Repeated pregnancy losses and failure of implantation after transferring good quality embryos in IVF constitute a particularly challenging topic in the area of reproductive medicine.

Dr Diamantopoulos strongly believes that it is not just attributed to bad luck.

He recognizes that an unsuccessful IVF cycle or an early miscarriage carries a tremendous emotional burden on the couples involved. Without giving his patients unrealistic expectations, he has the experience to offer a better chance of success by investigating the immune system and applying individualized immune treatments. 

Immune system is the defensive mechanism of the body against disease. 

Its role is to attack to any potentially damaging foreign bodies that it cannot recognise because they are genetically different to the body. 

Although the embryo has a different genetic code from the mother, a unique immunological response takes place to allow for the initial implantation and the subsequent development of the pregnancy.  

In some women the immune system may be overactive, reject the embryo or interfere with the hormones that are essential in pregnancy. This hostile response of the immune system may lead to infertility, miscarriage or even cause complications later in pregnancy.  

The complex mechanisms involved in the response of the immune system to the pregnancy have recently triggered great interest within the medical field. 

In the past decade considerable research efforts have been made to identify possible immunological causes associated with recurrent pregnancy losses and repeated IVF failures. Various research studies suggest that, in some women, an overactive immune system may increase the difficulty of getting pregnant, or increase the risk of miscarriage. However, there is no strong evidence to provide a clear answer regarding the value of immune testing nor whether the various available immunological treatment options, definitely improve the outcome.  

Considerable debate going on in the scientific community about the role of the immune system in promoting or preventing a healthy pregnancy, thus this area of Reproductive Medicine remains controversial. 

For an in-depth look at reproductive immunology, it is recommended to read: 

Is Your Body Baby Friendly?: Unexplained Infertility, Miscarriage and IVF Failure, Explained by Dr Alan E. Beer”

Dr Alan E. Beer is an internationally respected physician and research scientist, pioneer in the field of reproductive immunology.

The majority of patients Dr Diamantopoulos sees, have a complex medical and fertility history and often present having already experienced multiple failed fertility treatments elsewhere and/or recurrent miscarriages. Many of his Greek patients travel long distances to see him and many patients from overseas seek his advice. 

At the initial consultation a detailed medical and fertility history will be obtained to identify whether you are likely to have any immune issues affecting the process of implantation of your embryo. If deemed appropriate you will be given suggestions for immune testing. Be aware that the results for some of the tests may take up to 10 days to be ready. 

When all your results have been received, you will be advised on the most appropriate immune treatment at a follow-up consultation. Bear in mind that sometimes is necessary to repeat part of your immune testing and make changes to your immune treatment plan as your fertility treatment progresses. 

Reproductive immunology testing is not offered routinely as a first line test in everyone. It mostly applies in women with the following conditions: 

  • Multiple unsuccessful IVF/ICSI treatments  
  • Repeated pregnancy losses  
  • A history of “unexplained” subfertility 
  • A history of endometriosis combined with previous failed IVF/ ICSI treatment 
  • A medical history of known autoimmune disorders such as, Lupus, Rheumatoid arthritis, Crohn’s disease, Ulcerative colitis, Thyroid problems  

The results and the recommended treatment options will be fully discussed before your treatment.

To identify any immunological issues potentially associated with your infertility, IVF implantation failure or recurrent miscarriage the following blood tests could be suggested to you:  

Natural Killer (NK) Cell Cytotoxicity Assay 

Natural killer (NK) cells are a type of lymphocytes (white blood cells) protecting the body from infections by bacteria, viruses and possibly cancer cells. They constitute the most extensively studied group of immune cells. NK cells are the most abundant immunological cells in the lining of the uterus, and can therefore interfere with an implanting embryo. Excessive levels of NK cells have been associated with various fertility issues. 

NK cells can be tested through a blood test or through a biopsy from the uterus.  

Dr Diamantopoulos favors the blood test. Every time a woman gets her period, the endometrium with all its NK cells are shed and therefore, in the next period, the number of NK cells may be different. Furthermore, it is extremely unlikely to obtain a pure endometrial sample; if the sample is blood stained, will contain endometrial as well as blood NK cells, which will compromise the accuracy of the results. Moreover the blood test is less invasive.  

NK Cell Cytotoxicity Assay is a blood test that measures the killing power of NK cells against foreign tissue. It involves the culture of NK cells with target cells, which are similar to pregnancy tissue and reports the percentage of the target cells killed by the NK cells. If the NK cells are overactive against the foreign tissue, will show a high killing power. Furthermore by adding in the culture steroids, intralipid or IVIG it is checked whether the killing power of the NK cells can be reduced by these medications, determining which is the most suitable treatment option.  

TH1: TH2 Cytokine ratio

Cytokines are chemical messengers in the blood produced by the NK cells. They are proteins involved in systemic inflammation and regulation of immune cells. High levels of tumour necrosis factor (TNF-alpha), in particular, have been linked with reduced egg quality, implantation failure and miscarriage. 

Testing For Inherited and Acquired Thrombophilia

Some women have a condition called thrombophilia, which means that their blood forms clots more easily. It can be caused by a variety of genetic or autoimmune reasons. Thrombophilia can adversely affect the blood supply to the uterus and the growing embryo resulting in increased rates of implantation failure and miscarriage.  

Testing For Autoimmune Factors

Undiagnosed autoimmune diseases may be associated with an increased risk of pregnancy failure. The following antibodies are commonly checked for:  

  • Antinuclear antibodies (ANA) 
  • Thyroid antibodies (anti – TPO) & (anti – TG)  
  • Anti- DNA antibodies 
  • Anti-histone antibodies  
  • Anti –cardiolipin antibodies

Literature suggests that an overactive immune system is associated with lower implantation and higher miscarriage rates. It has been speculated that this may be improved by immunotherapy treatment. 

There are various treatments used to suppress the body’s natural immunity and you may be offered, alone or in combination, any of the following: 

Intralipid (ILP) 

Intralipid is a solution of fatty acids derived from soya beans and egg and is given intravenously as an infusion. It is effective in reducing natural killer cell cytotoxicity and TNF-a cytokines. There may be side effects, however they appear to be uncommon. Headache, fever, nausea or vomiting may be seen in about 5% of patients receiving intralipid therapy. Severe allergic reaction may occur, but is very rare. Therefore is not advisable to have Intralipids, if you are allergic to eggs, nuts or soya. 

Intravenous immunoglobulin (IVIg)

IVIg is a solution of concentrated and highly purified human antibodies derived from pooled human blood donors and is given intravenously as an infusion. IVIg has shown to normalise the killing power of natural killer cells in the blood. There may be side effects, however they appear to be uncommon. Headache, tiredness, palpitations feeling cold, development of skin rash and fever may occur in a minority of patients receiving IVIg. Rarely some patients may experience a severe allergic reaction therefore antihistamines are given during the transfusion. Regarding concerns about the risk of transmission of viral diseases through IVIg infusion, no cases of human immunodeficiency virus (HIV) transmission have been reported.  

Adalimumab (Humira)

Humira is a highly effective drug for reducing elevated TNF-alpha. It is used to treat rheumatoid arthritis, Crohn’s disease, ulcerative colitis and other autoimmune conditions. Humira is given in courses of subcutaneous injections and most patients experience no side effects with Humira. Occasionally a skin rash around the injection site may develop and some women may present flu like symptoms or troubled with irregular periods. 

Hydroxychloroquine (Plaquenil)

Hydroxychloroquine known under the brand name plaquenil is an oral medication in the form of tablets commonly used in the treatment of autoimmune conditions such as rheumatoid arthritis and lupus.Rare side effects include allergic reaction to the drug and vision problems. 

Low dosage corticosteroids

Corticosteroids including prednisolone and dexamethasone are oral tablets used to temporarily suppress natural killer cells and inflammation. The most common side effect is insomnia, which can be reduced by taking the tablets early in the day. Other side effects include salt and fluid retention, high blood pressure and high blood sugar. Most of the patients will take steroids until 12 weeks of pregnancy.

Clexane and baby aspirin

Thrombophilia and high levels of NK cells may compromise the blood flow to the uterus and the growing embryo. The use of blood thinners can improve the blood supply and reduce the risks of implantation failure and miscarriage. Clexane is a blood-thinner given in the form of daily subcutaneous (under the skin) injections, usually in the tummy. The majority of the patients experience no side effects except for bruising at the injection site. Another blood thinner commonly used is baby aspirin. Aspirin it is better to be avoided in patients suffering from gastrointestinal disorders such as stomach ulcer. Most of the patients will continue taking blood thinners until 12 weeks of pregnancy, but some patients may continue for a longer period in pregnancy.  

Progesterone supplements

Patients with immune related infertility may benefit from higher dosages of progesterone due to anti-progesterone antibody activity or inflammation. Progesterone supplements come in the form of intramuscular or subcutaneous injections, vaginal pessaries or gels as well as oral tablets and can be given alone or in combination. The most common side effect of progesterone treatment is constipation. Most of the patients will remain on progesterone support until 12 weeks of pregnancy, but some patients may require support for a longer period in pregnancy.