“Little of how we conduct IVF treatment is based on findings derived from “gold standard” randomized and controlled studies. They simply do not exist and, given the multitude of variables that influence IVF outcome, such studies would be virtually impossible to conduct reliably anyway. In fact if a book on IVF were to be constructed from only such statistically verified data, it would probably comprise no more than a few pages in length. That is why, like so much of medicine, IVF is a perfect example of an “art-science blend”. What is presented below is a personalized, stepwise approach to IVF that to a significant degree has become inculcated in the way we perform IVF at SIRM. It has evolved over a period of more than 3 decades in the infertility arena, and the births of >17,000 IVF babies in which I have been influential.”

This is a continuation of my last blog post. Part 1 can be found HERE

Egg Retrieval
Egg Retrieval (ER) involves a non-surgical procedure performed under conscious sedation. At SIRM, a qualified anesthesiologist is in attendance with the patient during the procedure. This is performed in a dedicated procedure room, where, under direct ultrasound guidance, a needle is passed along the side of a vaginal ultrasound probe through the top of the vagina into follicles (small fluid filled spaces that each contain an egg), within the ovary(ies). The follicular fluid is aspirated and collected in a test tube, which is promptly delivered to the embryologist(s) for analysis and processing. The procedure itself is relatively painless, however patients commonly experience some residual postoperative abdominal discomfort and /or cramping that rarely persists for more than a day or so. Postoperatively, all patients are given detailed instructions and are discharged within an hour or two with a prescription for analgesics (pain killers) and other medications as indicated.

Sperm Processing
A sperm specimen is usually obtained from the male partner through masturbation. On some occasions however, physical, medical and/or religious constraints demand that sperm be obtained through condom collection following intercourse, or by inserting a needle directly into the testicle(s) under local anesthesia and aspirating sperm. The two variations of this procedure are known as Testicular Sperm Extraction (TESE) and Percutaneus Epididymal Sperm Aspiration (PESA). TESE and PESA are procedures of choice in cases where there is blockage of the sperm ducts (as occurs following vasectomy or following severe injury or infection), where the man is born without sperm ducts (congenital absence of the vas deferens), or in cases where as a result of testicular failure, sperm does not reach the ejaculatory ducts.

Sometimes, in cases of retrograde ejaculation (seen after spinal injury, prostatectomy or advanced diabetes), sperm can be collected from the man’s bladder. Infrequently, in men with spinal cord injuries, ejaculation is facilitated by electrical stimulation (electro-ejaculation). Donor sperm, obtained from a sperm bank, can be used when indicated.

Fertilization in the Laboratory

Conventional IVF: In vitro fertilization literally means “fertilization in glass”. Fluid aspirated from ovarian follicles is examined in the embryology laboratory. The eggs are identified and extracted, and are placed in a specialized culture medium. Several hours later, approximately 50,000-100,000 processed sperm are placed around each of the eggs. The eggs and sperm are allowed to incubate together in a carefully controlled environment. Approximately 16-24 hours later, the eggs are inspected microscopically for fertilization as evidenced by the presence of two nuclear bodies. These binuclear unicellular bodies are referred to as “pro-nucleate embryos”.

Intracytoplasmic sperm injection (ICSI): Today, at SIRM, we perform virtually all IVF using ICSI. Studies have shown that there are really only advantages to this policy. The ICSI procedure involves the direct injection of a single sperm into each egg under direct microscopic vision. Initially, ICSI was used specifically to achieve fertilization in male infertility. When ICSI is employed in such cases, the IVF birth rate is unaffected by the presence and severity of the male factor. In fact, even when the absence of sperm in the ejaculate requires that ICSI be performed on sperm obtained through Testicular Sperm Extraction (TESE), the birth rate is no different than when IVF is performed for indications other than male infertility. Today, it is commonly used in conventional (non-male factor) cases. At SIRM, we advocate the use of ICSI in virtually all IVF.

Assisted Hatching: In selected cases where it is felt that the zona pellucida (the envelopment of the embryo/blastocyst) is unusually tough or thickened, a process known as assisted hatching (AH) may be employed. The process involves deliberately making a small aperture in the wall of the embryo (usually with a laser) so as to promote hatching (rupturing) and thereby facilitate implantation. It remains controversial as to whether AH actually improves pregnancy rates.

Selecting the Best Embryos for Transfer
Once embryo division (cleavage) has begun, the embryo will continue to divide at regular intervals. Embryos that divide the fastest are considered the healthiest and the most likely to implant.) The Graduated embryo scoring (GES) system which was developed by SIRM (2001) scores each individual embryo out of a maximum of 100 points. Embryos that on day 3 post fertilization have a GES of >70/100, are the ones that are most likely to develop into blastocysts and propagate healthy babies.

Microscopic Embryo and Blastocyst Grading: While embryos may be transferred 3 days after fertilization when they are divided to the 5-9 cell stage, it is my strong preference to wait until day 5-6 and then only transfer them if they reach the expanded blastocyst (100 cell+) stage of development. This is because embryos that fail to become blastocysts are almost always chromosomally abnormal (aneuploid) and are almost always incapable of propagating a healthy baby and are thus not worth transferring anyway. This does not mean that ALL those embryos that progress to blastocysts are chromosomally normal (euploid). They are not… but they do represent the ones that are most likely to be so. Blastocysts are graded on the basis of their cellularity, differentiation of their outer cellular layer (the trophectoderm), the inner core of aggregated cells (the inner cell mass) and the development of a demonstrable collection of fluid inside the blastocyst (an expanded blastocyst) Those blastocysts that contain more cells have a more expanded blastocele, a more prominent inner cell mass and have a well differentiated trophectoderm are the ones that are most likely to be “competent” (i.e. likely to propagate a viable pregnancy).

Comparative Genomic Hybridization (CGH) for the evaluation of eggs and embryos: In 2007, SIRM became the first to report on the clinical value of CGH testing for egg and embryo selection. This method allows for selection of those eggs/embryos that have a full component of chromosomes and therefore are most likely to propagate a healthy baby. CGH testing currently represents the most reliable method available to achieve this goal and is fast establishing a “new standard of care” in the field. We have repeatedly reported on the fact that the transfer of even a single CGH-normal embryo to a “receptive” uterus can yield a 60% -70% chance of a live birth.

Embryo Banking
For older women and those with diminished ovarian reserve (DOR), repeated egg retrievals combined with CGH embryo selection will permit stockpiling of “competent embryos” over a number of cycles. This process of “Embryo Banking”, by allowing women to vitrify (freeze) and store their embryos for subsequent dispensation can stall the biological clock and prolong fertility potential.

Embryo Transfer
Undoubtedly, embryo transfer (ET) is one of the rate limiting steps in IVF. It takes confidence, dexterity, skill and a soft touch to perform a good transfer. Of all the procedures in ART, this is arguably the most difficult to teach a training physician to conduct. It is a true art and we have seen many women fail to conceive simply because this procedure was not performed optimally.

Shortly before the embryo transfer, the embryos/blastocysts are put together in a single laboratory dish containing growth medium. The laboratory staff informs the clinic coordinator that the embryos are ready for transfer, and the coordinator prepares the patient and informs the physician that a transfer is imminent.

Embryos/blastocysts are transferred to the uterus via a thin Teflon catheter. This procedure is conducted under ultrasound guidance with the woman on her back (in the lithotomy position) and with a full bladder.

Today all embryo transfers should undoubtedly be performed under direct ultrasound guidance to ensure proper placement in the uterine cavity. This practice, properly conducted, will significantly enhance embryo implantation and pregnancy rates. We prefer to perform all embryo transfers when the woman has a full bladder. This facilitates the visualization of the uterus by abdominal ultrasound and causes reflex nervous suppression of uterine contractility. The patient is allowed to empty her bladder 10-15 minutes following the embryo transfer.

Transmyometrial Embryo Transfer (TMET): In rare cases where the shape or partial obstruction of the canal leading in to the uterus (i.e. the cervical canal) severely complicates conventional embryo transfer, this method can be used. The patient is first anesthetized, then, using sterile technique, a needle is passed along the side of a transvaginal ultrasound probe through the wall of the uterus, into the uterine cavity. A very thin catheter is then passed through the needle with its tip protruding into the uterine cavity. The needle is partially withdrawn and the blastocyst(s)/embryo(s) are injected. After the embryo transfer, the woman remains immobile for approximately one hour and is thereupon discharged with specific instructions.

Post Embryo Transfer Management
Immediately prior to being discharged following the embryo transfer procedure, an exit interview is conducted, wherein the patient/couple is/are given instructions on post-transfer care and follow-up.

Post-ET Hormonal Supplementation
This usually involves the administration of intramuscular injections of progesterone and/or vaginal suppositories (comprising estradiol valerate and micronized progesterone) until a blood pregnancy test is performed approximately eight days later (the chemical diagnosis of pregnancy). In selected cases, such progesterone treatment can be replaced with Crinone or Endometrin vaginal applications, once or twice daily. If the beta hCG pregnancy test is negative or the plasma hCG levels fail to rise appropriately in the ensuing days, all hormonal support is abruptly discontinued.

An ultrasound examination is performed approximately 2-3 weeks after the chemical diagnosis of pregnancy is made by blood testing, at which time designated patients with viable pregnancies receive a final administration of intralipid (in some cases additional monthly doses of intralipid must be administered).

Embryo Freezing (Cryopreservation)
There have been dramatic advances in the technology of freezing and storing human embryos for future use. We freeze embryos as blastocysts. The recent introduction of an ultra-rapid freezing technique known as “vitrification” has revolutionized embryo freezing. This method, by freezing embryos faster than the blink of an eye, eliminates ice formation in the blastomeres. Now, very few chromosomally normal embryos are lost in the freeze/thaw process, and pregnancy rates with thawed pre-vitrified blastocysts are hardly different from that reported following the transfer of fresh blastocysts.

“I do not intend, and it would indeed be presumptuous to suggest that the above approach should serve as a template for other RE’s to adopt. To the contrary, there are many alternative approaches that could well be equally efficacious, or perhaps even better. However after the >17,000 IVF births in which I have been influential all I can say is that this is a tried and tested approach, and most importantly…….. It works!”

Geoffrey Sher, MD