Crozer Fertility

Assisted Reproductive Technology:

Assisted Reproductive Technology employs the highest technology available to assist in achieving a pregnancy. The procedures included within this technology are gamete intrafallopian transfer (GIFT), zygote intrafallopian transfer (ZIFT) and in vitro fertilization (IVF), the latter used most frequently if not exclusively by some practices. ART includes treatment methods for many couples who suffer from blocked tubes, failed multiple infertility treatments and who are consequently labeled as unexplained infertility. Additional indications for ART include male factor infertility and endometriosis. Preimplantation genetic diagnosis has expanded the indications for IVF, as some patients are not necessarily infertile but need to employ this advanced technology to minimize the risk of having an affected child.

Since the birth of the first baby conceived from IVF in 1978, the field of ART has changed dramatically both clinically and within the laboratory. Progress in the field of reproductive medicine has lead to the impressive pregnancy and live birth rates following ART seen today. At the Fertility Center we have changed with the times to continually offer state of the art services to meet the needs of our patients.

Overview of IVF:

Controlled ovarian stimulation:

The very first step to any of the ART processes is to induce the development of multiple follicles in the ovary rather than the single follicle that matures in a monthly natural cycle. Reproductive Endocrinologists agree that that chances for pregnancy are greater if more than one oocyte is fertilized and transferred to the uterus during the IVF cycle. Multiple follicular development is accomplished by administering supraphysiological doses of the hormones naturally produced during the cycle (follicle-stimulating hormone and luteinizing hormone). Today these hormones (Gonal F, FSH and Luveris, LH) are recombinant, produced in culture, and are very pure. Their subcutaneous mode of injection renders the daily administration of FSH and LH more tolerable than the previous generation of fertility medication.

The natural production of these hormones must be suppressed to prevent spontaneous ovulation prior to the oocyte retrieval. This is achieved through the use of Lupron prior to (on day 21 of the previous cycle) or Lupron or Cetrotide at the start of the start of the cycle (cycle day 2). This regimen allows us to control ovarian hyperstimulation and the timing of the follicular aspiration. In addition to suppressing specific pituitary function, Lupron also assists to synchronize the follicles and produce a better quality cohort for retrieval.

Ovarian stimulation is monitored through transvaginal ultrasound and frequent hormone evaluation. Estrogen production by the growing follicles as well as direct measurement by ultrasound guides our interpretation as to when we should trigger final maturation with hCG. The hCG simulates the patient's natural LH surge responsible for the final pre-ovulatory changes in the oocytes, preparing them for fertilization. Even with pituitary down-regulation, spontaneous ovulation does occur, albeit rarely (3%). Thus some programs still monitor endogenous LH production throughout the stimulation cycle. To stimulate the final maturation of the oocytes in preparation for the retrieval, human chorionic gonadotropin (hCG, Profasi and Pregnyl) is administered ~ 36 hours prior to the oocyte retrieval.

Oocyte retrieval:

Oocyte retrieval is accomplished by transvaginal guided aspiration. This is a minor surgical procedure that can be performed in a physician's office under intravenous sedation, as the patient is asleep for such a brief period. The ultrasound locates the ovarian follicles and the distance from the vaginal ceiling. A guide attaches the retrieval needle directly to the ultrasound probe. In most instances the needle is passed through the vaginal wall during the aspiration. The follicular contents are examined in the laboratory and the oocytes separated from the fluid and cellular components. Laparoscopy has been described in the past as an alternate method for oocyte retrieval if the ovary is inaccessible through the vagina or even through the bladder. This procedure is used very infrequently. In more than 12 years and thousands of patients, this procedure has been employed only once at Crozer.

Culture and Fertilization:

After the oocytes have been identified, they are rinsed and incubated until it is time for insemination, either by conventional methods or via intracytoplasmic sperm injection (see ICSI). During the time of the retrieval the male specimen is prepared for insemination in the Andrology Laboratory. Approximately 6-7 hours after the retrieval the purified highly motile fraction is added to the oocytes for conventional insemination. At a concentration of ~30,000 motile sperm/ 3 oocytes. The culture dishes are returned to the incubator until fertilization is assessed the following morning. Oocytes are assessed for evidence of fertilization at 15-18 hours post insemination and returned to the incubators until growth is assessed the following day.

Embryo transfer:

The embryo transfer typically occurs 3 or 5 days after the oocyte retrieval. The procedure is performed in the clinic on an outpatient basis and no anesthesia or analgesia is used. The embryos are transferred to the uterus via a small catheter similar to that used during the mock transfer during your stimulation. The catheter is placed through the cervix into the endometrial cavity under ultrasound guidance. The embryo transfer is a quick procedure with essentially no discomfort. Patients remain in a reclined position in bed in our office for ~ 45 minutes after the procedure and are encouraged to resume normal activity the following day, with a few defined restrictions.

Pregnancy rate:

We strongly recommend that patients familiarize themselves with all parameters that define a good from a less successful program. The live birth rate following embryo transfer provides pertinent information regarding program quality. However, even the American Society for Reproductive Medicine cautions programmatic comparisons by statistics only since patient populations can vary between practices.

Additional services offered by the Fertility Center:

Intracytoplasmic sperm injection (ICSI).

Intracytoplasmic sperm injection (ICSI) was specifically geared towards the treatment of male-factor infertility. Its arrival in the early 1990's revolutionized the management of the poor quality semen sample. Compared with conventional insemination where a defined concentration of sperm is co-incubated with the oocyte, the ICSI procedure manually introduces a single sperm into a single oocyte. Originally thought of as an extremely crude method, the technique is advantageous in that it bypasses the physiological interactions normally necessary for sperm/egg interaction, which may be compromised in some samples. The procedure is performed in concert with an IVF cycle. The sperm injection process occurs on a specialized microscope, which permits direct visualization of the sperm, the egg and the introduction of the two gametes.

The first pregnancy at the Crozer Reproductive Endocrinology and Fertility Center resulting from ICSI occurred in 1994, only 2 years after the procedure was reported as successful in the literature. That same year at the Fertility Center twins were conceived using cryopreserved sperm from a testicular biopsy. The birth of the twins marked an event that so few programs in the world at that time experienced.

As with most innovative procedures, interest in the health of children conceived using ICSI surfaced along with its widespread use. Even though thousands of babies now have been born worldwide since its introduction, some studies show now that there is a slight increase in congenital defects following ICSI. However, some large-scale studies have refuted this evidence. Nonetheless, this evidence for increased incidence of defects may be related to the fact that pregnancy is now possible with sperm that naturally would never occur.

Assisted Embryo Hatching:

The oocyte and preimplantation embryo is surrounded by a gel-like coating, the zona pellucida, which offers protection during fertilization and transport through the reproductive tract. Through the early stages of development, in vivo and in vitro, the zona will thin as the embryo grows and expands. This thinning will eventually result in a breach of the zona whereby the embryo can escape, as the zona's protective role is unnecessary and actually inhibitory to implantation at this time.

It is thought that in certain classifications of patients, the embryo fails to hatch from the zona pellucida, therefore, implantation is not established. Assisted embryo hatching (AEH) is a laboratory procedure performed prior to embryo transfer. AEH is an attempt to assist in the natural hatching process by creating a small, chemically induced breach in the zona. We routinely perform AEH on women 38 and over, during frozen embryo transfers, after a previous failed attempt, if the zonae fail to thin in culture, and if the patient's baseline FSH is elevated.

Blastocyst transfer:

As implantation rates increased with advancements in both clinical and laboratory technology, the incidence of multiple gestation also increased. Extending the growth period of the embryos in culture (from days 2 or 3 to day 5) provided an additional power of selection for embryo transfer, as not all embryos possess the same capacity for growth. Embryos that continue to cleave appropriately during the extended culture period (days 4 and 5) have overcome a major hurdle in early preimplantation development and are considered inherently heartier than the remaining cohort which failed to progress.

We offer blastocyst culture to reduce the number of embryos transferred in any one cycle. Our goal is to reduce the chance of multiple gestation, which puts the pregnancy at a higher risk for loss, premature labor and pregnancy complications. As the blastocyst stage is more developmentally competent and physiologically appropriate for the uterine environment at this point of the cycle, it stands to reason that the implantation potential is greater.

We welcome the opportunity to discuss blastocyst transfer should any questions arise.

Preimplantation Genetic Diagnosis (PGD):

In 2003, the Fertility Center at Crozer added PGD to its repertoire of laboratory services. This state of the art laboratory procedure allows genetic testing on a single cell of the preimplantation embryo. PGD is employed to assess chromosomal aneuploidy (too few or too many copies of chromosomes), inversions (flipping of pieces of chromosomes) and translocations (when pieces of different chromosome segments switch location). Additionally, PGD may be used to detect single gene mutations such as those responsible for diseases such as cystic fibrosis, thalassemia, sickle cell and X-linked traits. The list for detection of single gene defects continues to expand as many mutations leading to a disease phenotype have been and are continuing to be identified.

The IVF process is generally viewed as the most aggressive procedure available for the treatment of infertility. When combined with PGD, IVF is a powerful practice that may be indicated for patient couples that are not necessarily infertile. Some of our PGD patients can achieve pregnancy quite easily but with a negative outcome. As a result of the IVF process, multiple embryos are available for genetic testing, which may translate into identifying a "normal" or unaffected embryo for transfer.

Our on-site biopsy team removes a one-two cells of the growing embryo approximately 48 hours after the fertilization check (approximately 72 hours after transvaginal follicular aspiration and 64 hours after insemination). This procedure, or embryo biopsy, is performed on all embryos that are minimally at the 6-8 cell stage. Following the biopsy, the embryos are returned to the incubators to culture an additional 48+ hours before the transfer. The cells are processed individually, with a protocol that is explicit to the type of genetic analysis indicated. Results are generated in approximately 48 hours, reviewed and the unaffected embryos are isolated for intrauterine transfer.

Even with 1-2 cells removed during the biopsy, the embryos continue to progress at a rapid rate in culture and are typically at the morula or early blastocyst stage on the afternoon of the scheduled transfer day. There is a very slight delay in growth compared to a non-biopsied cohort, however, there appears to be no difference in implantation potential. In fact, data from large center studies indicates that the implantation rate is more than double for age-matched controls not electing for biopsy and PGD. This observation is no doubt attributable to the selection of embryos based on the chromosomal complement rather than purely by morphology at the time of transfer. As we are learning from the PGD experience, embryo morphology does not correlate with genetically "normal" or "abnormal". With the increase in implantation rates, we are also observing a decrease in pregnancy loss, once again most likely attributed to the genetic complement of the embryos at the time of transfer.

To find out more about our PGD program, please contact one of our PGD team members.

Embryo cryopreservation:

Controlled ovarian hyperstimulation for IVF often results in the availability of more embryos then necessary for the embryo transfer. The Fertility Center provides cryopreservation at multiple stages of embryo development thus affording various options for future thaw cycles.

FAQ's

Do I need to have a minimal concentration of sperm in my ejaculate even for ICSI?

Certainly the more sperm available for any ICSI procedure provides a wider range of sperm to chose from at the time of the procedure. However, since each oocyte is in injected with a single sperm, theoretically we only need 1 motile sperm/mature oocyte retrieved. ICSI has provided an opportunity to achieve fertilization rates once not possible with male factor infertility.

Why not perform AEH on everyone?

Several studies have indicated that AEH does not appear beneficial when performed on all embryo transfers. The implantation and pregnancy rates did not differ with AEH in good prognosis patients. As with any form of embryo micromanipulation, there are risks involved, although minimal, which are not outweighed by the benefits in some classes of patients. Additionally, any micromanipulation means additional time out of the incubators and it is preferable to maintain natural conditions as much as possible.

Why not culture every IVF cycle to blastocyst?

Each oocyte and embryo has its own developmental competency, much of which is attributed to quality. Although stimulation regimens and culture technology have had some impact on growth potential, often the intrinsic quality of the oocyte or embryo would likely preclude in vitro growth to day 5. We assess embryo development on a day by day basis, and every case individually, to determine which day of transfer would best maximize the chances of achieving a pregnancy.

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Crozer-Chester Medical Center · 1 Medical Ctr. Blvd, A.C.P. Suite 531 · Upland, PA 19013 · 610 447-2727