Prof. Oladapo Ashiru
After Steptoe and Edwards first introduced human IVF in 1976, Johnston and Lopata in Australia (1980), the Joneses in the USA (1982), Ashiru, and Giwa-Osagie in Nigeria (1986) spread the procedure rapidly across the globe. At this period, we all believed that a successful outcome was merely dependent upon fertilizing eggs outside the body and then transferring the resulting embryos to the uterus. We understood very little about the factors that affected embryo competency or uterine receptivity. With the emergence of scientific knowledge, we can now address the variables involved in this intricate “seed-soil” relationship and treat them strategically. However, there remain many large voids in our knowledge. As more and more becomes known, we will hopefully become progressively better equipped to address the reasons for IVF failure and better help our patients go from infertility to family.
This month in ‘Human Reproduction’ a medical journal on Infertility and Reproduction, medical scientists from a reproductive Medical Center Hospital lead by Professor Zhang in China published an article on the role some substances in the lining of the wombs of women play as a cause of failure of In-vitro fertilization (test tube baby). Human Reproduction, Volume 33, Issue 5, 1 May 2018, Pages 832–843. They concluded that the expression of some of these substances called platelet and endothelial cell adhesion molecule 1 (PECAM1) and transforming growth factor β1 (TGF-β1) is significantly decreased in the mid-secretory endometrium in women with Repeated Implantation Failure, which may account for embryo implantation failure. The broader implication of these is that the knowledge can be used to develop potential therapeutic methods for Repeated Implantation Failure.
The stimulating discussion on this article has necessitated a review article on why IVF fails or repeatedly fails in some patients for the benefit of the Nigerian public. Many would be patients or those currently having issues with treatment would benefit from this review to be able to address their problem objectively with their doctors.
About ten years ago, I was at a fertility conference where an older Professor of mine in his late 70’s was extremely honest and just answered, its nature, and we only can’t control all the aspects of life or environment. And the more time I work in this area, the more I realize how little we actually know. Even with all the technology, the medication, the acupuncture, we sometimes do not understand. Today 10 years later even with additional findings on growth factors, environmental toxins and detoxification, I also had cause to tell members of my team at an academic brainstorming session that what I know now is very infinitesimally small compared to what may be understood in future. The most common reasons however are broken into:
The Quality of an Embryo
The quality of an embryo is determined by just two factors, sperm, and egg, the essential ingredients of life. If these two factor are in any way sub-optimal, then it can lead to issues of development and growth. Unfortunately, too many times, clinics will focus on egg quality and dismiss the sperm factor. They believe they only need to get one sperm, disregarding the potential quality issues of that one sperm. We do know that the development period of a man’s sperm is usually 90 days. I personally believe anything that he does within these 3 months will have a potential impact. Both positive and negative. We deal a lot with male factor; recently we had 4 cases where sperm counts were less than 8 million, well below the minimum numbers of 15 million and after 4-5 months have all improved to over 45 million, with one of the men’s counts going over 70 million. Now that is a massive change. Think of it like driving your car to work at 7 miles an hour and then 4 months later driving to work at 70 miles an hour. It really is a massive difference. Of course these results don’t improve for all men, if it’s a physical blockage, trauma or hormonal imbalance then unfortunately they won’t see much change in their numbers.
Egg Quality
It is much harder to improve, but there are still lifestyle changes that can improve the quality. Lifestyle is a big one, but it depends on all factors being equal. AMH (anti-mullerian hormone which is a particular hormone produced in women, that can be used to assess fertility potential) results, Age and Hormonal balance are essential. New information available in this area confirms that such lifestyle changes include a dietary elimination of food containing toxins. Such as large fish, as well as removal of already accumulated toxins, heavy metals, and pathogens (referred to as reproductive toxin and endocrine disruptors by many fertility associations and World Health Organization); through proper medical detoxification.
Poor Ovarian Response
There are times when some women do not respond well to the medication; it is almost like the body kicks back and says no. More and more clinics are now looking at the AMH test as a way to evaluate how well a woman will respond to the medication during her IVF cycle. It is still a relatively new method, there have been plenty of times where the AMH says one thing, and then when the clinics do a scan, the ovaries respond entirely differently. The recent workshop by the IFFS (International Federation of Fertility Societies) suggest combining the ultrasound count of the antral follicles, AMH and Day 3 FSH results to make an informed decision about ovarian recruitment and ovarian reserve. Just because you increase, the dosage of the medication does not mean it will improve the response. There is a tipping point with stimulation. Typically, women with high FSH or low AMH do not respond well, but that is not necessarily a negative thing. If this is the case, focusing on improving the quality should be the primary goal. I will always take the quality over quantity.
Implantation Failure
The uterine lining is one of the most important and final pieces to the jigsaw; it is where implantation occurs. After all the medications and scans, we retrieve a beautiful, healthy egg. We have some super sperm, and all is ready to create a fantastic embryo. Now only the implantation needs to happen. Unfortunately, in my experience, this is one of the most common reasons for an IVF cycle failure. The clinic will have done everything in its power to develop as many follicles as possible, find the best possible sperm for the fertilization, taken care of the fertilized embryos for a few nights and then transfer the most amazing embryos available. However, what they cannot do is predict the integrity of the lining of the womb, the environment that t will accommodate the embryos.
Polyps, cysts, reduced blood flow, thin lining, all contribute to an embryo not implanting after an IVF transfer cycle. Recently we have found the association between the presence of some heavy metals such as mercury from fish, antimony from car pedals, lead and implantation failure.
The Age Factor
Age has been the number one target for the cause of an IVF cycle failure, for many years, doctors believed that a woman’s age determined it, now we know better, the man’s age is as important, if not even more. There is little we can do or change about the age of our patients undergoing an IVF cycle. But what you can do is take care of you, spend 2-3 months before your treatment looking after yourself, with exercise, diet and lifestyle changes. There is so much you can do to improve your chances.
Autoimmune Issues
It is possibly the most controversial of all reasons, and today we have a 50-50 split with Fertility experts as to whether this is a cause. Some doctors will say no, it is not an issue, others the opposite, most definitely a concern. More and more tests are being developed to establish if it is a cause. It is basically where the immune system destroys an embryo before it can build implantation, all the way up to 8 weeks of a positive pregnancy. There are immune therapy approaches that will help implantation to occur, but again, there’s a 50-50 split as to whether these are a viable approach. However, it is something you should consider talking to your doctor about if you have had 3 or more failed IVF cycles or have experienced 2-3 miscarriages in a row.
Male factor
The sperm performs an intricate role in fertilization of the female egg and to do so, and they must be healthy, motile, and sufficient in quantity.
The sperm and eggs both have specific receptors on their surface that allow for their interaction and when that happens, enzymes produced from the sperm head that cause a hole in the outer membranes of the egg, allowing it to penetrate through.
A good number of recurrent IVF failure is due to the male factor. Recent studies have linked sperm DNA fragmentation to frequent IVF failure although few authors doubt this concept it is better to ear on the side of caution by the male avoiding things that can alter the sperm DNA.
There are a variety of etiologic factors associated with sperm DNA fragmentation and impaired internal cell integrity of the sperm (Chromatin). These causes are many and range from environmental conditions such as cigarette smoking, petrochemicals in oil and gas industries, pesticides, irradiation, excessive alcohol intake and chemotherapy to pathophysiologic conditions such as the presence of white blood cells in the sperm, varicoceles, and cancer. Even iatrogenic causes such as sperm cryopreservation associated with sperm DNA damage
Genetic & Chromosomal causes
The rate of chromosomal abnormalities in human embryos is one of the significant factors for IVF failure.
Various studies have shown that the rate of chromosomal abnormalities in human eggs (and therefore in human embryos) start to increase significantly after the mid-30s.
IVF with self-eggs in women over 40 years of age is known to result in poor quality embryos, almost 75% of which are chromosomally abnormal. Hence, the low rate of IVF success in older women.
We now know that older eggs have an inefficient spindle apparatus that is unable to line up the chromosome pairs correctly. Pairs of chromosomes are not appropriately split, leading to an alteration in the required balance of 23 chromosomes per egg.
Chromosomal anomalies in the sperm can also lead to chromosomally abnormal embryos, but that incidence is reported to be small at 1% to 2% of cases as compared to about 20% to 90% of human eggs.
The preimplantation genetic screening (PGS) testing determines the chromosomal competence of an embryo.
The Way Forward
Moving forward from a negative cycle is difficult and trying to figure out your next steps can be even more confusing. By understanding the leading causes of IVF failure and how you can prevent these is a motivating way to begin another cycle.
There are three fundamental reasons why IVF fails. The first is that embryo(s) transferred to the uterus were “incompetent” (abnormal and thus unable to propagate a viable pregnancy). In most cases, this is due to an irregular number of chromosomes in the embryo (aneuploidy). In the remainder, is expected to genetic or molecular embryo abnormalities.
The second reason is an underlying implantation dysfunction that prevents the embryo from properly attaching to the uterine lining. The most typical causes for this include:
a) A thin endometrium (measuring less than 8 mm) at the peak of estradiol stimulation. (That is, at the time of the hCG trigger or the initiation of progesterone administration)
b) Surface lesions that protrude into the uterine cavity (scarring, polyps, and uterine fibroids) that create a local adverse environment that prevents implantation.
c) The immunologic dysfunction results in implantation failure.
The third reason relates to the technical difficulty in the performance of embryo transfer, which is a rate-limiting factor. It is an undeniable fact that not all doctors are equally skilled at the execution of this critical step of the IVF process. The use of Transabdominal Ultrasound Guided Embryo Transfer (TUGET) should minimize this issue and increase pregnancy rate (Ashiru et al. 2007).
IVF failed – what next?
Summary for a second try with IVF:
Get an honest estimate from your IVF doctor on your chances for success rates with a second IVF try
If there were difficulties with the ovarian stimulation or low numbers of eggs – consider modifications to the drug protocol
If there were average or good looking embryos for transfer, but none implanted, try IVF a second time at the same or a different IVF clinic
If there were significant egg and embryo quality issues, it is most likely due to an egg problem or an IVF lab quality control problem. Therefore, consider changing the IVF clinic to a program with higher in vitro fertilization success rates to see if these issues were due to egg quality – or a problem with the ovarian stimulation, or a challenge in the IVF lab
Donor sperm, donor eggs, or donor embryos could be future considerations, but those are usually further down the road than after one failed IVF cycle.
The uterus can be the problem, the new factors causing implantation failure must be evaluated and removed. The uterus is not always receptive for embryo implantation.
Overall, IVF success rates are only slightly lower for second attempts as compared to first IVF tries. Couples with the best egg quality are more likely to get pregnant on their first try, but this is balanced out to some extent by potentially learning from the first failed cycle and making adjustments to maximize success for the second in vitro fertilization attempt.
