IVF in Older Women Using Their Own Eggs - Embryo Banking Offers an Excellent Option

Until recently, for many infertile older women and those with diminished ovarian reserve (DOR) who wanted to have a baby, IVF using donated eggs offered the only realistic option. Many who were unwilling to use donor eggs often nonetheless attempted IVF (often repeatedly) with their own eggs, only rarely succeeding in having a baby. The recent introduction of selectively banking genetically tested, “competent” embryos over several IVF cycles and subsequently (in a later cycle) transferring only those found to be chromosomally normal, could offer many such women/couples a realistic alternative to IVF with egg donation, while offering them an opportunity to have their own genetic offspring.

It is mainly the chromosomal integrity of the egg, rather than the sperm that determines whether the embryo will be “competent” (i.e. have the potential to develop into a normal baby). It is the age of the woman that most profoundly impacts the likelihood that the mature egg will have a full contingent of chromosomes (a “euploid” egg), necessary to achieve embryo “competency.” By way of example, up until about 35 years of age, fewer than 50% of a woman’s mature eggs will be euploid, and thus upon fertilization, more than half will have an irregular chromosome component (i.e. “aneuploid”) and thus be “incompetent.”

Incompetent embryos either will fail to develop normally, fail to attach (implant) in the uterine lining, miscarry, or even result in a chromosomally abnormal baby (e.g. Down syndrome). As a woman ages beyond her mid-30’s the incidence of egg/embryo aneuploidy increases such that by the time she reaches her mid forties, more than 90% of her eggs/embryos will be aneuploid and incompetent.

To make matters worse, the older the woman, the closer she gets to the time that her ovaries run out of eggs and she stops ovulating and menstruating (i.e. menopause). The 6-8 years prior to menopause (i.e. the climacteric or pre-menopause) which is characterized by 1) diminishing ovarian reserve (DOR) with an associated progressive reduction in the number of available number of mature eggs at the time of egg retrieval, and 2) building resistance to fertility drugs.

To complicate matters further, it becomes ever more difficult in the face of DOR, to protect developing eggs during stimulation with fertility drugs in the hope of minimizing the incidence of egg/embryo aneuploidy. This is why, unless a very customized and individualized approach to ovarian stimulation is used in older women and those with DOR, the incidence of egg/embryo aneuploidy may even approach 100%. It also serves to explain why IVF success rates plummet with diminishing ovarian reserve and with advancing age, and why the relentlessly ticking biological clock often creates in them a profound sense of urgency and even desperation to have a baby before their time runs out.

Confronted with the reality that advancing age and diminishing ovarian reserve will inevitably reduce the likelihood of an IVF pregnancy, as well as increasing the risk of miscarriage, in all probability, come at considerable emotional and financial cost, many such women often choose to undergo IVF using the eggs derived from a younger egg donor.

Embryo banking offers many older women an those with DOR a realistic and cost-efficient alternative to IVF with Egg Donation: The recent introduction of Embryo Banking at SIRM now offers an alternative to egg donation for many older women, as well as those with prematurely diminishing ovarian reserve (DOR) who otherwise would have a very small chance of having a baby with their own eggs. This is provided, of course, that they still have an ability to produce some ovarian follicles in response to fertility drugs.

Embryo banking involves a process whereby several blastocysts are accumulated (stockpiled) over two or more IVF cycles. After each such cycle, the embryos are biopsied for CGH analysis, taken to the blastocyst stage of development and then vitrified (ultra-rapidly frozen and banked). All biopsy specimens accumulated over several such cycles are held for as long as it takes to complete the scheduled IVF egg retrieval cycles, whereupon they are collectively dispatched for a single CGH analysis (to reduce testing costs). When the results return, the “incompetent” (CGH-abnormal) embryos are discarded while the “competent” ones are stored (cryobanked) for a subsequent embryo transfer. With this method, the transfer of even a single “competent” embryo is capable of achieving almost a 70% chance of a viable pregnancy, regardless of the age of the woman.

IVF-Egg Donation: Matching, Testing and Monitoring the Embryo Recipient and the Egg Donor

For an ever-increasing number of infertile women, advancing age or diminished ovarian reserve (DOR) associated with the onset of menopause or ovarian disease precludes them from producing the “competent” eggs that are necessary to achieving a viable pregnancy. In the vast majority of cases, such women will usually have a healthy uterus and thus, provided that they are free of medical disorders that would compromise a pregnancy, will usually be quite capable of bearing a child once “competent embryos” are transferred to their uterus. Accessing “competent” embryos will usually require utilizing eggs taken from the ovaries of young egg donors.

The choice of treatment is highly personal and should be considered in light of the financial and emotional costs involved. The further the woman’s age advances beyond 40 yrs and/or the closer she gets to the menopause, the more likely it becomes that she would require multiple attempts at IVF to have even a reasonable chance of achieving a viable pregnancy with her own eggs. However, after the age of 43, the adverse effect of age on the egg’s chromosomal integrity (“competence”) so reduces the likelihood of successful IVF, that egg donation represents the most rational choice. The effect of age on IVF outcome is largely negated through the use of donor eggs. This is because the donor eggs derived from a younger woman (usually less than 35 years of age) are usually healthy. In addition, newer methods for preparing the embryo recipient's uterine lining help optimize the chance of healthy implantation.

IVF with egg donation involves preparing the uterus of the embryo recipient (the “intended mother”) with hormones while stimulating the donor’s ovaries with fertility drugs. The eggs are harvested and then fertilized with designated sperm in an embryology laboratory. One or more embryos are then transferred to the uterus of the embryo recipient. Upon conceiving, the embryo recipient then carries the baby(ies), hopefully to full term.

There several ways by which Egg Donation can be conducted, and the steps taken in preparing for the process are profoundly affected by the approach chosen:

1. Conventional Egg Donation: This is the basic format used for conducting the process of egg donor IVF. It involves synchronizing the menstrual cycles of both the recipient and the donor by placing the donor and the recipient on a birth control pill, so that both parties start stimulation with fertility drugs simultaneously. This ultimately allows for precise timing of the fresh embryo transfer.
   


2. 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 in advance. Her eggs are fertilized with designated sperm and the resulting blastocysts are frozen (vitrified & cryobanked) for subsequent transfer to an embryo recipient’s uterus in a subsequent cycle. 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 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 previtrified blastocysts is >95% and the pregnancy rate per transferred pre-vitrified blastocyst is at least the same as for fresh transfers. The cost for Staggered IVF-ED is also not greater than is the case 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.
   


3. CGH Embryo Selection in IVF with Egg Donation: The introduction of Comparative Genomic Hybridization (CGH) allows full embryo chromosome analysis (karyotyping) and confidence that CGH-normal embryos so selected will have a high likelihood of being “competent” (i.e. capable of producing a healthy baby). In fact, CGH-normal embryos will each provide >60% chance of a baby per embryo transferred. Combining CGH embryo selection with Staggered IVF Egg Donation thus further enhances the efficiency of the process and allows us to limit the number of embryos transferred to 1 or 2, thus virtually eliminating the risk of “high order” multiple pregnancies (triplets or greater).
   


4. Use of a Donor Egg Bank: Another imminent advance in the arena of IVF with egg donation is the emergence of donor egg banking. Being able to freeze and bank donor eggs would solve most of these challenges. By using vitrification to freeze eggs, we are now capable of improving the birth rate per warmed/thawed egg by a factor of 7 (from a previous average of 1-4% per egg to about 27%). In the future, through an electronic catalog, recipients will be able to select and purchase CGH-normal eggs that have been retrieved from donors, genetically tested, then frozen. Thereupon, the selective transfer of 1 or 2 embryos derived from these chromosomally normal eggs could achieve a >60% pregnancy rate without the risk of initiating high-order multiple pregnancies in the process. At the same time, this approach will drive down the cost while reducing both risk and inconvenience to the patient.

Egg donation is associated with several benefits. First, in most instances, more eggs are retrieved from the young donor than are required for a single attempt at achieving a pregnancy, so that there are often several embryos left over for storage (cryopreservation/freezing) and use in a future IVF cycle. Second, because of the relatively high level of “competency” of the younger donor’s eggs the risk of miscarriage is also considerably reduced. Third, the low occurrence of chromosomal birth defects (e.g. Down Syndrome) when embryos that are derived from the eggs of a young donor implant, diminishes the necessity for the performance of invasive preimplantation genetic testing such as amniocentesis or chorionic villus sampling (CVS).

The indications for egg donation/IVF are:

• Severely diminished ovarian reserve (DOR) as might be evidenced by ovarian resistance or failure to respond to stimulation with fertility drugs.


• Repeated prior low rate of fertilization of the woman's own eggs in prior IVF attempts, even with intracytoplasmic sperm injection (ICSI).


• Ovarian failure due to menopause, surgery, radiation, or chemotherapy for malignant diseases.


• The presence of chromosomal or genetic disorders that have a high likelihood of being transmitted via the woman's eggs to the offspring.

Most IVF programs employ the services of a reputable egg donor/surrogacy agency with access to many donors and surrogates. All egg donors are thoroughly screened before entering a cycle of treatment (see below).

While we strongly recommend to aspiring parents that the identity of the ovum donor be anonymous, we do accommodate the needs of those individuals/couples who prefer to use a known donor. However, the arrangements to use a known donor must be clearly defined and agreed upon at the outset.

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, as do the sperm provider and embryo recipient. (See below)

Finally, the couple and the egg donor independently visit with our clinical 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.

Stimulating with Fertility Drugs and Monitoring the Egg Donor
The egg donor is treated with one or more gonadotropins (e.g., Recombinant FSH [FSHr], e.g. Follistim, Gonal F, Luveris) and/or Menotropins (e.g., Menopur) in order to stimulate development of enough follicles to optimize the number of mature eggs available at egg retrieval. In preparation for this treatment, the donor will be asked to commence taking a combined (monophasic) birth control pill (BCP) for ten days or longer. Thereupon, she will receive daily GnRHa (e.g., Lupron, Buserelin, Decapeptyl) injections in combination with the BCP for about 2 days. At this point, the BCP will be discontinued and the GnRHa therapy continued. About 5-8 days later, with the subsequent onset of menstruation, the donor will have her blood tested for estradiol and usually (especially if her blood estradiol level is >70pg/ml), will have a baseline ultrasound examination to exclude the presence of ovarian cysts and to confirm that her ovaries are ready to be stimulated with gonadotropins.

Sequential ultrasound examinations and blood estradiol levels are monitored starting on the 7th day of gonadotropin therapy. Usually, one to four additional days of gonadotropin therapy will be required to allow the follicles to develop optimally, at which time she will receive a “trigger” injection of hCG 10,000U intramuscularly. About 36 hours later the egg retrieval will be performed with the donor under conscious sedation.

Central to conducting conventional IVF-egg donation, is the need that the embryo recipient’s and egg donor’s cycles be synchronized as closely as possible so that the endometrial lining of the embryo recipient's uterus can be optimally prepared for embryo implantation. This is achieved by administering the BCP and Lupron to the recipient in the same manner as for the donor (see above). By lengthening or shortening the duration of BCP treatment, it is a relatively easy matter to synchronize the cycles of the embryo donor and recipient. When Staggered IVF egg donation is used, such synchronization becomes redundant and unnecessary (see above).

Preparing for ET by Building the Embryo Recipient's Uterine Lining

1. Hormonal Injections: The embryo recipient receives estrogen in the form of biweekly injections of estradiol valerate (E2V) (on Tuesdays and Fridays). The embryo recipient’s blood is drawn one day prior to each scheduled E2V injection to measure E2 concentrations in order to determine the subsequent dosage. The recipient also undergoes ultrasound examinations to evaluate the development of her endometrial lining.
   


2. Special considerations in women with estrogen deprivation (non-menstruating): Women with estrogen deprivation due to Ovarian Failure, who have not been receiving hormone replacement therapy (HRT) for more than 2 months should, in my opinion, first receive estrogen priming for a few months before undergoing ET. This is because in such cases, the few weeks of estrogen administration prior to ET is insufficient to prepare the lining of their uteri for ET without prior estrogen priming for 2 or more months. The reason for this is that in the absence of regular estrogen administration through HRT, the endometrial linings of many such women will have reduced responsiveness to estrogen, making them far less likely to conceive following ET. Those that do are much more likely to miscarry.
   
   Thus, in my opinion, it is important for women with prior prolonged estrogen deprivation, first to receive cyclical estrogen HRT for at least 2 months in order to grow the uterus and prime the endometrium so as to render it more receptive to subsequent implantation HRT for ET. In the process, both implantation and pregnancy potential will be enhanced.
   

Selective Use of Sildenafil (Viagra) to Improve Endometrial Development

In some cases, a thin (<9mm) endometrium can be successfully treated by administering vaginal sildenafil (Viagra) suppositories until progesterone therapy begins. The sildenafil will in many cases enhance response to estrogen by improving uterine blood flow, which is capable of improving the uterine lining.

Preparatory Tests That should Be Performed

A. EMBRYO RECIPIENT
Examination, PAP smear and mammogram; TSH; prolactin; Rubella antibodies; Blood group (ABO/Rh); Hep B; Hep C; HIV; Chlamydia antibodies; Syphilis; Natural Killer (NK) cell Activity (K-562-target cell test); Cervical cultures (ureaplasma and gonococcus); Sonohysterogram (saline sonogram).

B. SPERM PROVIDER
History & Physical Examination; Semen Analysis; Semen Cultures (gonococcus, ureaplasma); TSH; Blood group (ABO/Rh); Hep B; Hep C; HIV; Chlamydia antibodies; Syphilis.

C. EGG DONOR
History & Examination; PAP smear; FSH; E2; AMH (on cycle day-3); TSH; prolactin; Rubella antibodies; Blood group (ABO/Rh); Hep B; Hep C; HIV; Chlamydia antibodies Syphilis; Natural Killer; cervical cultures (gonococcus & ureaplasma); Genetic tests (e.g. cystic fibrosis and Tay Sachs disease, Sickle Cell disease, Thalassemia, etc).

*Next week I will address Embryo Banking; an exciting alternative to Egg donation for women who have DOR but are unwilling to consider IVF- Egg Donation as an option.

IVF Case Study #12: Egg Donation IVF Done Conveniently Using a Novel Approach, Staggered IVF with CGH Embryo Selection

Our 12th case study deals with a couple who lived abroad in Saudi Arabia and wished to come to SIRM-Las Vegas for IVF with egg donation. They had a history of five prior IVF failures using her own eggs. The husband had a very hectic and busy professional schedule. Thus, they wanted to optimize convenience, minimize the time away and to do so with as little hassle as possible, without increasing cost and without compromising success. I proposed a novel approach to egg donor IVF which achieves all these objectives: “Staggered IVF” using CGH for embryo selection, all done at a distance. This approach separates the egg donor cycle from the embryo transfer cycle and allows the recipient couple to plan for a time when they will have to spend less than half the usual time period away from home. I have highlighted the process in this post.

Background: Fatima, a 42 year old woman and her perfectly fertile male partner, Mohamed, had been trying to conceive through in vitro fertilization (using her own eggs) for approximately 4 years. During that time they had undergone 5 failed IVF attempts. Largely due to a combination of advancing age and diminishing ovarian reserve (her most recent FSH on day 3 was 17.1 mIU/ml and her AMH levels were 0.2), Fatima had been unable to propagate good quality eggs or embryos. With this in mind, they elected to come to SIRM-Las Vegas for IVF with egg donation.

The Problem: This couple lived in the Middle East (Saudi Arabia), and were both very busy professionals. For this reason, having to travel all the way to Las Vegas and spend up to 2 weeks away from home and work, posed a significant problem. Moreover, they were concerned about the possibility (albeit unlikely) of making the long journey and spending significant time away from home, only to find that there were no good quality embryos available for transfer, thus making their entire investment in time, money and emotion for naught.

The Solution: I presented the couple with the option of doing “Staggered IVF with Egg Donation at a Distance” and using CGH for embryo selection. Using this approach, they would not even have to leave home for the United States until they were assured of having “competent” embryos available for transfer. Because they were using donor eggs, Fatima would not need to be at our clinic until shortly before the embryo transfer. Moreover, the date they would have to arrive in Las Vegas would be chosen to meet their convenience and would be known to them well in advance allowing them to arrange their schedules conveniently. In all, the time spent with us would be less than a week. Finally the process of CGH embryo selection would afford them about a 70% chance of success.

Why Staggered IVF with Egg Donation is a Preferred Option for Couples Traveling from a Distance
This option involves separating the cycle of donor stimulation, retrieval and fertilization, from the cycle in which the recipient undergoes embryo transfer. Needless to say, the partner’s sperm must be available at the time of the donor egg retrieval, but this rarely presents a problem, since arrangements can almost always be made to have a frozen (cryopreserved) sperm sample forwarded to us well in advance of the retrieval.

The donor egg retrieval is thus usually performed while the recipient couple remains at home awaiting a report on the number and quality of embryos generated through IVF. In many instances (as was the choice in the case of this couple), we take embryo selection beyond the level of defining embryo “competency” on the basis of development to the blastocyst stage. Instead, the couple wisely decided to biopsy all viable embryos and to test them for their chromosomal integrity using metaphase CGH.

This approach of Staggered IVF with Egg Donation is ideally suited to meet the needs of busy couples, especially those who plan on traveling out of their area for IVF with egg donation.

• It should be clarified that with the introduction of ultra rapid embryo freezing (vitrification), the embryos are not adversely affected. More than 95% will survive the freeze/thaw and upon being transferred will have at least as good a chance at propagating a viable pregnancy as do their fresh (non frozen) counterparts. This is in stark contrast to what used to be the case when conventional (slow) freezing was used to store embryos. The slow cooling-down process led to ice crystal formation within the cells of the embryos, thereby damaging many of them. This reduced their post-thaw survival and resulted in poor pregnancy rates.
  
  Conversely, with vitrification, the embryo is frozen about 600 times faster…so fast that it prevents ice crystal formation. The embryos are thus not damaged and survive the thaw in prime condition. Furthermore, the baby rate per thawed blastocyst using this freezing method is no different than is the case for freshly transferred blastocysts.
  
  
• Since blastocyst vitrification does not harm the embryos significantly, it is possible to hold them in cryostorage for as long as needed without prejudice. Thus, recipients can avoid the complexities and inconvenience of having to be present in tandem with the egg donor during the cycle of IVF. Not only is this more convenient, but it prevents the recipients from inadvertently coming into contact with the otherwise “anonymous” egg donor. It also allows the luxury of scheduling the embryo transfer procedure to meet the needs of their calendar. Finally, it reduces the required time away from home by at least half.
  
  
• I have previously alluded to the fact that embryos that fail to progress to the blastocyst stage are almost always chromosomally abnormal (aneuploid and “incompetent”) and thus not viable for transfer. The old adage that transferring embryos earlier on into the uterus would provide a more favorable environment for their development is fundamentally flawed. There is simply no evidence to support this contention.
  
  Furthermore, by allowing embryos to progress to the blastocyst stage, many of the aneuploid (“incompetent”) ones will be culled out along the way. The addition of CGH embryo selection further refines the process of eliminating those embryos that have no chance of developing into viable pregnancies. Thus, one can improve the pregnancy rate dramatically by transferring even a single CGH-normal blastocyst, and in the process avoid the temptation of transferring numerous embryos with the risk of high order multiple gestations (triplets or greater) and all its associated hazards.

Selecting an Egg Donor: We proceeded to help the couple identify a suitable egg donor through a Las Vegas-based third party parenting agency “Footsteps to Family” (www.footstepstofamily.com). Five potential egg donor candidates were identified. They ultimately settled on Claire, a 29 year old single woman who had a proven track record - with a successful pregnancy in one of my patients approximately 2 years prior. We arranged to have a cryopreserved specimen of Mohammed’s sperm sent to us.

The Egg Donor’s IVF Cycle: The egg donor underwent controlled ovarian stimulation (COS) and egg retrieval (ER). She produced 19 mature eggs (MII’s) These were fertilized using intracytoplasmic sperm injection (ICSI) resulting in 13 morphologically sound day-3 embryos that were all biopsied for CGH testing. Eight progressed to the expanded blastocyst stage and were promptly vitrified and cryobanked. The biopsied DNA specimens derived from those embryos that had developed into blastocysts were sent out for metaphase CGH testing, where it was determined that four (4) were chromosomally normal (euploid) and thus likely to be “competent”.

Preparing the Recipient (Fatima) for a Frozen Embryo Transfer (FET): At this point, the couple set a date to travel to the US (Las Vegas) for an embryo transfer two months later, at a time that would be most convenient for them. The plan was to transfer 2 CGH-normal embryos to her uterus. Fatima went through a screening process at home in Saudi Arabia, based upon guidelines set by us and overseen by her SIRM Clinical Coordinator. This preparation included general medical clearance (physical examination, EKG, chest x-ray, mammogram and blood testing). Fatima had her uterine cavity evaluated by saline sonography (sonohysterogram) and we arranged for her to have a blood sample sent to Reproductive Immunology Associates (RIA) in Van Nuys, CA for an alloimmune and autoimmune evaluation. This would help to exclude an underlying immunologic implantation dysfunction (IID). Her husband was also evaluated clinically and had a repeat semen analysis done, along with semen cultures. The results of all these tests indicated that there were no significant problems with either partner.

Fatima was placed on a birth control pill and began receiving twice weekly injections of estradiol valerate (E2V) 4 mg along with 0.75 mg of dexamethasone daily. Within 10 days of initiating E2V therapy, the couple arrived in Las Vegas. I performed a vaginal ultrasound evaluation and determined that she had an excellent, trilaminar uterine lining that measured 10 mm in thickness, and that her blood estradiol was in the therapeutic range of 500-1000 pg/ml. At this point, we started administering intramuscular progesterone in oil (PIO) daily, and 5 days later, two CGH normal blastocysts were thawed. Both survived and were transferred to her uterus that same day.

Outcome: Fatima subsequently conceived. Her progesterone/E2V/dexamethasone therapy was continued until the 10th week of pregnancy whereupon the dexamethasone was slowly tailed off within a week thereof. A subsequent ultrasound examination performed 3 weeks later confirmed a perfectly viable twin gestation that progressed to delivery of healthy twins (2 girls) by caesarian section at 37 ½ weeks. Now, with the babies almost 2 years old and Fatima having concluded a period of successful breastfeeding, they are targeting a 2nd attempt. This time they only want a single CGH normal blastocyst transferred in order to avoid another multiple gestation.

Conclusion: IVF with egg donation is highly successful, with the vast majority of women conceiving within 2 or 3 embryo transfers. By combining this simple and effective procedure with CGH and staggered IVF (separating the cycle of egg retrieval from the cycle of embryo transfer) the efficiency, the success and convenience of the process is markedly enhanced at no additional financial cost to the patients. Finally, the fact that this process provides some assurance to patients that they are highly likely to reach embryo transfer often makes this approach much more desirable than traditional IVF.

Addendum: IVF is an ART-Science blend and not all practitioners agree on the same strategies. Thus, in the final analysis, it is important, after discussion with your personal doctor, to follow his/her advice to the letter.

IVF Case Study #11: Recurrent Miscarriages Due to Alloimmune Implantation Dysfunction (IID)

Here in our 11th case, we discuss a couple who had experienced eight (8) prior 1st trimester miscarriages due to a hitherto undiagnosed immunologic implantation dysfunction (IID). We identified the underlying cause as a shared, “partial DQalpha match" with uterine natural killer cell activation (NKa). Treatment involved Intralipid (IL) and prednisone, down-regulation of NKa followed by IVF using CGH embryo selection to identify genetically “competent” embryos. Once the CGH results were available, a frozen embryo was transfer performed (Staggered IVF), in which a single blastocyst was transferred (SBT). Upon establishing successful implantation, IL/steroid therapy was continued until the 24th week. She gave birth to a full-term healthy baby girl. This discussion centers on the importance of establishing an early diagnosis of IID in all cases of RPL and why IVF with a single blastocyst transfer of a CGH-selected chromosomally “competent” embryo was the favored approach in this case.

Background
Monica and her partner Andrew were 34 years and 37 years of age, respectively, when they first presented to me with a history of eight (8)recurrent first trimester miscarriages over a period of four (4) years. Fetal cardiac activity had been observed prior to the miscarriage in all but two cases. D&C’s were conducted to evacuate the uterus after 5 of the 8 miscarriages, and products of conception were submitted for chromosomal analyses (karyotyping). Pregnancies number 1 (male), 7 (female), and 8 (male) yielded products of conception with normal chromosomal configurations or karyotypes (i.e.”euploid”).

In 3 cases, the spontaneous miscarriages were deemed (through ultrasound examination) to have been “complete”, thus no D&C’s were done and no products were available for karyotyping. The 1st three miscarriages occurred prior to 8 weeks gestation while the last two occurred between 10 and 12 weeks gestation. The first 4 pregnancies occurred spontaneously, the next three followed intrauterine inseminations (IUI) with clomiphene citrate ovulation inductions, and the last pregnancy occurred with a second IVF attempt.

Both Monica and Andrew had their blood tested for structural chromosomal abnormalities known as translocations….None were present. Monica underwent hormonal evaluation to exclude subtle causes of ovulation dysfunction (FSH, LH, luteal phase estradiol, and progesterone/prolactin) and had tests for thyroid function, all of which were normal. A hysterosonogram (HSN), (also known as a saline sonogram) done prior to her initial IVF attempt confirmed the absence of surface lesions involving the uterine cavity, and an ultrasound examination of the uterine lining (done prior to ovulation/egg retrieval) consistently revealed an adequate endometrium (trilaminar configuration and a thickness of >9mm).

A thrombocytopenia panel done on Monica’s blood, aside from a heterozygous single mutation, showed no major problems in this regard. Both Monica and Andrew tested negative for reproductive ureaplasma infection and Andrew had normal semen analysis and SCSA tests...

Clearly, while Monica and Andrew had undergone all standard tests for causes of RPL, no testing had been done for an alloimmune or autoimmune cause for immunologic implantation dysfunction. Accordingly I had the following immunologic tests performed:

1. Monica’s blood : Antiphospholipid antibodies, Antinuclear antibodies, Immunophenotype, and antithyroid (antithyroglobulin and antimicrosomal) antibodies, Natural Killer Cell activation (NKa) - using the K-562 Target Cell Test
2. Both Monica and Andrew’s blood: DQalpha and HLA matching
   

The results of these tests revealed that Monica was NKa positive and that she and Andrew shared a “partial” DQalpha match (one of two DQalpha genes matched).

I strongly recommended that they proceed with a cycle of Staggered IVF with CGH embryo selection (see below). Monica’s COS cycle was launched with her coming off a birth control pill (BCP) and using a modest agonist-antagonist Conversion (stimulation) Protocol (A/ACP). I treated her with prednisone from the 1st day of stimulation. This was continued throughout the cycle. On cycle day 7, Monica received an infusion of 20% intralipid. She produced 11 mature (MII) eggs at ER. Following ICSI, these propagated 8, 5-9 cell, day-3 embryos.

These embryos were biopsied for metaphase CGH analysis (full karyotyping) and were then allowed to continue in culture to the blastocyst stage. At that time, the four embryos that made it to this stage were vitrified and cryobanked for future dispensation in a later cycle after the CGH results were returned and reviewed (Staggered IVF ). Two of the four blastocysts were found to be CGH-normal (euploid) and thus were classified as “competent”.

In a subsequent hormone replacement cycle, one was transferred to her uterus (the others three were kept in storage for future use). She conceived and subsequently gave birth to a healthy baby girl at term. Steroid/IL therapy was continued through the 24th week of pregnancy.

A Rational Approach to Managing Recurrent Pregnancy Loss
In more than 75% of cases, early miscarriage is caused by a chromosomally defective embryo (aneuploidy). In the remaining 25% of cases, pregnancy loss is due to uterine (endometrial) rejection of the embryo (i.e. implantation dysfunction). The latter can be due to an anatomical defect involving the uterine cavity (polyps, fibroids and scarring), a thin (inadequate) endometrial lining, or an immunologic implantation dysfunction (IID). However, since embryo aneuploidy occurs sporadically, it rarely repeats over and over in the same person. When this happens (i.e. RPL), the cause is more likely to be due to implantation dysfunction – of which there are two varieties:

1. Alloimmune Implantation Dysfunction – This is the most common immunologic cause of recurrent miscarriages. here is how it works: With fertilization, the sperm contributes genetic material to the fertilized egg or embryo. That is why an implanting embryo, is in about 90% of cases immunogenetically different from the mother's genotype...Yet, in spite of this difference the embryo is accepted and allowed to continue to develop into a viable pregnancy. This so called "paradox of pregnancy" is due to magnificent immunologic adaptations in the uterus, brought about by interaction ("communication) between an immunologically distinct embryo and the predominating immune lymphocytes in the uterine lining known as natural killer (NK) cells. Sometimes (in <10% of cases) the embryo and the mother might share certain similarities involving genes known as DQalpha and HLA. When this happens, after repeated exposures of the uterus to consecutive matching pregnancies, uterine NK cells (as well as and other immune cells known as cytotoxic lymphocytes) begin to release excessive amounts of cytotoxic cytokines that attack the embryo's trophoblast (root system) , thereby initiating a rejection process that often precipitates a first trimester miscarriage.
   
   Such alloimmune implantation dysfunction is thus a relatively common immunologic cause of recurrent first trimester miscarriages , making testing for alloimmune similarities in both partners an important part of the evaluation of non-chromosomal recurrent pregnancy loss. This requires comparing the mother’s and father’s HLA and DQ alpha genetic status for “matching similarities”.
   
   When the sperm provider and the embryo recipient share one or both DQ alpha genes and/or have several other HLA genes in common, implantation failure can occur, usually manifesting as early RPL (and sometimes, albeit less common, as “unexplained” infertility or IVF failure). However, for such alloimmune matching to lead to implantation dysfunction (e.g. miscarriage) there must be associated activation of uterine NK cells (NKa) as evidenced by the K-562 Target cell test and/or increased endometrial TH-1 cytokine activity determined through sampling. In the absence of such NKa, even the severest form of alloimmune matching will not prevent a perfectly normal pregnancy from occurring.
   
   
2. Autoimmune Implantation Dysfunction is the most common cause of immunologic failed implantation. This usually presents as “unexplained infertility” and/or “unexplained IVF failure” rather than miscarriage. Autoimmunity is an immunologic reaction produced by the individual to his/her body’s own cellular components. The most common autoantibodies that form in such situations are: a) Antiphospholipid antibodies (APA); b) Antithyroid antibodies (ATA); c) Antiovarian antibodies.
   
   But as with alloimmune implantation dysfunction, it is only when uterine NK cells become activated (NKa) and start to release excessive amounts of TH-1 cytokines, which attack the root system of the embryo, that implantation potential is jeopardized. Since autoimmune implantation dysfunction is often genetically transmitted, it is not surprising that it is more likely to exist in women who have a family (or personal) history of primary autoimmune diseases such as lupus erythematosus (LE), scleroderma, clinical or subclinical hypothyroidism, and rheumatoid arthritis.
   
   Reactionary (secondary) autoimmunity can occur in conjunction with any medical condition associated with widespread tissue damage. One such gynecologic condition is endometriosis (where 1/3 of cases have associated NKa). Autoimmune implantation dysfunction is usually immediately lethal to the implanting embryo. This is because it destroys most of the embryo’s root system from the get-go. That is why it most commonly presents as “unexplained infertility” or “unexplained (often repeated) IVF failure” rather than as a miscarriage.

Selective Immunotherapy for RPL: Both alloimmune and autoimmune implantation dysfunction are amenable to timely and appropriately administered selective immunotherapy with steroids (Prednisone/dexamethasone) and intralipid (IL) therapy. Achievement of optimal success with IL/corticosteroid therapy requires that the treatment be initiated well before ovulation takes place (about 7-14 days prior to anticipated implantation).

Reaching a diagnosis and developing a treatment plan for Monica and Andrew: The fact that at least three of Monica’s prior miscarriages were associated with chromosomally normal (euploid) pregnancies strongly suggested to me that her RPL was not due to embryo aneuploidy. By exclusion it had to be due to an implantation dysfunction. Since prior ultrasound examinations had shown that she generated a well-developed endometrium, it was apparent that Immunologic Implantation Dysfunction lay at the root of her recurrent miscarriages. This prompted immunologic testing that confirmed that she had NKa - apparently due to alloimmune dysfunction resulting from a partial DQa match with Andrew. This is what formed the basis for my proposing intralipid and steroid therapy that, in the event of pregnancy, would be continued through the 24th week of pregnancy.

An Argument for Staggered IVF with CGH Testing
Any exposure of Monica’s endometrial NK cells to an embryo with a matching DQa (derived from partner’s sperm) would evoke a local response in the uterus that would cause the release of TH-1 cytokines and the subsequent rejection of any/all embryos in the uterus at the time. Therefore, with the couple’s partial DQalpha match, each embryo propagated by Andrew’s sperm would have a 1:2 chance of matching Monica’s DQalpha type (there is currently no reliable way to determine which embryo(s) would “clash”). It follows that if more than one single embryo was to be transferred and one of these “matched", it could lead to the rejection of both embryos and a failed embryo transfer. That is why I strongly advocate for the transfer of only one embryo at a time in cases of partial DQalpha matching.

Moreover, because of the partial match in his case, each embryo transferred would have a 1-in-2 chance of being accepted by the uterine immune system. This meant that each embryo transferred would have half the chance of propagating a pregnancy as compared to what would otherwise have been the case in the absence of such an alloimmune match with accompanying NK cell activation.

Since Intralipid therapy will only protect the non-matching embryo from rejection, the chance of Monica having a baby when one embryo is transferred was reduced from about 25% to about 12% using traditional embryo selection methods. I thus favored increasing those odds through CGH embryo selection. In this way, the chance of such a “competent” embryo propagating a baby would be about 35% in her case (half of 70%)…much better odds, don’t you think? Implementation of this approach mandated that IVF be used.

Conclusion: Immunotherapy in IVF still represents a “much debated” issue, with many RE’s (albeit a declining number) still stubbornly refusing to even consider its relevance. However, Monica and Andrew’s case represents one of many examples where failure to evaluate IID in cases of “unexplained” infertility, “unexplained” IVF failure and RPL results in a couple “spinning their wheels” with significant emotional, financial and even physical consequences.. Patients with such issues should demand of their RE’s that they investigate and treat such issues.

Addendum: IVF is an ART-Science blend and not all practitioners agree on the same strategies. Thus, in the final analysis, it is important, after discussion with your personal doctor, to follow his/her advice to the letter.

IVF Case Study # 10: Embryo Adoption Following Successful IVF in a Woman with Endometriosis

This post continues our series of IVF case studies. Here in our 10th case, we discuss a couple with infertility due to endometriosis plus an immunologic implantation dysfunction (IID) who conceived twins through IVF. This couple had two leftover cryobanked embryos that they did not want destroyed. Instead they chose to donate them to adoptive parents. Our discussion focuses on the effect of endometriosis on IVF outcome and tackles some of the procedural and ethical considerations associated with embryo adoption.

Background
Jennifer and her husband, Jim, two very religious Evangelicals, presented to me in 2009 after six (6) years of infertility, wanting to have a baby. She was a 35 year-old normally ovulating woman, with patent Fallopian tubes, no pelvic adhesions, but with mild endometriosis (diagnosed through laparoscopy). Jim was a perfectly fertile male with normal sperm parameters. The couple had previously tried unsuccessfully, to conceive on their own for 4 years. After visiting an infertility specialist, she underwent three (3) cycles of clomiphene citrate and had four (4) attempts at gonadotropin-induced controlled ovarian stimulation (COS) with intrauterine insemination induction, without achieving a pregnancy.

Based upon the above history, it was clear that IVF treatment was required. The couple began the process of pre-IVF evaluation during which I found that Jennifer had an immunologic implantation dysfunction (IID) associated with antiphospholipid antibodies (APA) and Natural Killer Cell activation-NKa (as measured by the K-562 target cell test). I performed one (1) cycle of IVF using an agonist antagonist conversion protocol (A/ACP) to achieve optimal COS. We treated her APA with Lovenox, and her NKa with dexamethasone and intravenous Intralipid (IL).

Egg retrieval (ER) yielded twelve (12) eggs, eight (8) of which were mature (MII’s). ICSI was performed resulting is the development of four (4) good quality day-5 blastocysts. I transferred two (2) fresh blastocysts to her uterus and the IVF laboratory vitrified (cryobanked) the remaining two (2) blastocysts. Jennifer immediately conceived and at thirty seven (37) weeks gave birth (vaginally) to a set of healthy twin boys.

Addressing the Issue of Leftover Frozen Embryos
Last year, the couple presented at my office to discuss what to do with their cryobanked blastocysts. They did not want the embryos destroyed, but instead preferred to have them “adopted” out. Accordingly, they wanted to know what policies and procedures SIRM had in place to facilitate this process.

I informed Jennifer and Jim that for reason of protecting the future parents’ (as well any offspring’s) right to privacy, and in an attempt to avoid any future conflict of interest between the biological and adoptive parents, our policy is not to divulge the identity of the prospective embryo recipient couple to the biological parents. They were willing to accept this, but insisted on having a say in selecting the prospective recipient couple. They wanted any babies resulting from their conceived embryos to have a healthy support system and wanted them to be raised in a devout Christian religious setting such as their own.

I agreed to having them take part in the selection process, provided that the recipient couple could retain their anonymity. Since they were willing to donate their embryos free of charge, I agreed to provide my services in processing and transferring these blastocysts to the recipient couple, free of charge.

Jennifer and Jim helped select a recipient couple from a long waiting list of candidates. I screened, evaluated and prepared the female partner using estrogen/progesterone hormone therapy and transferred the two (2) thawed (warmed) blastocysts to her uterus. She conceived and is currently about 5 months pregnant with a healthy singleton boy.

About Endometriosis and IVF
The natural conception rate for healthy ovulating women in their early 30’s (who are free of endometriosis) is about 17% per month of trying and 80% per year of actively attempting to conceive. Conversely, the conception rate for women of a comparable age who have mild or moderate pelvic endometriosis (absent or limited anatomical disease) is about 3% per month and 40% after 3 years of trying. The reduced conception rate in women with endometriosis can, in large part, be attributed to one or more of the following:

1. Toxins in the Peritoneal Fluid: Women with endometriosis (regardless of severity) are believed to have “toxic factors” in their pelvic peritoneal fluid. These "toxins” reduce the fertilization potential of eggs discharged during ovulation. IVF, which involves extracting eggs before they are released, bypasses this effect. This, at least in part, explains why normally ovulating women who have mild to moderately severe pelvic endometriosis are about 5 times less likely to conceive per month of trying than women with infertility due to other types of organic disease. It also serves to explain why the use of fertility drugs, IUI, or corrective surgery in ovulating women with mild to moderate endometriosis hardly improves the chance of achieving a successful pregnancy.
2. Immunologic Implantation Failure: We have previously reported that about 30% of women with endometriosis show evidence of increased Natural Killer Cell activity (NKa). In such cases, selective immunotherapy with steroids and Intralipid can counter associated IID and lead to successful IVF many times. To be effective, Intralipid therapy must commence well in advance of embryo transfer.
3. Endometriomas: These are cystic lesions (often called “chocolate cysts”) within the ovary that result from the accumulation of altered “menstrual blood” produced by the endometrial lining. Endometriomas can activate the surrounding ovarian connective tissue (stroma), which can compromise egg development and quality. Thus, any ovarian endometrioma that is more than 1cm in size should, in my opinion, be removed surgically or through a simple office procedure called “sclerotherapy” at least 6 weeks prior to the IVF cycle.
4. Pelvic Scarring and Adhesions: Endometriosis and/or its surgical treatment can result in local scarring, which can compromise tubal function and egg pick-up by the Fallopian tubes.

About Embryo Adoption
Embryo adoption refers to the situation in which a woman receives embryos to which she and her partner have not contributed biologically. When one or both partners are infertile, donor sperm and/or donor eggs must be used if the woman is to become pregnant. Previously, adoption of a child would have been such a couple’s only option if donor eggs/sperm were not feasible. Now, however, prenatal embryo adoption can be an alternative to adoption of a baby or child. I perform these procedures because I believe that apart from the fact that embryo adoption occurs far earlier than baby adoption, there is otherwise little difference between the two processes.

Embryo adoption is a very sensitive issue. There is an enormous inherent burden of responsibility placed on the treating medical team to screen all candidate couples through thorough and meticulous clinical, psychological, and laboratory testing.

Most couples undergoing IVF who have a baby will choose to hold on to the remaining embryos in case they want to have another child later on. Many of those that know that they do not want another baby usually will prefer to have their left-over embryos destroyed rather than donate them to a recipient couple. Some would rather donate such embryos for scientific research or for the propagation of embryonic stem cells for medical treatments. Few are willing to donate their embryos for adoption by a recipient couples. That is why there are currently so few embryos available for adoption and why the waiting list of hopeful recipient couples is so very long.

It is also an undeniable fact that less than 1-in-10 couples seeking to adopt embryos will ultimately gain access to them. And because the best embryos are usually transferred fresh (leaving the poorer quality ones available for adoption), less than 20% of those who receive adoptive embryos ultimately end up with a baby.

Conclusion: In my opinion, Embryo Adoption provides a highly commendable solution to dealing with leftover cryobanked embryos. And to me, it is far less fraught with ethical dilemmas than is destruction of such embryos or even using them for scientific research. Unfortunately, so few adoptive embryos are available that the waiting list of recipients keeps growing.

Addendum: It is important to understand that IVF is an ART-Science blend and not all practitioners agree on the same strategies. Thus, in the final analysis, it is important, after discussion with your personal doctor, to follow his/her advice to the letter.

IVF Case Study # 9: Embryo Banking in an Older Woman With Recurrent IVF Failure and Diminished Ovarian Reserve

This continues our series of IVF case studies. Here in our 9th case, we discuss a couple in whom maternal age, diminished ovarian reserve (DOR), and the protocol for ovarian stimulation had compromised the number and quality of eggs/embryos generated, resulting in repeated prior IVF failures (four). This couple was introduced to Staggered IVF with Embryo Banking and went on to have a beautiful IVF baby girl after a single embryo transfer procedure.

Background
Melissa, a regularly/normally ovulating woman was 42 years of age when I first saw her as a patient. Her husband was a perfectly fertile man who had proven his fertility by fertilizing Melissa’s eggs in prior IVF attempts, having normal sperm parameters, and having initiated two pregnancies in a prior relationship. Melissa had never before conceived. She and her husband had been trying to conceive for about 3.5 years. The cause of their infertility was tubal blockage (without evidence of a fluid collection- i.e. hydrosalpinx) complicated further by diminished ovarian reserve (DOR). Her uterine cavity was regular by sonohysterogram. Her uterus was normal by ultrasound examination, as was her ability to produce a good uterine lining (endometrial thickness was >9.0mm) at the time of natural ovulation.

Melissa‘s DOR was evidenced by her blood FSH/E2 of 14.3 MIU/ml/61 pg/ml on the third day of a spontaneous menstrual cycle, and by resistance to controlled ovarian stimulation (COS) with gonadotropins during four prior failed IVF attempts. In spite of receiving 350U of Follistim+ 150U Menopur for up to 12 days, using a “microflare” Lupron protocol, her highest peak [E2] was only 715 pg/ml. She produced at best, 6 eggs, with 2-4 being mature (MII’s). These, upon being fertilized by ICSI, propagated 1-3 poor quality embryos which by the day of her scheduled embryo transfer day (day 3), were consistently 6 cells cleaved and more than 20% fragmented.

Early on in the course of my discussions with the couple, I explained that since Melissa was 42 years of age and had DOR, her biological clock was working against her. As I have written about frequently here, it is the chromosomal integrity (karyotype) of the embryo that will ultimately determine its “competence”, i.e. its ability to develop into a viable pregnancy . Furthermore, it is the chromosomal make-up of the egg (rather than the sperm) that in most cases determines embryo “quality.”

As a refresher, two factors play a predominant role in determining egg/embryo “competence.” The first and most important is the woman’s age (rather than ovarian reserve as determined by basal FSH/AMH ). Before age 35, about 1:2 eggs are chromosomally normal (euploid/competent) but by the time a woman enters her early to mid-forties, 9:10 of MII eggs are chromosomally abnormal (aneuploid), regardless of her ovarian reserve. The protocol of controlled ovarian stimulation (COS) used can also influence the likelihood of embryo “competence”, by affecting egg development. Moreover, the eggs of women with DOR are especially vulnerable to implementation of “recipe-type” ovarian protocols of stimulation.

Melissa was facing both age and DOR issues. By altering the ovarian environment, DOR makes it much more difficult to secure an ideal environment for egg development during COS, thereby increasing the likelihood of poor egg development. This, in turn, also adversely impacts embryo quality as well as IVF outcome. This is why in such cases, an individualized approach to ovarian stimulation is so crucial.

Because of her age and ovarian reserve, I recommended to Melissa that she use CGH karyotyping to screen her embryos for competence in order to optimize her chances of success. This would allow us to select the best (“competent”) embryo(s) for transfer to the uterus based on it/them being chromosomally normal (euploid). In fact, in our experience, transferring one such “competent” embryo to a receptive uterus results in a live birth almost 70% of the time.

Thus, if we could be certain that the embryo being transferred was CGH-normal, her chance of having a healthy baby would be unaffected by her age. However, at her age and with her having significant DOR, she would almost certainly only produce a few eggs per ER. As such, even if we protected the potential of those eggs to develop normally by using an individualized approach to ovarian stimulation (the agonist/antagonist conversion protocol - A/ACP), only about 1:10 would likely turn out to be chromosomally normal (euploid) or “competent”. Thus, by using a conventional approach to IVF, her odds of conceiving would still be low.

Embryo Banking: The recommended approach!
I suggested to Melissa and her husband that they use an Embryo Banking approach. This would involve her completing 2-3 cycles of stimulation, egg retrievals, and fertilization without proceeding to fresh embryo transfers. All eligible embryos would be biopsied on day 3 for subsequent CGH analysis, taken to the blastocyst stage (advanced embryos) and then frozen by vitrification (ultra-rapid freezing/banking) for later transfer to the uterus in a subsequent cycle. I call this approach “Staggered IVF.” Those embryos that did not make it to blastocyst would be discarded (since those that fail to reach this advanced stage are aneuploid and “incompetent” anyway).

In this way, she could hopefully accumulate (over a period of 4-6 months) several competent (CGH-normal) embryos and transfer 1-2 of these to the uterus, greatly increasing her chance of having a baby. Moreover, since most miscarriages as well as many developmental birth defects (e.g. Down syndrome) are also due to chromosomal irregularities (aneuploidy) these risks could also be minimized by CGH testing.

In addition, if we were able to cryobank multiple CGH-normal embryos, the couple might have an opportunity to come back a few years later and have another baby, something that would otherwise be highly unlikely.

Another advantage to the embryo “stockpiling” approach is that the cost of a 2-3 cycle Embryo Banking package is much less than the cumulative cost of 2-3 individual cycles of IVF with CGH. This is because with Embryo Banking “packages,” a single embryo transfer is done once all IVF cycles (included in the package) have been performed. Then, a single genetic CGH test on all embryos stockpiled over the 2-3 cycles is performed after all banking cycles have been completed (rather than a separate CGH test after each retrieval/fertilization batch).

Treatment and Follow-up
The couple chose to undergo Embryo Banking. In their 1st IVF cycle, using an A/ACP (LA-8) protocol, we retrieved 7 eggs (6-MII’s) that produced 5 embryos (all were biopsied for CGH testing). Two expanded blastocysts developed and were vitrified/banked. In the 2nd cycle there were once again 7 eggs (4 MII’s) harvested, producing 4 embryos (three were biopsied), but none made it to blastocysts. In the 3rd and final IVF cycle we harvested 9 eggs (all were MII’s), which produced 6 embryos (all were biopsied for CGH testing). Three (3) blastocysts were vitrified and cryobanked.

In total, they ended up with 5 cryobanked blastocysts. The results of CGH testing identified only one (1) that was CGH-normal. This blastocyst was transferred to her uterus and Melissa conceived about 7 months after her 1st ER (i.e. 2 months after the 3rd ER). At 14 weeks gestation, she underwent a confirmatory amniocentesis and a few weeks ago gave birth to a healthy normal baby girl.

Conclusion: In my opinion, Embryo Banking offers women who are running out of time a unique opportunity to put the biological clock “on hold” and optimize their chance of having a baby before they run out of time. In the process, their odds per embryo transfer of having a baby is dramatically improved and the risk of miscarriage and chromosomal birth defects is minimized. Embryo Banking also removes the extreme pressure to achieve success with each individual cycle of IVF. And by providing older women and those with DOR with the ability to store several “competent” embryos before time runs out for them, it opens up the possibility of coming back several years later for a second baby. As such, embryo banking represents a major advance in the IVF therapeutic armamentarium.

Addendum: It is important to understand that IVF is an ART-Science blend and not all practitioners agree on the same strategies. Thus, in the final analysis, it is important, after discussion with your personal doctor, to follow his/her advice to the letter.

IVF Case Study # 8: An Older Woman With Recurrent IVF Failure, Diminished Ovarian Reserve and Immunologic Implantation Dysfunction

This continues our series of IVF case studies. Here in our 8th case we discuss a couple who had experienced 22 previously unexplained IVF failures who had diminished ovarian reserve (DOR) plus immunologic implantation dysfunction (IID) and subsequently conceived when treated with an agonist/antagonist conversion protocol with estrogen priming and selective immunotherapy to down-regulate activated natural killer cells (NKa).

Background
Christine, a 42 year old physician from Australia had endured 23 prior unsuccessful fresh embryo transfers over a period of more than a decade. By the time I got to know her she had severely diminished ovarian reserve (her day-3 FSH was 26MIU/ml).

Follow-Up
After a lengthy telephone consultation with her, I urged her to send a blood sample from Melbourne, Australia to a reputable Reproductive Immunology Reference Laboratory in Southern California for testing to screen for immunologic implantation dysfunction (IID). It soon became apparent that she had an autoimmune thyroid condition (antithyroglobulin and antimicrosomal antibodies) along with activation of uterine Natural Killer Cells (NKa+). After controlled ovarian stimulation (COS) using an aggressive agonist/antagonist conversion protocol with estrogen priming, and pre-treating her immunologic implantation dysfunction (IID) with selective immunotherapy, I harvested just three eggs. We subsequently transferred two embryos to her uterus. She conceived in this cycle and gave birth to a healthy baby boy nine months later.

Commentary
This case shows that there is no merit in doing IVF over and over again in the face of repeated prior failures, without making a strong effort to determine the reason for such failures. In Christine’s case, by the time I saw her for the first time, she already had severely diminished ovarian reserve (DOR) as well as an immunologic implantation dysfunction (IID) linked to Natural Killer cell activation (NKa). We addressed the severe DOR by stimulating her with an agonist/antagonist conversion protocol plus estrogen priming and harvested 3 mature eggs (MII’s) and transferred 2 good quality embryos. We addressed the IID through selective immunotherapy by down-regulated her NK cell activity and corticosteroid therapy to establish a favorable uterine environment. She duly conceived.

This case also demonstrates that in women with severe DOR, diminished egg/embryo quality can in part be effectively by using an individualized approach to ovarian stimulation such as the agonist-antagonist conversion protocol with estrogen priming; LA10-E2V.

Addendum: It is important to understand that IVF is an ART-Science blend and not all practitioners agree on the same strategies. Thus, in the final analysis, it is important, after discussion with your personal doctor, to follow his/her advice to the letter.