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.