Introduction
We all know that in life we can rarely have everything at once: education, career, partner and children. Every step needs time and energy and we of course want to do it properly.
Equally, a successful and efficient IVF process requires the same approach.
We seldom have patients coming to us for their first IVF or IUI cycle. Our patients come to us after multiple IVF failures and miscarriages and these patients usually have more than one reason why their pregnancies did not happen or are sadly lost.
To be able to solve each reason for an IVF failure or miscarriages within our IVF process we take it one step at a time.
Reasons for IVF failure and pregnancy loss
The reasons for IVF failure and pregnancy loss can be divided into two groups: embryonic and maternal.
Embryonic reason for IVF failure and pregnancy loss means there is some reason inside the embryo. Due to these internal reasons the embryo is not viable and cannot develop, even in the best maternal conditions.
Maternal reasons of IVF failure and pregnancy loss includes reasons within the female organism and can be explained by hormonal, immune or uterine factors.
Embryonic reasons for pregnancy loss and IVF failure
Embryonic reasons for pregnancy loss and IVF failure are the most powerful and at least 75% responsible for the outcome of the fertility treatment and pregnancy.
1. Genetic situation in human embryos
- Human embryos in women after the age of 35 often have an abnormal amount of chromosomes [Fragouli et al., 2012]
- An abnormal number of chromosomes in the embryo almost always leads to a pregnancy loss at the pre-implantation stage (implantation failure) or at the post-implantation stage (miscarriage) [Scott at al., 2012]
- An abnormal number of chromosomes are almost always exclusively from the egg.
- The older the eggs are the more likely It Is that the embryo will have chromosome abnormalities.
- The influence of chromosome abnormalities on the embryo’s morphology in pre-implantation stage (till day 5 incl.) is insignificant [Alfarawati et al., 2011]
What proportion of embryos at blastocyst stage are expected to have a normal number of chromosomes?
- Every second blastocyst is expected to have a normal number of chromosomes in the age group 35-37;
- Only one in 8 blastocysts is expected to have a normal number of chromosomes by the age of 43.
Proportion of blastocysts with a normal number of chromosomes in women of different age groups:
| 35-37 years | 38-40 years | 41-42 years | 43-44 years |
| 46% | 33% | 19% | 13% |
[S. Munne et al. Blastocysts needed to transfer at least one euploid embryo: data from 10,852 pre-implantation genetic screening (PGS) cycles. Fertility Sterility September 2015 Volume 104, Issue 3, Supplement, Pages e13–e14]
Is there any way to identify which of the ‘good-looking’ blastocysts have a normal number of chromosomes and which have an abnormal amount?
— Yes! This is called genetic testing of embryos; PGT-A (PGS)
2. PGT-A — Genetic testing of human embryos
What is PGT-A?
PGT-A — Preimplantation Genetic Testing for Aneuploidies (Aneuploidy – an abnormal number of chromosomes). This genetic testing of embryos locates the normal embryos, from those available. By excluding abnormal embryos from future use the live birth rates are increased per embryo transferred.
What is the purpose of PGT-A?
PGT-A does not make embryos better. PGT-A selects embryos with a normal number of chromosomes from those available.
What does PGT-A do?
PGTA-A tests the number of chromosomes in DNA taken from embryos. Embryos with an abnormal number of chromosomes will not lead to a healthy live birth, hence they are excluded from use. Embryos with a normal number of chromosomes are used for the embryo transfer.
What are the goals of PGT-A?
- To increase pregnancy rates
- To reduce miscarriage rates
- To increase live birth rates per embryo transfer
- To shorten the time to pregnancy (reduce amount of embryo transfers before pregnancy)
What are the numbers?
STAR1 Trial Compared with SART(National Summary report USA 2014 - 2017) Pregnancy outcomes
STAR — 20-week ongoing pregnancy rate per transfer, note that all 20-week ongoing pregnancies resulted in a live birth
SART — Live birth rate per SET transfer
Would you benefit from using PGT-A?
Women aged 35 and older have a significant increase in live birth rates per each embryo transferred after PGT-A, in comparison to control (no PGS).
What is the process for PGT-A?
- A small piece of the embryonic external layer (future placenta) is taken by a pipette;
- Each blastocyst is frozen,
by vitrification, after the biopsy; - From the sample taken the DNA is extracted,
multiplied and tested for 23 pairs of chromosomes; - Embryos with an abnormal number of chromosomes
are excluded from future use; - Embryos with a normal number of chromosomes
can be used for embryo transfer.
Have questions?
Maternal reasons for pregnancy loss and IVF failure
Maternal reasons for pregnancy loss and IVF failure can be hormonal, immune reasons or conditions inside the uterus. Often, we deal with a combination of these reasons in our patients.
1. Missing the implantation window — the main reason of implantation failure in fresh IVF cycles
The process of embryo “sticking”, attaching in the uterus, is called implantation. Implantation starts with recognition of certain receptors on the surface of the endometrium by receptors on the surface of the hatched embryo.
The implantation window is the time frame in which these receptors are present in the endometrium, which is usually 5-7 days after the beginning of Progesterone production by the ovulated follicle.
Normally, in a natural cycle, Progesterone production starts from the day of ovulation. Embryos are then essentially ready to start implantation on day 5-7 of their development.
Nature has synchronized these two processes of embryonic and endometrial readiness for implantation very cleverly:
- The Embryo is ready to implant 5-7 days after ovulation.
- The Endometrium is ready for implantation 5-7 days after ovulation
The Embryo is ready to implant 5-7 days after ovulation
The Endometrium is ready for implantation 5-7 days after ovulation
Synchronized process in the ovaries and uterus in a natural menstrual cycle
FSH stimulates follicular growth from day 4 to 14
A follicle with an egg inside grows and produces Estrogen
Estrogen grows the lining in the uterus
Ovulation releases an egg and times the implantation window
Progesterone production starts immediately after ovulation
Progesterone is responsible for making the endometrium receptive to the embryo
The Endometrium becomes receptive to the embryo 5-7 days after progesterone production begins (implantation window)
However, ovarian stimulation may desynchronize these 2 processes: the readiness for implantation of the embryo and the endometrium. This happens due to supra-physiological levels of hormones in the body. In many stimulated cycles progesterone production starts too early - already several days before egg retrieval (which is the equivalent of ovulation).
Should progesterone productions start earlier than the day of embryo creation (egg retrieval or ovulation day), the receptors in the endometrium, which could have recognized the embryo, would be present earlier. When the embryo reaches the blastocyst hatching stage, the receptors in the endometrium will no longer be there and this dialogue between the embryo and the endometrium will not be possible. Implantation will not take place!
Desynchronization of the embryo’s and endometrium’s readiness for implantation is one of the most frequent reasons for implantation failure in fresh IVF cycles
2. Restoring the dialogue between the embryo and the uterus by taking it one step at a time in your IVF process
This absence of dialogue between the embryo and the endometrium can be avoided by carrying out one task at a time.
The first step is to create competent eggs and viable embryos by using an individually tailored stimulation process. During this stimulation, we must focus only on the follicles, eggs and embryos. It is not possible to take care of the endometrium just yet.
When the blastocysts are ready, we stop time for them by freezing them gently. When we have stopped time for the embryos, we can then move our focus to the optimal preparation of the uterus ready for the embryo transfer.
For the embryo transfer we will choose a separate cycle in which we will focus on endometrium: to transfer an embryo into the most optimal endometrium at the most optimal time. Usually, 1 menstrual cycle is necessary after the stimulated cycle for ovaries to stop producing residual amounts of progesterone. Therefore, we recommend a one cycle break between the egg retrieval and embryo transfer.
Other maternal reasons such as hormonal, immune and uterine Issues and how we can optimise them, we will discuss below in our step-by-step IVF process.
Have questions?
Your IVF Journey: One Step at a Time
We rarely have patients that have just one reason for their pregnancy loss and/or IVF failures.
To be able to address each reason for previous failures, or losses, we carry out our IVF process carefully, step by step. In each these steps, we focus on solving one or more of these reasons.
Each step of your IVF journey will have its own focus and goal:
| Steps in your IVF process | Goal | Focus |
| Cycle 1: Your Stimulation Cycle | Viable Embryo at Blastocyst stage; normal for 23 chromosome pairs |
|
| Cycle 2: The Training Cycle | Receptive Endometrium |
|
| Cycle 3: The Embryo Transfer Cycle | Implantation |
|
| Your treatment after the Embryo Transfer until Live Birth | Baby |
|
Cycle 1
Your Stimulation Cycle
The Goal: to have a viable embryo at blastocyst stage, normal for 23 chromosome pairs
We are often asked, if it is thanks to PGT-A (PGS) for improving egg and embryo quality, that we are known for?
No, PGT-A is only a method of embryo testing. It helps to eliminate good looking, but abnormal blastocysts from use. It does not make your embryos better – it locates those embryos with a normal number of chromosomes from those that are available.
To be able to test good looking embryos at blastocyst stage, we first need to create them. This may be challenging, especially in patients, who have not had any blastocysts in previous attempts. We respect these challenges and know how to deal with them.
How to achieve viable blastocysts, even if past attempts have resulted in no blastocysts at all?
Step 1. Your Individualized stimulation
The Goal: competent eggs with sufficient levels of energy
Two women of the same age and the same AMH levels may benefit from different stimulation schemes. We gain knowledge and a good feeling based on your medical history, test results and information about your previous IVF attempts. When you thoroughly Inform us of the information about your past IVF attempts, you create the basis for us to find the most successful stimulation path for you.
During two weeks from the beginning of the cycle till ovulation (or egg retrieval) eggs need to multiply their energy resources hundreds of times. It is clear enough that energy is needed to create a viable embryo. A sperm does bring half of a genome, but only the egg possesses the power stations for the production of the embryo. They are called mitochondria, if a cell was a city, mitochondria would be this city’s power plants.
Individualized, balanced and the appropriate length of stimulation helps eggs collect enough energy for fertilization and embryonic development.
We also recommend vitamins and supplements aimed at increasing egg energy levels.
Step 2. A Gentle, quick and painless egg retrieval
The Goal: one follicle — one mature egg
We take great care in making the egg retrieval gentle, quick and painless, this ensures that the egg retrieval day will be a good day for all our patients.
During egg retrieval, we focus on every single follicle and every single egg. If our patient would like to proceed towards egg retrieval having even just one single follicle, we will go for it and do our very best.
Step 3. First class process in our EmbryoLab
The Goal: Blastocysts, Normal for 23 Chromosome Pairs
- Elegant and soft IVF and ICSI procedures
- Careful and reliable blastocyst growing
- PGT-A (genetic testing of embryos to find the normal ones from those available)
Little embryos are like children or flowers: they need to be talked to in a nice way and handled with love and care. Our embryologists feel like they look after flowers or work in a kindergarten, rather than growing embryos :)
Svetlana Shlykova, the leading embryologist at O.L.G.A. Clinic is in love with flowers and her grandchildren. The Embryos in her lab also gain all this special love she has to give.
Step 4. Gentle freezing of your blastocysts by vitrification (FREEZE ALL)
The Goal: to stop time for the embryos and use this time for optimizing your maternal side before embryo transfer
- Why don’t we transfer fresh embryos? — Because endometrial receptivity in stimulated cycles is lower than in natural cycles, or cycles on HRT.
- Why do we freeze all embryos? — We freeze all embryos to stop time for them for a while so that we gain 1-2 months to focus on your endometrium and other maternal factors.
- Why not try with a fresh embryo right away and then try with a frozen embryo later, if fresh transfer didn’t work? – Because many patients will have just the one usable embryo and we must create VIP conditions for its transfer to achieve maximal result.
- Why are we not afraid “to risk the embryo by freezing It”? — Because we have above 95% survival rates after freezing/thawing via vitrification.
Cycle 2
Your Training Cycle
The Goal: to prepare receptive endometrium
Cycle Nr2 is the cycle after your egg retrieval and before your embryo transfer cycle
A. Training cycle using Estrogen and Progesterone
Treatment in a pre-cycle usually consists of natural or synthetic estradiol and progesterone hormones; to imitate the phases of the normal menstrual cycle. We call this pre-cycle a training cycle, because this helps us evaluate your endometrial response to certain hormonal dosages in advance and choose the right hormonal dosage specifically for you in your embryo transfer cycle. Also, hormonal therapy with estradiol and progesterone helps to restore endometrial receptivity, even in those patients who have had impaired endometrial receptivity previously.
During this training cycle hysteroscopy and other treatments such as antibiotics, antiviral medicines, growth factors and immune therapy can be done if there is an indication, all of this Is done to create the best possible basis for the next cycle – Cycle Nr3, Your Embryo Transfer cycle.
Preparing for your Embryo Transfer will include CycleNr2 and CycleNr3. The goal of the medication used for your embryo transfer is to make sure your endometrium is ready for implantation, in the best way and at the right time.
B. Hysteroscopy followed by medication
After we have had an opportunity of viewing your endometrium at different stages before and during stimulation and at the egg retrieval, we will come back to you with information as to whether we see any sonographic signs of polyps, adhesions or other structures in endometrium, which may reduce the chances of implantation. If we see those potential reasons for IVF failure, we will recommend a Hysteroscopy.
A Hysteroscopy is an endoscopic investigation of uterine cavity – looking at the uterus from inside!
‘Hysteroscopy’ comes from the Greek meaning: “Hyster” =“Uterus” and “Scopy” = “Looking”.
If a hysteroscopy is required, we will use your Cycle Nr2 to carry out the procedure so that there is no time wasted.
Hysteroscopy provides us with the opportunity to look inside your uterus via a natural pathway, with the help of a video camera. During hysteroscopy, any abnormal findings can be treated micro-surgically and chances for implantation are improved.
In our clinic, we do full surgical hysteroscopy under general anesthesia; which means we have the opportunity to infuse liquid in the uterus to straighten all the little corners of uterine cavity so as to see all the hidden details which may not be seen by quick office based hysteroscopy.
Having straightened the uterine cavity with full overview and whilst the patient Is not suffering from any pain, we have the opportunity to see and correct all the abnormal findings: big polyps and micro-polyps, scar tissue and carry out endometrial scratching. Scratching is like peeling for the uterine skin; it makes it fresher, smoother, with better blood flow and more attractive for the embryo, in all different kinds of ways.
Scratching, which is a nice “peeling for the uterus” — can be done to improve blood flow and facilitate implantation.
Depending on the findings and micro-surgical treatment during hysteroscopy, we will recommend specific treatment: growth factors after having removed scar tissue and for thin atrophic endometrium, antibiotics and antiviral medicines for chronic inflammation and/or immune therapy; including intralipids in cases where autoimmune is suspected.
In some cases, such as with endometriosis, we may recommend longer treatments after hysteroscopy to suppress the endometriosis and its negative influence on implantation.
All the medication which need to be taken after hysteroscopy and up until the embryo transfer, can be bought in our neighbouring pharmacy, if necessary.
After hysteroscopy, removal of polyps or scar tissue, scratching, hormonal, immune and blood thinning therapy, it will be much easier for an embryo to attach.
Hysteroscopy findings can explain why it may be so hard for embryos to attach and grow
Luxurious environment for your VIP embryo after hysteroscopy and treatment
C. ERA test
During hysteroscopy, we can also do an ERA test. ERA is an abbreviation for “Endometrial Receptivity Array”. The aim of the ERA test is to confirm on which day, after the beginning of progesterone supplementation, the endometrium is most receptive to the embryo. ERA test checks endometrium for readiness for implantation based on checking for genetic expression profiles in the endometrium during the implantation window.
In the majority of women, the implantation window lasts around 60 hours and takes place around day 6 of progesterone supplementation. However, in 20-30% of women the implantation window may be earlier or later than that and we wish to investigate this in patients who come to us after multiple unsuccessful attempts.
D. Down-Regulation
If the hysteroscopy has not found a reason for postponing your embryo transfer later than the Cycle Nr3, a “down-regulating” hormone is given at the end of the Cycle Nr2. The aim of this down regulation injection is to avoid premature ovulation. Premature ovulation may make the timing of your implantation window different from the one chosen for your embryo transfer.
The duration of down regulation treatment, without estrogen coverage in the hormonal scheme aimed at embryo transfer, does not exceed 7 days, so the undesired symptoms are highly unlikely to appear in such a short period of time.
Cycle 3
Your Embryo Transfer Cycle
The Goal: to achieve successful implantation
A. Medication to grow a receptive endometrium
After you have stopped estradiol and progesterone in your previous cycle (“Cycle Nr2 = The Training Cycle”), menstruation begins, and this is the beginning of your Cycle Nr 3.
Your endometrium preparation continues with estrogens to help your lining gain the optimal thickness ready for the embryo transfer. You will monitor the growth of your lining with the help of ultrasound, at your local doctor, to see how thick it is and if any additional estrogen doses are required.
The doses of estrogen that we prescribe for embryo transfer are much lower than estrogen levels in pregnancy which are created by the placenta.
We also use growth factors to boost the endometrium in patients who have had difficulties to grow it previously, low molecular heparins to improve the blood flow in the uterus before, during and after the embryo transfer, intralipids and IVIGs to influence immunity of the potential mother to the embryo in certain patient groups. After having thoroughly studied your medical history we add the necessary medication to your treatment plan on an individual basis.
B. Progesterone
Six days before the planned date of your embryo transfer you will start with progesterone. If your ERA test has shown your implantation window to be earlier or later than that, we will adjust the beginning of progesterone accordingly.
This time you will need to take two forms of progesterone at once: vaginal pessaries/vaginal cream + injections. Why both? - This combination is the best way to reduce the incidence of break through bleeding, early miscarriage and increase the chances of your pregnancy progressing.
However, we know that just creating your pregnancy is not yet the final result. The final result is your Baby!
C. The Embryo Transfer Itself
Our standard practice is a Single Elective Embryo transfer.
Live birth rates, per single embryo transfer after PGT-A, at our clinic are 50%. This means 50% of transfers of a single embryo normal for 23 Chromosomes in our clinic, result in live birth.
The transfer of two embryos will not increase pregnancy rates considerably but will significantly increase the life/ health risks for the mother and the children if a twin pregnancy occurs.
That is why we stick to the concept of preserving our high success rates, not through Increasing the number of transferred embryos, but through clinical strategy and laboratory excellence.
Your Embryo transfer day is a very important day for every patient. All the recommendations about medication and further process are done by our doctors and nurses the day before so that on your embryo transfer day you are feeling confident and comfortable that all the steps following the embryo transfer are secured. We prepare for your embryo transfer to be a soft, gentle procedure and a happy experience.
Have questions?
Treatment after your Embryo Transfer until Live Birth
The Goal: A Baby
Once your embryo has been transferred into your uterus you will continue to take Estradiol and Progesterone for 10 days before taking a pregnancy test (this will be a blood test). Should the test result be positive, you will carry out an ultrasound scan 3 weeks later to confirm your pregnancy.
You will continue with your hormonal medication until 12-13 weeks of pregnancy when the placenta becomes mature and produces enough hormones to support the pregnancy itself. From this stage of pregnancy, you will not usually need more specific support than you would need In a naturally conceived pregnancy and the prognosis of carrying it to the full term, is very good. After most of your hormonal support is discontinued, you will only take progesterone, in a low dose, up to week 32 to keep your cervix long, strong and closed and to reduce the risk of a late miscarriage, or an early birth. In some cases, we recommend continuing with low dosages of Aspirin and low molecular Heparin to improve function of the placenta and reduce risk of late complications in the pregnancy such as preeclampsia.
We will also continue our dialogue with you, up to positive pregnancy test, ultrasound examination and onto livebirth, advising and supporting you throughout this journey.
This is because we know that the pregnancy alone is not the desired result. The result is a baby in your arms.
Please contact us to arrange your telephone consultation with one of our doctors, this will allow them to talk personally with you about your medical history and then advise you on your ideal treatment plan for having a baby.
We hope we can help more women become mothers using their own eggs. So, if you wish to discuss your situation and options with our doctors, please contact us!
Vocabulary
Aneuploidy — an abnormal number of chromosomes. An abnormal number of chromosomes in cells of embryos, makes an embryo’s development stop. It is responsible for 70-80% of pregnancy losses in the first 12 weeks of pregnancy.
Blastocyst — the stage that a human embryo normally reaches on day 5 of development. This is the stage on which the embryo implantation process begins.
Chromosome — is a unit of genetic information in a cell which contains DNA and proteins. Abnormal number of chromosomes in cells of embryos, makes an embryo’s development stop. An abnormal number of chromosomes in embryos, is responsible for 70-80% of pregnancy losses in the first 12 weeks.
Endometrium — the lining covering the uterine cavity.
ERA test — is an abbreviation for “Endometrial Receptivity Array”. The aim of an ERA test is to confirm on which day, after the beginning of progesterone supplementation, the endometrium is receptive to the embryos, and hence implantation will be most probable.
Estradiol — the main female hormone responsible for growing the lining in the uterus. Estradiol is produced by the growing follicle in the ovary.
Follicle — a mature follicle is a 2 cm bubble containing a 0,1mm egg. Follicles are located in the ovary.
Hatching — a process of embryo leaving the eggshell. After hatching, a chicken would be able to simply walk away and take care of itself. A blastocyst takes care of itself in its own way too: its receptors look for receptors in the endometrium to attach to, in order to be able to continue living.
Hysteroscopy — endoscopic check of uterus. “Hyster” = “Uterus” and “Scopy” = “Looking” in Greek. Hysteroscopy is done via the natural pathway. Hysteroscopy enables surgical treatment of problems inside the uterus which may be responsible for IVF failures
Implantation — the process of recognition and connection between receptors on the surface of the embryos and the surface of the endometrium followed by invasion of the embryo into the endometrium.
Implantation window is a time frame under 72 hours when special receptors are present on the surface of endometrium, which can recognize receptors on the surface of embryos to start the implantation process.
Live birth rates — are calculated per embryo transfer. Live birth rates show percentage of embryo transfers which resulted in live birth.
Ovulation — when the egg Is released from the ovary
PGT-A (PGS – historical name) — Preimplantation Genetic Testing for Aneuploidies. This genetic testing of embryos at the blastocyst stage, finds embryos normal for 23 pairs of chromosomes, from those available. By excluding abnormal embryos from use, live birth rates are increased per embryo transferred and time to ongoing pregnancy is shortened. PGT-A is applicable in women of 35 years of age and older.
Progesterone — the main pregnancy hormone. Progesterone production by the ovary begins at ovulation. Progesterone influences the endometrium and times its readiness for implantation — implantation window.
Receptor — is a protein structure on the surface of one cell, which recognizes another receptor on the surface of another cell (like a key and lock). With the help of receptors cells, they can communicate with each other. An example of such dialogue: implantation dialogue between embryonic cells and endometrial cells during the implantation process.
Please contact us for a telephone consultation, this will allow one of our doctors to talk to you about your medical history and personally advise you about your ideal treatment plan for having a baby.
We hope we can help more women become mothers using their own eggs. If you wish to discuss your situation and options with one of our doctors, please contact us now!
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