RECCURENT IVF FAILURE

Some infertile patients undergo many IVF cycles and produce embryos, but the embryos consistently fail to implant for unexplained reasons. This is called IVF failure or implantation failure.

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. These patients as labeled as having recurrent implantation failure , which is actually just a waste paper basket diagnosis which means we really do not know why the embryos we transfer do not implant for these women.

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.

Our pregnancy rates in patients who have failed IVF cycles elsewhere is very high, because we can transfer more embryos in difficult patients ( unlike fertility clinics in UK and Australia, where the number of embryos which can be transferred is limited by law). 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). In our fertility clinic, we customise the number of embryos we transfer for each patient we treat, rather than just blindly follow a guideline ( which has been laid down for the general population, without considering each individual’s specific problem).

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, we offer the option of aggressive superovulation, with high doses of HMG, in order to help them grow more eggs, so we have more embryos to transfer.

Sometimes the reason for IVF failure is because the embryo transfer was technically difficult, because of cervical stenosis. This means that the transfer is often traumatic, and is associated with bleeding. For these patients, if their fallopian tubes are open, we prefer transferring their embryos into their fallopian tubes( ZIFT , zygote intrafallopian transfer) so that we can bypass the cervix and place the embryos directly in the fallopian tubes. This ensures a very high pregnancy rate.

Another group of patients who often do poorly in other IVF clinics are those who have PCOD. Because many doctors are so worried about the danger of OHSS ( ovarian hyperstimulation) in these patients, they often end up superovulating these patients badly, and retrieve few poor quality eggs, compromising the pregnancy rate. In our fertility clinic, we prevent OHSS by carefully aspirating each and every follicle at the time of egg retrieval, and flushing it repeatedly with a double-lumen needle, until it collapses completely. By removing the follicular cells which are responsible for producing VEGF and causing OHSS, we have been able to prevent OHSS in PCOD patients very successfully in our fertiliy clinic by using this novel technique.

Successful embryo implantation depends upon the health of the embryo, and one of the reasons embryos may fail to implant is that they may be chromosomally abnormal (even though they look normal). Research has shown that the incidence of chromosomal abnormalities even in good looking embryos is as high as 50% ! On an intellectual level , we understand that there are broadly only two groups of reasons for failure of implantation. One could be that the embryos are not of good quality; while the other is that there is a problemwith endometrial receptivity .

Unfortunately, because it is still very difficult for us to pinpoint what the problem is in an individual patient, there is a lot of hocus-pocus and mystery surrounding the treatment options for these patients . They are emotionally very vulnerable and very desperate . They will often keep on changing doctors , and each new doctor will offer his own particular flavor of some magic potion in order to solve the problem. This could range from using intravenous Intralipids; to doing PGD for comprehensive chromosomal screening; to using immunotherapy for treating NK ( natural killer ) cells .

A lot of this is extremely speculative stuff ; and I feel a better treatment option would be one which is based on sound science. This would be to grow all the embryos to blastocyst stage; freeze all of them; and then transfer them in the next cycle. While this may seem to be a lot of hard work, there is a sound scientific basis to this approach. Growing embryos to blastocyst stage ( rather than transferring them on Day 2 or 3) is the best way we have today of ensuring that the embryos are competent. While it’s true that not all blastocysts are genetically normal , which is why not all of them will implant , given the state of the technology available today, this is the best approach we have for making sure that the embryos are viable. If the embryos do not grow upto the blastocyst stage in the incubator in vitro (assuming that the IVF lab is experienced and competent ), this means that means the problem for recurrent implantation failure is quite likely to be an embryo problem. This is especially true when patients with recurrent implantation failure have had multiple failed IVF cycles with only Day 2 or Day 3 transfers ; and the earlier IVF clinic has not tried to grow their embryos to the blastocyst stage.

While the fact that their embryos have arrested in vitro; and have failed to develop to blastocysts ( which means they will not have any embryos to transfer at all) can break their heart , at least this way they know where the problem lies , so they can then approach their next treatment cycle armed with more intelligence . This approach provides valuable information, rather than leave patients groping in the dark. Why not transfer the fresh blastocysts ? This is because endometrial receptivity may be suboptimal in a super ovulation cycle , because of all the hormones which have been injected. Because the thrust of superovulation is to focus on growing good-quality eggs , sometimes we may not be able to optimize endometrial receptivity at the time at which the eggs are ready for retrieval. Once we have frozen all the blastocysts, we can then focus all our energies in the next cycle on improving endometrial receptivity. This approach allows us maximize the chances of implantation, because we are transferring good-quality blastocysts into an optimally prepared endometrium.

This approach allows us to use sound scientific principles , without resorting to a lot of expensive hocus-pocus , to maximize chances of success in this group of heartsink patients . Only very skilled IVF labs can offer this kind of service, because it needs a lot of expertise and experience to do this successfully. It is also more expensive ! We are often asked what we feel about immune testing for patients with repeated IVF failures . Patients who have had failed IVF cycles even though apparently perfect embryos were transferred, are understandably upset, frustrated and distressed. They are looking for answers as to why they are not getting pregnant, and a plausible reason is that their body is “rejecting” their embryos. This is why immune testing for patients with reproductive failure has become very fashionable recently. There is a long list of expensive tests which many labs now perform – and these include: DQ Alpha, Leukocyte Antibody Detection, Reproductive Immunophenotype, ANA (Antinuclear Antibody), Anti-DNA/Histone Antibodies, APA (Antiphospholipid Antibodies), Natural Killer Cell Assay and TJ6 Protein. This mind – boggling range of catchy acronyms conceals the fact that no one knows whether the immune system is really responsible for the failure of the embryos to implant in these women. Many labs use different protocols to carry out these tests, which are still poorly standardized. This means that results for the same test from different labs vary widely, making interpretation very difficult. Also, intelligently interpreting these tests in individual patients is virtually impossible, because of the considerable overlap in the results in normal fertile women and those who are infertile, since many fertile women will also have abnormal results when subjected to these tests. Sadly, most labs do not bother to standardize their test results by doing them on normal fertile women. This means that if a woman who has had an IVF failure is subjected to these tests and has an abnormal result, her doctor happily jumps to the erroneous conclusion that he has now “diagnosed ” the reason for the IVF failure, little realizing that the abnormal result could just be a “red herring”, since “abnormal ” results are often found in “normal ” fertile women as well.

(These are called ” false positives ” – test results which are abnormal (‘positive’), even though the patient has no disease. ) Unfortunately, most infertility specialists do not really understand much about the immune system, or what these test results mean, and are so happy to be able to offer any treatment at all to these desperate patients, that they often do so mindlessly.

What about those patients who have had multiple IVF failures, and then do finally have a healthy baby after immune therapy ? While these patients ( and their doctors) are happy to credit the immune therapy with their success, the fact remains that there is no evidence to suggest that it was in fact the immune therapy which resulted in the successful pregnancy. This common post hoc ergo propter hoc (after this , therefore because of this) logical fallacy is based upon the mistaken notion that simply because one thing happens after another, the first event was a cause of the second event. All IVF clinics have had many patients who have finally conceived after multiple IVF attempts, even though there was no change in the treatment protocol whatsoever. Sometimes, it just needs a bit of luck , patience and perseverance !

This is why we do not suggest that patients with repeated IVF failures do any of these immune tests. The results do not really influence the treatment plan – and why do a test if it’s not going to change your treatment?