Failed Implantation

Normal Implantation

In normal circumstances, after an egg is ovulated, if there is sperm in the area, fertilisation can occur. When the DNA from these two gametes is combined, it becomes a zygote. After going through cleavage (division), it becomes a morula and on day 5, a blastocyst. The blastocyst will ultimately hatch from the protective 'shell' which has surrounded the embryo through its early development. This is called the Zona Pellucida. It is this mass of hatched cells which, once free from its shell, will implant into the lining of the uterus.

Implantation is defined as the process by which the embryo attaches to the endometrial surface of the uterus and invades the epithelium and then the maternal circulation to form the placenta. Before the initiation of implantation, however, both embryo and endometrium should embark on an elaborated process of cross-talk. From the clinical point of view, implantation is considered to be successful when gestational sac is diagnosed by ultrasound.

Receptivity Window

Endometrial receptivity occurs 6 days after the post-ovulatory progesterone surge and lasts about 2 to 4 days (about days 20 to 24 of the menstrual cycle).

Stages of Implantation

There are three stages of implantation:

1. Apposition: the embryo seeks its position on the endometrial tissue and remains immobile while it is oriented, so that its internal cell mass points towards the endometrium to allow the proper formation of the placenta later on.

2. Adhesion of the embryo to the maternal wall.

3. Invasion of the placental cells, making contact with the maternal blood. This process is controlled by cytokines, which are molecules that modulate the dialogue between embryo and endometrium.

Causes of Failed Implantation

1. Multifactorial

• Maternal anatomic factors, including congenital uterine abnormalities, endometrial polyps, uterine fibroids, adhesions, hydrosalpinxes, endometriosis, etc.
• Male factors, when severe oligoasthenozoo-spermia was diagnosed or increased sperm DNA fragmentation.
• Genetic abnormalities, where embryos with good morphology have aneuploidy.
• Hormonal or metabolic disorders (uncontrolled diabetes, thyroid disease, variations in the prolactin level, etc.)
• Infections.
• Thrombophilia or antiphospholipid syndrome.
• Immunological factors.
• Psychological factors, lifestyle.

2. Impaired Endometrium:

Unsuccessful attempts with the transferring of high grade embryos, due to thin (≤6 mm) endometrium, with or without variations in vascularity.



3. Impaired cross talk between endometrium and embryo:

Unexplained failure to achieve pregnancy after ET of good quality embryos, without any anatomical and histological changes in uterine cavity and endometrium, without any other disturbances in patient, patient-partner and embryos.

Which Tests Can Be Done?

1. Maternal Blood Tests

• Clotting screen: this test looks for likelihood of blood clots which are a known cause for failed implantation. If needed. Aspirin or Heparin injections can be given to thin the blood and prevent it from happening again.
• Immune screen: this test looks for increased levels of uterine natural killer cells and auto antibodies which can be responsible for repeat failures. Steroids, intralipids and medication can be given to suppress the immune system but its use is controversial.

2. Uterine lining tests

• Hysteroscopy: to check for scar tissue, fibroids, polyps which might impact implantation.
• Endometrial receptivity array: a small amount of endometrium is removed and analysed for 200 genes known to be associated with implantation. It also helps identify the ‘window of implantation’ and plan for the next transfer

3. Paternal tests

• Sperm DNA Fragmentation: to check the sperm DNA for damage. ICSI might be suggested if DNA damage is identified.

4. Embryo factors

• Genetic screening: includes a biopsy of the embryo before transfer to identify chromosome abnormalities.
• Assisted hatching: consists in weakening an area of the embryo’s shell to improve the chances of implantation.