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:
- 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 startstimulation with fertility drugs simultaneously. This ultimately allows for precise timing of the fresh embryo transfer.
- 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 beblastocysts 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.
- 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).
- Use of a Donor Egg Bank: Another imminent advance in the arena of IVF with egg donation is the emergence ofdonor 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 therapycontinued. 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 liningof 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
- 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.
- 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 receiveestrogen 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) suppositoriesuntil 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.