What are the main reasons for embryo implantation failure?

The successful onset of pregnancy depends on a number of events, among which the implantation of the embryo is one of the most important. For successful implantation, a well-prepared developing embryo, a receptive endometrium and the correct connection between them are important. If the implantation of the embryo repeatedly does not occur, this is called recurrent implantation failure (RIF), and is a serious challenge for the reproductive specialist and the couple.

What does the diagnosis of re-implantation failure mean?

To date, the most accurate definition of repeated embryo implantation failure is considered to be if transferring at least three good quality embryos into the uterine cavity, there is no confirmation of pregnancy before the age of 37. Another definition: after the transfer of three euploid (chromosomally healthy) blastocysts in a woman older than 37 years. During the IVF program, implantation is confirmed by visualization of the fetal egg on ultrasound 2 weeks after the transfer of the blastocyst (five-day embryo) into the uterine cavity.

Implantation is the process of attaching an embryo to the uterine cavity. Implantation occurs in 3 stages: apposition, adhesion, invasion. After apposition – the initial, unstable contact of the blastocyst with the surface of the endometrium, contacts are formed between the embryo and the epithelium in the uterine cavity. With adhesion, the contact between the embryo and the endometrium becomes tighter – this is a necessary condition for invasion (introduction into the endometrial tissue). It is important that the endometrium is ready to support the implantation of the embryo in a strictly defined period of the menstrual cycle (usually 5-6 days after ovulation, which corresponds to the 19-20th day of the menstrual cycle). It is during this period in nature that the embryo at the blastocyst stage enters the uterine cavity and is ready for attachment. The endometrium may not be receptive to the embryo in other phases of the menstrual cycle.

What are the reasons for the failure of embryo implantation?

The causes of implantation failure are divided into embryonic, uterine and systemic.

• Embryonic factor

We know that the chromosomal status of an embryo affects its ability to implant properly. Embryos with the wrong set of chromosomes (aneuploid) embryos, regardless of the age of the mother, have a low rate of successful implantation. In addition to embryonic euploidy, other genetic changes such as mutations or changes in methylation may contribute to implantation failure. Apart from genetic factors, the quality of the embryo also plays an important role in implantation. Regardless of other factors, a good quality embryo has a higher implantation success rate than an embryo of lower morphological quality. It is for this reason that the morphology of the embryos must be evaluated.  

• Uterine factor

Certain disorders in the uterus that can adversely affect embryo implantation

1. Congenital changes of the structure of the uterus (bicorporal uterus, bicornuate uterus or unicornuate uterus, cavity septum).
2. Endometrial disorders, such as synechia (adhesions), endometrial polyps, excessive growth of the endometrium (hyperplasia), or fibromyomas that deform the cavity.
3. Thin endometrium – endometrial hypoplasia (as a rule, the consequences of curettage and interventions in the past, in which there is inability to properly grow the endometrium). Endometrium thickness lesion can occur when there is a changes of blood coagulability due to a deterioration in the nutrition of the endometrium.
4. Displacement of the “implantation window” of the endometrium – which leads to a shift in the period of endometrial receptivity to the embryo on other days, not physiological, to the natural “implantation window”.
5. Hydrosalpinx (the presence of an inflammatory process in the fallopian tube, usually after suffering inflammatory diseases and hypothermia). The contents of the inflamed fallopian tube enter the uterine cavity and violate the conditions for proper implantation of the embryo.
6. Adenomyosis (endometriosis changes in the uterine wall in which the endometrium grows into the muscle layer).
7. Chronic endometritis (inflammatory process) and changes in the microbiome (microflora) of the endometrium. The presence of increased peristalsis of the uterus.

• Systemic causes

Among the most studied systemic changes for their impact on implantation failure are:

1. Endocrine disorders (most often pathologic condition of the thyroid gland – hypothyroidism, an increase in the level of prolactin – hyperprolactinemia, an excess of testosterone formation in the ovaries or adrenal glands – hyperandrogenism, insulin resistance – excessive production of insulin in the body).
2. Thrombophilia (disturbances in blood coagulation and vascular conditions) – in this case, excessive concentration of the blood occurs, which prevents the proper growth of the endometrium and the nutrition of the embryo to ensure implantation. Due to excessive thickening of the blood, the embryo during implantation cannot receive sufficient nutrition from the mother’s vessels and give the appropriate signal to the mother’s body about the onset of pregnancy. This factor can also affect pregnancy.
3. Immunological changes (common in autoimmune diseases – for example, AIT, rheumatoid arthritis, in which the woman’s immune system produces antibodies against the endometrium and the embryo, which prevents successful attachment).
4. Changes associated with lifestyle (smoking affects the state of blood vessels and ensure proper nutrition of the embryo), unhealthy diet, excess weight prevents implantation. Work and contact with harmful substances, radiation, certain varnishes and paints, taking certain drugs also affect the possibility of proper development and attachment of the embryo.

Possible Solutions for Repeated Embryo Implantation Failures  

Following the many recommendations suggested for recurrent embryo implantation failures, the following should be assessed:

1. Preimplantation genetic testing (PGT-A) allows the transfer of chromosomally healthy embryos and reduces the time to achieve pregnancy.
2. Transfer at the blastocyst stage (five-day embryonic stage) provides a better selection of embryos and gives more information about the quality of the embryo to be transferred.
3. Assisted laser hatching (laser thinning of the shell of the embryo to facilitate hatching and attachment): There is evidence that assisted hatching may promote embryo implantation in cases of RIF. To perform an embryo biopsy, laser hatching will be included in the PGT-A.
4. It is important to study and, if necessary, correct hormonal disorders that affect implantation and pregnancy. We recommend that the determination of the main endocrine indicators is mandatory even at the stage of preparation for planning a pregnancy, regardless of the method of conception.
5. Investigation for genetic thrombophilia and exclusion of folate metabolism disorder. In case of clinically significant disorders, the use of blood dilution and split forms of folic acid and vitamin B12 are recommended.
6. Hysteroscopy should be performed if changes are suspected that can be corrected with this method, such as a uterine septum. Hysteroscopy is performed to resect synechia or polyps, as well as fibroids that deform the uterine cavity.
7. The study of antiphospholipid antibodies (diagnosis of APS) in women with RIF should be carried out on a personalized basis (taking into account a possible personal or family history of autoimmune diseases).
8. A large amount of data has been accumulated that the transfer of an embryo in a cryocycle significantly increases the rate of successful pregnancy. Because physiologically correct conditions are created in the endocrine system of a woman compared to embryo transfer in the cycle of stimulating the growth of follicles.
9. The exclusion of chronic endometritis is carried out when performing hysteroscopy or a pipel biopsy of the endometrium. After determining a chronic inflammatory process in the endometrium, we prescribe an anti-inflammatory treatment. Followed by monitoring the effectiveness of treatment.
10. Discussing the importance of a healthy lifestyle and nutrition, correcting the deficiency of essential microelements and vitamins in the body can improve pregnancy success rates.
11. Definitions of “implantation window” – endometrial receptivity test. It is based on a possible desynchronization between the endometrium and the embryo due to the displacement of the “implantation window”. In this case, a personalized transfer of the embryo into the uterine cavity is carried out, taking into account the result of the “implantation window” test.
12. To date, genes that affect the proper development of the embryo and gestation are known. In our clinic, we study genetic panels in women with RIF.
13. It should be noted that the quality of spermatozoa, the male factor and certain genes significantly affect the correct fertilization, development and success of embryo implantation.
14. The study of immunological causes affecting implantation.
15. Ovarian stimulation: In cases of increased response to follicle stimulation, we recommend to avoid fresh transfer by freezing the embryos for transfer in a subsequent cycle.

As seen, the success of implantation and pregnancy meet with many factors. Often these reasons can be combined.

With faith and the right mindset for the main result, the teamwork of the couple and the reproductologist, such situations as RIF are surmountable.