This is the fourth in a series of 10 responses to common questions/concerns about IVF treatment.


Question #4 How likely am I to be successful and how many attempts might it take?

This is one of the most common questions posed by patients undergoing In Vitro Fertilization. It is also one of the most difficult to answer honestly. All too often a patient is glibly quoted a percentage as if it would apply to anyone in her age category. Nothing can be further from the truth, and any patient undergoing IVF should be cautioned that such a response should immediately raise a red flag and evoke skepticism.

IVF is a complex process whose success or failure depends upon the harmonious interaction of a multitude of variables that differ from patient to patient. In large part, a successful outcome, i.e., the birth of a healthy baby, requires a successful interplay of factors that are analogous to those involved in the successful growth of a healthy plant in a garden. In both cases, success requires that a good quality seed be delicately planted in a receptive soil. In the case of IVF, the seed is the embryo, the soil is the uterine lining and the gardeners are the RE and the IVF laboratory. You cannot expect a successful outcome when a poor “seed” is planted in a good soil, when a good “seed” is planted in a poor soil or when the seed is planted in the wrong season or by a poor gardener. Accordingly, when it comes to IVF outcome, it is the factors that influence the quality of the embryo, the receptivity of the soil and the competency of the IVF team that play a deciding role.

Against this background let us analyze how the following factors influence IVF outcome:

1) Embryo Quality

A) Age of the egg provider: In the absence of severe sperm dysfunction, it is predominantly the chromosomal integrity of the egg that will determine embryo competency (the ability to propagate a viable pregnancy). Eggs with an irregular number of chromosomes (“aneuploid” eggs), will either fail to fertilize, or will propagate an “incompetent” (aneuploid) embryo, i.e., one that is incapable of attaching and/or developing into a healthy pregnancy. Since age of the woman is the main determinant of egg aneuploidy, it follows that as a rule, the older the woman, the lower will be the yield of competent embryos. When compared with other mammals, humans have the highest incidence of egg aneuploidy. Since most infertility and miscarriages (as well as chromosomal birth defects) are due to egg aneuploidy, it should come as no surprise that we as a species have the poorest reproductive performance of all mammals. In fact, at age 30-35 about 60% of human eggs are aneuploid, and thus incompetent. This incidence increases rapidly with age such that by the early to mid 40’s the incidence of aneuploidy is higher than 90%. In addition, with advancing age and encroachment of the menopause comes diminishing ovarian reserve. This translates into fewer eggs being available for processing and fertilization. The combination of declining egg competency and fewer eggs being available explains why above 35 years of age there is a profound decline in IVF success rates.

B) Sperm Quality: The advent of Intracytoplasmic Sperm Injection (ICSI) vastly enhanced the ability to force fertilize eggs. This dramatically improved IVF pregnancy rates which hitherto had been dismal when IVF was performed in cases of moderate to severe male infertility. Notwithstanding this, it is a fact that the poorer the quality of the sperm, the lower the fertilization rate, and the greater the likelihood of sperm aneuploidy contributing to embryo incompetence. Therefore, male factor infertility does play a role in IVF outcome in spite of ICSI. In general, pregnancy rates are lower when the sperm is poorer and miscarriage rates are higher. There is also an increase in certain developmental disorders in the resulting children, and in the subsequent incidence of infertility in the male offspring. The latter is probably due to the fact that a gene that is responsible for male factor infertility is carried on the Y chromosome (XY = male) and therefore passed on from father to son. While age can affect sperm function, it is rarely a significant factor when it comes to IVF outcome.

C) Protocol for Ovarian Stimulation: As outlined in an article on this blog entitled “An Individualized Approach to Ovarian Stimulation for IVF”, patients with diminished ovarian reserve as well as those who are over the age of 40 years require a customized and individualized approach to controlled ovarian stimulation (COS). The ovarian follicles in such women are very sensitive to overexposure to the male hormones produced by surrounding tissue (theca) in the ovary. Unfortunately, these are the very women that either overproduce the hormone LH (which stimulates ovarian male hormone-testosterone production) or are hypersensitive to it. In addition, certain protocols of ovarian stimulation do not protect the eggs from overexposure to testosterone in the early stage of COS (e.g., the use of antagonists such as Ganirelix or Cetrotide starting on day 6-8 of stimulation). So-called “flare protocols” exacerbate the release of LH early in COS with the same effect. There is compelling evidence to suggest that overexposure of developing eggs to testosterone and other male hormones can increase the likelihood of aneuploidy and thereby compromise IVF outcome.

D) Laboratory Expertise: Another vital component in assuring a good quality embryo is a well seasoned embryology team. It is also true that most IVF labs have such required expertise. One caveat is that the performance of certain technical procedures such as ICSI, egg/embryo biopsies (e.g., PGD) and assisted hatching (AH) require extensive experience. No doubt, the longer the egg or the embryo is kept outside the incubator in order to perform such procedures, the poorer the results will be. This perhaps explains why smaller IVF programs where fewer such procedures are performed will often have lower success rates when it comes to the treatment of male infertility and the performance of egg/embryo microsurgical procedures such as PGD or AH.

2) Uterine Receptivity
Approximately 30% of female patients at the average IVF program will have a uterine impediment to embryo implantation. This can be due to a thin or inadequate uterine lining or the presence of surface lesions (e.g., polyps, scar tissue, or fibroids) that can interfere with implantation. In addition, about 20% of women undergoing IVF have an immunologic implantation dysfunction. In my personal practice where more than 80% of the patients I treat have had 3 or more prior IVF failures, the incidence of undiagnosed immunologic implantation dysfunction is probably in the vicinity of 50%. Unfortunately, many IVF practitioners refuse to accept the concept of immunologic implantation dysfunction and when their patients fail to conceive in spite of repeated embryo transfers, they recommend egg donation. The problem is that in the presence of an intractable implantation dysfunction, egg donation will also be unsuccessful. Failure to evaluate for and address such issues will inevitably reduce or eliminate the potential for successful IVF in such patients.

3) IVF Team
Successful IVF demands that a rehearsed relationship exist between all members of the team (nurses, doctors and laboratory staff). Without such a relationship outcomes will be poor regardless of individual expertise. The performance of the embryo transfer is a critical step in IVF and this demands a lot of experience as well as self confidence on the part of the RE. Unfortunately, when it comes to this procedure, there is a wide variation in expertise. Poor technique with regard to embryo transfer is one of the most significant variables affecting IVF outcome. In my almost 30-year career in the IVF arena, I’ve had that opportunity of observing scores of doctors performing embryo transfer and have witnessed good as well as atrocious technique when it comes to ET and the results obtained by such practitioners was reflective thereof.

So, when you are glibly quoted an IVF outcome statistic, you should demand of your doctor that he/she address how the above variables apply to your specific situation. Do not simply rely on verbal assurance. Worse still, do not rely on reported statistics by SART/CDC where the results presented are based upon self generated data presented by the IVF center, and largely published as fact without any oversight, validation or auditing. It is for this reason that I personally no longer report data to SART/CDC (other SIRM physicians may feel compelled to do so because several insurance companies require such reporting as a condition of reimbursement). To me this has become a matter of principle. I was a founding member of the forerunner to SART (the “IVF Special Interest Group”) and will be more than happy to report to SART/CDC as soon as the required accountability is in place. Until such time, I regard the situation as “the fox guarding the henhouse” and refuse to participate.

Outcome Based Reporting
At SIRM, we have developed a novel method of reporting IVF statistics known as the Outcome Based Reporting System (OBRS) which reports IVF statistics under age categories but sub-categorizes the success rates on the basis of “categories of complexity” which attempt to analyze several other important variables (cited above) that can influence IVF outcome.

The decision as to how many attempts at IVF a patient/couple should undergo is a different matter altogether. IVF is expensive, and since insurance reimbursements are available to less than 20% of those in need in the US, it follows that the pocketbook will determine access as well as the number of attempts at IVF that are feasible. From a pure medical standpoint however, the time to stop trying is when there is no remediable explanation for failure. This means that patients who fail to conceive need to take the necessary steps to best identify the reason for failure before deciding on future cycles, even if this requires getting a 2nd, 3rd or 4th opinion. In general, if IVF does not result in a baby after numerous embryos have been transferred over 3 attempts, it is probably time to move on. The good news is that couples/patients who are willing and able to avail themselves of all IVF-related options including egg donation and/or gestational surrogacy as well as embryo adoption, will in more than 90% of cases ultimately be rewarded with a baby. Unfortunately, few can afford this luxury.