Egg Freezing for IVF

Egg Freezing: Fertility Preservation (FP) & Commercial Donor Egg Banks

 

The bottom line is that because of the traumatic effect of freezing on egg viability and “competency” the statistical chance of each frozen/ thawed egg ultimately resulting in a baby is only at best 6-8%. So, while success rates following the transfer of embryos derived from frozen eggs have indeed improved substantially over the last 5-10 years, they remain significantly lower than when embryos derived through fertilization of fresh (not frozen) eggs, are transferred.

Since the birth of the 1st “frozen egg baby” in the mid 1980’s, fewer than 3,000 births resulting from the fertilization of thawed eggs have been reported, worldwide. Compare this to > 4.5 million IVF babies born worldwide in the same time period, and > 2,000,000 babies resulting from the transfer of frozen embryos. Harvesting eggs for freezing typically involves giving a woman fertility drugs to stimulate her ovaries to produce multiple eggs, and then harvesting those eggs from her ovaries using ultrasound guided needle aspiration. In average cases (where the mean age of the woman is <36yrs), it takes about one cycle of fertility drug administration to harvest 10 to 15 eggs.

Presently, in cases where embryos derived from the eggs of women under 35 years are frozen, survive the thaw and are transferred to the uterus, the birth rate per embryo transfer is about 35%. In those cases where the eggs were derived from women between 35yrs and 40yrs of age, the birth rate is about 25-30% per embryo transfer (ET) procedure. For women of >40yrs the comparable birth rate per ET is about 10-15%.

While on the face of it, this sounds like a reasonable outcome (especially when it comes to younger women), it should be borne in mind that many eggs do not survive the freeze/thaw and a significant number of those that survive, fail to fertilize. Moreover, of those that do fertilize, a significant percentage fail to progress to progress to the expanded blastocyst stage of development (regarded as being the ideal stage for ET).  That is why depending on their age, women who elect to bank their eggs for fertility preservation (FP) are encouraged to undergo as many egg retrieval procedures as needed in to bank 12-20 eggs before having some degree of confidence, of ultimately being rewarded with a live birth. Since the percentage of eggs that are chromosomally normal (euploid) and “competent”) declines with advancing age, the older the woman becomes, the greater will be the number of eggs (and egg retrieval procedures) needed. .

The ability to accurately identify eggs that are numerically chromosomally normal (“euploid”) and are thus the ones most likely, upon being fertilized and transferred to the uterus,  to propagate a live birth is of particularly relevance. Given that in young women, less 50% of eggs are euploid and by the  mid-forties, that percentage drops to below <10%, it follows that potential for a successful outcome using frozen eggs  largely hinges on their chromosomal integrity (“competency”).

In October 2008, my associate, Levent Keskintepe PhD and I became the first to report (Journal, “Reproductive Biomedicine Online”) on a process that allows for a several fold improvement in the baby-rate per (frozen) egg. It relies upon the selective storage and dispensation of chromosomally (karyotypically) normal (euploid-“competent”) eggs.  The process we described and reported on, relied upon removing the 1st polar body from mature  (MII) eggs  for the performance  of preimplantation genetic sampling (PGS) using metaphase- Comparative Genomic Hybridization (mCGH), followed by the selective storage of only those found to have all 23 chromosomes (i.e. euploid) intact. This resulted in a baby rate of 27% per frozen egg (a 3-fold improvement), an 85%+ , freeze/thaw survival rate, an 80% successful fertilization rate and > 60% birth rate following  the transfer of 1-2  two  blastocysts. While highly effective, this complex process is currently not cost-effective and as such, unfortunately did not gain mainstream acceptance.

    • Indications for egg freezing:
  1. Female fertility preservation (FP)

This refers to the process whereby a woman’s eggs are frozen (cryopreserved) and banked for future use. It has been estimated that the potential demand for FP using frozen eggs exceeds that for conventional IVF by a factor of 4-6 times. The need addresses:

        • Women who face a looming prospect of losing their ovarian function – either because of impending menopause, pending surgical removal of their ovaries, and/or exposure to radiation therapy and/or chemotherapy,
        • Women who anticipate delaying or deferring childbearing, ,because of :
          • Career demands
          • Not being ready to commit to a permanent relationship
          • They feel that by deferring egg banking the ever advancing biological clock might later render them less able or unable to conceive.
        • Women/couples undergoing in vitro fertilization who are opposed to embryo freezing on moral, ethical or religious grounds.

While the demand for FP is growing rapidly, a word of caution is appropriate here: Women need to be encouraged to bank their eggs at a younger age (<35y) where their chance of the eggs frozen being euploid (“competent”) is greatest and…older women should be cautioned that their ability to propagate viable (usable) eggs diminishes with advancing age. Regardless of age, all should be made aware of the fact that it could take several egg retrievals to generate enough frozen eggs to provide a reasonable chance of subsequently having a baby. Finally, in my opinion, women of >40y (especially those with diminished ovarian reserve-DOR) should be advised against egg banking, primarily because of the inevitability of an age-related decline in egg “competency”. For such women, the banking of PGS-tested, euploid embryos is in my opinion, preferable (even if this would require the use of donor sperm).

2. Banking for Egg Donation.

In this scenario, viable eggs derived from young egg donors are stored and subsequently made commercially available for IVF and embryo transfer to women for whom egg donor-IVF provides the only means by which they can go from infertility to family.

It has been estimated that in the United States alone, more than 15, 000 IVF procedures involving the transfer to the uterus of embryos (fertilized eggs) derived from donor eggs are performed annually. This comprises approximately 15% of IVF treatment cycles in the United States.  In addition, a growing number of IVF/egg donation-seeking couples travel abroad in search of lower cost treatment. In the last few years, numerous frozen egg banks have sprung up, offering access to non-genetically tested cryobanked eggs. As a result, more and more egg donor agencies are offering commercially available banked, donor eggs as an alternative to the use of fresh eggs derived through a designated and dedicated egg donor.

In spite of the convenience associated with the use of donor eggs available through commercial egg banks, I presently am NOT in favor of this approach. First, there is little (if any) financial benefit in using such banks. Second, for reasons cited above, frozen eggs are less likely than are fresh eggs, to generate viable embryos.. Third, it is presently indisputable that embryos derived from fresh (non-frozen) eggs and transferred to the uterus yield an overall success rate that is about 20-25% higher than when those derived from cryobanked eggs are used. My opinion is of course likely to adjust subject to advancing technology and of course, the ultimate adoption of selectively banking PGS-tested, euploid eggs.

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Egg Donation-Fashioning Rational Expectations: Preparation; Donor Selection; Using Fresh versus Frozen (Banked) Eggs; Financial/Ethical Considerations; The Process; Outcome!

For many women, disease, the physiological decline in ovarian reserve (DOR) and spontaneous or pathologically induced menopause will preclude pregnancy using own eggs. For such women, the performance of IVF using the eggs of a chosen young third party (egg donor-ED) offers an excellent to go from infertility to family. For such women, ED offers several advantages:

  • More eggs are retrieved from a young donor than would ordinarily be needed to complete a single IVF cycle. As a result, there are often supernumerary (leftover) embryos for cryopreservation and storage.
  • Since eggs derived from a young woman are far less likely to be chromosomally abnormal (aneuploid) and incompetent. As such the risk of miscarriage and birth defects such as Down’s syndrome is considerably reduced.

It has been estimated that in the United States alone, more than 15, 000 IVF procedures involving the transfer to the uterus of embryos (fertilized eggs) derived from donor eggs are performed annually. This comprises approximately 15% of IVF treatment cycles in the United States.  In addition, a growing number of IVF/egg donation-seeking couples travel abroad in search of lower cost treatment.

Most, if not all, egg donor agencies provide a detailed profile, photos, medical and family history of each prospective donor for the benefit and information of the recipient. Agencies generally have a website through which recipients can access donor profiles in the privacy of their own homes in order to select the ideal donor.

Interaction between the recipient and the egg donor program may be conducted in-person, by telephone or online in the initial stages. Once the choice of a donor has been narrowed down to two or three, the recipient is asked to forward all relevant medical records to their chosen IVF physician. Upon receipt of her records, a detailed medical consultation will subsequently held and a physical examination by the treating physician or by a designated alternative qualified counterpart is scheduled. This entire process is usually overseen, facilitated and orchestrated by one of the donor program’s nurse coordinators who, in concert with the treating physician, will address all clinical, financial and logistical issues, as well as answering any questions. At the same time, the final process of donor selection and donor-recipient matching is completed.

What are the characteristics of the “ideal egg donor”?

  • A mentally and physically, fully informed egg donor
  • Age between 21 and 35 years.
  • Normal ovarian reserve (an AMH of >L2.0ng/ml or 15pmol/L)
  • Regular ovulatory menstrual cycles
  • A history of previously having generated numerous mature eggs in prior egg donation cycles.
  • A woman who has previously experienced  one or more pregnancies that advanced beyond the 1st trimester, herself
  • Someone with prior experience with ED where upon fertilization of her eggs and the subsequent transfer of resulting embryos to the uterus of another, propagated one or more healthy babies. Such a track record makes it far more likely that such an ED will have “good quality eggs”. Furthermore, the fact that an ED readily conceived on her own lessens the likelihood that she herself has tubal or organic infertility. This having been said, the current shortage in the supply of egg donors makes it both impractical and unfeasible, to confine donor recruitment to those women who could fulfill such stringent criteria for qualification.

 

Screening of Egg Donors

Genetic Screening: The vast majority of IVF programs in the U.S. follow the recommendations and guidelines of the American Society of Reproductive Medicine (ASRM) for selectively genetic screening of prospective egg donors for conditions such as (but not necessarily limited sickle cell trait or disease, thalassemia, cystic fibrosis and Tay Sachs disease. Consultation with a geneticist is available through about 90% of programs.

Psychological Screening: Since most donors are “anonymous,” it is incumbent upon the donor agency or the selected IVF program to determine the donor’s degree of commitment as well as her motivation for deciding to provide this service. Many recipient couples in the U.S.A tend to be very much influenced by the “character” and demeanor of the prospective egg donor, believing that a flawed character is likely to be carried over genetically to the offspring. In reality, unlike certain psychoses such as schizophrenia or bipolar disorders, character flaws are usually neuroses and are most likely to be determined by environmental factors associated with upbringing. They are unlikely to be genetically transmitted. Nevertheless, egg donors should be subjected to counseling and screening and should be selectively tested by a qualified psychologists.

Drug Screening: Because of the prevalence of substance abuse in our society, we selectively call for urine and/or serum drug testing of our egg donors.

Screening for STDs: All egg donors should be tested for sexually transmittable diseases .While it is highly improbable that DNA and RNA viruses could be transmitted to an egg or an embryo through sexual intercourse or IVF, women infected with viruses such as hepatitis B, C, HTLV, HIV etc., should in my opinion be disqualified from participating in IVF. Although evidence that prior or even existing infection with Chlamydia or Gonococcus will affect egg/embryo competency, the existence of such infections introduces the possibility that the egg donor might have pelvic adhesions or even irreparably damaged fallopian tubes that might have rendered her infertile. Such infertility, subsequently detected might be blamed on infection that occurred during the process of egg retrieval, exposing the caregivers to litigation.

Screening Recipients

  • Medical Evaluation: while advancing age, beyond 40 years, is indeed associated with an escalating incidence of pregnancy complications, such risks are largely predicable through careful medical assessment prior to pregnancy. The fundamental question namely: “is the woman capable of safely engaging a pregnancy that would culminate in the safe birth of a healthy baby” must be answered in the affirmative, before any infertility treatment is initiated. For this reason, a thorough cardiovascular, hepato-renal, metabolic and anatomical reproductive evaluation must be done prior to initiating IVF in all cases.
  • Infectious Screening: the need for careful infectious screening for embryo recipients cannot be overemphasized.
  • Immunologic Screening: Certain autoimmune and alloimmune disorders (see elsewhere) can be associated with immunologic implantation dysfunction (IID). In order to prevent otherwise avoidable treatment failure, it is advisable to evaluate the recipient for autoimmune IDD and also to test both the recipient and the sperm provider for alloimmune similarities that could compromise implantation.
  • Disclosure and Consent
    Preparation for egg donation requires full disclosure to all participants regarding what each step of the process involves from start to finish, as well as potential medical and psychological risks. All parties should be advised to seek independent legal counsel so as to avoid conflicts of interest that might arise from legal advice given by the same attorney. Appropriate consent forms are then reviewed and signed independently by the donor and the recipient couple.
  • Choosing a Known versus an Anonymous Egg Donor: While I strongly recommend to aspiring parents that the identity of their chosen egg donor be anonymous, I do accommodate the needs of those individuals/couples who prefer to known egg donor. However, the arrangements to use a known donor must be clearly defined and agreed upon at the outset. In the USA, >90% of egg donation is done through the solicitation of anonymous donors, usually recruited through a state-licensed egg donor agency. Far less frequently, these agencies, provide “known donors” by special arrangement. In the majority of cases where known donor are used, it is by virtue of a private arrangement with friends or family members. In cases where recipients feel the need to know or at least to have met their chosen egg donor, they should be cautioned that once the donor knows the recipient, there is often a risk that they might consciously or unconsciously make subsequent efforts to maintain a visible link and this can cause considerable disruption in recipient couple-family dynamics.

A word of caution: Most embryo recipients fully expect their chosen donor to yield a large number of mature, good quality eggs, sufficient to provide enough embryos to afford a good chance of pregnancy as well as several for cryopreservation (freezing) and storage. While such expectations ore often met, this is not always the case. Accordingly, to minimize the trauma of unexpected and usually unavoidable disappointment, it is essential that in the process of counseling and of consummating agreements, the respective parties be fully informed that by making best efforts to provide the highest standards of care, the caregivers can only assure optimal intent and performance in keeping with accepted standards of care.

Categories of Egg Donation:

  • Conventional egg donation: The standard (traditional/conventional) approach to IVF-Egg donation involves using fresh/non-frozen eggs. It involves having to match egg donors with recipients and the simultaneous coordination of the egg donor and recipients. It starts with the chosen egg donor undergoing medical and psychological screening followed by ovarian stimulation with fertility drugs to promote egg development. Synchronously, the embryo recipient (i.e. the patient) receives injections and other hormones to prepare her uterus in order to maximize the chances of successful embryo implantation. Once the egg donor has been optimally stimulated with fertility drugs, she is given a “trigger shot” (usually of hCG) and 34-38h later an egg-retrieval (ER) is performed, her eggs are harvested (usually conscious sedation) though ultrasound guided transvaginal needle aspiration and are then fertilized with designated partner’s (or donor) sperm. Three to six days later (depending bon embryo development), the most advanced (best quality) one or two (rarely more) embryos are transferred to the recipient’s hormonally prepared uterus. She then receives daily intramuscular and intravaginal supportive hormones. About 7-10 days later, a blood hCG measurement is made and if positive, is repeated 2 -4 days later. In the event of an adequate rise in blood hCG levels, supplemental estrogen/progesterone therapy continues and an ultrasound is performed 2-3 weeks later to determine whether a viable clinical pregnancy has taken hold. If so, hormone therapy continues to the 10th week of pregnancy at which time it ceases. The process is both painstaking, complex and emotionally and physically taxing. Moreover, it requires exquisite timing and coordination between the (usually anonymous) egg donor and the recipient.
  • Staggered-IVF Egg Donation:With this approach, there is no need for the egg donor and recipient cycles to be synchronized. Here, the donor’s cycle of stimulation and egg retrieval are conducted independently. The fresh donor eggs are fertilized with designated sperm, embryos are generated and ultra-rapidly frozen (vitrified) in advance and kept (stored) until a subsequent embryo transfer time is established for months or even years The ability to separate the ER cycle from the ET cycle, markedly increases the convenience for all parties, and at the same time, removes a great deal of stress from the equation because it provides the embryo recipient with confidence that there will almost certainly be advanced embryos (blastocysts) available when she comes for ET. Moreover, the ET cycle can be scheduled to be performed at the convenience of recipient, and the time needed at our center to perform ET is virtually cut in half. Most important of all is the fact that embryo vitrification by and large will not compromise good quality embryos. This means that the freeze/thaw survival rate of pre-vitrified blastocysts is >85% and the pregnancy rate per transferred pre-vitrified blastocyst is at least as good as when fresh embryos are transferred. The cost for Staggered IVF with egg donation is also no greater with Conventional Egg Donation. Staggered IVF with Egg Donation is best suited to those couples/individuals whose location (usually from afar) and/or calendar, requires much tighter scheduling of their egg donation experience. There is currently a definite shift the paradigm, away from “conventional fresh donor egg IVF” to “Staggered IVF embryo cryobanking”. The process is far less complex, less stressful, more convenient and no more expensive.

Every attempt is made to find a matched donor that meets the embryo recipients’ needs. Issues such as physical characteristics, race, ethnic background, religion, etc. are all taken into consideration and fully disclosed. The donor is screened and undergoes detailed medical evaluation (see above).

Finally, the couple and the egg donor independently visit with a clinical nurse coordinator, who will outline the exact process step-by-step and develop a calendar that outlines every step they will go through. Once all the evaluations have been completed, a date to begin treatment will be selected.

Subsequent Disclosure to Offspring: A “Tough “decision to make! Then there is the issue of whether and when disclosure should be made to the children resulting from egg-donor IVF, regarding their discordant genetic roots.  While I respect the intent/motives and the right of recipient parents to inform their offspring regarding their genetic link to a third party, I personally do not favor doing so. However if it is ultimately decided to make such a disclosure, I would suggest waiting until the children have reached maturity (well into their teen years) before doing so. A young immature child is in my opinion, less likely to be able to handle such an emotional event

Final Considerations:

  • Use of Egg Donor Agencies: Most IVF programs employ the services of a reputable egg donor agency with access to many donors and surrogates. All egg donors are thoroughly screened before entering a cycle of treatment (see below).
  • Frozen eggs from a Commercial Egg Bank: In this scenario, viable eggs derived from young egg donors are stored and subsequently made commercially available for IVF and embryo transfer to women for whom egg donor-IVF provides the only means by which they can go from infertility to family. In spite of the convenience associated with the use of donor eggs available through commercial egg banks, I presently am NOT in favor of this approach. First, there is little (if any) financial benefit in using such banks. Second, for reasons cited above, frozen eggs are less likely than are fresh eggs, to generate viable embryos.. Third, it is presently indisputable that embryos derived from fresh (non-frozen) eggs and transferred to the uterus yield an overall success rate that is about 20-25% higher than when those derived from cryobanked eggs are used. My opinion is of course likely to adjust subject to advancing technology and of course, the ultimate adoption of selectively banking PGS-tested, euploid eggs.
  • Preimplantation Genetic Screening (PGS)-Egg Donation: About 12 years ago, my associate, Levent Keskintepe and I were the 1st to introduce into the IVF clinical arena and report on the benefits associated with complete numerical chromosomal assessment (karyotyping) using Comparative Genomic Hybridization (CGH). The more recent introduction of Next Generation Gene sequencing (NGS) has improved the process and utility of embryo PGS substantially.  NGS allows full egg/embryo chromosome analysis providing a 70- 80% assurance that the embryo(s) so selected for transfer are highly likely to be “competent” (i.e. capable of producing a healthy baby). Such PGS-embryo selection provides about a 50% chance of a baby per transfer of 1-2 chromosomally normal (euploid-competent) embryos.  At the same time it virtually eliminates the risk of “high order” multiple pregnancies (triplets or greater). Moreover, since numerical chromosomal irregularities (aneuploidy) are responsible for most miscarriages, the use of CGH also significantly reduces this dreaded complication. This having been said, about 50% of eggs derived from women <35y are chromosomally normal (euploid) anyway. Thus the success rate with transferring up to 2 blastocysts propagated by such untested (non-PGS tested) blastocysts yields a pregnancy rate that is comparable to that reported when PGS-normal blastocysts are transferred. Thus given the considerable additional cost of doing PGS testing, it is my opinion that the performance of PGS on embryos derived from donated eggs is somewhat redundant and as such I do not advocate its routine use in the egg donation setting.
  • Financial ConsiderationsThe fee paid to the egg donor agency per cycle usually ranges between $2,000 and $8,000. This does not include the cost associated with psychological and clinical pre-testing, fertility drugs, and donor insurance, which commonly range between $3,000 and $6,000. The medical service costs of the IVF treatment cycle ranges between $8,000 and $14,000. The donor stipend can range from $2,000 to as high $50,000 depending upon the exotic requirements of the recipient couple as well as supply and demand. Thus the total out of pocket expenses for an egg donor cycle in the United States range between $15,000 and $78,000, often putting egg donation outside the financial capability of many couples needing this service.
  • Moral, Legal & Ethical Considerations: The “Uniform Parentage Act” which has been adopted by most states in the United States declares that the woman who gives birth to the child will be regarded as the rightful mother. Accordingly, there has to date not been any grounds for legal dispute when it comes to maternal custody of a child born through IVF with egg donation in the majority of states.  In a few states such as Mississippi and Arizona the law is less clear but nevertheless, as yet, has not been contested. The moral-ethical and religious implications of egg donation are diverse and have a profound effect on cultural acceptance of this process.  The widely held view that everyone is entitled to their own opinion and has the right to have such opinions respected, governs much of the attitude towards this process in the U.S.  The extreme views on each end of the spectrum hold the gentle central swing of the pendulum in place.  This attitude is a reflection of the general acceptance in the united states of diverse views and opinions and the willingness to allow free expression of such views and beliefs provided that they don’t infringe on the rights of others.
  • The growing gap between need and affordability: This has spawned a number of creative ways to try and make IVF with egg donation more affordable. Here are a few examples:
    • Egg Donor Sharing, where one comprehensive fee is shared between two recipients and the eggs are then divided between them. The downside is that fewer eggs are available embryos for transfer and/or cryopreservation.
    • Egg Bartering, where in the course of conventional IVF, a woman undergoing IVF remits some of her eggs to the clinic (who in turn provides it to a recipient patient) in exchange for a deferment of some or all of the IVF fee. In my opinion, such an arrangement can be fraught with problems. For example, in the event that the woman donating some of her eggs fails to conceive while the recipient of her eggs does, it is very possible that she might suffer emotional despair and even go so far as to seek out her genetic offspring. Such action could be very damaging to both her and the recipient, as well as the child.
    • Financial Risk Sharing. Certain IVF programs offer financial risk sharing (FRS) which most recipient couples favor greatly. FRS offers qualifying candidates a refund of fees paid if egg donation is unsuccessful. FRS is designed to spread the risk between the providers, and the recipient couple.

So where do we go from here?  Can and should we, cryopreserve and store eggs or ovarian tissue from a young woman wishing to defer procreation until it becomes convenient?  And if we do this, would it be acceptable to eventually have a woman give birth to her own sister or aunt? Can or should we store viable ovarian tissue through generations. Should egg donation simply become a future source of embryos generated for the purpose of providing stem cells, to be used in the treatment of disease states or to “manufacture” fetuses as a source of spare body parts? If the answer to even some of these questions is yes…what about the checks and balances. Who will exercise control and where what form should such control take? Are we willing to engage this slippery slope where the disregard for the dignity of the human embryo leads us to the point where the rights of a human being are more readily ignored?