WHAT IS THE ‘IMPLANTATION WINDOW’ IN FERTILITY TREATMENT AND HOW TO IMPROVE IT?
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Implantation Failure in IVF – Why does it happen and how to prevent it?

Esther Marbán, MD
Gynecologist & Fertility Specialist , Clinica Tambre

Category:
Embryo Implantation, Failed IVF Cycles

implantation-failure-prevention
From this video you will find out:
  • What is the definition of embryo implantation?
  • What are the main causes of embryo implantation failure?
  • What kind of tests are included in a standard Recurrent Implantation Failure (RIF) evaluation?
  • What options and solutions are offered in cases of Recurrent Implantation Failure (RIF)?

Implantation Failure in IVF – Why does it happen and how to prevent it?

During this session, Dr Esther Marbán, Gynaecologist & Fertility Specialist at Clinica Tambre, discussed the most common causes of implantation failure in IVF treatment, as well as possible solutions and outcomes.

Failure of Implantation: Causes and Definition

Implantation is the process through which the embryo attaches to the endometrium, allowing its continued development. It involves multiple steps and is both fascinating and complex. Successful implantation depends on various factors, such as the quality of gametes (eggs and sperm), embryo quality, the timing and technique of embryo transfer, and effective communication between the embryo and the endometrium. Additionally, proper luteal phase support is crucial to enhance the chances of successful implantation.

Traditionally, failure of implantation was defined as the inability to achieve pregnancy in women under 40 years old after transferring at least four good-quality embryos in fresh and frozen embryo transfer cycles. However, this definition has evolved due to advancements in assisted reproductive technologies. Nowadays, embryos are often screened before the transfer, and we don’t strictly require four previous failures to classify implantation failure. In many cases, if a patient has experienced one or two previous failures, it is considered indicative of implantation failure. In such situations, additional tests are recommended to determine the underlying cause.

What Failure of Implantation is Not

If a patient is 40 years or older and has not had her embryos tested, it is likely that the quality of the embryos themselves is the primary reason for implantation failure. Other factors may also contribute, but embryo quality plays a significant role. In cases where a patient has a low ovarian response and only transfers a few untested embryos, the chances of successful implantation are reduced. Again, the quality of the transferred embryo plays a crucial role. Certain medical conditions, such as endometriosis or hydrosalpinges, can affect implantation. It is essential to consider these factors when evaluating implantation failure. Structural abnormalities in the uterine cavity, such as polyps or fibroids, can also hinder successful implantation.

Factors Affecting Implantation and Possible Solutions

Implantation is a crucial step in the success of fertility treatments. However, several factors can contribute to the failure of implantation. In this article, we will discuss some common factors that may hinder successful implantation and explore potential solutions. One essential factor for successful implantation is the quality of the endometrium. Insufficient endometrial thickness can lower the chances of implantation. Therefore, it is crucial to ensure that the endometrium is in optimal condition before proceeding with embryo transfer.

One common cause of implantation failure is genetic or clotting abnormalities in the patient. Factors such as Factor V Leiden, Factor II mutation, Factor XII mutation, and MTHFR mutation can affect implantation. Additionally, deficiencies in protein C, protein S, and antithrombin III can contribute to implantation failure. Consultation with a haematologist is recommended to explore additional treatments such as aspirin or heparin to mitigate the risks associated with these conditions.

Immune system dysregulation can also lead to implantation failure. Thyroid antibodies and antiphospholipid syndrome are potential causes of implantation failure and miscarriages. Treatment for these conditions often involves the use of aspirin or heparin to improve implantation success rates. Another aspect of the immune system that can impact implantation is alterations in natural killer (NK) cells. Patients with abnormal NK cell activity may experience higher rates of implantation failure and miscarriages. Specialized immunologists can provide treatment options such as corticoids or gamma globulins to optimize the immune system and improve the chances of successful implantation.

The HLA system plays a crucial role in establishing compatibility between the embryo and the mother’s immune system. In cases where there is a poor match between the HLA systems of the couple, the risk of implantation failure, miscarriage, and complications like preeclampsia increases. Transferring a single embryo is highly recommended for these patients. When using donor sperm or eggs, selecting donors based on HLA compatibility can help minimize the potential risks associated with this system.

Gluten sensitivity and celiac disease can affect reproductive health in some patients. Screening for specific antibodies associated with gluten-related disorders can help identify individuals at risk of reproductive issues. For those at risk, adopting a gluten-free diet is often recommended to optimize their chances of successful implantation.

Structural abnormalities in the uterus, such as fibroids, polyps, or adenomyosis, can hinder implantation. Thorough uterine assessment through techniques like three-dimensional scans and hysteroscopy can provide valuable insights into the condition of the uterine cavity. Identifying and resolving any issues found during these assessments can significantly improve the chances of successful implantation.

Achieving the ideal endometrial conditions for embryo transfer is crucial. The endometrial thickness, typically between 7 and 12 millimetres, and the presence of a triple-line endometrium are significant factors in planning embryo transfer. Natural cycles or alternative therapies may be used to improve endometrial conditions, especially for patients who do not respond well to conventional medications.

Some patients may have difficulties responding to standard ovarian stimulation medications. In such cases, additional treatments like gonadotropins may be used to stimulate the ovaries. It is crucial to find the right balance in stimulation to optimize both follicular growth and endometrial conditions.

Platelet-Rich Plasma (PRP) and its Role in Implantation

Platelet-rich plasma (PRP) has emerged as a promising treatment to enhance endometrial thickness and improve implantation success. By using the patient’s own blood sample, PRP can be prepared and administered to create a favourable environment for implantation. This relatively new treatment has shown positive results for patients with recurrent implantation failure or thin endometrium.

Determining the window of implantation, and the optimal time for successful implantation, is crucial. Tests like ERA (endometrial receptivity analysis) help personalize embryo transfers. Additionally, evaluating the uterine microbiome is important, as an imbalance can hinder implantation. Tests like the time-lapse metagenomics assay and other assessments help identify potential issues and allow for appropriate treatment.

Sperm quality is equally important in the success of implantation. Basic semen analysis provides information on concentration, motility, and morphology. However, specialized tests like single and double-stranded DNA fragmentation analysis help assess the potential for successful fertilization and embryo development. Identifying any genetic issues in sperm DNA can guide treatment decisions, such as pre-implantation genetic screening (PGS) to select healthy embryos.

Embryo Quality and Selection

The quality of embryos plays a vital role in implantation success and reducing the risk of miscarriage. Embryo development and classification help determine which embryos are most suitable for transfer. In cases where chromosomally healthy embryos are challenging to obtain, pre-implantation genetic screening (PGS) can be performed to exclude embryos with genetic abnormalities.

Conclusions

When faced with the failure of implantation, a multidisciplinary approach involving gynaecologists, immunologists, and haematologists can provide a comprehensive assessment. Each specialist’s expertise contributes to a thorough understanding of the patient’s situation and offers potential.

 

- Questions and Answers

I’m 43. I managed to get 1 euploid embryo with my own eggs PGT-A tested what can I do to maximize the chances of implantation look for the best implantation window ERA test or something else?

I would suggest considering a thorough approach. Firstly, have a 3D scan to exclude potential factors affecting implantation. Conduct a receptivity test and an ERA (endometrial receptivity assay). Additionally, perform the Chronical infection test (EMMA and ALICE) to assess uterine health. This comprehensive assessment will help optimize your chances.

How important is it to have a TSH lower than 2.5 prior to transfer? Would a higher TSH impact chances of implantation?

It’s crucial to aim for a TSH level lower than 2.5 before transfer. Higher TSH levels can affect both implantation and increase the risk of miscarriage. Maintaining TSH within this range supports a successful outcome.

I heard that a high percentage of blastocysts can be non-viable after PGT-A testing. Should all good embryos be PGT-A tested for better chances of implantation?

In our clinic, we test embryos with optimal quality to ensure viability. Embryo quality doesn’t guarantee chromosomal health, so testing is essential. Generally, for patients under 35, around 50% of embryos can be expected to be viable.

‘m 43 and have a thin uterine lining. I’ve tried red raspberry leaf tea. Any other recommendations for improving my uterine lining?

To address your thin uterine lining, start with a 3D scan or hysteroscopy to identify potential issues. Rule out chronic endometritis and consider adding aspirin, vitamin E, and possibly PRP treatment to enhance endometrial thickness and receptivity.

I’m 35 and experienced implantation failures. I have PCOS and OHSS history. Could PCOS affect embryo quality and implantation?

PCOS might impact embryo quality and implantation, though it’s not definite. The cause could be multifactorial. Besides PCOS, embryo quality and endometrial conditions play vital roles.

‘m 40+ and had implantation failures. Would a hysteroscopy be recommended even if there are no suspicions of issues?

A hysteroscopy might provide useful insights even without apparent issues. Combining it with a 3D scan can help diagnose potential factors affecting implantation.

My uterine lining won’t thicken beyond 6.8mm. Should I keep attempting transfers with this thickness?

If your endometrial lining has a good triple-line appearance at 6.7-6.8 mm, it might still be viable for transfer. PRP treatment could be considered to improve thickness.

I had a chemical pregnancy with a low TSH. Should I transfer at a higher TSH level to avoid a drop?

Maintaining TSH at an appropriate level is crucial. While very low TSH might affect implantation, it’s advised to have it under control before transfer.

When should I start levothyroxine for improved thyroid hormone implantation?

Ideally, aim to have your TSH below 2.5 before starting the embryo transfer. However, some endocrinologists might recommend lower levels.

Can PGT-A testing be done on frozen blastocysts, or is it better to test fresh embryos?

PGT-A testing on frozen embryos is possible, but not ideal. Fresh embryo testing is generally preferred as it avoids extra steps and potential stress on the embryos.

Is laparoscopy recommended for patients with multiple implantation failures?

Laparoscopy isn’t necessarily recommended solely for implantation failures. Advanced diagnostic techniques like three-dimensional scans and MRIs can offer valuable information without the need for laparoscopy.

Do you recommend PGT-A for all patients in your IVF program?

PGT-A isn’t recommended for all patients. It’s beneficial for older patients and those with certain factors, but it might not improve outcomes for everyone.

What do you do when there’s fluid buildup in the uterus after estrogen treatment?

If there’s fluid in the uterus before transfer, adding estradiol and waiting might help resolve the issue. A thicker endometrium can sometimes eliminate the fluid.

What’s the best progesterone level after embryo transfer with egg donation?

We recommend a progesterone level above 10.5 nanograms per milliliter before embryo transfer.

Is there a connection between diminished ovarian reserve and implantation failure?

Diminished ovarian reserve doesn’t directly correlate with implantation failure. Factors like age, embryo quality, and potential abnormalities play a role.  

What should I do if my uterine lining won’t thicken beyond 6.8 millimeters?

If your triple-lined endometrium appears good at 6.7-6.8 millimetres, it might be suitable for transfer. Consider PRP treatment to enhance thickness.

Can a drop in TSH affect implantation success?

Extremely low TSH might impact implantation. It’s important to maintain TSH within a suitable range before transfer.

What’s the recommended progesterone level after embryo transfer with egg donation?

The aim is for a progesterone level above 10.5 nanograms per milliliter before embryo transfer.

I had a failed implantation transfer due to fibroid. I am told I need a myomectomy, but more increase in adhesions after the surgery will make things worse. Can I use donor eggs? I don’t know if the fibroid is affecting the cavity or just close to it. Is the size of the fibroid significant for implantation? Should it be removed before embryo transfer?

If the fibroid is affecting the cavity, it should be removed before embryo transfer. The size of the fibroid matters, and if it’s outside the uterine cavity, around six centimeters, it’s not excessively high and likely won’t affect implantation.  

Regarding laparoscopy, my MRI showed endometrium on my right ovary. Should I undergo laparoscopy just for endometriosis? Is it worth it if I’m not experiencing severe pain?

If endometriosis isn’t causing severe pain, undergoing laparoscopy might not be necessary. It’s not worth it unless there are significant reasons to do so.

‘m 37. What is the success percentage for transferring a day 5 embryo without testing? I’ve done Thrombophilia’s analysis, endometrial tests, and microbiota.

The implantation rate for a 37-year-old patient would be around 35% without embryo testing. If you check the embryos and transfer healthy ones, the rate increases to around 60%.

I’ve had 2 abnormal EMMA tests in the past. Do I need another EMMA before my upcoming transfer? I’m taking immunosuppressants and have a history of clotting issues.

Consider using probiotics and improving the endometrial environment. If there’s no infection and probiotics help, it might be sufficient.  

When is Prednisone and Intralipids suggested versus Prednisolone alone? Is it necessary to have aspirin and heparin? Does heparin alone help enough? I’ve been prescribed Prednisolone and Clexane for my transfer.

Treatment depends on specific patient factors. Depending on the situation, treatment starts at different times. Aspirin is primary prophylaxis, prednisone starts around 20 days before transfer, heparin about one week before. Factors determine treatment.

In the diagnosis of chronic endometritis, what type of antibiotics are typically used? Is a test of cure performed? Any experience with intra-cavity antibiotics?

Antibiotics depend on the specific infection. A test of cure might be required. Intra-cavity antibiotics are not used due to potential unknown effects.

Can one take both aspirin and blood thinner injections during FET? Is it okay to combine aspirin and heparin?

Yes, aspirin and blood thinner injections can be taken together during Frozen Embryo transfer.

After many failed treatments, should I consider surrogacy for recurrent implantation failure? Is it recommended?

Surrogacy might be an option, but it depends on individual circumstances. However, surrogacy is not allowed in Spain.

Is there a way to get my body back to normal after down-regulation and suppressed cycle? My follicles and endometrium aren’t growing.

Your body will return to normal gradually after being down-regulated for a long time. It might take some time for your menstrual cycles to become regular again.

I’ve had 9 IVF rounds with no success. Considering a natural cycle with donor eggs. Any suggestions to improve implantation chances?

Using donor eggs increases the chances of success. Focus on embryo quality. A natural cycle might be a good option if your body responds well.  

What is the percentage of success after recurrent implantation failure investigation? Can you predict success rates after thorough investigation?

Success rates vary based on individual factors, such as the cause of implantation failure, patient age, and overall health. It’s challenging to provide a specific success percentage.

Is it common to recommend a natural cycle for patients? When is a natural cycle recommended?

Natural cycles are recommended for patients who have irregular responses to medication and who might benefit from a more natural approach to embryo transfer. It’s an option we offer to various patients based on their specific situations.  
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Authors
Esther Marbán, MD

Esther Marbán, MD

Dr Esther Marbán has been part of Clínica Tambre’s medical team since 2010. She is a gynaecologist specialized in Human Reproduction with a brilliant academic career. In fact, she obtained a special honourable mention in her Master’s Degree in Human Reproduction that she completed during 2009-2010 (organised jointly by the Spanish Fertility Society and the Faculty of Medicine of the Complutense University of Madrid). Dr Marbán is known for her restless and proactive personality and her innate talent for empathizing with people which she proves every day by working with patients.
Event Moderator
Caroline Kulczycka

Caroline Kulczycka

Caroline Kulczycka is managing MyIVFAnswers.com and has been hosting IVFWEBINARS dedicated to patients struggling with infertility since 2020. She's highly motivated and believes that educating patients so that they can make informed decisions is essential in their IVF journey. In the past, she has been working as an International Patient Coordinator, where she was helping and directing patients on their right path. She also worked in the tourism industry, and dealt with international customers on a daily basis, including working abroad. In her free time, you’ll find her travelling, biking, learning new things, or spending time outdoors.
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