In this webinar, Harroula Mathiopoulou Bilali, B.Sc., MMedSc, a molecular biologist specialized in reproductive health, and founder & CEO of Ferticeutics Co., a medical/pharma company that provides advanced health and fertility products, services and therapeutics has been discussing microbiome as a new parameter that should be checked if you have had multiple IVF failures. Her goal is to help people struggling with infertility address their problems. During her presentation, Harroula analysed the latest data on the microbiome, which has been a hot topic in the last decade. Nowadays, more and more scientists from different areas of science are involved in this specific sector.
Harroula started her talk with the most challenging question in IVF: why IVF fails? It’s very frustrating because many times, you do not have an answer. If you have experienced multiple IVF failures, you probably know that age is one of the most important factors that affect IVF.
Along with age comes egg quality, bad egg quality can result in IVF failure. However, we should remember that bad egg quality is not only because of advanced reproductive age. You can have bad egg quality because you have PCOS (Polycystic Ovarian Syndrome) or endometriosis. You can experience an IVF failure because there are hormonal imbalances, bad semen parameters, chromosomal issues, uterine abnormalities, endometrial thickness problems, you may experience a bad embryo transfer, which can happen as well. Also, the stimulation protocol that was used to stimulate the ovaries was a bad one or the wrong one for the patient. Sometimes, IVF can fail because you may have a high body mass index (BMI). There may be thyroid issues that have not been addressed or not solved. There is some conflicting data regarding immunology and natural killer cells for IVF failure, also thrombophilia, infections including infections of the endometrium. There are many other parameters, we are trying to find the factor that could probably affect the IVF failure.
In my personal view, being an infertility specialist for more than 15 years now, I believe that we need to address all those factors, but many times instead of adding more tests, it’s probably better to simplify things a little bit.
We start looking for all the factors that I mentioned above, but many times there are two main areas that we forget to consider. There is one new we should start considering more, and it has to do with stress. There is available data that supports the idea that preventing or decreasing maternal stressors may have a positive outcome on pregnancy. Also, ESHRE ( The European Society of Human Reproduction and Embryology) has released a new set of guidelines that included recommendations for lifestyle modifications for recurring pregnancy loss patients.
Last but not least, in the last 10 years, the microbiome has become a very important factor in fertility and the success of an IVF procedure. The vaginal microbiome and the endometrial microbiome is often discussed. However, there is a new parameter that every IVF patient should consider checking before starting another IVF procedure, and it is the microbiome of the gut.
The human microbiome is considered to be an organ composed of all the communities of bacteria, viruses, fungi that live inside our body.
The human microbiome is composed of communities of bacteria, viruses and fungi that have greater complexity than the human genome itself. It has an estimated 100 trillion microbes, the bulk of which live in our gut. Large-scale metagenomic projects, such as The European Metagenomics of the Human Intestinal Tract and the Human Microbiome Project, have reported 3.3 million unique protein-encoding genes as compared with the entire human genome, which has around 23 000 genes. These studies have described the beneficial functions of the normal gut microbiota on health down to the genetic level.
Why is the microbiome so significant? Why should we start considering it more when we’re talking about infertility or fertility as well?
It’s because the human microbiome has extensive functions such as development of immunity, defence against pathogens, host nutrition including production of short-chain fatty acids important in host energy metabolism, synthesis of vitamins and fat storage as well as an influence on human behaviour making it an essential organ of the body without which we could not function correctly.
Since 2003, more and more data and there are many various clinical trials. Harroula shared four of the most interesting ones. It was concluded that not only there are some good microbes in the vagina, we know that the endometrium has its own microbiome as well.
In this study, it was demonstrated that women with Lactobacillus dominated endometrium undergoing IVF have been shown to achieve higher rates of successful implantation (60.7% vs. 23.1%) and life birth (58.8% vs. 6.75%) rates compared to those with non-Lactobacillus dominated endometrium(Gardnerella, Streptococcus and other organisms present).
In 2003 and then in 2014, it was mentioned that:
Moreover, vaginal dysbiosis reduces the local defences against sexually transmitted pathogens, and ascension of pathogens up the fallopian tubes can affect reproductive health.
A few months ago, Juan Garcia-Velasco et al.,2020 demonstrated that:
Lifestyle changes, especially those that affect nutrition, can lead to changes in the gastrointestinal microbiome and could have a positive impact in infertile patients.
From Greek, it means (dys-, ‘bad’) and (biosis, ‘way of living’), and it is any interruption that occurs in the balance of the microbiota. The difference between the microbiota and the microbiome is that microbiota refers to the total number of the communities of the microbes we have in our body. The microbiome refers to them as well, but also to the genome, the DNA, the genetic information that all these microbes have as well.
Dysbiosis is defined by an imbalance in bacterial composition, changes in bacterial metabolic activities, or changes in bacterial distribution within the gut (or any other organ). The three types of dysbiosis are:
1. Loss of beneficial bacteria
2. Overgrowth of potentially pathogenic bacteria
3. Laws of overall bacterial diversity
In most cases, these types of dysbiosis occur at the same time. Dysbiosis has been associated with diseases such as Inflammatory Bowel Disease (IBD), Obesity, Type 1 and Type 2 Diabetes, Autism, certain gastrointestinal cancers and infertility.
It has been shown, in the patients whose endometrium was dominated by the beneficial microbes, it was these patients who had 58.8% versus 6.75% of live birth rate. Therefore, we all should start thinking very seriously about improving our microbiome before any IVF treatment.
Another finding was released in 2014, which showed that the endometrial microbiome is very important for two reasons regarding implantation.
The first has to do with the procedure of implantation itself and the environment that is created for the embryo to find the perfect environment for implantation and the pregnancy. Besides the perfect environment for the implantation to occur, there is also supporting data that states that a good microbiome, a healthy endometrial microbiome, can also alter the hormone levels such as estradiol and especially progesterone. We need to have a balanced progesterone profile for implantation and a successful pregnancy to occur.
The microbiome affects fertility via nutrition and fertility via disease because it can promote inflammation, and it can also increase other increased susceptibility to other diseases that can also harm fertility itself.
What disturbs the microbiome and leads to dysbiosis?
Many patients, even the ones starting their IVF procedures, try to eat healthily, but at some point, they start eating more junk food and sugar, or they turn to alcohol, especially if they are very stressed. They take all these antibiotics in the course of their IVF treatment, and sometimes they take painkillers because of the pain after stimulation. The stimulation protocols themselves include hormones. Because of this, no diagnostic tests confirming that this woman’s microbiome is affected negatively is needed. Especially after multiple IVF failures, couples experience multiple negative feelings, and they often worsen their lifestyle and habits leading to microbiome imbalances.
When you have an optimized microbiome, you can absorb all the vitamins that you are taking through your food and supplements better. When you have a good microbiome, you can have better psychological resilience, you are less stressed. The microbiome directly affects the brain through the gut-brain axis. Lots of data support the idea that people with depression and high-stress levels have a disturbed microbiome. If we need to optimize a couple before another IVF cycle, Harroula suggests assessing and optimizing the microbiome, not only the vaginal one.
There are four proven ways to improve your microbiome regardless of whether any tests were performed. You should eat a variety of probiotic foods to boost good bacteria. Eating probiotic foods increases the overall communities of beneficial microorganisms. You need to add to your diet things like yoghurt, kefir with live and active cultures, choose low- or no-sugar varieties because sugar impairs healthy bacteria, fermented pickles, sauerkraut, kombucha, apple cider vinegar. What about probiotic supplements? According to Harroula, every single IVF patient should have a probiotic supplement. However, it is crucial to balance your nutrition as well because this is how biology works. This is how you can support the whole function of the gut and your vagina, and your endometrium.
Secondly, add prebiotic foods to feed the gut microbiome. Prebiotics are foods that fuel the healthy microbes in the gut. These foods are usually high in prebiotic fibre, but microbes are going to break down, and they include Flax seeds, Chia seeds, legumes, vegetables such as asparagus, artichokes, garlic and onions.
Another thing is to practice stress management techniques. Stress can influence the microbiome too. High-stress levels contribute to a poorly functioning gut, the body’s longest nerve, the vagus nerve, goes straight from the gut microbiome to the brain. Having very high-stress blocks the vagus nerve’s function. Ongoing stress prevents your gut from working properly.
To improve your microbiome, you also need to stay active to keep your body healthy. Exercise and physical activity can help your gut, not only by supporting a healthy weight but also by positively affecting the microbiome. Even 10 minutes of mild walking a day has proven benefits. Gentle activities such as walking, cycling, yoga or swimming can keep you moving and improve your overall well-being and your fertility.
It is best to introduce all those things at least 3 months before any treatments to improve your microbiome, to improve a better egg quality and sperm quality, hormonal balance and endometrial health. The reason it’s 3 months is that it takes approximately 75 days for new sperm to develop, and it takes approximately 90 days for a new egg to completely mature.
First of all, Harroula always advises her patients to stop and take a short break to reassess the situation, organize their medical history before any next IVF attempt. Don’t go to the next IVF cycle in a hurry. Another thing is to break bad habits and build good ones before assessing. Address your lifestyle, nutrition, sleeping patterns, think outside the box, ask for help and make a plan to start creating good habits that will protect your mental health and will bring your sexuality back. Finally, try to understand what is your diagnosis sometimes, even after so much testing, the diagnosis can be missed. You should also optimize, besides your vitamins and your lifestyle and everything that has to do with your lifestyle is optimizing your microbiome.
Carlos Simone, one of the most highly acclaimed scientists in the field of assisted reproduction as an editor of the issue of ‘Fertility & Sterility’ has named the opening: Preconceptional care: do we have to care? The take-home message is to try to optimize everything before your next IVF cycle including your microbiome.
In this issue’s, Views and Reviews’ we provide data to suggest that modern preconceptional care should become a key component of reproductive medicine, not only to improve implantation and pregnancy rates but also to reduce perinatal morbidity and mortality, further optimizing the health for mothers and children and setting the states for the child’s adult life.
It’s the most crucial period, 3 months before another IVF to optimize everything, it is ‘the window of opportunity’ to improve your lifestyle, your microbiome, sleep patterns, to improve your exercise regime, and that will have a positive impact on fertility.
At the end of her presentation, Harroula shared her first microbiome and health coaching success story. The patient was 39 years old with unexplained infertility, five years of infertility. She came with a package of hundreds of results and tests, and procedures. Harroula asked her to reassess the situation, and they started working together and with a fertility specialist. They started changing the patient’s lifestyle, her sleeping patterns, her attitude towards life, her microbiome, her sexuality, and she was successful in her first IVF attempt in a natural cycle. She could not believe that she was pregnant.
Yes, of course, and what happens with dehydration and the lack of water in the body? Apparently, for survival issues, the reproductive system is not the one that keeps us in conditions of survival. That is the one that our organism does not care about, so that comes from a long, long time ago. The water is taken from our reproductive system, and when we are dehydrated, and we don’t cover the 8 to 10 glasses of water per day needed for homeostasis of our body, you have a less optimal environment. Dehydration also affects hormonal balance in the body because water is very important for hormonal homeostasis. If you do not have enough water in your system, you have hormonal imbalances as well. You don’t need hormonal imbalances when you’re thinking about endometrial function and implantation. So, the answer is yes, and not directly but there are at least 3 different proves that lack of water can alter endometrial function. I prefer tap water compared to plastic bottled water. If you can have a good filter that takes some of the bad bacteria in the water off, but I would not worry so much about that, to be honest.
I wouldn’t put so much stress in the body right now. Detox is not always something easy for the body because it’s a new situation. My advice is that from now on, it’s not about detoxing, it’s about starting a healthy diet. There’s only one good fertility diet, and that diet is the Mediterranean diet that has lots of fruits and vegetables. Some years ago there was a great study done that showed that women that ate more fruits were getting pregnant quicker, it’s probably because of the antioxidants, it worked even better than eating vegetables, another good nutrition. They have a very good impact on fertility, so I wouldn’t do detox now, but I would start having a healthy diet to support everything.
IBS is one of the microbiome diseases, I would suggest to get in touch and be in close contact not only with your reproductive specialists but also with your doctor that is looking after your IBS problems. I believe that you should make some changes and increase the health of your gut and include all these four stages that I recommended probiotics, stress management, good nutrition, and exercise. I definitely believe that you should start those changes and control your IBS in the best way that you can increase the homeostasis in your microbiome.
This is not a question with an easy answer. Every time that you go so deep, you need to have the whole medical history of the couple. IBD has high levels of inflammation, and this, in general, is not good for the body and especially for fertility. High levels of inflammation have a big impact on fertility. What I do with my patients before any IVF cycle, I have a hematologist that we work closely together. I strongly believe that everything should be consulted with an expert in their field. I mean, I don’t want to do things that a hematologist or a reproductive immunologist does. In our team, we have a doctor who assesses problems like IBD or Celiac disease, or other immune problems before any IVF cycle, and we have a very specific protocol for that patient. In regards to immune testing, I would probably recommend performing them but not any immune testing, it doesn’t mean that because you have this, you should have a practitioner that can define and personalize what kind of immune testing you may need. Hysteroscopy and IBD, I don’t know if there is any connection. Generally, as a rule of thumb, and especially if you’re doing donor eggs and if they’re PGD tested by doing hysteroscopy, you will also assess where the embryo is going to be transferred. That would also be advisable, but probably your doctor would be more appropriate to answer this. In our practice, and my husband who’s a medical doctor, he’s an obstetrician-gynecologist specialized in reproductive medicine, we recommend hysteroscopy.
There are four stages, this is the basic thing that we should all do. I’m about to receive accreditation as a microbiome expert. I had to go back to the university because microbiome infertility is the next revelation in the field of fertility. When I started studying the microbiome, the first thing that I did was to get worried about where am I having all this sugar from, so I could never believe how bad sugar is for the microbiome. The first thing to do if you want to start tomorrow just cut sugar. I don’t want you to cut sugar completely, even when I’m doing fertility coaching with my patients, I don’t like radical measures that say don’t do this, don’t do that, don’t eat sugar anymore. I prefer to work with tools. If you like to have some organic dark chocolate that is full of tryptophan and magnesium and it’s good for the endometrium and your mental health – you can have it.
Let’s say every afternoon right along with some almonds or walnuts. You can also have some honey with your tea. I want to put you in the mindset that everything that makes you happier and brings your stress down, you should do it, so you can improve your microbiome by taking little steps every day. One day you reduce the sugar a bit, you go out for walking even 10 minutes of walking every day has proven signs that can improve the microbiome. Then you try to improve your sleeping patterns, then try to put more prebiotic fiber in your nutrition protocol, then start having a yogurt every single day, little steps every day, and you’re there, you can do it, I’m sure you can, all of you can.
As I’ve mentioned, you don’t need to cut it down completely. You should cut down Coke, you should cut down unwanted sweets, you can replace bad sweets with good sweets. When you want something sweet, the brain can only understand that you gave it something sweet, it cannot understand if you’re giving it chocolate or a very unhealthy sweet, the only thing that is recognized as something that sweet. So, gradually you can have something sweet, but it can be really healthy like yogurt with live bacteria inside, with live culture bacteria inside, and you can add some very good honey that has anti-inflammatory capacities, and there you have it. You can have some chocolate when you feel you want some comfort food, but this chocolate needs to be of good quality with more than 78% cocoa beans inside and as little sugar as possible. So no, I don’t believe you should cut it completely unless there is a medical reason for you to do it.
It’s not only how long it will take to improve the endometrial microbiome, it also has to do with what you can also improve. Let’s say that your endometrial microbiome is not so disturbed, but at the same time, you need to improve the quality of your eggs. What we need to understand is that egg quality, bad egg quality, good egg quality, it’s not an independent factor. Sometimes, I have patients who didn’t succeed, and they say that they had multiple failures because they had very bad egg quality, but at the same time, you’ll see that the sperm was not good as well, and then you see that the nutrition is bad, the patient is not sleeping properly, the working conditions are very, very stressful, etc. Why don’t we take that person as a whole and address every single problem instead of just saying okay, how do you improve egg quality? Even if you’re using donor eggs, if the general health of the recipient is not good, you may fail again, even if egg donor cycles may go up from 75 to 85% success rates, so everything has to do with good preparation. Invest in the 3 months before going for the transfer.
I don’t have enough data to support that, and I’m looking forward to new data coming probably in the next 1 or 2 years. I cannot recommend something that I do not have enough scientific data to support. Generally speaking, as a rule of thumb just before a transfer, the best thing I do recommend is normal body function, nothing really extra. You’re doing a transfer, you are already stressed, what you need to do is eat properly, sleep properly and cuddle, find a supporting environment, do not add things that don’t have scientific evidence that can support that they can improve success rates before transfer because then you do not know what is working, what has gone wrong and what you can do better next time. Reproductive science many times is much simpler than we think. I insist on focusing on the basic ones.
Sometimes, I have patients that do yoga because they believe that yoga and meditation help them with stress management because another friend may have done yoga or meditation for stress management, but it’s not working for them. I ask them why aren’t you changing, what you’re doing to relieve your stress, you cannot live your life with all that stress every day, and especially now with COVID-19, we need to address every single problem especially, if it has to do with an anxiety disorder. I do believe that every single patient that accepts the fact that they have an anxiety disorder, already have done the first step towards a better situation, so they really need to be supported by their doctor. If you’re not happy with what you’re getting, just ask for a second or third opinion. I don’t believe in too many opinions, but in that case, if you believe that you have not found the solution to your problem, just simply try to find the solution to your problem.
In our practice, but there are more complex ways to check the microbiome. We’re taking two things I’m doing a vaginal culture test, we take a specimen from the vagina all around and also the cervix deep inside, and we check for dysbiosis. It’s a very comprehensive test, I collaborate with the pathophysiologist and a gastroenterologist who is also assessing my patients if they have all these symptoms that I mentioned before like the bloating and the diarrheas and constipation and the fatigue, etc. I rely on his expertise to see if we need extra testing to see if the gastrointestinal tract is healthy or not. I have those two doctors that I collaborate with to check both the reproductive microbiome and the gut intestinal microbiome, and when I get my answers and when everything is clear, and it is either dysbiosis, or there is an inflammation of the gut, then we apply all the evidence-based protocols to improve the microbiome with probiotics and differentiation in the nutrition. These four steps that I’ve already mentioned above.
First, it’s not about disappointment because every single menstrual cycle has its own characteristics and its own hormonal profile. One thing that we do know is that it doesn’t matter how many eggs you may have because we do know that if you have 15 to 18 good eggs, one of those would be a successful pregnancy. These are the statistics that we have up to now, every 15-18 or every 25 egg can be the one that will support a pregnancy successfully. I wouldn’t be disappointed, it all has to do with the whole situation. I don’t know why you have so many eggs not used, and it’s not that the long protocol will as successful as this previous one next time. The reality is that if you can’t be sure that if you use the long protocol, you will get eggs. I prefer as well as my husband the long protocol over the short protocol, it goes more smoothly with the ovarian cycle, but you cannot be sure that if you are over the age of 40-41 that the long protocol will be successful. If you came to me, I do believe that I would also go for the short protocol. If this fails, it has to do with what your doctor knows, your medical history, and how your hormones are in the last cycles. If you’re ovulating properly, and if your FSH is right, I would do it, but it would be riskier compared to the short protocol. I do not believe that changing clinics after 1 failed IVF is a good thing because it adds extra frustration as well. I believe that you need to build trust with the doctor that is looking after you.
There are some cheese out there like Roquefort and that can help your microbiome, and there’s this greek cheese called Katiki, and I am sure that if you google it, you’ll find cheese that has live cultures inside. If there are no other contraindications, I don’t think that you should completely stop eating cheese. But keep in mind that cheese has a very high-fat content, and sometimes you do not want to have other hormones coming from animal fat that can probably disturb the estradiol balance in a woman’s body. If you just eat everything in moderation, it will not do any harm.
Microbiome and menopause have a very big connection. Menopause and perimenopause cause a drop in estradiol levels and all these imbalances in the hormones. The microbiome is directly affected by it. This is one of the first things you should look after when you are going through this phase in your life, but I want you to understand that it’s not only if you have this and probably a little bit expensive test to check your microbiome, don’t worry so much about testing. As I told you, there are also more medical ways to test the microbiome through endometrial biopsies and specialized cultures and PCR and Next Generation Sequencing (NGS) for the genome of the microbes. Biotechnology and new sciences are growing so fast that we have at least 6-10 different ways to check dysbiosis and the microbiome either in the endometrium, vagina, stomach, and guts. I want you to understand that besides testing, start implementing parameters that will improve the microbiome anyhow. Start doing things to improve it anyway, especially if you are in perimenopause or going through menopause already. Menopausal hormonal abnormalities affect the microbiome. There is a new science that has to do with menopause and the microbiome in the oral cavity. This is how much menopause and the alterations in the hormonal balances affect the microbiome. If you’re going through this phase, start implementing procedures that will improve your microbiome even if you do not check it.
We should always eat healthily with a little bit of unhealthy. You have to understand that you’re not eating healthy because you’re having an embryo transfer, it doesn’t matter if it’s frozen or it’s a fresh cycle. You should eat healthy because you deserve to eat healthily, you deserve the best and be in your best position possible. Fertility diet although, we say the word diet, it’s not a diet, it’s nutrition, so you cannot have a break from good nutrition, you can have a break from a diet. If you are on a very strict diet, then yes, but if you’re eating properly, and if you’re having great nutrition, you just do not need to break it because you’re already doing it. While you are having good nutritional habits, it is okay, if you want to have something sweet or even a glass of wine from time to time. I hate alcohol consumption during IVF procedures because it destroys the microbiome, provokes hormonal imbalances, it has high toxicity. Generally speaking, pregnancy and alcohol is a no, trying to conceive and alcohol again is a no, even though you will have one glass of wine, that would not be the reason for not having a successful frozen embryo transfer. If you’re having an embryo transfer, and you eat pizza every day and drinking fizzy drinks – don’t do that, just eat properly, basic things like fruits, vegetables and drink water.