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Dr Mohan Raut and Dr Mugdha Raut, Co-founders of Immunotherapy Centre for Prevention of Repeated Miscarriages, elucidate on the reasons for failed pregancies, and the benefits of immunotherapy in preventing recurring miscarriages

Miscarriage is always a traumatic experience for couples, but going through it several times is devastating. The emotional, physical and financial trauma is not the end of their troubles – repetitive miscarriages can mean the loss of valuable ovarian time for the patient, along with frustration and disappointment for the couple and the doctors involved. Recurrent pregnancy loss is defined as two or more failed clinical pregnancies. The risk of pregnancy loss increases with successive pregnancy loss. The chances of having a miscarriage are around 11-13 per cent. After one miscarriage the risk is 18 per cent. After two miscarriages, it shoots up to 40 per cent. One per cent of all women suffer from repeated miscarriages (RM).

Causes of RM
The usual reasons for pregnancy loss are chromosomal abnormalities (genetic), defects in the uterus, infections in the body or the uterus and hormonal defects (thyroid disorders, diabetes, polycystic ovarian disease etc). In 50 per cent of couples, these causes are not present. In these couples, the cause of RM may possibly be immunological.

Immunological factor in miscarriages
Our body has a defence system called the immunological system. It protects us from any foreign substance or organisms like bacteria or viruses. Even in any organ transplant, such as kidney transplants, the body accepts that kidney which immunologically matches the recipient. When there is a pregnancy, 50 per cent of the foetus is from the father, who may be immunologically different from the mother. However, it is not rejected by her body, as the pregnancy is protected by certain immunological mechanisms. In some women, these mechanisms are disturbed, leading to an immunological reaction against the pregnancy which in turn causes a miscarriage. This process may repeat itself in subsequent pregnancies, leading to RM.

Treatment of repeated miscarriages
Treatment of couples with RM involves performing all possible tests to rule out the usual causes as mentioned above. If they are within normal parameters, certain specialised immunological tests are done to confirm the presence of an immunological cause. Immunotherapy treatment is provided to these select couples.

What is immunotherapy?
Immunotherapy is treatment involving the modulation of the immune response. This is done so as to induce certain immunological changes in the mother’s body so that immunological rejection of the foetus is prevented in cases of RM.

History of immunotherapy
Some women who had repeated miscarriages were given blood transfusions for unrelated reasons. Later, it was found that they had subsequently had full-term deliveries. Hence, for some years, random blood transfusions were used as treatment for RM. However, further research demonstrated that the lymphocyte component of blood was helping women conceive. Thereafter, such patients were given pooled lymphocytes as treatment. Finally use of the lymphocytes of the patient’s husband was started.

Diagnosis of immunological factor
In a case of RM, it is important to rule out all known causes before testing for immunological factors. Hence, one must rule out genetic, anatomical, infection, endocrine and thrombophilia factors.

The immunological factor in recurrent miscarriages can be confirmed by conducting certain tests, which are based on following observations:

  • The endometrium of non pregnant patient of RM shows a high concentration of natural killer cells
  • The number of activated natural killer cells is greater in the peripheral blood
  • Certain cytokines (immune molecules that control immune cells) are found to be of a higher level in patients with RM.

The immunological tests are:

  • Lymphocyte crossmatch
  • NK cells in blood
  • Immunophenotype
  • NK cells in endometrium

Role of immunotherapy
Two kinds of immunotherapy are used in patients with RM and implantation failure:

  1. Active immunotherapy: This procedure is also known as lymphocyte immunisation therapy or LIT. When it is conducted, lymphocytes from the husband, or pooled donor lymphocytes are used to cause immune-modulation in the mother, leading to the prevention of RM.
  2. Intravenous immunoglobulin: In this procedure, immunoglobulin injections are used to prevent immunological rejection.

Patient selection
As stated earlier, it is very important to conduct all possible investigations related to the causes of RM. Once these factors are ruled out, immunological tests are done to ascertain whether immunological causes definitely exist.

Active immunotherapy (LIT)
LIT involves the separation of a type of white blood cells, (lymphocytes) and injecting them into the patient. This is a day care procedure and involves a 4-6 hour stay at the centre. After the therapy, a pregnancy is planned between 4-6 weeks after the procedure and the next year, so as to achieve the best results.

Intravenous immunoglobuline (IVIg)
IVIg has been used to treat both pre-implantation and post implantation recurrent pregnancy losses. Multiple injections of IVIg are required.

Minor side effects of treatment with IVIg include nausea, vomiting, chills chest pain. Other theoretical side effects are transmission of infection and allergic reactions. IVIg treatment requires multiple injections and is rather expensive.

Risks of immunotherapy
LIT may be associated with minor side effects like pains and itching at the injection site. Sometimes, there may be mild fever, but there are usually no major side effects. Other side effects are minor, and include those caused by treatment with IVIg which have been enumerated earlier.

Worldwide experience
Immunotherapy for RM has been practised across the globe. There are trials which have proved the effectiveness of immunotherapy in several cases. It has been shown that LIT was in fact more effective in primary aborters (those with one living child). Also, the effect of LIT increased with the number of previous miscarriages. IVIg has been found to be more effective in secondary aborters (those with a previous living child). In Mumbai, we have provided immunotherapy treatment to 350 couples with RM. The success rate was 88.71 per cent.

Conclusion
Repeated miscarriages are a devastating experience for a couple. After treating couples who have known risk factors, a large number of couples remain in whom the immunological factor could be responsible. A proper diagnostic work up, followed by the appropriate immunotherapy treatment, can help these couples fulfil their dream of having a healthy baby.

As new technologies emerge and a better understanding of how the many components of the immune system interact to aid in the growth of the foetus, new treatments will be available to help women with RSA or implantation failures.

Almost 40 per cent of unexplained infertilities and as many as 80 per cent of unexplained pregnancy losses could be due to immunological problems. Couples with RM will surely benefit from immunological testing. Further, couples with good embryos that fail to implant during IVF procedures are good candidates for immunological screening and treatment.

Active immunotherapy is an effective treatment for unexplained primary RM when re-treatment antipaternal antibodies are absent. IVIg is effective in secondary RM. Thus, immunotherapy presents itself as a ‘ray of hope’ to couples facing the problem of repeated miscarriages. It gives them a chance to have a healthy baby and have the family they always dreamed of.

 
Express Healthcare, March 2014, Part 1
Express Healthcare, March 2014, Part 2