This interview originally ran on The Egg Whisperer Show with Dr. Aimee.
To watch the episode, and learn more, please visit her website at https://draimee.org/how-to-avoid-implantation-failure-during-ivf-with-guest-dr-geoffrey-sher
Dr. Geoffrey Sher is joining me again, and this time we are going to talk about implantation failure during IVF. Dr. Sher is co-founder of Sher Fertility Solutions (SFS) and an internationally renowned expert in the field of assisted reproductive technology, and influential in the births of more than 17,000 IVF babies. I hope that one day, I’ll be able to say the same thing about myself. Over the last 30 years, he has helped fashion the entire field of ART after training under the fathers of IVF, Dr. Patrick Steptoe and Robert Edwards. He established the first private IVF program in the United States in 1982, then later expanded his practice to include several centers throughout California before founding the first Sher Fertility Solutions in Las Vegas. He’s also the author of several books, In Vitro Fertilization: The ART of Making Babies, which is now in its third edition.
Dr. Aimee: Welcome back. We’re going to talk about implantation failure during IVF. Why the heck do these embryos not stick and grow? First question, what is implantation, can you explain it?
Dr. Geoffrey Sher: Thank you. When an embryo reaches the uterus, it engages in a crosstalk with the endometrial cells. This involves a molecular exchange involving cytokines leading to the embryo sinking its “root system” (trophoblast) into the endometrial lining to ultimately form the “placenta” which of course is the “lifeline” of the developing conceptus. This progressive expansion of the trophoblast brings it more and more into contact with the endometrial cells… including the immune cells.
Dr. Aimee: The trophectoderm is that layer of cells on the outside of the embryo that we typically biopsy when we’re doing genetic testing. Is that right?
Dr. Geoffrey Sher: That is correct.
Dr. Aimee: I’ve had patients say things to me like, “I really wish that my embryo would have even miscarried.” I think sometimes people even think of an embryo not sticking and growing and miscarriage as the same thing. Is implantation failure the same thing as miscarriage?
Dr. Geoffrey Sher: It depends on how you look at it. When an embryo reaches the uterus and it tries to implant its root system, it engages in a “crosstalk” (involving the cytokine network) between the embryo and the cells of the endometrium. Now, if the embryo is defective or abnormal, it’s unable to engage in an orderly and functional “dialogue.” Many of these embryos are lost before the woman even knows she was pregnant. Others may limp along and be lost when the embryo runs out of steam, a few days or weeks later.
I often refer to the interaction between the embryo and the uterine lining as a “seed-soil” type relationship. The embryo is the seed, the uterine lining, the soil. Using this analogy, an early implantation can fail because the seed is “defective” (as with a chromosomally abnormal embryo) or it can be the soil that is unreceptive. Of course, if the soil is non-receptive, then we have an implantation dysfunction linked to lack of uterine receptivity.
Dr. Aimee: What are the most common reasons for that to happen? It’s so frustrating. We work so hard for these embryos. How would you describe it to a patient of yours when they ask you, “Why did my normal embryo not stick and grow?”
Dr. Geoffrey” First, we must assume that the diagnosis of the embryo being normal is based upon its appearance under a microscope, its development under the microscope over time, or as a consequence of it being euploid (having exactly 46 chromosomes). If an embryo has less or more than 46 chromosomes it is aneuploid and unable to propagate a normal baby (‘i.e., incompetent”).
However, to assume that because an embryo is normal based purely on its microscopic appearance or even on it being euploid on PGS/PGT-A testing, is not always accurate. The truth is that a normal looking embryo can be abnormal for non-chromosomal reasons. It can be genetic rather than chromosomal defects. Such defects are not apparent through PGS/PGT-A testing. In fact, when it comes to assessing “embryo competency”, such testing is only about 65% reliable. In about 35% of the time genetic or metabolic factors cause embryo “incompetence”. Unfortunately, this is an area we know very little about. So, when people say, “My embryos looked good, they tested good, but I didn’t get pregnant, and therefore there must be something else wrong,” that’s not always the case. The embryo could still be “incompetent” for reasons that we as yet cannot identify reliably.
Now, if a truly normal embryo doesn’t attach it could be because of the uterus not being receptive (a “soil” rather than a “seed” issue) and that is what “implantation dysfunction” and this conversation centers on.
Your listeners should understand that in about 90% of cases where the failure of an embryo is due to a lack of uterine receptivity (rather than embryo “incompetency,” one of three (3) causes could be in play
The first is that the thickness of the uterine lining might be inadequate. If the uterine lining is too thin, the embryo might initially try to attach, but fail to do so properly because there’s nowhere for its root system to permeate sufficiently to adequately fulfill the nutritional, respiratory, and endocrinologic function of the developing placenta. I first published on this in 1990, reporting on the fact that ideally the uterine lining should be better than 8mm in thickness around the time of spontaneous or induced ovulation to support orderly placentation. At first, we suggested that there should also be a triple line (trilaminar) ultrasound configuration for implantation to be successful. However, we have come to realize that this is not essential. Rather it is the “thickness” of the lining that really matters.
To be honest with you, Aimee, if I have a lining in a patient of under 8 millimeters, I won’t even do the transfer. I’ll recommend deferring it, trying to find the cause of the problem, and solving it before coming back to do the transfer in a later cycle. Of course, it takes about seven or eight days of exposure to estrogen for that lining to thicken optimally, to proliferate to that level of thickness. You can’t measure it reliably, earlier than that. But if after seven or eight days of estrogen exposure, be it in the natural cycle, be it in a stimulated cycle, or be it in an embryo recipient cycle, it should at least reach 8 millimeters. That’s in terms of the thickness of the lining.
The second factor is the regularity of the inner contour of the uterine cavity. Let me establish a very simple concept. Every one of your listeners has heard of the intrauterine contraceptive device (IUD). However, few realize that an IUD does not prevent pregnancy. You put it in the uterus to establish what we call a “foreign body reaction”. The uterus recognizes that there is a foreign body, so it attempts to evict that foreign body, and it does so by attracting immune cells to the uterus. These attack and evict the embryo when it reaches the uterine cavity and tries to implant. With an IUD, a woman gets pregnant, but loses the pregnancy very early on, before pregnancy can be diagnosed even by a blood test.
In the same way, a little polyp, a fibroid tumor protruding into the cavity of the uterus, or scarring, due to surgical damage or inflammation can act as a foreign body a foreign body in the uterus, and reject the embryo by the same mechanism as an IUD rejects a pregnancy.
The third factor is one that I recognize and it’s somewhat controversial. To me, it’s as clear as day. These are immunologic factors, which we spoke about previously and that I won’t go into here again. These occur in women who themselves or in their family history give a history of an autoimmune condition or endometriosis (regardless of its severity) and can have activated uterine natural killer (NK) cells. As I explained in a prior interview with you, we need normally functioning uterine NK cells to survive as a species because they direct/regulate the implantation process. However, when “activated” they release certain types of growth factors which are called cytokines that destroy the roots of the embryo.
We address the natural killer cell activation (Nka) using steroids, Lovenox, and intralipid infusions. We used to use IVIG, but it’s too expensive, there are too many side effects associated, and it is a blood product which, in this day and age of HIV and Hepatitis-B is best avoided if possible.
Then there is another variety of immunologic cause which has nothing to do with autoimmune disease. This happens when the partners share a certain transplant gene known as DQ Alpha/HLA, an HLA gene. The embryo inherits these genes from the sperm and if this paternal antigen is shared by both partners, the embryo will be regarded as an invading organism and this can trigger “activation” of natural killer cells that will then attempt to evict the embryo.
Those are the three that I consider to be the most important. It’s very important to identify which one you’re dealing with because treatment will differ. If it’s not one of the three, above mentioned factors, then you need to examine for other causes that sometimes can play a role.
Dr. Aimee: At what point do you work a patient up for, I don’t like the word failure, I like to call it implantation issues. It sounds a lot milder, a word that I can deal with. I wouldn’t want anyone to label me as having something that is a failure.
Let’s say I’ve had one transfer; it was not successful. Would you do the work up at that point, or would you wait until the next transfer doesn’t work? Basically, I’m asking at what point would you start going through these three different workups? Obviously, lining thickness is from the beginning, and checking out the cavity. At what point would you go to your third type of implantation failure and do the work up for that?
Dr. Geoffrey Sher: Firstly, I agree with you, the term failure has a negative connotation, so I prefer to use the term, “Implantation Dysfunction”.
Dr. Aimee: I like that.
Dr. Geoffrey Sher: I think it’s a gentle way of making clear that you can only address a problem if you have a diagnosis. At what point do I consider it to be a problem? Whenever a woman has predisposing factors such as unexplained IVF failures, recurrent pregnancy loss (RPL); Repeated failures after transferring chromosomally normal embryos or cases of “unexplained “infertility. Clearly, if there is nothing to suggest an obvious cause for their problem, I become very suspicious, especially in a younger woman in her early to mid-30s where two in three eggs should be normal anyway.
Dr. Aimee: I imagine that when you hear that term, unexplained, you break down what the possible explanations are for your patients, just like I do.
Dr. Geoffrey Sher: I agree with you. Infertility is rarely truly “unexplainable”. We may not yet be smart enough to know all the causes, but in the vast majority of cases, if you look into it, if you dig deep, you’ll find an explanation and you’ll be able to address it. I think with infertility, you always must look for a cause until you’ve run out of options
Dr. Aimee: What a brilliant interview today. Thank you, Geoff. I appreciate your insight on this extremely important topic because I feel like while we do so many IVF cycles in this country, the majority don’t work. I think a lot of the things that you explained to us today will resonate so much with all our listeners all around the world.
Dr. Geoffrey Sher: I think that’s true! If you look at the IVF success rates, very few people are going to get pregnant with one attempt.
Unless you’re doing things like egg donation or you’re doing IVF on younger women with normal ovarian reserve, who have blocked tubes your chances of success are under 50/50, so it’s going to take more than one attempt in most cases. Most people going into IVF should be realistic about their chances of success. They need to understand that even given the best case scenario success cannot be guaranteed, even if we do the right things, because in the final analysis, we don’t create life.
Dr. Aimee: I love that. At the end of the day, humans don’t create life. That is so true. We can certainly do our best.
Where can patients find you if someone is interested in doing some of the testing that you explained to us, especially as the third type of implantation dysfunction, how can they get that workup done?
Dr. Geoffrey Sher: First of all, I’d like to recommend that people go to my website, www.Sherivf.com. I wrote a book on immunologic factors and recurrent pregnancy loss that can be downloaded free of charge from my website. You don’t have to be a patient to get that book. The book is only 45 pages long. I wrote it to meet a need because, unfortunately, there’s not a lot out there about a very important and complex issue.
By the way, I wish to be clear, I have consulted with several people that have come to me from you, and I’ve always sent them right back. This is because I really respect your expertise. However, there might be some areas where I can illuminate things. So, if they want to talk with me I’ll be happy to speak to them. All they need to do is call my assistant, Patti Converse and set up an online consultation with me. Her telephone number is 702-533-2691.
Dr. Aimee: Wonderful. You mentioned PGT just a little bit ago. I would love to have you come back another time. Can we talk about that as our next topic in our fertility expert series with Dr. Sher?
Dr. Geoffrey Sher: I would be delighted. Thank you so much for inviting me.
Dr. Aimee: Thank you again. We’ll see you soon.