Possible Causes of Repeated Failed IVF Cycles

The in vitro fertilization [IVF], process is a complex assisted conception procedure that involves 1. the male and female patient, 2. the clinical team and 3. the eggs and sperms on one side. We could look at it that a repeated failed cycle could arise from any of these sets of important players in this scenario. We can look at it a simple way , Sometimes, there will be clear-cut reason but often there is no answer.

The recommendation will be to try another cycle of IVF and if that fails, try another and so on until out of sheer exhaustion- physical and mentally- a person stops doing IVF. In this physician’s experience, it is critical when faced with multiple cycles of IVF, to try and determine when enough is enough. Approaching the answer to this question requires evaluating various aspects of the IVF process in an attempt to define why multiple attempts at IVF have failed. dividing the world of IVF into the world of the embryo and the world of the uterus offers a starting point for this investigation.
A failed cycle could be that the patient did not respond to the expected level of follicular development, the inability to collect eggs at harvesting time, the inability of the eggs to fertilize using all conventional methods of inducing fertilization, which is the coming together of the egg and sperm, to fuse, or finally the failure of the transferred embryo to implant.

Pregnancy rate following one cycle of IVF and ET can be as high as 60%. But even in the very successful units, some couples fail repeatedly. The causes for repeated implantation failure (RIF) may be because of reduced endometrial receptivity, embryonic defects or multifactorial causes. Various uterine pathologies, such as thin endometrium, altered expression of adhesive molecules and immunological factors, may decrease endometrial receptivity, whereas genetic abnormalities of the male or female, sperm defects, embryonic aneuploidy or zona hardening are among the embryonic reasons for failure of implantation. Endometriosis and hydrosalpinges may adversely influence both.
Implantation dysfunction is a common cause of repeated “unexplained” IVF failure with good embryos. This is especially the case in young ovulating women who have normal ovarian reserve and have fertile partners.

• Failed IVF is a frustrating situation for couples and their fertility doctors.
There is an equation that we can use to illustrate the implantation process:
• Quality of the embryos + receptivity of lining of the uterous = chance for implantation and pregnancy
• We know that many human embryos will arrest (die) before day 5
• Unfortunately, embryonic arrest also occurs after day 5
• Some of the embryos that we transfer that “ look good” will die after we put them in the uterus
• This is the explanation for IVF failure in the large majority of cases
• The problem is rarely the male sperm , and uncommonly the uterus
• It is usually a weakness in the embryo that leads to failed implantation
• On the average, only about 25% of transferred embryos continue to develop and become kids
• This percentage of implanting embryos is greatly dependent on the age of the female.
• We see about 50% implant under age 35
• We see about 12% implant at age 41-42.

When IVF does not work after numerous attempts – switching the uterus is not likely to result in success. However, the egg donation experience teaches us that switching to eggs from a young egg donor would be very likely to be successful.

This tells us that the problem is not the uterus but is the egg quality . Therefore, it works when we switch to different eggs from a young woman.

Some animal species have much higher implantation rates per embryo transferred than humans do. Human IVF is not as efficient due to the relative weakness of the human egg as compared to those animal species.

This is not to say that the sperm and the uterus are not sometimes contributing factors in the IVF success equation. However, the sperm and the uterus are relatively minor factors as compared to the major factor of egg quality.
•Genetic and chromosomal issues causing causing failure of implantation in IVF

We know that one of the major factors contributing to in vitro fertilization failure is the high rate of chromosomal abnormalities in human embryos.

As women age the incidence of chromosomal abnormalities in mature eggs increases significantly. Studies have shown that starting in the early 30s, the rate of chromosomal abnormalities in human eggs (and therefore in human embryos) starts to increase significantly.

The rate continues to increase with advancing female age so that by the mid-40s a very high percentage of human embryos are chromosomally abnormal (over 75%).

It is believed that this is mainly due to problems with the spindle apparatus in the egg nucleus. The spindle is involved with properly lining up and segregating the chromosomes as the egg matures at the time of ovulation.
Older eggs have an inefficient spindle apparatus that does not line up the chromosome pairs properly and “mistakes” are made when splitting pairs of chromosomes. This leads to eggs that do not have the proper balance of 23 chromosomes – and will result in a chromosomally abnormal embryo if fertilized.

It has been shown that about 1% to 2% of human sperm are chromosomally abnormal on the average – as compared to about 20% to 90% of human eggs (depending on female age).

PGS preimplantation genetic screening can be done on embryos prior to transfer to evaluate chromosomal competence.
Research have identified a biological process that may cause the failure of embryo to attach to the uterus wall after IVF, raising the possibility of future treatments.

Recent studies have found that microRNA levels are altered in the endometrium of women with repeated implantation failure. But how these molecules might affect the attachment of the embryo was previously unknown.
Scientists at the University of Manchester’s Institute of Human Development have found that they may do so by inhibiting another molecule – insulin-like growth factor receptor 1 (IGFR1) – that was not previously known to have a role in the attachment process.

•Defective endometrium: this is the status of the linning of the womb.
Repeated implantation failure (RIF) is determined when embryos of good quality fail to implant following several in vitro fertilization (IVF) treatment cycles. Implantation failure is related to either maternal factors or embryonic causes. Maternal factors include uterine anatomic abnormalities, thrombophilia, non-receptive endometrium and immunological factors. Failure of implantation due to embryonic causes is associated with either genetic abnormalities or other factors intrinsic to the embryo that impair its ability to develop in utero, to hatch and to implant. New methods of time-lapse imaging of embryos and assessment of their metabolic functions may improve selection of embryos for transfer, and subsequent outcomes for IVF patients, as well as for those diagnosed with RIF.
•Defective embryonic development : Chromosomal abnormalities of the male or female partner, the gametes or the developing embryo may burden embryogenesis.

•Endometriosis : Endometriosis as a cause for RIF has not been investigated directly; however, all markers of reproductive process, including ovarian response, embryo quality, implantation and PRs, are decreased in endometriosis, especially in severe diseases .

•Hydrosalphinx: Patients with hydrosalpinges have lower implantation and PRs Hydrosalpinx fluid is commonly slightly alkaline and may contain cytokines, prostaglandins or other inflammatory compounds. These compounds may have either direct embryo-toxicity or adversely affect the endometrium. . Reflux of hydrosalpinx fluid into the uterine cavity may result in decreased affinity of the embryo for the uterine wall.

A functioning and receptive endometrium is crucial for embryo implantation. During the menstrual cycle the endometrium undergoes both morphologic and biologic changes that prepare it for interaction with the embryo, and ultimately for successful implantation. Once all biological changes transpire, the embryo can attach, invade the endometrium and finally implant. This crucial stage lasts for a few days and is referred to as the “window of implantation”. For occurrence of the “window of implantation”, the endometrium must proliferate, increase in thickness and then, after ovulation, adequately respond to progesterone and become receptive. Ultrasound examination of the thickness and appearance of the endometrium is an easily performed means of assessing morphological changes occurring in the endometrium during the follicular phase, and is thus used as a measure to predict successful implantation. Indeed, several studies have reported a strong association between endometrial thickness and successful . The minimal adequate endometrial thickness for successful implantation, as measured in the late proliferative phase, varies between studies, with a range of 6–8 mm. However, although rare, some investigators have reported successful implantation in an endometrium of no more than 5 mm thickness .

Thin and unresponsive endometrium, especially following surgical interventions in the uterine cavity is difficult to treat and obviously contributes to implantation failure. Several approaches have been implemented to increase endometrial thickness, and presumably prepare it for the “window of implantation”. Treatment with high dose oral estrogen or vaginal estradiol application, intended to increase the estradiol level in the serum, as well as in the vicinity of the endometrium, has demonstrated only marginal success . Similarly, treatment with low dose aspirin or vaginal sildenafil which presumably increases blood flow to the uterus, consequently improving the response to estradiol, were rather disappointing . Our approach is to freeze embryos when a thin endometrium is noticed, and to transfer them in a natural cycle, if possible; or alternatively, in an artificial cycle, while applying increased dosages of estradiol, for as long as three weeks before progesterone is added. Once progesterone is added, estradiol treatment dose can be lowered, or switched again from the vaginal to the oral route. Nevertheless, once all modes of treatment fail, surrogacy should be offered as an option.

The definition of RIF refers to the transfer of good quality embryos that do not result in implantation. Embryo quality is assessed by morphologic criteria, under the assumption that the embryos, although transferred on either day 2 or 3 after fertilization, would continue to develop in utero, reach the blastocyst stage and then implant. However, even embryos that are morphologically defined as good quality may cease to develop in utero and fail to progress into a blastocyst stage. This may be due to either suboptimal local conditions or intrinsic factors within the embryos. Several approaches have been suggested for overcoming these obstacles, among them zygote intra fallopian transfer (ZIFT), blastocyst transfer, sequential ET and embryo co-culture system.

Improved implantation can be achieved by
Hysteroscopy correction of uterine cavity, myomectomy, treatment of thin endometrium , endometrial stimulation, treatment of the embryos [ PGD , co cultures, assisted hatching , blastocyst transfer ] , and improved embryo transfer technique.