The new parameter you should definitely check after multiple IVF failures

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.

Why IVF fails?

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.

Microbiome – research

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.

Dysbiosis – definition

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.

The impact of diet and lifestyle on gut microbiota

What disturbs the microbiome and leads to dysbiosis?

• junk food
• consumption of too much sugar
• drinking alcohol
• stress
• the use of antibiotics
• the use of painkillers
• hormones

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.

Common symptoms of dysbiosis

• a bad breath
• an upset stomach
• nausea
• constipation
• diarrhoea
• difficulty urinating
• vaginal or rectal itching
• bloating
• chest pain
• rush or redness
• fatigue
• having trouble thinking or concentrating
• anxiety
• depression

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.

Ways to improve the microbiome

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.

Case study – a success story

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.