Nidation is a crucial event in the achievement of a pregnancy. The embryo must make contact with the mucous membrane of the uterus. This membrane must be in a particular state to allow the contact to occur. Next, the embryo must grow into the mucous membrane of the uterus. Many treatments fail in the nidation phase. For us, it is a particular concern to improve nidation.
Repeated implantation failure
Repeated implantation failure means that within the boundaries of the IVF treatment pregnancy failed to result even though good quality embryos were transferred to the patient. The causes can be a problem with the embryo or with the patient or rather with the environment in the uterus.
Problems concerning the embryo
The most common changes concerning the embryo are genetic anomalies. Due to the discoveries of pre-nidation diagnosis (PID, PGD) we know that 30% to 90% of fertilized eggs exhibit genetic mutations. This percentage correlates strongly with the mother’s age.
- Sperm cells can also show genetic mutations (DNA fragmentation)
- Thickening of the egg cell shell can impede the “hatching” of the embryo
Problems concerning the patient
Organic mutations in the mother can be hereditary (anomaly of the uterus, uterus duplex, uterus septum, etc) or can be newly derived (myoma, polyps, adhesions). A regular healthy immune system is necessary for successful nidation in the uterus. Immunological problems can be a possible cause of nidation failure.
The hormonal stimulation as well as the response of the endometrium to estrogen and progesterone after ovulation is equally important.
Inflammations and infections in the uterus can also hinder the nidation of an embryo.
What options exist to resolve these problems?
- A genetic test of each partner (chromosomal study)
- Special sperm examination (DNA fragmentation, hyaluronic acid binding)
- Removal of infections
- Immunological examinations
- Resolution of blood clotting disorders
Special methods concerning nidation failure
We offer a high number of methods to improve the possibility of nidation. These include among others assisted hatching, nidation injection and nidation curetage, embryoglue, FertiGrow and seminal plasma flushing. These methods can be helpful for couples who already experienced several failed attempts. We implement new medical findings in our daily routine and conduct scientific studies in our Institute. Below you can find detailed information on our special methods.
In order to achieve pregnancy the embryo must leave its shell, the zona pellucida. This is essential for the success of the treatment. To facilitate this process a special method called assisted hatching was developed. This method involves making a hole in the shell of the embryo. This hole can be made with the aid of a pipette, a special laser or with a biological acid. It is not clear which of these methods is the most successful, meaning which results in the highest pregnancy rate. The following patient groups can benefit from the assisted hatching procedure:
- Women over 37 years of age
- Increased FSH levels before treatment
- Individuals with decreased embryo quality
- Embryos with observably thicker zona pellucida (egg shell)
- Earlier unsuccessful treatments
How will this method be implemented?
This method requires a lot of experience. As mentioned above, however, this method does not necessarily guarantee higher chances of achieving pregnancy.
Assisted hatching can be conducted through a variety of techniques:
- Mechanical assisted hatching: through micromanipulation with a glass needle (pictures below). The embryo will be held on one side with a special pipette. A delicate needle will be pushed through the egg shell without disturbing or injuring the cells within. The egg shell will be carefully rubbed between the pipette and the needle until a slit forms.
- Laser assisted hatching: through direct contact by the laser
- Through bundled laser light: guided over the microscope lens
It has been observed that the supply of a key hormone at the time of nidation genereally leads to an increased pregnancy rate. This GnRH – analogue is subcutaneously administered on the 6th day after the egg cell removal via one single injection.
When we first started using this method routinely we were pleased to see that our competitors also adopted this procedure and started offering it to their patients.
It should not be employed, however, when many egg follicles have developed as this can lead to over-stimulation.
Noteworthy research indicates that small stimulation of the mucous membrane in the cycle before the actual treatment cycle can increase the pregnancy rate. This stimulation can be created by means of a minor curettage. This is performed in the second half of the menstrual cycle, meaning before the actual stimulation begins. Even if the menstruation follows a curettage procedure, the positive effect remains.
The nidation curettage cannot be compared to a traditional curettage. This procedure involves only a small plastic instrument inserted into the uterus of the patient in order to remove a small amount of the mucous membrane.
Embryoglue® is a special medium for the embryo transfer which eases the embryo’s adhesion to the mucous membrane of the uterus via the use of biochemical signals. This is a culture medium specially developed for the embryo transfer. The consistency of embryo glue is similar to that of the liquid of the mucous membrane of the uterus and contains an important substance called Hyaluronan. This medium wraps itself around the embryo and assists in bonding of the embryo to the mucous membrane via its ‘sticky’ properties.
In order to reinforce existing literature the Kinderwunschzentrum conducted a study involving 114 patients. This included IVF patients that had already experienced several unsuccessful IVF attempts as well as suffering from poor embryo quality.
From the results of the study we can recommend embryo glue in the following situations:
- Age >35 and second failure of nidation
- Poor embryo quality regardless of age
More information on embryoglue: Information “Embryoglue”
Research of the human microbiome is one of the youngest medical breakthroughs, especially the microbiome of the intestine is widely discussed. Also known is the microbiome of the vagina, but new findings show that the uterus also includes important bacteria – with a high impact on the female fertility. So far there were no tests in Austria, but now we offer testing and therapy of the uterine microbiome in cooperation with a partner institute.
In the recent past a lot of studies dealt with the function and impact of microorganisms on the human body. A team around Carlos Simon from the company Igenomix (Valencia, Spain) examined the uterine microbiome for the first time ever. Results showed that most of the examined women had a microbiome which constisted of more than 90% lactobacilli. The occurence of other germs or a relative lack of lactobacilli can significantly reduce fertility. When a woman had an LD-microbiome within the uterus (which means lots of lactobacilli), nidation was successful in 60,7% – with a NON-LD microbiome only in 23,1%. When a lack of lactobacilli was detected, the pregnancy rate went down from 70,6 to 33,3% and the share of live births reduced from 58,8% to 6,7%.
Now for the first time ever the EMMA test (Endometrial Microbiome Metagenomic Analysis) developed by Carlos Simon is available in Austria. We the Kinderwunschzentrum brought this test to Austria for the first time ever. Now we can examine the microbiome before in-vitro fertilization – this is a new chance especially for women with repeated implantation failure. These test help to determine chronical imflammations of the uterus as well as an unfavourable composition of the microbiome. In order to do the genetic diagnostics we will take a small biopsy from the endometrium. After getting the results we will conduct an individual therapy, for example with lactobacilli or antibiotics.
An important consideration is the receptiveness of the endometrium at the time of transfer. The embryo can only implant itself into the endometrium during a particular time frame, normally between the 19th and 21st cycle day (i.e. 5-7 days after ovulation). This time frame is referred to as the implantation window.
Approximately 25% of all patients who have experienced repeated implantation failure have a so-called delayed implantation window. This means that the uterine mucus is not receptive for the embryo at the time of the embryo transfer, but at a different point in time. This implantation window can be diagnosed with an Endometrial Receptivity Array (ERA).
To perform the ERA diagnosis, at the time of the planned embryo transfer a small tissue sample of the uterine mucus lining is removed using a thin catheter (similar to the kind used for an embryo transfer).
ERA – test result
If the endometrium is receptive, this means that the embryo can be implanted at this time. The embryo transfer can then be performed in the following cycle at the same time point.
If the endometrium is not receptive, this means that the implantation window is delayed. In this case a new, personalized implantation window is suggested that is again examined by ERA. Once the optimal implantation window has been identified, the embryo has optimal chances to implant itself in the following cycle.
An IVF attempt can fail if the mucosa is not of optimal quality (size, layer and capacity to absorb fertilized egg cells). New studies from the USA point out that „G-CSF” supports nidation of a fertilized egg cell (embryo) in an ideal way and the subsequent preservation of pregnancy. The substance „G-CSF” has been used for years to stimulate the formation of new white blood cells. Apparently, this substance can aid the uterus in growing and so enhance the capacity to absorb whilst working against possible rejection by the body.
We established this method in August 2011 in our labs as the first European centre. We offer this treatment routinely to patients, where nidation repeatedly failed following the embryo transfer. We recommend the usage of „FertiGrow” based on the following indications:
- patients with repeatedly low structure of mucosa (less than 6-7 mm)
- patients who have undergone several surgical treatments on the uterus (curettage after an early or late abortion)
- failure of nidation at least twice
- known Ashermann syndrome
- patients where alternative methods for building up the mucosa (e.g. estrogen therapy) were inefficient
„FertiGrow” is applied directly free of pain into the uterus. This is conducted speedily and stress free during the egg cell collection. Thus, an additional appointment is not necessary.
A current study reports an increase in pregnancy rates through the use of hCG-flushing (human chorionic gonadotropin) just after the ovum pick-up.
Effects of hCG-flushing:
- the immunological tolerance of the uterus is positively influenced regarding the implementation
- the blood circulation of the uterus is increased
- the surface cells have more ability to retain the embryo
- the uterus muscles are less likely to convulse (this minimizes the risk of the embryo being repelled)
- an increase in progesterone receptors in the endometrium is achieved, this hormone is crucial in the implantation process
Directly after the ovum pick-up the uterus is flushed with 500 units of hCG. This flushing procedure is integrated into the ovum pick-up procedure and so does not involve further time or effort for the patient. Up until now no complications regarding the hCG-flushing have been observed and there are no indications that this treatment is harmful to the embryo.
In some patients the immune systeme exhibits an increased number of natural killer cells and for such cases we recommend a treatment with Multi-Lipid (SMOF) infusions. Multi-Lipid (SMOF) is an intravenous vegetal emulsion based on four different kinds of fats: soybean oil, medium-chain triglycerides, olive oil and fish oil, which is rich in Omega-3 fatty acids. It was originally developed for artificial (intravenous) nutrition and has for many years been used routinely in post-surgical care. Several studies have shown that the nidation but also the live birth rate have been influenced positively.
When are the Multi-Lipid (SMOF) infusions used for an IVF treatment?
- increased rate of natural killer cells
- repeated miscarriages or biochemical pregnancies without detectable reasons
- Autoimmune diseases such as Hashimoto-Thyreoiditis
- Coagulation disorders
Time / frequency of the infusions
Multi-Lipid (SMOF) does not work immediately so the first infusion should take place in the pre-cycle (the month before treatment starts). The 2nd infusion subsequently takes place on the day of the ovum pick-up. Several studies have shown that in 99% of patients the natural killer cells were suppressed one week after the 2nd infusion. In the event of a positive pregnancy test the treatment can be continued once every four weeks until the 12th week of pregnancy.
Foreign research groups have established the positive influence of seminal fluid on nidation. For this purpose, a part of the seminal fluid – the seminal plasma – is separated from the cell parts and flushed into the patient’s uterus with the aid of a thin catheter. Along with our foreign partner institutes, we have observed an increase in the pregnancy rate, and recommend this method to all couples that experienced repeated nidation failures. So far no complications resulting from this procedure have been observed. Minor inflammatory reactions of the mucous membrane can occur, however, these usually pass without discomfort. The results of this method are promising. We would like to point out that this is not a routine procedure.
IMPORTANT: This method is also only suitable for those patients who had embryos of good quality transferred. This method is not recommended if earlier attempts involved embryos of reduced quality or the quantity of egg cells or embryos was too small.