers would be required, which carry the mitochondrial genetic material.

In absence of any human research on “gene editing” for mothers who carry these genes, and in absence of any decisions by the Food and Drug Administration about permitting the investigation of “three parent IVF,” women with mitochondrial diseases in this country are currently left with no other option but using donor eggs if they wish to have children and prevent transmission of the diseases they carry to their offspring.

At the same time, it appears increasingly likely that in the not too distant future one or the other technology will become available to prevent transmission of these horrible diseases from mother to child in humans. In practical terms this means that, while today we still have nothing to offer to so-affected women, tomorrow we may!

For women affected by mitochondrial diseases it, therefore, may be worthwhile to consider fertility preservation via egg-freezing while their eggs are still “young.” Once one of these two techniques becomes available for clinical use, we then can use those “young” eggs to create embryos, which will give us much better pregnancy chances than “older” eggs.

We, therefore, encourage women with mitochondrial genetic diseases to contact CHR’s Fertility Preservation Program, headed up by Vitaly A. Kushnir, MD, by calling 212-994 4400 or via our website. Fertility preservation attempts via egg freezing in such circumstances are currently, of course, still speculative and, therefore, for yet another reason have to be considered “experimental.”

The Futility of Infertility Treatments

It has been quite some time since we addressed in these pages the subject of “futile” infertility treatment. We then noted that the ASRM defines “futility” as chances of live birth below 1%.

Our colleague William D. Schlaff, MD from Jefferson Medical College in Philadelphia, Pennsylvania, recently brought an interesting view point to the discussion in an opinion piece in Fertility & Sterility, the official journal of ASRM (2015;103:626-627), titled “Autonomy, futility, and good business in reproductive medicine: is the slope getting more slippery?”

What we found most interesting about his piece was the openness of his analysis why and how IVF centers historically have avoided providing IVF services to very poor prognosis patients. He correctly noted that with expanding IVF center numbers in the U.S. (now almost 500), lack of treatment capacity no longer holds water as a good explanation, and that at a time when “ART success rates must be publically reported, it is imperative to acknowledge that these cases provoke many discussions and significant concern about the potential impact on good business.”

In other words, what Schlaff is openly acknowledging is that IVF centers have been withholding IVF treatments for rather selfish reasons (i.e. because the low chances of success in such patient would negatively affect a center’s business prospects in attracting patients because such patients, of course, reduce a program’s overall pregnancy and delivery rates, which are publically reported). Yet, at the same time (and, therefore, above noted title of his opinion piece) he also notes how our specialty increasingly has accepted the importance of respecting patient autonomy in requesting such cycles.

Schlaff is honest enough to acknowledge that he “feels no clinical ambivalence or professional remorse in informing 43-year-old (or older) women that he respects their request but was unwilling to offer them an IVF cycle.” Yet, he also “appreciates that many respected colleagues are far more open to considering such requests,” and admits that he is “a bit uncomfortable about the degree to which ‘business’ of IVF intersects with respect for (patient) autonomy in these cases.”

CHR very much sympathizes with Schlaff’s discomfort because no other IVF center in the U.S. (and likely the world) proportionally treats as many poor prognosis patients as CHR. Every time we explain to such patients how low their chances are with use of their own eggs and how much better chances, likely, would be with use of “young” donor eggs, we experience this discomfort. In so many ways, it would be so much easier (and probably also more profitable) to simply be able to say we don’t offer IVF to patient like you and, if you want us to continue helping you, you have to use donor eggs!

But this would be the easy way out, especially since over half of CHR’s new patients heard exactly these words at one or more IVF centers before presenting to CHR. Moreover, while most, indeed, are true poor prognosis patients, surprisingly many are what we call “iatrogenic” (i.e. medically-induced) poor prognosis patients.

We define patients as “iatrogenic” patients referred into egg donation if their prior repeated IVF failures, in our opinion, were not maximally managed. This includes cases where poor prognosis patients did not receive maximal ovarian stimulation, underwent embryo culture to blastocyst stage and/or underwent preimplantation genetic diagnosis (PGS), and repeatedly ended up with no embryos for transfer before being advised to go into egg donation.

It is important to differentiate between real poor prognosis patients and “iatrogenic” poor prognosis patients because the latter will experience much higher pregnancy and live birth chances than the former.

We have on many prior occasions noted in these pages that CHR does not see it as our responsibility (and/or ability) to tell patients how to live their lives, and how to make life-determining decisions. Instead, we consider it our responsibility to advise patients what their options are, and what their pregnancy and live birth chances are with the various options at their disposition. It then is the patients’ decision whether they wish to receive treatment and what treatments.

We, thus, appreciate Schlaff’s honesty in presenting the issues and share his concerns about the intertwining of medical and business concerns in modern-day IVF practice. At least from CHR’s vantage point our concern of patients being prematurely “forced” into egg donation cycles, however, by far exceeds concerns about a significant number of futile IVF cycles being conducted. We, simply, do not see this happen, and where IVF cycles, indeed, may be futile, they usually are conducted at the request of patients who, simply, need to find closure, knowing they tried it all, before moving to egg donation.

In Focus:

 This feature presents microscopic images from CHR’s laboratories, edited by our Director of the Division of Laboratories and Senior Scientist, David F. Albertini, PhD.

FOCUS bocf2

Circles inside circles … that is what our image of the month will first be perceived as and with closer inspection, the detailed genetic structure of an oocyte is what is revealed.

The large red circle demarcates the boundaries of the oocyte itself with many hair-like appendages that represent communication pathways with the cells that nurture the oocyte. The smaller red circle shows the perimeter of the oocyte nucleus within which reside the chromosomes, seen here as blue threads and the nucleolus (green) where special clusters of genes reside.

 

A Few Words About Surrogacy (gestational carriers)

When a woman either cannot or does not wish to carry her own pregnancy, the use of so-called gestational carriers has, especially in the developed world, increasingly become vogue. The process is often called “surrogacy,” though that term is not really accurate in these circumstances since it initially was devised for cases were women contributed their eggs and also carried the pregnancy for couples. As the term “surrogacy” is now used in most cases, the surrogate does not contribute her own eggs, and only serves as carrier of pregnancy. Therefore, the term gestational carrier appears more accurate and appropriate.

Legal considerations

Surrogacy is legal in the U.S. but is legally not defined in many states of the Union. This means that many states do not have so-called surrogacy laws, which define the biological parents (i.e., the individuals, who contribute egg and sperm and “own” resulting embryos, which then are implanted into the uterus of the gestational carrier) as the legal parents of the born child. Concomitantly, these laws protect the gestational carrier from biological parents refusing to assume parenthood after a child is born.

If children are born after such surrogacy in states without surrogacy laws, biological parents, therefore, often have to adopt the children from the gestational carrier. Surrogacy agencies, which provide a majority of gestational carriers in the U.S. are, therefore, usually located in states, which do have surrogacy laws.

Once a surrogacy law is on the books, biological parents and gestational carriers can enter into legally binding agreements securing the transaction legally for parents, gestational carrier and offspring without further needs to clarify legal circumstances after the birth of a child.

New York State currently does not have a surrogacy law. Surrogacy is, therefore, not legally defined in the state. CHR, nevertheless, routinely performs quite large numbers of surrogacy cycles but, in absence of such a law in the state, defines them legally as so-called directed (i.e., “open”) embryo donations from biological parents to gestational carriers. CHR, however, insists as a condition for performing such cycles that parents and carrier have executed appropriate legal papers in a state where a surrogacy law exists and where the child will be delivered. CHR also strongly advises parents and carriers to obtain individual legal advice from qualified attorneys before entering into such contractual agreements.

Finding a good gestational carrier (surrogate)

In contrast to egg donation, where CHR, likely, maintains the largest and most diverse pool of by CHR carefully selected egg donors, CHR does not maintain a pool of gestational carriers. The first reason is that, as noted above, New York State does not have a surrogacy law; another reason, however, is the legal complexity of surrogacy in contrast to egg donation. We strongly feel that the process requires careful legal management in protection of all involved parties and, therefore, management by legal experts.

CHR, therefore, works with and recommends a number of reputable surrogacy agencies, though many of our patients select their own agencies. In some cases, our patients choose a surrogate privately ­— often a friend, relative or otherwise previously known person. Choosing a reputable surrogacy agency is of great importance because, unfortunately, a number of such agencies have over the years proven to be anything but reputable.

The choice of a gestational carrier is always the patient’s, but CHR offers and suggests that we review the medical qualifications of the surrogate. Since in New York State we have to consider gestational carriers recipients of “open” embryo donations, the surrogates, anyhow, have to become CHR patients. Their medical evaluation by CHR is, therefore, part of the process, and does not create additional costs. Though patients are the ultimate arbiters of their gestational carriers, we have had occasions when we recommended against use of suggested carriers. In most cases our patients agreed with our recommendations, and selected another carrier; but sometimes they did not, and that, of course, is their right.

Costs of surrogacy

The expenses surrounding surrogacy can vary greatly, and CHR usually encourages patients to compare cost structures between agencies. CHR derives no financial benefits whatsoever from referring patients to surrogacy agencies, and also has no other motivations to prefer one to another, except our patients’ best interest.

Gestational carriers in other countries

Because costs of surrogacy in the U.S. are quite high, increasing numbers of patients are choosing gestational carriers in other countries. Especially India, Thailand, Nepal and Mexico have developed “surrogacy industries” of considerable size.

We have transferred on occasion embryos into other countries for such surrogacies, though frankly are somewhat skeptical about this practice. While there are many very knowledgeable and competent colleagues in these countries, there are also others where we are not as comfortable. At times, it is difficult to judge IVF centers in these countries, and we, therefore, usually caution our patients to be very careful in choosing surrogacy centers outside the U.S.

We are also concerned about surrogacies in third world countries because surrogate monitoring is difficult. Research in recent years has developed increasing evidence of the importance of so-called epigenetic influences during pregnancy. What this means in practical terms is that we increasingly have recognized that environmental influences during pregnancy to a very significant degree determine how our genes later in life will work. The uterine environment during pregnancy is, therefore, of great importance. What this means on a lighter note is that it may make quite a difference whether a gestational carrier, for example, during pregnancy consumes a Mediterranean or a curry-heavy Indian diet.

Whether a woman requires a gestational carrier for medical or social reasons, carefully selected gestational carriers can offer a wonderful option toward pregnancy. We hope to have offered some additional insights through this brief summary.

 

CHR in the Media

In an April 16 article on tests  that allow women to select their best IVF embryo, Scientific American quoted Norbert Gleicher, MD, CHR’s Medical Director and Chief Scientist,  as saying Early Embryo Viability Assessment tests are not for everyone. “In order to get the benefit of selection and say it’s helping to find the best one there has to be a ‘best’ embryo—and if all of them are just average the system won’t create a benefit,” Dr. Gleicher said. The test is also relatively expensive and not all insurance companies cover it.

 

Staff spotlight:

Magda_Cartveli

Magda Cartveli, RN

Clinical Supervisor

This month, our staff spotlight is on one of the faces at CHR patients know best, Clinical Supervisor Magda Cartveli.

Magda started with CHR as a medical assistant in 2010. She was quickly recognized for her outspoken and vivacious demeanor. Patients and medical staff came to know Magda as both extremely thorough and caring. In less than two years she was promoted to clinical coordinator becoming a vital, go-to person for patient treatments at CHR. She passed the NCLEX exam in 2014 to become a registered nurse and was promoted again to Clinical Supervisor.

Originally from the Republic of Georgia, Magda also has a bachelor’s degree in journalism and an associate’s degree in nursing. Magda worked at a large multispecialty clinic before joining CHR.

-The CHR
“Fighting for every egg and embryo!”

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.