Implantation immunology

The critical role of inflammation during embryo implantation


In recent years, the role and importance of the immune system for both successful implantation and safe progress and development of the foetus during pregnancy, have been increasingly recognised. What seems to be the main problem is one thing – dysregulated inflammation. Let us explain what this means:

The interaction between the developing embryo and the maternal immune system is tightly regulated to ensure successful implantation and establishment of pregnancy, and inflammation is one of the key mechanisms involved in this process.

Implantation is a complex process that involves interaction between the embryo (trophectoderm) and the uterine lining (endometrium). During this process there is mutual exchange of substances and chemicals. This is sometimes referred to as ‘embryo-maternal cross talking’ or embryo-maternal communication and is a highly coordinated process.

Inflammation plays a significant role in embryo-maternal cross talking, particularly during implantation and early pregnancy. The interaction between the developing embryo and the maternal immune system is tightly regulated to ensure successful implantation and establishment of pregnancy, and inflammation is one of the key mechanisms involved in this process. At this time, a controlled immune response ensures that the uterus is favourable for successful implantation and that the uterine environment is tolerant of the developing embryo.

In any pregnancy, the embryo and the placental site (trophectoderm), is regarded by the woman’s body as a foreign body and a reaction against it by the immune is expected and crucial, especially in the early stages of implantation and pregnancy.  During implantation, the invading trophoblast cells from the embryo come into direct contact with the maternal endometrial tissue. This interaction triggers a series of immune reactions including localised and controlled inflammation at the embryo implantation site (where the embryo touches the uterine lining and starts developing blood circulation). The inflammatory response helps the embryo to ‘stick’ and is essential for facilitating trophoblast invasion into the uterine lining and the subsequent formation of the placenta.

Regulation of inflammation

Inflammation at the maternal-foetal interface is regulated by a delicate balance between pro-inflammatory and anti-inflammatory factors. The invading trophoblast cells release various factors, including cytokines and chemokines, which attract immune cells to the site of implantation. These immune cells, such as macrophages and natural killer cells, contribute to the inflammatory response by releasing additional signalling molecules.

Inflammation is a perfectly normal physiological response and a necessary procedure for every successful pregnancy. It is also essential, however, that this local irritation is tightly controlled and does not last more than 24-48 hours in order for a pregnancy to develop successfully.


The purpose of inflammation during implantation

The inflammation promotes changes in the structure and composition of the endometrium which facilitates the attachment of the embryo during the initial implantation. It is additionally involved in the significant tissue remodelling processes that take place in the endometrium and which also supports implantation, such as angiogenesis (formation of new blood vessels) and the breakdown and repair of tissue. For example, it helps to remodel the maternal blood vessels, ensuring sufficient blood supply to the developing embryo.


Excessive inflammation or an inappropriate immune response

An imbalanced or dysregulated inflammatory response can have detrimental effects on embryo implantation and pregnancy. In some cases, the body does not accept the pregnancy as it should and continues the initial reaction for longer and with greater intensity. This causes excessive or uncontrolled local inflammation during embryo implantation and the small placental vessels, essential for the initial feeding of the foetus, are often obstructed by small blood clots. This results in the growth retardation of the embryo and almost always followed by the death of the early-stage foetus. As such, chronic inflammation or dysregulation of the immune response may lead to implantation failure or pregnancy complications, such as recurrent miscarriages or preterm birth.

On the other hand, there are cases where there is insufficient inflammation or impaired immune tolerance which results in inadequate trophoblast invasion and placental dysfunction. Thus, a fine-tuned balance of inflammation is crucial for successful embryo-maternal cross talking. The immune system and inflammatory processes play a vital role in mediating the dialogue between the developing embryo and the maternal environment, ensuring proper implantation and establishment of a healthy pregnancy.

In most cases of unexplained infertility and repeated miscarriages, dysregulation of inflammation and immune response is the key to the problem. Very often in these cases the women believe that the problem lies with the quality of their eggs, but even after changing the egg, as a last resort, miscarriage still occurs. A few other women become pregnant in the normal way, but unfortunately end in early miscarriage.

Life Clinic's Contribution

With over 15 years of experience, Life Clinic is one of the world’s leading clinics in immune research and treatment, having developed its own treatment protocols, investigative techniques and monitoring procedures of the immune system (both before and during pregnancy). The nowadays, these protocols are widely accepted by many doctors and clinics around the world, and are used to treat difficult cases with unexplained infertility and recurrent miscarriages with high success rates.

New protocols

Dr. Dimitri Papanikolaou created and implemented the world’s first medical protocol for the support of normal conception in women with immunological problems, and with amazing results.

He also developed the first protocol in the world to support the entire pregnancy in women with immunological problems. It has enjoyed much success with significant improvement in pregnancy outcomes and maternal safety, which is particularly relevant since many of these women have increased chances of pregnancy complications including reduced foetal growth and development, pre-eclampsia and more.

Cost and safety

Until recently, immunological therapies were much more expensive than the IVF treatment itself and were more likely to present complications, because of the medications often used (IVIG).

The introduction of INTRALIPID infusions into the reproductive immunology arsenal, and the treatment follow-up using much simpler blood tests, have greatly reduced costs and dramatically increased treatment safety.

Dr Dimitri Papanikolaou was the first reproductive immunologist in Europe to apply the Intralipid in reproductive immunological treatments. It is a relatively cheap drug that is now widely accepted for its safety as well as for its multiple benefits in managing a successful pregnancy.

The process of implantation and trophoblast invasion is currently considered as the most limiting factor for the establishment of pregnancy. Molecular interactions at the embryo–maternal interface during the time of adhesion and subsequent invasion are crucial to the process of embryonic implantation. 

implantation of a blastocyst
Implantation of a blastocyst into the endometrium
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