IVF treatment always exacts a profound emotional and financial toll on patients/couples. Needless to say, the financial burden is often crippling; however, ask any woman who has undergone IVF, and she will likely tell you that the emotional impact was by far the most devastating….especially when the IVF treatment cycle failed to bring her a baby.
Even in the most capable medical hands and treating the easiest cases, the transfer of up to two advanced embryos (blastocysts) will at best yield a 40%-45%% chance of a live birth after a single attempt . After 2 fresh embryo transfers plus as many frozen embryo transfers (FET) as available left-over blastocysts will allow, the comparable success rate can approach 80%. This is why when a viable pregnancy fails to happen, the question of why it failed, will invariably arise. It is always incumbent upon the treating physician to carefully evaluate for a possible remediable cause, before trying again.
Currently, more than 70% of the IVF patients I treat have had at least 2 prior failed attempts before consulting with me and well over 50% have failed IVF at least 3 times prior to seeking my services. I could cite many cases where patients have even endured as many as 10 or more prior IVF failures or losses after miscarriages. But there is one case in particular that is permanently embedded in my memory and which highlights the importance of an individualized approach to treating infertility patients, especially when it comes to those with prior IVF failures.
The patient was a 42 year old physician who hailed from Australia. She had endured 23 prior unsuccessful embryo transfers over a period of more than a decade. By the time I got to know her she had developed severely diminished ovarian reserve (her day 3 FSH was 26MIU/ml). After a lengthy telephone consultation with me, I urged her to send a blood sample from Melbourne, Australia to a reputable Reproductive Immunology Reference Laboratory in Southern California for testing, to screen for immunologic implantation dysfunction (IID). It soon became apparent that she had an autoimmune thyroid condition (antithyroid antibodies) plus activation of uterine Natural Killer Cells (NKa+). After putting her on an aggressive agonist/antagonist conversion protocol (A/ACP) with estrogen priming and treating her with selective immunotherapy, I harvested (just) three eggs and subsequently transferred two embryos to her uterus. She conceived on this cycle and gave birth to a very healthy baby boy nine months later.
So then…what are the most common reasons for “unexplained” IVF failure, and what can be done to deal with them?
To adequately address these two all-important questions, we first need to recognize and understand that with the exception of poor technical skill in performing embryo transfer (ET), IVF failure is virtually always due to one of the following two causes, which I will address below:
- Embryo “Incompetence” (about 80%)
- Dysfunctional/failed embryo implantation (about 20%)
What is critical to understand here is that it is the chromosomal integrity (“competence”) of the embryo that is the main determinant of its ability to propagate a normal pregnancy. It is almost always the egg (rather than the sperm) that determines this factor. Only a mature egg (MII) that is numerically chromosomally normal with 23 chromosomes (i.e. euploid) at the time of egg retrieval can propagate a “competent” embryo. No manipulation in the IVF laboratory, can cause an egg that has an irregular quota of chromosomes (aneuploid) to propagate a competent/euploid embryo (i.e. 46 chromosomes). Patients should be highly skeptical of any suggestion to the contrary. Simply stated, an embryology laboratory can only grow competent embryos from competent eggs.
Thus, egg competency at the time of egg retrieval will ultimately determine the ability to generate competent embryos for embryo transfer. By the time the egg is extracted, the “die has been cast” What this means is that aside from the woman’s age – which influences the percentage of her eggs that will have the potential to develop into euploid mature (MII) eggs following hormonal stimulation – the only manner by which we as IVF physicians can influence egg quality is by applying an individualized approach to ovarian stimulation. Without such an approach, egg development will often be compromised (especially in older women, in those with PCOS, and in women with DOR). The subsequent implementation of the “trigger shot” would thereupon be much more likely to cause disorderly rearrangement of egg chromosomes, leading to a greater likelihood of egg /embryo aneuploidy.
Today, through the use of full embryo chromosomal. preimplantation genetic screening-(PGS) we can identify “competent”, euploid embryos for selective transfer. The use of this technique is both diagnostic (in that it allows us to determine whether the cause of IVF failure is embryo incompetence or an implantation issue) and therapeutic (in that we can thereupon selectively transfer up to two embryos at a time and achieve better than a 60% pregnancy rate while keeping the early miscarriage rate well below 10% and virtually eliminating the chance of high-order multiples (triplets or greater). PGS embryo selection is of special relevance and value in cases of older women or those with DOR for whom “Staggered IVF” with embryo banking is of particular value (see elsewhere on this blog).
Dysfunctional or Failed Implantation
Endometrial thickness: We previously have published that an ideal endometrium measures at least 8mm (and preferably >9mm) in thickness at the time of maximal estrogen stimulation and that failure to achieve this goal, commonly leads to failed implantation. We subsequently reported on the fact that in many such cases, if appropriately administered prior to egg retrieval and/or before the initiation of progesterone therapy, vaginal sildenafil (Viagra) by improving uterine blood flow can within 48-72 hours cause a significant improvement in endometrial growth.
Uterine surface lesions: We have also pointed to the importance of excluding the existence of surface lesions that protrude into the uterine cavity (polyps, fibroid tumors or scarring) as they can, by creating an adverse uterine environment, lead to failed implantation. Only a hysteroscopy or a sonohysterogram (saline ultrasound) can diagnose the latter which needs to be treated surgically before embarking on IVF. A dye-X-ray or hysterosalpingogram (HSG) is too inaccurate to accomplish this.
Immunologic factors: Then there is the ever-important (albeit commonly overlooked) issue of immunologic implantation dysfunction (IID) that should always be looked for and addressed in cases of unexplained or repeated IVF failure. Frankly, since IID will rarely occur in the absence of uterine natural killer cell activation (NKa) and most of my IVF patients come to see me because of unexplained prior repeat failures in I test almost everyone initially for Nka. If the test result comes back positive, I expand immunologic testing to look for the underlying cause. This having been said, since selective immunotherapy with intralipid (IL)/steroids/ Lovenox is so often successful in reversing the IID it is in my opinion important to always have a high index of suspicion regarding the possibility that IVF failure could be due to IID.