One of the most frustrating problems in infertility today is IVF failure - also called implantation failure. This refers to infertile patients who have undergone many IVF cycles and produced beautiful embryos - but the embryos have consistently failed to implant for unexplained reasons. Many patients who fail an IVF cycle often give up. Not only are they disappointed, they are also upset about the fact that their doctor does not usually give them a clear explanation for why the IVF cycle failed - or what they can do differently the next time, to improve their chances of success. While some stop for financial reasons, others come to the conclusion that they are destined to never have a baby; and admit defeat prematurely. Implantation failure can be divided into three areas: Problems with the embryos, problems with the “host uterus” and problems in the interaction between the embryo and uterus. Usually the reasons are poor egg/sperm/embryo quality, less number of embryos available for transfer, poor endometrial lining, very high estradiol levels, difficult embryo transfer, and too high or too low placement of embryos.
Various attempts to improve success in repeated IVF failure include
Transfer of more number of embryos- While transferring more embryos does increase the risk of high-order multiple pregnancies, this risk is negligible in difficult patients (for example, the older women or women with previous failed IVF cycles
Aggressive superovulation- The other common reason for a failed IVF cycle is a poor ovarian response, which means patients get few eggs and few embryos. For these patients, aggressive superovulation, with high doses of HMG is done in order to help them grow more eggs, so we have more embryos to transfer.
Difficult embryo transfer- Sometimes the reason for IVF failure is because the embryo transfer was technically difficult, because of cervical stenosis, or acute angulation of cervix. This means that the transfer is often traumatic, and is associated with bleeding. For these patients, Hysteroscopy and trial transfer is done in cycle prior to IVF cycle.
High estradiol levels- Another group of patients who often do poorly are those who have PCOD. Ovulation induction is done carefully so as to have average number of follicles only.To prevent OHSS each and every follicle is aspirated carefully at the time of egg retrieval, until it collapses completely. This helps in removing the follicular cells which are responsible for producing VEGF and causing OHSS. If still there is risk of OHSS, embryos are frozen for future use.
Blastocyst transfer- is a viable method for improving the chance for IVF implantation. In fact, the combined data from the Centers for Disease Control indicate that at every age group, the chance for IVF implantation is higher with a day five transfer than a day three transfer. The main disadvantage of blastocyst transfer is that the rate of blastocyst development is still limited (about 30%). Patients with multiple failed previous IVF ET cycles will frequently exhibit poor responses to gonadotropin therapy and have few embryos available. Therefore, blastocyst culture and transfer may not be the best approach for all patients with repeated implantation failure.
Assisted Hatching- Before an embryo can implant in the lining of the uterine cavity, it must first break out or “hatch” from the shell that surrounds it. This allows the embryo to come into direct contact with the cells of the uterine lining. This shell around the embryo is called the zona pellucida. It has been thought by some researchers that IVF implantation may fail in some cases because of the inability of the embryo to hatch out of the zona pellucida. Furthermore, some studies seemed to show that if the hatching process was assisted by creating an artificial opening or thinning of the zona pellucida, the chances for IVF implantation could be increased. Assisted hatching was first performed in the early 1990s. Many different variations of the original technique have been described. However, to this day, the effectiveness of assisted hatching remains controversial. Several well designed randomized controlled studies have been published which have attempted to prove whether assisted hatching improves the chance for IVF implantation. The results have been mixed. Roughly one half of the studies showed an improvement in the IVF implantation rate while the other one half showed no improvement. In some cases, the groups that were subjected to assisted hatching techniques, had lower implantation rates. There does appear to be some risks associated with assisted hatching. The zona pellucida helps protect the integrity of the embryo during early embryo development. By removing the zona pellucida, the embryo may have a greater chance of splitting. In fact, studies have shown an increase in the rate of identical twinning when assisted hatching is used. Identical twinning carries greater risks to the babies than fraternal twinning. At the current time, assisted hatching must be viewed as an uncertain method to treat IVF implantation failure.
Uterine infection- The inside of the uterine cavity is normally considered to be a sterile environment. It has been strongly suspected that infection of the uterine cavity with bacteria may cause an inhospitable environment that would lead to failure of embryos to implant. A recent study in IVF patients suggested that toxins in the uterus from current or previous infections had an adverse impact on implantation. At best, treating for presumed intrauterine infections is uncertain as a method to increase the chances for IVF implantation.
Immune factors- The immune system is designed to protect individuals from infection with microorganisms and to fight off abnormal processes in the body like cancer. On occasion, the immune system can malfunction and cause harm to an individual through a variety of different mechanisms. In the areas of IVF, infertility and recurrent pregnancy loss, there has been an extensive amount of investigation as to the role of immune factors in the reproductive process. Unfortunately, many of these studies have been poorly performed and this has led to many erroneous conclusions.
Some studies suggest endometrial disruption or irritation in a cycle prior to IVF cycle improves the receptivity of endometrium.
Prophylactic salphingectomy- in patients with severe tubal damage and hydrosalphinx improves the success rate, Reflux of hydrosalphinx fluid into the uterine cavity may result in mechanical factors diminishing embryonic endometrial apposition, or may have toxins that adversely affect embryo and endometium.
Preimplantation genetic diagnosis- There is clear evidence that implantation failure in women of advanced ageis closely linked to embryonic aneuploidy. Studies indicate that while increased implantation efficacy was not proven, PGD for aneuploidy reduced the rate of embryo loss after implantation.
Donor eggs or donor sperm is an alternative option to improve success in cases with repeated poor quality eggs or embryos in previous IVF cycles.
Coculture methods- Vero cells (monkey kidney epithelial cells) have been documented to be beneficial, but presents medical (risk of infection) and ethical challenges. Various cellular preparations and protocols exist for autologous coculture , that require clinical judgment to ensure that the best environment for human embryos is being provided.