Implantation after IVF – problems and solutions

Dr Robert Najdecki, the scientific director at Assisting Nature centre in Thessaloniki paid us a visit in order to speak about implantation problems. As some of you may already know, despite all the advances in reproductive medicine and all the progress made in the past few decades, the process of embryo implantation still remains the least understood part of pregnancy.

While the method by which embryos implant themselves within the uterus is understood on a basic level, the exact specifics are yet to be properly mapped out by fertility specialists. In order to help us understand how implantation actually works, Dr Najdecki chose to share a couple of patient stories with all of us. Before that, however, we need to understand what implantation failure actually is.

Implantation failure

The term “implantation failure” is used to describe patients who have never shown increased hCG levels, as well as those in whom ultrasound evidence of a gestational sac was not found. It can apply to both patients undergoing assisted reproduction treatments as well as those who are trying to conceive naturally. There’s also the big bogeyman – repeated implantation failure. This term is used to describe patients in whom embryos don’t implant despite repeated attempts using assisted reproductive technology.

There are many factors which influence the implantation process. The environment inside the uterine cavity is a major one – from the thickness of the endometrial lining to its bacterial flora, the uterus must be ready to accept the embryo. Implantation relies on the successful cross-talk between the embryo and the uterus, with facilitation by many different factors, such as growth factors, cytokines, cell adhesion molecules, and transcription factors.

Large congenital abnormalities within the uterus – polyps, fibroids, and others – are well known to have a negative effect on embryo implantation. Smaller anatomical variations, however, are less understood and the degree to which they influence reproductive function isn’t fully known; however, they should not be underestimated.

Changes in endometrial receptivity may also contribute to repeated implantation failure. One of these changes may be the shift in optimal implantation timing. The Endometrial Receptivity Array test, also known as ERA, is used to determine how the optimal implantation window changes, based on 238 genetic markers.

The embryos themselves are an important piece of the puzzle. Their quality and health have a major impact on their odds; basically, the healthier they are, the better. Aneuploid embryos – those displaying chromosomal anomalies – aren’t well known for their implantation success. Even if they do, they carry additional risks to themselves and the mother which makes them a non-option.

Fortunately, PGT-A testing (previously known as PGS) allows embryologists to only choose those embryos which are genetically healthy, or euploid. In fact, modern embryology allows a staggering level of insight into embryo health, which has led to increased success rates.

Natural Killer cells derive their name from their ability to destroy leukemic cell lines. Many studies reveal that patients suffering from recurrent implantation failure have elevated levels of NK cells in both the uterus and the peripheral blood. These, as well as other autoimmune bodies are involved in biochemical pregnancy loss. Additionally, hereditary thrombophilias may be involved in unexplained pregnancy loss. Immunosuppressants and antithrombotic agents are used to manage these issues.

While other factors also have an impact on implantation, the embryo quality, uterine health, and autoimmune issues influence the process the most.

Real patient IVF story:

– 36 year old woman,  conceived naturally twice; both of those pregnancies ended with a miscarriage

Now, lets discuss patient stories. The first case Dr Najdecki brought up concerned a 36 year old woman, recently married. She managed to conceive naturally twice; both of those pregnancies, however, ended with a miscarriage. She decided to try IVF. Two blastocyst stage embryos were transferred, however the patient did not end up pregnant. So, Dr Najdecki had a puzzle on his hands.

The first order of business was testing – a hysterosalpingography and uterine ultrasound revealed nothing out of the ordinary. Clearly, deeper investigation was required. It was a hysteroscopy that revealed the true reason for implantation failure – a partially septate uterus. It’s one of the more common deformations of the uterus, occurring during fetal development – before birth. Some women can go their entire lives without knowing they’re affected, and that’s what happened to our patient.

Septate uteruses are called that because of a membrane of skin – the deformity – divides the uterus in half. This membrane is called the septum. Treatment, fortunately, is very simple – a minimally invasive surgery to cut away the membrane. This is what our patient went through; a hysteroscopic septum excision. Additionally, Dr Najdecki recommended endometrial scratching; essentially, creating a small, controlled wound in the endometrial lining. This causes the uterus to grow its lining even thicker to compensate, which in turn leads to a higher chance of a successful implantation.

Following all of that, the patient and her medical staff decided on performing another embryo transfer during the next cycle. Two blastocyst embryos were transferred, and, wouldn’t you know it – a successful pregnancy occurred. Our story ends with the birth of two healthy children.

– healthy 45 year old woman, very low ovarian reserve, AMH measured less than 0,1ng/ml

The second patient was a healthy 45 year old woman with a very low ovarian reserve – her AMH measured less than 0,1ng/ml. Before seeking Dr Najdecki’s help, she underwent an embryo transfer at another facility with a negative result. Once she was under Assisting Nature’s help, it was decided to place her in an exclusive egg donation program with additional PGT.

Her husband’s sperm was severely oligoasthenozoospermic – which basically means his semen had very low motility and sperm count. Twelve total eggs were used, eleven were successfully fertilised. Only six embryos managed to reach the blastocyst stage. PGT diagnostics revealed that out of those six, only two embryos were genetically healthy.

Eggs are tricky – not all of them are made the same. Some oocytes are of higher quality than others; in turn, that means not all eggs become embryos. This depends on the donor’s age and health, the stimulation protocol used and other factors.

The term blastulation rate is used by embryology laboratories to express the percentage of oocytes that reach the blastocyst stage. Assisting Nature boasts a blastulation rate of over 50%, which means for every six oocytes they fertilise, at least three will reach the blastocyst stage.

Sperm, however, is not the same; over the years, the average sperm morphology in the male population has been on the decline. Environmental, lifestyle and health factors are to blame. Emotional stress, smoking, excessive alcohol consumption, exposure to environmental toxins – these factors and more cause sperm quality to drop dramatically.

Obviously, sperm quality affects embryo quality. Low-quality sperm often results in aneuploid embryos being generated. As we already mentioned, embryos with chromosomal abnormalities are less likely to implant. By simply choosing euploid embryos, the pregnancy rate per embryo transfer rises to a level above 60%.

Out of the two euploid blastocysts that were generated, one was transferred with a positive result – the patient was pregnant and gave birth to a healthy baby boy. The second embryo was frozen for further use.

– 43 year old woman undergoing an egg donation programme, one transfer of two euploid blastocysts failed to take hold

Sometimes, however, just choosing the right embryo is not enough. Patient number three was a 43 year old woman with a regular cycle undergoing an egg donation programme at Assisting Nature. One transfer of two euploid blastocysts failed to take hold.

Further investigation was required. A diagnostic hysterescopy was performed, although it didn’t reveal any anatomic abnormalities. An endometrial scratch was performed and a second transfer attempt was scheduled.

The combination of choosing an euploid blastocyst and increasing endometrial receptivity through an endometrial scratch – 10 days after a double blastocyst transfer, the patient had a positive blood pregnancy test. She eventually gave birth to a healthy baby.

Dr Najdecki sums up his presentation by concluding that recurrent implantation failure is a complex problem with a wide variety of causes and mechanisms. Fortunately, the variety of available treatment options is just as wide. As each patient’s needs and medical situation is different, personalised medicine is the best approach to dealing with their implantation issues. In general, however, adding PGT and endometrial scratching to the egg donation cycle, along with post-implantation treatment using immunosuppressants and antithrombotic agents as needed does a lot of work toward increasing the chances of a successful implantation.