In Vitro Fertilization: Failed IVF
Don’t Give Up! Pregnancy is Possible After a Failed IVF Cycle
An unsuccessful in vitro fertilization (IVF) cycle can be emotionally and financially devastating. We know this well, because most of our patients come to us after having at least one failed cycle at another fertility center. At CHR, we specialize in helping patients with tough cases of infertility - and we know that failed IVF cycles can provide clues for a successful next treatment.
Our confidence on this issue derives from the fact that we have helped so many patients over the years to conceive, in spite of their long histories of unsuccessful fertility treatments. Many patients come to CHR after their first or even second and third fertility centers give up on them, denying them further treatments unless the patients agree to use donor eggs. CHR is committed to helping patients get pregnant with their own eggs.
After a failed IVF cycle, the important question is whether we can improve upon the unsuccessful cycle. At CHR, we learn from each cycle that did not lead to a successful pregnancy. That’s the only way to get better, and that is the core of our center’s existence. As a fertility center that has been at the forefront of fertility treatment for the last three decades, we have developed treatment options that no other fertility center can offer to patients with multiple failed IVF cycles.
If you are one of these patients with multiple failed IVF cycles, consider contacting CHR for a second opinion!
Reasons IVF Cycles Fail
"Failed IVF" is a vague term that can refer to several different situations:
- Cycle cancellation, prior to egg retrieval, because not enough follicles are produced;
- No eggs or only inadequate-quality eggs are retrieved;
- Retrieved eggs don't fertilize of fertilize inadequately;
- No embryo is available for transfer into the uterus;
- Transferred embryos may not implant for a variety of reasons;
- And that, of course, will mean no pregnancy after embryo transfer.
IVF Cycle Cancellation
Amongst patients who come to us after cycle cancellation, a number of major problems stand out. The one most frequently encountered is that most fertility centers routinely cancel IVF cycles if the patient does not demonstrate a minimal number of follicles on ultrasound. Such cancellations make sense only if there is a better ovarian stimulation protocol that can be applied in a subsequent cycle.
However, if a patient with diminished ovarian reserve (DOR, evidenced in part by high FSH) is already on maximal stimulation, what would be the purpose of a cycle cancellation? In such cases, nothing better can be offered in a subsequent cycle. Such a cancellation may end up wasting the patient's last good chance of pregnancy, because time is usually not on her side for patients with diminished ovarian reserve. When dealing with DOR, the prudent approach often is to retrieve what few eggs do develop, rather than letting them "go to waste." A pregnancy ultimately takes just one egg and one embryo!
Failure Due to Inadequate Ovarian Stimulation
Another problem we see in failed IVF cycles is that patients are not given an ovarian stimulation protocol that suits their "ovarian age." The reason is that stimulation protocols are too often chosen based on a patient's age. However, younger women may suffer from undiagnosed premature ovarian aging (POA): Their ovaries behave "older" than they should at their age. Those ovaries then need to be stimulated like ovaries of an older woman--a point that is very frequently overlooked. For a successful IVF treatment, patients must be given ovarian stimulation protocols based on their ovarian age, not their physiological age!
No Pregnancies from Multiple Mini-IVF Cycles
There is another worrisome trend that has developed in recent years: some centers aggressively market the so-called "mini-IVF," which utilizes a smaller amount of milder medications during the ovarian stimulation phase. Proponents argue that milder ovarian stimulation produces higher-quality eggs, and results in better pregnancy chances. As attractive as it may sound, there is a problem with this concept: None of these proponents has ever reported data that would really confirm these claims!
Indeed, trying to confirm this concept, CHR investigators recently did a comparative study of such "mini-IVF" and regular IVF cycles and were unable, even in young women with entirely normal ovarian reserve, to demonstrate either clinical or economic benefits of "mini-IVF." Very much to the contrary: "Mini-IVF" produced lower pregnancy rates and showed no cost advantages.
Yet, "mini-IVF" is widely propagated for women with much poorer prognosis - women with diminished ovarian reserve (DOR) - who are likely to do even worse than the young, normal women investigated in this CHR study. With mild ovarian stimulation as used in "mini-IVF," DOR patients face an astonishing 50% cycle cancellation rate, unheard of in any responsible IVF protocols.
At CHR, Our Approach is Different
We are not afraid to use more aggressive forms of ovarian stimulation, if ovarian reserve test results and thorough examination of the patient show that low ovarian reserve requires such treatment. By careful monitoring during ovarian stimulation, most of the negative side effects of stronger ovarian stimulation can be avoided, and pregnancy rates are better. CHR's basic philosophy is to "fight for every single egg."
Therefore, we will go to retrieval for even a single egg in some patients, if a patient manages to produce one follicle. While pregnancy chances are obviously small with retrieval of only one egg (and the risk of not retrieving an egg from a single follicle is considerable), it takes only one egg and one embryo to establish pregnancy.
Many CHR patients can confirm this fact: their voices are heard on our success stories page. Differences in CHR philosophy derive from the fact that CHR patients are different from patients at practically all other fertility centers. Having very few eggs is quite normal at CHR. A large majority of our patients come to our center because they already know, from prior IVF experiences elsewhere, that they produce only very small numbers of eggs, and that they need a fertility center that will fight for those few remaining eggs.
With the help of dehydroepiandrosterone (DHEA) and our individualized ovarian stimulation protocols, we have learned to get the most out of these patients' older-behaving ovaries. Most patients who come to CHR after previous experiences will tell you that they, at CHR, end up with more eggs and embryos than they did before, and they are of better quality. Every egg and embryo counts, because every egg and embryo represents pregnancy chances!
Poor Quality Eggs & Poor Quality Embryos
An IVF cycle can be unsuccessful even with good numbers of eggs (and embryos) if egg quality is poor. Egg quality reflects about 95% of the final quality of an embryo. Poor egg quality, therefore, always leads to poor embryo quality. The quality of sperm, while not unimportant, is nowhere near as important as egg quality.
Embryos from low-quality eggs often fail to develop properly. In an IVF cycle, embryos are observed for 3 to 5 days as they grow in the lab, before they are transferred into the uterus. On the third day, good-quality embryos should reach 6- to 8-cell stage, and have a more or less regular shape. Embryos that don't reach this stage within the first few days of development cannot be used for embryo transfer. In addition, some embryos that do reach this stage may be aneuploid (have chromosomal abnormalities). Aneuploid embryos, if they implant at all, are usually miscarried early in the pregnancy, thus also resulting in "failed" IVF.
Therefore, as many of our patients already know, it is not just the number of eggs that is important. The quality of eggs is also crucial for the success of IVF. In this context, our development of dehydroepiandrosterone (DHEA) in women with DOR becomes important. Our initial finding was simply that DHEA supplementation increases the IVF pregnancy rates, especially in women with DOR. However, over the years, we have also confirmed that DHEA supplementation improves egg quality, improves embryo quality, and reduces aneuploidy (chromosomal abnormalities) in embryos.
By using DHEA along with a well-designed IVF protocol for each patient, CHR physicians have been able to achieve once unthinkable results: Women with a long history of failed cycles and/or very low ovarian reserve are conceiving in significant numbers, and with their own eggs!
Conditions That Can Prevent Embryo Transfer
IVF cancellations can also happen when the patient develops medical complications that make it impossible to transfer embryos to her uterus. Two such conditions are ovarian hyperstimulation syndrome (OHSS) and inadequate development of endometrium.
OHSS is a rare side effect of ovarian stimulation. In most cases, OHSS is mild and only causes minor to moderate discomfort. In women with low ovarian reserve, OHSS is exceedingly rare, and rarely of concern. When OHSS is more severe, however, embryo transfer may need to be cancelled, and all embryos are frozen for future use. Significant OHSS is usually, though not always, preventable with proper monitoring and adjustments in fertility drugs during ovarian stimulation. Women with polycystic ovaries (PCOS) are generally at highest risk, and must be monitored carefully.
The other condition, inadequate endometrium, is also rare but can be a frustrating challenge. Most patients develop good enough endometrium (lining of the uterus) to receive their embryos. When a patient's endometrium is slow to develop, various medications can be used to help encourage the proliferation of the endometrium. These conventional medications are enough for a majority of IVF patients, and these patients have their eggs retrieved and embryos transferred.
In a small number of patients, however, endometrium can remain thin and unresponsive to conventional treatments. Since a thickness of 7 mm is considered minimal for a decent chance of embryos implanting, inadequately thin endometrium can be a reason for cancellation of IVF cycles. When embryos are transferred despite inadequate endometrium, the transfer usually results in implantation failure.
CHR reported in the journal Fertility & Sterility a new, promising treatment with granulocyte-colony stimulating factor (G-CSF) for women with endometrium that is resistant to standard treatments. To see if the successful use of G-CSF to treat unresponsive endometrium in four patients reported in the original study could be generalized, we subsequently conducted a clinical trial of G-CSF. This clinical trial, however, failed to demonstrate a significant improvement in endometrial thickness, implantation rates or pregnancy rates. CHR is currently conducting a separate G-CSF clinical trial to determine whether G-CSF may be effective in a more tightly controlled patient population.
Inappropriate Use of Preimplantation Genetic Screening (PGS) or PGT-A
Preimplantation genetic screening (PGS), or preimplantation genetic testing for aneuploidies (PGT-A), has become a very common reason why IVF cycles fail, especially in recent years. PGS/PGT-A has been marketed heavily to IVF centers and fertility patients by testing laboratories without sufficient evidence that the test improves IVF outcome parameters, and CHR has been vocal about the harm it does to patients, particularly to patients who do not produce a large number of embryos to select from.
We have seen too many patients come to CHR after going through PGS/PGT-A at other centers, where all of their embryos tested “abnormal” and their IVF cycles were cancelled without embryo transfers. Considering that over a hundred healthy births have been born after transfers of embryos that were deemed “abnormal” by PGS/PGT-A in the last few years, these patients may have had a good chance of having healthy babies. While PGS/PGT-A may have a place in a very limited number of circumstances, CHR physicians usually advise patients not to undergo this expensive yet unproven test.
Unexplained IVF Failures – Possible Autoimmune Involvement
Perhaps the most frustrating of IVF failures may be the ones for which no apparent reason can be found. A factor, often overlooked in investigation, is the autoimmunity (immunity against oneself) in the female patient.
The impact of female autoimmunity and excessive inflammation on reproduction has been contentious among IVF experts, but evidence in published literature suggests that even subclinical autoimmunity (autoimmunity that doesn't require medical treatment and is not obviously apparent) can negatively impact fertility. Norbert Gleicher, MD, Medical Director of CHR and an internationally renowned expert of immunological infertility, emphasizes that when repeated IVF failures appear to have no cause, autoimmunity should always be suspected. At CHR, patients with evidence of autoimmunity receive a variety of immunological infertility treatments to keep their autoimmunity in check. This has resulted in many successful in vitro fertilization births in women with previous autoimmune-related IVF failures.
In 2010 CHR investigators were able to demonstrate a genetic marker for autoimmunity, which, likely, reduces the pregnancy chance with IVF to a significant degree. This paper appeared in the prestigious electronic medical journal PLoS ONE. Autoimmunity appears much more important in designing a successful fertility treatment plan than is widely appreciated.
What to Do When IVF Cycles Fail
Even when every step—from ovarian stimulation to egg retrieval to embryo transfer—goes as planned, the reality is that a certain percentage of women will not see a positive pregnancy test. IVF pregnancy rates, overall, have improved tremendously in the three decades since the technique was initially introduced, but it still is not perfect. Especially among women with DOR (either due to natural age or due to premature ovarian aging), negative pregnancy tests are unfortunately still common, and patients who still want to work with their own eggs have to expect that it may take more than one cycle to conceive.
The important question is whether we can improve upon unsuccessful cycles. At CHR we learn from every unsuccessful cycle. Every IVF cycle that did not lead to pregnancy is discussed and dissected in our weekly conference. This is the only way to get better. And getting constantly better is at the core of CHR's existence. As a fertility center that has been pushing the boundaries of fertility treatment for the past three decades, CHR has treatment options that other centers cannot offer.
IVF with Donor Eggs
One of the most important things to remember about IVF treatment is that it only works about half the time in the best of cases. So, sometimes the patient needs to have multiple cycles to get pregnant and deliver a baby. Other times, a woman who is older or has "premature aging" of her ovaries might not have a successful IVF cycle.
In these cases, which are not that uncommon at CHR due to our special expertise in treating women with ovarian aging, patients may opt to use donor eggs. Donor IVF allows the woman who otherwise would have no chance for pregnancy carry and deliver her own baby using the sperm from the husband. Donor egg cycles are usually less expensive than adoption. CHR also offers an embryo adoption program that has been very successful.
Norbert Gleicher, MD, leads CHR’s clinical and research efforts as Medical Director and Chief Scientist. A world-renowned specialist in reproductive endocrinology, Dr. Gleicher has published hundreds of peer-reviewed papers and lectured globally while keeping an active clinical career focused on ovarian aging, immunological issues and other difficult cases of infertility.