What is reproductive immunology?

There is much debate about the role of the immune system in promoting or preventing a healthy pregnancy, especially in patients with recurrent IVF-failure and recurrent miscarriages. One reason that might be thought of as explanation for the repeated miscarriages is the idea, that the immune system may reject the pregnancy.

Generally, the immune system fights off invading cells that have a different genetic pattern to the own body. These invaders can include viruses /bacteria or transplanted organs. A fetus has also a different genetic pattern, because it carries the genes from both parents.

So, in a normal pregnancy, it is thought that the body does something to stop the fetus being rejected - in other words, to suppress the normal immune response. However, there is no convincing evidence that immune rejection of the fetus does actually ever happen in women with fertility problems.

Reproductive immunology includes a range of tests and treatment to do with the patient´s immune system in pregnancy.

What are Natural Killer (NK) cells?

Immune system cells that help the body in fighting infections are called Natural Killer (NK) cells. Recently, the idea that these NK cells may attack the fetus considering it an invader has risen. Hence, in certain cases, it may be suggested that a blood sample is taken to evaluate the levels of NK cells in the blood. If their levels are high, then drugs may be suggested to suppress them.

However, many scientists question this approach, because it is not clear whether

  • Natural Killer (NK) cells normally found in the blood attack the fetus or not
  • Measuring and then suppressing the level of NK cells in the blood affects the chances of having a successful pregnancy

NK cells, a type of lymphocyte (an immune cell),normally circulate in the blood. But, there are certain immune cells found in the lining of the womb that resemble NK cells in more than one way, hence they are called uterine NK cells.

But there are two main differences between them:

  • Uterine NK cells: Are found only in the lining of the womb during early pregnancy (the stage at which embryo implants itself and the placenta is developing) and not in the blood. Therefore, scientists strongly doubt the fact that some meaningful information about uterine NK cells can be obtained from a blood sample.
  • There exists no evidence or reports that uterine NK cells are destructive and attack placental or embryonic cells.

What do uterine NK cells do?

Uterine NK cells are present in the womb at implantation during early months of pregnancy, in fairly large numbers. It appears, that they play a role in linking the placenta to blood vessels and set up a healthy supply line to the fetus. However, scientists till date are not clear on how this process occurs.

What tests are offered?

Measurement of the level of NK cells in the blood and the efficacy how they kill invader cells. But these blood tests cannot measure or test for uterine NK cells, they will only measure NK cells only present in the blood.

Hence, there is no evidence that there is any strong link between the number and activity of NK cells in the blood and uterine NK cells. So these tests, and any treatment based on them, are usually done in early stages itself. But, there is little scientific evidence to show they are actually effective.

What treatments are offered and what are their possible side effects?

There are some empirical treatments to "suppress NK cells", which are not accepted amongst Physicians believing in evidence based medicine.

  • high-dose steroids
  • Intravenous immunoglobulin (IVIg)
  • Tumour necrosis factor-a (TNFa) blocking agents
  • Infusion of “intralipids”

These treatments are not licensed for use in reproductive medicine. Like any other medical intervention procedure, these too carry certain risks and potential side effects. Additionally, there is no widely accepted scientific explanation of any benefits that these treatments may have in reproductive medicine.


Corticosteroids are a type of drug or a synthetic hormone, which is useful in suppressing immune responses. They are commonly used in arthritis, asthma and other autoimmune disorders treatments.

However, the advantages of using steroids in the first three months of pregnancy is not known. Also, it is unclear if the risk to the baby outweighs any possible benefits. Corticosteroids if taken in pregnancy, do pose a small risk of poor fetal growth, but apart from this there is little risk to the fetus.

A clinical trial for a corticosteroid (prednisolone), tested the effect of on pregnant women, who had previously suffered two or more unexplained miscarriages. The study found that prednisolone did not prevent miscarriage and in turn increased the risk of high blood pressure, diabetes and premature birth.

Intravenous immunoglobulin (IVIg)

IVIg is made from antibodies extracted from the blood plasma of many different donors. It is mainly given by anintravenous drip as a treatment for immune deficiencies and autoimmune diseases.

IVIg carries varied and sometimes unpredictable risks:

  • Headache, muscle pain, fever, chills, low back pain, thrombosis (blood clots), kidney failure and anaphylaxis (a bad reaction to the drug), are some side effects that have been reported. But, they are reported in less than 20 patients and are generally mild. Since the immunoglobulins are taken from donor blood, there is the possibility of introducing blood-borne infections, such as hepatitis, HIV (Human Immunodeficiency Virus) or CJD (Creutzfeldt-Jakob-Disease).
  • IVIg contains antibodies. During pregnancy, antibodies cross the placenta into the bloodstream of the fetus. Therefore, in theory, IVIg antibodies could enter the fetal bloodstream, where they might react against some of the baby´s cells. However, this has not been seen in practice.

A detailed review of the risks associated with IVIg states the practitioner considering IVIg for an unproven use must seriously weigh the potential benefit versus potential harm because of its varying and sometimes unpredictable immune-modulatory effects.

TNF-a blocking agents

Tumor necrosis factor (TNF) is a chemical produced by immune system cells, such as NK cells, which promotes inflammation and allows the immune system to attack the source of infections. TNF-a blocking agents are drugs used to block the effect of TNF - stopping inflammation but making the attack on infection less effective - and are routinely used in the treatment of arthritis, asthma and other immune disorders.

The risks of using TNF-a blocking like Enovel, Remicade and Humiraagents are:

  • The makers of Remicade (infliximab) warn that using it may increase the risk of septicemia, chronic infections such as tuberculosis, cancer of the lymphatic system, liver problems, white blood cell disorders and strong reactions to the drug.
  • The long-term effects of infliximab exposure on the developing immune system of the baby is unknown
  • Humira (adalimumab) is not licensed for use in implantation failure (when the embryo fails to embed itself in the lining of the womb). Its effects on reproduction and fetal development are unknown.


Intralipids are a fat emulsion liquid, containing fatty acids, soybean oil, egg yolk and glycerine, which are given intravenously. The proposed use for intralipids is total parenteral nutrition or severe poisoning.

It is known to have many adverse effects ranging from allergic reactions, hyperthermia, thrombocytopenia, hypercoagulability, anti-neutrophil activity, pancreatitis to elevated liver enzyme levels.

Also, the long term impact of these on the child is not known. About the impact of using Intralipids to improve pregnancy rates, the results are not consistent and need to be researched further.

What evidence is there to show these treatments work?

These tests and treatments are very new. They are based on claims that women who have repeated miscarriages or failed IVF had raised levels of NK cells in the blood and on studies of pregnancies in these women after being treated with IVIg.

However, the research studies may not be valid because of the differences between blood NK and uterine NK cells, and because the sample of patients was small, there are doubts about the value of the research results.

In conclusion there is little scientific proof that these treatments are effective in improving the chance of having a baby.

For further information, please book an appointment with IVI Middle East Fertility Clinic.

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