Reproductive immunology: implantation failure and recurrent early pregnancy loss
Successful pregnancy requires three things: a capable embryo, a capable uterus and immune acceptance. For decades we have understood that not all embryos are capable. Genetic abnormality is the most common cause of miscarriage and implantation failure. The advice offered following the first miscarriage in women who conceive naturally is “it’s just one of those sporadic things, try again”. But when recurrent miscarriage occurs after natural conception, or for patients who undergo IVF with repeated excellent quality embryos transferred and yet have no success, other factors must play a part.
The question has been pondered for years as to the role of the immune system in successful pregnancy, but evaluation has proven to be scientifically challenging. Clinicians are divided on opinion as to the role of the immune system, and it is hard to get patients to sign up for a randomised study as all couples want a baby so are unwilling to sign up to the placebo medication!
We at Barbados Fertility Center have been testing and treating women for many years and indeed are one of the many leaders of Reproductive Immunology practice within the IVF field. We have seen hundreds of cases of repeated miscarriage or IVF failure be successfully treated with the use of immunosuppressive regimes to not test and offer treatment when indicated.
What is reproductive immunology?
Reproductive immunology is a field of medicine which studies the interaction between the immune system and reproductive organs. Research has suggested that during a normal pregnancy, a unique type of immunity occurs that stops the body rejecting an embryo as a foreign body and aids the growth and development of the foetus. If this immunity does not work properly, embryos may not implant or may be rejected early after implantation. A number of important components of the immune system have been recognised as key players to successful pregnancy.
Antibodies are molecules that are produced by white cells that can attach to cell membranes and change how the cell communicates with other cells or tissue interfaces. There are thousands of identified antibodies but the ones which are particularly associated with complications in implantation and pregnancy include: Antiphospholipid antibodies and anti-thyroid anti-bodies. The potential impact has been well documented in scientific studies for years. Testing for antibodies is a simple and readily available blood test, done by most general laboratories.
Thrombophilias; It is now recognised that a number of inherited or acquired disorders of blood clotting exist. In normal pregnancy the ability of the mother’s blood to clot in the placenta is supressed to allow flow through the fetal-maternal circulation. If a woman has an inherent increased ability to form blood clots this can affect this process and negatively affect pregnancy – implantation failure, miscarriage, pre-eclamptic toxaemia, intrauterine growth retardation and even unexplained intrauterine death have all been shown to be increased in women with thrombophilias. Tests can be done to diagnose specific thrombophilias.
What are NK cells and TNFα?
Natural Killer (NK) cells are one type of immune cell – normally circulating in blood. These express CD56 and as their name suggest have the ability to directly kill foreign or abnormal cells. Elevated levels or functionality can be harmful to the reproductive process and block successful implantation, even when the embryo is capable. They produce cytokines and specifically TNFα.
Th1 and Th2
T helper cells are present in a balance. It has been found that women with recurrent IVF failure or miscarriages have the balance of these cells shifted towards Th1. TNFα is one of the most potent cytokines released by TH1 cells.
Reproductive immunophenotype is the detailed study of white bloods cell. The majority of white cells are lymphocytes, of which there are a number of subtypes, which play different roles in the immune defence. Conventional microscopy can assess simple analysis of the numbers of certain types of white cells, for example, which are lymphocytes. However, to assess the subtypes of lymphocytes requires specialised techniques which assess the protein molecules and categorise these further into B and T cells and natural killer cells. This type of detailed analysis is referred to as a reproductive immunophenotype.
All our patients are screened for the most common immunology problems such as antibodies, before starting assisted reproductive treatment. Those women at high risk of more profound immune factors such as women who have an autoimmune disease or who have a history of repeated failed IVF, recurrent implantation failure or pregnancy loss, undergo to a comprehensive investigation panel including NK cells and Immunophenotype assay. The results of the immunological panel are careful analysed and interpreted to choose the best medication and the correct dose that more efficiently addresses the defect being observed.
While not every miscarriage or IVF failure is due to an immune cause there are many cases that careful evaluation and, if necessary, treatment is the crucial factor to a successful pregnancy. Thanks to our long experience in this field, we have successfully treated hundreds of patients with positive results using a personalised therapeutic protocol with the right combination of medications, which specifically targets their underlying immune component to their infertility.