IVF practitioners in the United States commonly attribute the wide dichotomy in IVF success rates to variability in expertise of the various embryology laboratories. This is far from accurate. In fact, other factors such as wide variations in patient selection and the failure to develop individualized protocols for ovarian stimulation or to address those infective, anatomical and immunologic factors that influence embryo implantation are at least equally important.
Even though this post will focus on IVF failure in spite of transferring “good quality embryos”, I feel compelled to briefly address the issue of embryo quality. In my opinion, many cases of “unexplained” IVF failure are due to the fact that many (if not most) embryos judged through conventional microscopic grading as being optimal in quality, in fact have numerical chromosomal defects (aneuploidy) that render them “incompetent” (incapable of producing a healthy pregnancy). Such incompetent embryos are thus often erroneously regarded as being of high quality. While embryo aneuploidy occurs in women of all ages, its incidence increases from about 60% in women under 35 years of age to more than 90% by the age of 45. It is for this reason that blastomere biopsies, with comparative genomic hybridization (CGH) which identifies each and every chromosome, might be regarded as a valuable diagnostic tool in many cases of unexplained IVF failure.
Another problem pertaining to distinguishing viable (“good quality”) embryos from non-viable (“poor quality”) ones, lies in the fact that virtually all IVF centers culture embryos in groups in petri dishes. This practice precludes careful individualized evaluation of those morphologic and/or biochemical changes in early embryo development, which can help predict implantation potential of each embryo. In the year 2,000, we introduced the Graduated Embryo Scoring (GES) System where we grow (culture) each fertilized egg separately rather than in batches (as is most commonly done in most other IVF centers). By so doing we are able to better assess the embryo’s developmental milestones and so more competently evaluate its potential to propagate a viable pregnancy.
One of the most important procedures conducted during an IVF cycle is the actual embryo transfer. Embryo transfer differs from most other steps involved in the IVF procedure, which attempt to mimic mother nature. In "normal" conception, the blastocyst reaches the uterus 5-7 days after ovulation, via the Fallopian tubes. In the United States, in the past , we most commonly performed embryo transfer 3 days after the egg retrieval. As such, embryos were prematurelybeing placed in the uterus via the cervical canal. In attempt to overcome this “dissynchrony” and improve pregnancy potential, many IVF programs opt to either replace a greater number of embryos on day 3 or to transfer fewer embryos on day 5 or 6 post-fertilization – as blastocysts.
Equally important as performing embryo transfer on day 5-6 is the actual embryo transfer technique itself. This needs to be performed delicately with minimal trauma, and under ultrasound guidance so as to insure proper placement of the embryo(s) in the mid-uterine cavity. The need for such ultrasound guidance cannot be overemphasized. The embryo recipient is instructed to have a full bladder. We use a soft catheter, which is introduced gently via the cervix into the uterine cavity. An abdominal ultrasound probe allows for the visualization of the tip of the catheter and the transfer of embryos into the center of the uterine cavity, preferably without touching the fundus of the uterus
But, even with "good quality" embryos and excellent embryo transfer technique, implantation can be thwarted by such factors as:
• anatomical abnormalities in the uterine cavity (e.g. scarring, polyps and encroaching fibroid tumors)
• a thin endometrial lining
• immunologic rejection of the embryos.
Several studies performed both in the United States and abroad have confirmed that a dye X-Ray or hysterosalpingogram (HSG) will often fail to identify small endouterine surface lesions (in about 30% of cases). This is significant because even small uterine lesions have the potential to adversely affect implantation. Hysteroscopy is the traditional method for evaluating the integrity of the uterine cavity in preparation for IVF. It also permits resection of most uterine surface lesions, such as submucous myomas, intrauterine adhesions and endometrial or placental polyps. All of these can and indeed often do, interfere with implantation by producing a local inflammatory response, similar in nature to that which is caused by an intrauterine contraceptive device.
Sonohysterography (a saline ultrasound examination) has all but supplanted hysteroscopy to assess the uterine cavity in preparation for IVF. Here, a small amount of a sterile saline solution is injected into the uterine cavity, whereupon a vaginal ultrasound examination is performed to assess the contour of the uterine cavity.
In 1989 we became the first to report on the fact that ultrasound assessment of the late proliferative phase endometrium following ovarian stimulation in preparation for IVF, permits better identification of those candidates who are least likely to conceive. We noted that the ideal thickness of the endometrium at the time of ovulation or egg retrieval is >9mm and that a thickness of less than 8 mm bodes poorly for a successful outcome following IVF.
Then in 1993, we were able to show that sildenafil (Viagra) introduced into the vagina prior to hCG administration can improve endometrial growth in many women with poor endometrial development. Viagra’s mechanism of action is improvement in uterine blood flow with improved estrogen delivery…thereby enhancing endometrial development.
Immunologic factors also play a role in IVF failure. Some women develop antibodies to components of their own cells. This autoimmune process involves the production of antiphospholipid, antithyroid, and/or antiovarian antibodies – all of which may be associated with activation of Natural Killer (NK) cells in the uterine lining. Activated NK cells (NKa) release certain cytokines (TH-I) that if present in excess, damage the trophoblast (the embryo’s root system) resulting in immunologic implantation dysfunction (IID). This can manifest as “infertility” or as early miscarriages). In other cases (though less common), the problem is due to alloimmune dysfunction. Here the genetic contribution by the male partner renders the embryo “too similar” to the mother. This in turn activates NK cells leading to implantation dysfunction. These IID’s are treated using combinations of medications such as heparin, Clexane, Lovenox, corticosteroids and intralipid (IL).
“In the pursuit of optimizing outcome with IVF, the clinician has a profound responsibility to take an individualized approach aimed at favorably influencing the biological environment for both egg/embryo maturation and implantation. Doing so will maximize the chance of a pregnancy and promote the noble objective of optimizing the quality of life after birth.”
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