Fertility Preservation News Aug/Sept, 2015

Some new information on the effects of egg freezing

In this issue of Fertility Preservation News we focus on a newly released study published by CHR investigators Vitaly A. Kushnir, MD and colleagues in the prestigious Journal of American Medical Association (JAMA) entitled “Outcomes of fresh and cryopreserved oocyte donation”1. The study examined data in the 2013 Annual Report of US IVF Center Outcomes published by the Society for Assisted Reproductive Technology (SART)2, and for the first time shows clinical outcomes of Banked frozen donor eggs IVF cycles, which allows comparisons to cycles using fresh donor eggs.

The data are of considerable importance because, unlike previously published small-scale clinical studies of oocyte cryopreservation experiences3, they reflect nationwide real-world experiences with egg freezing in the best possible patient population: young and highly selected egg donors.

In this best possible patient population the JAMA study demonstrated that egg freezing works well, though still not as well as fresh eggs in establishing pregnancy and leading to live births.

FPN 15-05 chart 2
For those thinking about freezing their eggs for social reasons (i.e., social fertility preservation) this study offers important new insights into egg freezing: A first point, of course, is that frozen eggs are a little less efficient in leading to pregnancy than fresh eggs. In practical terms that means that, in calculating how many eggs should be frozen to establish a desired statistical likelihood of pregnancy, we have to freeze a little more than we would have estimated based on fresh transfer experiences.

FPN 15-05 chart 1

But it is also important to recognize that the data in the JAMA study involved the best possible prognosis patients in IVF, young healthy egg donors. If even in this best possible patient population frozen eggs perform poorer than fresh eggs, it is very likely that this difference between efficacy of fresh and frozen eggs will further increase with advancing age. In other words, as women who want to freeze their eggs are advancing in age, we have to assume rising loss in pregnancy potential from every frozen eggs. Therefore, as women age, they will have to freeze increasing egg numbers to maintain potential future pregnancy chances.

As women age, they, however, produce fewer and fewer eggs per ovarian stimulation cycle. The logical conclusion, therefore, is that, as women age, they will need more and more egg freezing cycles to maintain future pregnancy chances with their cryopreserved eggs.

Though not directly addressing the issue of social egg freezing, the JAMA study, therefore, reemphasizes that oocyte cryopreservation for social reasons should be done at as young ages as possible.

The American Society for Reproductive Medicine (ASRM) lifted the experimental label off egg freezing for medically indicated fertility preservation in January of 2013. At the time, ASRM cautioned against widespread so-called “social” (elective) egg freezing and donor egg banking stating that: “there are not yet sufficient data to recommend oocyte cryopreservation for the sole purpose of circumventing reproductive aging in healthy women because there are no data to support the safety, efficacy, ethics, emotional risks, and cost-effectiveness of oocyte cryopreservation for this indication” and that “while data are reassuring, more widespread clinic-specific data on the safety and efficacy of oocyte cryopreservation in this population are needed before universal donor oocyte banking can be recommended.

We previously noted in Fertility Preservation News that social egg freezing, unfortunately, has been excessively commercialized. The JAMA study suggests that frozen donor egg banking is quickly following. Here at CHR we are concerned about this trend not only for medical (lower pregnancy rates) but also for ethical reasons since commercial egg banking enhances the trend toward commoditization of eggs.

On the other hand, donor egg banking also offers clear advantages for IVF centers, well described in the JAMA paper. It, therefore, appears important that professional organizations, like ASRM, establish carefully thought out guidelines for the profession as social egg freezing and donor egg banking are quickly evolving as commercial industries.

1. Kushnir VA, Barad DH, Albertini DF, Darmon SK, Gleicher N. Outcomes of fresh and cryopreserved oocyte donation. JAMA, 2015, 314:623-624

2. Society for Assisted Reproductive Technology, National Data
3. Cobo A, Meseguer M, Remohi J, Pellicer A. Use of cryo-banked oocytes in an ovum donation programme: a prospective, randomized, controlled, clinical trial. Hum Reprod2010;25:2239–46.


Egg and embryo freezing a new option for carriers of single gene diseases

So-called monogenetic (or single-gene) diseases worldwide affect 10 of every 1000 newborns. In all cases, a single abnormal mutation of DNA in a single gene on a single chromosome is present in every single cell of the body, causing a specific disease, depending on the functions of affected genes. Over 10,000 human diseases are currently considered monogenetic in nature. They are responsible for heavy loss of human life and for significant health care costs: For example, approximately 40% of all hospital-based pediatric care is dedicated to the treatment of monogenetic diseases.

These diseases are inherited dominant, recessive and X-linked or their inheritance can be mitochondrial. Dominantly inherited diseases come from one parent; recessively inherited diseases require that both parents carry the same abnormal gene to find clinical expression in one of their children. X-linked diseases, almost exclusively are only expressed in male offspring. Mothers always transmit mitochondrial diseases, caused by mutations in a tiny amount of non-nuclear DNA in cytoplasmic structures called mitochondria, since only maternal mitochondrial DNA is passed on to offspring.
By screening high-risk populations, medical science has developed strategies to prevent transmission of these genes into next generations and birth of potentially affected children. To cite only a few example, screening of parents of African descent for sickle cell disease, of Ashkenazi Jews for Tay-Sachs and other Ashkenazi genetic diseases, and of individuals of Mediterranean descent for thalassemia minor has, therefore, become routine practice in the U.S. In addition, practically all pregnant women are screened for cystic fibrosis, the most frequent monogenetic disease in the general population and for other prevalent gene defects.

Such screening prior to pregnancy has become popular because preimplantation genetic diagnosis (PGD) allows couples at risk for transmitting such conditions to test their embryos in an in vitro fertilization (IVF) cycle before transfer into the uterus, thereby preventing pregnancies with affected embryos. Since in dominantly inherited conditions approximately half, and in recessive conditions a quarter of all embryos will be affected, PGD requires large embryo numbers. Especially older women, who usually produce fewer eggs and embryos, therefore, often end up without transferrable embryos.

A new procedure, however, now offers additional hope: Recently developed so-called CRISPR-Cas systems allow editing, regulating and targeting of the genome, using engineered nucleases, which literally permit pinpoint removal of abnormally mutated genes and/or their replacement with normal genes. Studies in animal models have already established their potential technical efficacy.

Utilization of CRISPR-Cas systems in humans has, however, become a point of major scientific contention, with prominent scientists arguing in favor of a complete research moratorium, and others (this author included) favoring cautious step-by-step introduction of these new editing techniques to the human experience, including an only temporary moratorium on transfer of so-treated embryos into human uteri until safety of these techniques has been established.

Caution is, indeed, warranted for scientific as well as ethical reasons. Scientifically, safety of these techniques in treating human eggs and/or early embryos has to be established before clinical utilization can be advocated. Ethically, these new techniques raise concerns because DNA editing of eggs and/or early embryos “crosses the germline.”

This phrase denotes that, once DNA is edited at such early developmental stages, the newly introduced “edit” will be not only distributed into all cells of a given human but also into her/his future offspring. Many ethicists, rightly, consider this a step in human evolution that should be taken only with great caution.

Technical progress in CRISPR-Cas systems is, however, breathtakingly quick. Hardly a week passes without publications of yet other breakout papers in leading science journals. CRISPR-Cas systems, therefore, with considerable likelihood will find human applications in the foreseeable future. This potential, however, already has clinical relevance now for those who carry known monogenetic disease-inducing mutation, and are planning on having children in the future.

In women, reproductive potential is reflected in egg numbers and egg quality. Both decline with advancing age. Eggs from younger women, therefore, have better potential to lead to pregnancy. We, therefore, believe that carriers of single-gene diseases may be well advised to preserve their eggs at youngest possible ages. Considering rapidly evolving and improving CRISPR-Cas systems, it now appears highly likely that, sometimes in the near future, when ready to have children, they then will have the option of either correcting the genetic defect in all frozen eggs or fertilize their frozen eggs with partner sperm and correct the defect in so produced earl-stage affected embryos.

The same also applies to couples, which shared genetic risks. They now have the option of freezing embryos at their earliest stages after fertilization. Once an embryo is cryopreserved, it is preserved in time, and embryos produced with younger eggs have again outcome advantages. When at a later point utilizing frozen embryos, CRISPR-Cas, hopefully, will already allow genetic embryo editing before transfer into the uterus.

For those who know that they carry monogenetic risks in eggs and/or sperm, recent developments in genetic editing, thus, suggest that within the foreseeable futures we may be able to “fix” those defects by utilizing CRIPR-Cas techniques. The “younger” eggs and embryos we then have the opportunity to work with, the higher will be pregnancy chances.

There, of course, are no guarantees that CRIPS-Cas systems will ever find application in human embryology; but the time appears right to take the chance. See a qualified geneticist or fertility specialist for further information and advice. The younger you are when you preserve your eggs and embryos, the better!


Ovarian Tissue Cryopreservation

Ov Tissue

The upcoming August issue of the Journal of Assisted Reproduction and Genetics (JARG) will review major advances in the field, especially on the topic of ovarian tissue cryopreservation and use for autologous transplantation and restoration of ovarian function. In particular, the journal examines results from the first 60 live births from this procedure.

CHR’s Senior Scientist and Director of the Division of Laboratories, David Albertini, PhD, produced this image of cryopreserved and thawed human ovarian cortex. The photo comes from his studies with Professor Evelyn Telfer at the University of Edinburgh.

-The CHR
Fighting for every egg and embryo