Success after Failed IVF. The embryologist Perspective.

In this session, Carol Lynn Curchoe, PhD, TS (ABB), a Founder of ART Compass, a Fertility Guidance Technology & Senior Embryologist, has been talking about success after a failed IVF attempt.  Dr Curchoe explained what is crucial to look for in the IVF lab, discussed some of the experimental technologies that can help you achieve a positive outcome, all that based on her own experience as a senior embryologist.

Dr Curchoe began her presentation by listing things that are most important to have a successful IVF cycle. These are healthy oocytes, sperm, uterus, IVF lab factors and then operator skills. 

Healthy oocytes

Dr Curchoe stated that the primordial follicles in the ovary are being recruited 120 days earlier than what you have available today. It’s crucial to remember that your antral follicle count started to develop 120 days ago. It might give you hope to think that you have some control over the environment these oocytes are growing and developing in.
Dr Curchoe explained that it is possible to grow and culture the embryos and gametes in the lab, but it’s impossible to improve their quality. Therefore, it starts with what you can do in your body to help the embryologists in the lab. We know, for a fact, what impacts oocyte quality is insulin metabolism, and that comes down a lot to your consumption of simple carbohydrates.

I want to encourage you to think about what you should be eating at every meal instead of what you shouldn’t be eating. If we start to think about it that way like: ‘I should eat an avocado every day, I should try to eat some tomato every day, I should try to eat one apple a day then all of a sudden we lose the craving for the bad foods.

Another thing Dr Curchoe discussed was BMI. Women of all BMIs can conceive, but when you’re having trouble conceiving, losing just 5% of your body weight and decreasing your BMI by just a little into the healthy area is so impactful for fertility and IVF outcomes. Dr Curchoe followed that if we start to make some of those healthy changes, we will see that 5% is much easier to achieve than we were previously thinking.

We should also focus on are substances such as alcohol, tobacco, in a lot of areas of the United States, it’s THC, prescription drugs and also supplements. Supplements can fall into the good category, the neutral category like there’s nothing in there, or the bad category where they’re containing things that we don’t know are in there. They can contain hormones or molecules similar to hormones, but they’re disrupting what our bodies should be doing and what we need our doctors to do during our stimulation protocols.

Therefore, you need to start making such changes at least 120 days before your retrieval, you want to cut down or cut out as much of your nicotine, tobacco, alcohol, caffeine just cut down on anything in your environment. Take recommended supplements, such as vitamin D, folic acid and coenzyme q10, which is helpful. Most people think cholesterol is something bad. However, you have to remember that sex hormones are made from the cholesterol molecule itself. You have to have good healthy levels of these fats for your body to make your sex hormones, it’s all-important.

Dr Curchoe clarified that a lot of time, health, and wellness practitioners mention something called estrogen dominance. They start prescribing progesterone based supplements, and it’s crucial to keep in mind that those can interfere badly with fertility.

Healthy sperm

A sperm cycle is much longer than we think it is. It goes from 40 days to up to 76 days on the very long side. One of the things that we think about with sperm is something called DNA fragmentation, we want the DNA strands to be whole. We don’t want them to have been assaulted and bombarded by the environment, we need those strands to be unbroken or unfragmented to make healthy embryos. In the lab, we see that embryos fertilize, but then they arrest at day-3. That day-3 arrest comes from the quality of the sperm at the time of fertilization a lot.

Two of the things that can help with DNA fragmentation and quality are temperature and the environment. Many times men have these jobs where they’re getting very hot, they have to wear a lot of equipment, or they’re working with a laptop directly on their lap. We need the testicles, the site of sperm production, to remain a couple of degrees colder than the body. Professions like construction workers, firemen, or anything where the environment can be impacting sperm quality and the temperature can be very hot or very high.

When it comes to supplements and substances, it’s the same, you should start at least 80 days before. There are some male fertility supplements, and there are sometimes a lot of testosterone-based supplements and anything that contains a hormone you should be very wary of. It’s best to talk to your doctor, disclose everything you’re taking. The supplements that are very well accepted for increasing sperm quality are the same ones increasing oocyte quality, take the folic acid, vitamin D and the coenzyme q10.

BMI and obesity, in general, in both men and women, has a very big impact on hormone production and gamete quality. Reducing the BMI down to a healthy level and getting low-impact exercise every day can help your insulin metabolism and help to take that glucose out of your bloodstream, which can impact gamete quality.

Healthy uterus

We can make healthy embryos in the lab, but if we don’t have a healthy uterus capable of supporting a pregnancy, it won’t matter. A couple of things that patients can look at nowadays are the endometrial receptivity tests. We want the endometrium to be synced with the age of the embryo. At times, it is necessary to take progesterone for a longer period to prepare the uterine lining and help to increase the uterine endometrium receptivity. The Receptiva DX test can tell us if there are low levels of endometriosis going on before we transfer the embryos back to the uterus. Usually, people don’t start looking at those things until after they’ve had a failed FET or a failed transfer with the genetically normal embryo.

The second thing Dr Curchoe mentioned is genetics. Your set of genetic mutations. This is ranging into the realm of personalized medicine. Some mutations can cause you to metabolize folic acid differently and also make your blood clot more. Both of those things can sustain your ability to have a healthy pregnancy. Folic acid is very important for neural tube closure and defects. The clotting aspect is really important for being able to establish a pregnancy and then maintain it. Small blood clots can form in the capillaries of the placenta between the mother and the baby, and then the nutrient exchange has a more difficult time because of those blood clots.

The uterine microbiome is another aspect that Dr Curchoe discussed. The uterine epithelium is consistent with the epithelium of the cervix and the vagina. Our microbiome colonizes our entire body, we have a gut microbiome, a skin microbiome, we have these organisms that live with us, have evolved with us and help to keep us healthy. Microscopic bacteria do everything from producing different vitamins to different sugars in your reproductive tract. It even produces some proteins that can help with the crosstalk between the embryo and the endometrium.
We want to make sure that we’re eating a lot of healthy prebiotics, you want to eat the food your bacteria wants to digest. You can take probiotics, but we need those bacteria to be in our vagina and our endometrium. Therefore, taking them in your stomach is less desirable than eating the food that will cause the healthy bacteria to proliferate.

Dr Curchoe also suggested that we should be cutting down on our antibiotic use in general. Those antibiotics in our environment, or for example, taking them when we have a virus and not a bacterial infection, can impact our microbiome everywhere in our gut, our vagina, our skin. All available literature shows that the bacteria species of Lactobacillus are the important ones to help us maintain a healthy microbiome.

IVF lab factors

In the US, we’ve switched almost all of our cycles to ‘freeze all cycles’. We’re doing upwards of 80 to 90% of PGT-A, which is the pre-implantation genetic testing for aneuploidy, and that can tell you whether the embryos we made have a normal number of chromosomes or an abnormal number of chromosomes. Part of the freeze-all strategy is to let your body go back to baseline after you’ve bombarded it with all of those stimulation medications. We will biopsy and freeze the embryos and then hopefully get those genetic testing results back and be able to transfer a genetically normal embryo to your uterus.

Regarding mosaic embryos and culture to day-7, Dr Curchoe explained that she likes to have both mosaicisms reported from the genetic testing company and physicians willing to transfer mosaic embryos.

I have seen mosaic embryos go on to produce successful pregnancies, and I think that there’s ample evidence of that in the literature. I’m also a big fan of culturing embryos to the seventh day. For a variety of reasons, embryos can be slow-growing, and in general, we have seen that embryos that come back genetically normal have up to a 30% success rate. A lot of labs are not yet culturing to day-7, but I think that will become a widespread best practice.

When it comes to IVF add-ons, such as ICSI (Intracytoplasmic sperm injection), Embryo glue, Assisted hatching, which is performed at two different time points. The first is usually around day-3 or around the time of biopsy. Then the other is when we thaw the embryo, and we’re preparing it for transfer. Sometimes, we like to help the embryo to escape the membrane called the zona pellucida around it. The embryo needs to escape that membrane to implant in your uterus.

Some other experimental technologies are not widespread yet but probably will be in the next couple of years. The Zymot chip is a way to prepare sperm where it swims through channels similar to how it would swim through your cervix. It is thought that separating the sperm that way gives better quality sperm at the end with less DNA fragmentation. It has been selected more naturally as it would be in your body. It eliminates the step that we do in the lab, which is where we centrifuge the sperm, and fling it to the bottom and the side of the test tube that we’re centrifuging. It is potentially causing some stress to the sperm or some damage.

Another technology is called PICSI, which stands for Physiological Intracytoplasmic Sperm Injection, and it allows the sperm to bind to the dish with the same protein that it would use to bind the egg. We’ll be picking the sperm that looks the most normal, which has also bound to this certain spot on the dish.

I’m not the biggest fan of PICSI, but I know some people have used it, and again it’s hard to tell what made a cycle successful on a second or third go-round when it finally succeeds. The use of the PICSI dish could be something that people consider.

There are also a couple of different oocyte treatments. One of them helps collected immature oocytes to become mature in the lab. Those oocytes have a bit less of a success rate because they were not mature at the time of the retrieval, but it may be giving patients a chance, it probably still needs a little bit of development as well as using the Calcium ionophore (CA+) to activate oocytes.

The last experimental technology that Dr Curchoe mentioned was Artificial Intelligence. The basic concept is that the computer can look at images of embryos or videos of embryos and help pick the embryo that’s going to be successful the fastest. Ultimately, we’d like this to go in the field as a replacement for biopsy. During the embryo biopsy, we pluck about 4 to 6 cells off the embryo, and it slightly damages it. Right now, it’s the best technology we have to say whether those embryos are normal or not.

Finally, artificial intelligence now is all about these images and videos of embryos. However, the gold standard would be to analyze all of your data as a patient. Your demographics, your infertility diagnosis, everything about you in conjunction with the embryo images gives us tools for the prognosis and diagnosis of your infertility or your cycle. We’re not quite at that point yet where everything is connected in the realm of AI, though.

Operator skills

In the US, we start with looking at SART or the CDC, Center for Disease Control and Prevention success data. Every country has the equivalent of a governmental agency that oversees the success rates of Assisted Reproductive Technologies. The more important thing is that the clinic you go to is not falsely advertising their success rates on their website. Make sure that whatever your clinic is advertising matches the data that they’re reporting.

A recent paper from Italy was released in 2020 that shows a huge difference in the operators or the people performing the embryo transfer. The embryo transfer is a key procedure for success, and it seems like once clinicians learn how to perform the embryo transfer, the number of embryo transfers that they have after that doesn’t make them better. It is probably because they learn this procedure, and then they don’t interact further with other clinicians to keep modifying that procedure after they learn it. Therefore, for embryo transfer, it’s best to use soft catheters, no bed rest, as some studies have shown to negatively impact implantation and clinical pregnancy rates. Then to use an ultrasound guide, you want to guide the catheter through the cervix and into the perfect spot in the uterus to drop the embryo off.

The Vienna consensus defines the key performance indicators for both the clinical and the IVF lab, and they guide embryologists competencies.

As an embryologist, I check my statistics to the Vienna consensus. I want to know how is my fertilization rate, how is my blastocystery, and so on. The skill does matter, and I think a lot of times with picking a clinic, you as the patient are weighing a clinic that may charge more for a cycle but gets their patients pregnant faster versus a clinic that charges less for cycles, but you might need more than one cycle. Then, by the time it all adds up, that could become very costly for you.