Evaluation of IVF Outcome does not readily lend itself to “Evidence-Based Scientific Scrutiny”

The dictionary defines “evidence based medicine” as follows:

The practice of medicine in which the physician finds, assesses, and implements methods of diagnosis and treatment on the basis of the best available current research, their clinical expertise, and the needs and preferences of the patient…….

This definition does not suggest that adoption of new advances be confined to only that which has been proven through “gold standard” statistical analyses.

Self-proclaimed IVF authorities often glibly assert that acceptance of new methods be predicated upon results obtained through “evidence-based gold standard” analyses (usually randomized controlled studies). Yet, most advances in the field of assisted reproduction have come through tried and tested  experience-based evaluations.

In the field of medicine and particularly when it comes to Reproductive Medicine the vast majority of clinical advances have resulted from experience-based (longitudinal) implementation of tried-and-tested methods rather than through randomized studies. Let me here cite but a few indisputable examples in the field of assisted reproductive medicine:

  1. IVF has emerged as a more effective method than surgery, to treat tubal damage.
  2. IVF is more successful than surgical tubal reversal in the treatment of women who have had a prior tubal ligation.
  3. IVF (and ICSI) rather than intrauterine insemination is a preferred method for treating infertility due to male factor and  moderately severe and severe cases of  endometriosis
  4. IVF is more successful than gamete or zygote intrafallopian tube transfer (GIFT or ZIFT.
  5. Ultrasound guided embryo transfer is superior to blind embryo transfers.
  6. Intracytoplasmic sperm injection (ICSI)  is a much more successful way to achieve pregnancy in cases of male infertility than alternatives such as sub-zonal insemination (SUZI).
  7. Artificial insemination (AI) is best conducted using concentrated (seminal plasma-free) sperm rather than whole sperm and should be delivered as intrauterine insemination (IUI) rather than being deposited in the upper vagina. ( I was the first to publish on the use of IUI as far back as in 1984)
  8. Success rates with embryo freezing performed through vitrification are far better than when conventional (slow) freezing is used.
  9. The transfer of embryos subjected to full chromosomal analyses using preimplantation genetic sampling (PGS)  ,particularly when it comes to women >35Y of age, enhances IVF outcome as compared with conventional IVF
  10. Next generation gene sequencing has emerged as a superior  method for performing PGS.

Consider the fact that in order for randomized controlled studies to be properly conducted and be reliably requires that all variables (other those being evaluated) have to be kept stable. Only then, through randomly assigning cases to one or other leg of the study can variations in the tested variables be determined. However, when it comes to reproductive medicine, it is impossible to stabilize and control the non-tested variables, thereby virtually negating liable interpretation of results. You see, IVF involves an interplay between a multitude of variables all of which are subject to variation and profoundly affect IVF outcome. Here are but a few examples of such variables. :

  • Maternal and paternal age
  • Egg and sperm “competency”
  • Ovarian reserve
  • The medications and protocols used for ovarian stimulation and their implementation
  • Monitoring of ovarian stimulation

Just consider the following: By far, the most important variable that influences IVF outcome is “embryo competency”. This is largely (but not exclusively) a function of the egg’s (rather than the fertilizing sperm’s) chromosomal integrity. For an embryo to be able to propagate a normal healthy baby, it must be euploid (i.e. it must have precisely 46 chromosomes). If there is even one more/less than 46 chromosomes present in its cells (a condition known as “aneuploidy”), such an embryo would be “incompetent” and would either fail to attach to the uterine lining, miscarry, or result in a child with a birth defect such as Down Syndrome.

If we were to dismiss any innovation that had not been proven through gold standard trials, the field of Reproductive Medicine would not have progressed to the point it has reached today. I and the team I have assembled around me over the last 34 years have been responsible for a number of such innovations. Here are but a few examples of innovations we have introduced, none of which (for the reasons cited above) were proven through gold standard testing, yet most of which have since been adopted by many,  into the main-stream of IVF practice.

  • Individualized protocols for ovarian stimulation.
  • The agonist/antagonist conversion protocol (A/ACP) with and without estrogen priming to selectively improve follicle/egg development.
  • The role activated endometrial natural killer cells in causing embryo implantation dysfunction and the importance of down-regulating such activity with intravenous immunoglobulin-G (IVIG)/Intralipid/steroid/heparin therapy in the treatment of Implantation failure.
  • Intrauterine (artificial) insemination (IUI) of processed or “washed” (spun down) sperm which I was the first to introduce and publish on (Fertility and Sterility) in 1984.
  • Ultrasound measurement of endometrial thickness to assess implantation potential.
  • Use of Vaginal Viagra to improve the uterine lining.
  • “Prolonged coasting” to prevent severe ovarian hyperstimulation syndrome (OHSS).
  • Measurement of HLA-g in the media surrounding developing embryos to assess their quality.
  • Complete chromosomal embryo karyotyping to identify the most “competent” embryos for transfer.
  • Complete chromosomal egg karyotyping to identify the most “competent” eggs for egg banking.

The fact that more than 70% of IVF failures and miscarriages are due to embryo aneuploidy, and that prior to CGH, most such chromosomal irregularities went unrecognized means that this important variable was unaccounted for in virtually all studies that used IVF outcome as the end point. This effectively negates the interpretation of most prior statistical evaluations in IVF.

IVF is a classic example of an “art-science blend”. While one can control scientific concepts, you cannot control the “art-side” of things. The latter involves the enormous interpersonal and intrapersonal variation in approach, judgment, skill-set and execution of technical tasks involved in the preparation for, and implementation of, IVF treatment. This renders the using controlled randomized studies in the IVF setting largely pointless. In fact, were an IVF text book to be compiled of only those processes, procedures or treatments that were absolutely proven in this manner…….. it would at best be a single page in length.

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