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.
IVF project is a big project and may become emotionally and medically overwhelming for both, patients, and professionals. As every big project may be split in several smaller projects for efficient process and result, we divide IVF also in several smaller projects with their individual processes aimed at intermediate goals which result in a baby.
We describe our step-by-step approach here, please allow some time and read it step by step to get the full picture.
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.
I. Embryonic reasons for pregnancy loss and IVF failure
Picture 1. 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.
I.1. Genetic situation in human embryos
- Human embryos in women after the age of 35 often have an abnormal number 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.
Diagram 2. Proportion of blastocysts with a normal number of chromosomes in women of different age groups:
[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]
In the data we collected in O.L.G.A. Clinic from 2019 to 2022 these proportions of chromosomally normal blastocysts depending on the age of woman are nearly the same.
Diagram 3. Proportions of chromosomally normal blastocysts depending on the age of woman. O.L.G.A. Clinic PGT-A data from 2019 to 2022.
Is there any way to identify which of the ‘good-looking’ blastocysts have a normal number of chromosomes and which have an abnormal number?
— Yes! This is called genetic testing of embryos; PGT-A (old name — PGS)
I.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?
PGT-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 a baby (reduce number of embryo transfers before baby)
What are the numbers?
Diagram 1. 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). In many cases (repeated pregnancy losses and implantation failures) younger women also benefit from PGT-A.
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?
II. 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.
II.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
II.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?
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 5-6 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, 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 and on individual indications.
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 a specific molecule or 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!
Because of multiple reasons of miscarriages and IVF failures we split IVF process in parts to solve each of them and achieve live birth
By Dr. Olga Zaytseff
The founder of O.L.G.A. Clinic
How to identify challenges, grow competent eggs, create viable embryos and screen them
By Dr. Olga Zaytseff
The founder of O.L.G.A. Clinic
This webinar about optimizing uterus by hysteroscopy, boosting uterine lining by specific medication, precise timing of embryo transfer with the help of ERA test, hormonal and immune treatment
By Dr. Elena Lapina
Head doctor and co-founder of O.L.G.A. Clinic
How to identify and solve them to achieve successful pregnancy and live birth
By Dr. Elena Lapina
Head doctor and co-founder of O.L.G.A. Clinic
Hot and controversial topics explained from the very beginning — basic genetics, indications, embryo biopsy and freezing, challenges, results and new frontiers
By Dr. Anna Gusareva
Embryo Lab Chief at O.L.G.A. Clinic
How embryos are created and grow in the lab? How embryologists make sure that embryos feel at home in the lab? How to choose the best embryo that will result in live birth?
By Dr. Anna Gusareva
Embryo Lab Chief at O.L.G.A. Clinic
How to make decision and process comfortable and friendly for you, and your result — efficient.
By Dr. Olga Zaytseff
The founder of O.L.G.A. Clinic
Valeria shares different aspects of her work and show even examples of excellent egg donor choices based on physical characteristics and non-physical parameters, such as education, personal motivation, occupation...
By Valeria Sergeeva
The leading egg donation expert at O.L.G.A. Clinic
Egg donation… Embryo adoption…
How normal is the whole process? Who are the donors and what I should/can know about them? Where is the border of my influence?
By Valeria Sergeeva
The leading egg donation expert at O.L.G.A. Clinic
We prepared a very special video where egg donors personally tell about themselves, their principles of life, their reasons to donate and the philosophy of this huge project called "Egg Donation" at O.L.G.A Fertility Clinic
By Valeria Sergeeva
The leading egg donation expert at O.L.G.A. Clinic
By Tatiana Varzaeva
Perinatal psychologist at O.L.G.A. Clinic
