Immunity, cytokines & recurrent pregnancy loss

Introduction :

Miscarriage is a distressing event in a woman’s life. When it occurs repeatedly, it causes tremendous physical, mental and psychological trauma but also has a lot of social impact. The immune system of our body plays an important part in maintenance of pregnancy and its dysfunction can affect the growth of pregnancy.

I am going to discuss about an obstetric condition associated with Immune dysfunction, leading to repeated loss of pregnancy also known as Recurrent Pregnancy Loss (RPL).

Unexplained Recurrent Pregnancy Loss

Causes of RPL

Recurrent Pregnancy Loss (RPL) is defined as 2 or more miscarriages (ASRM) either consecutive or along with one or more live births. The incidence of RPL is 2%. Though there are certain known causes of RPL, in almost 50-60% of RPL, the etiology is not known and is labelled as “unexplained” RPL. In majority of these so called “unexplained” RPL, the underlying cause can be alloimmune rejection of pregnancy. Thus, immune system plays a major role in the etiology of “Unexplained” RPL.

Immune System

The immune system protects us from any foreign invader into our body. It builds a reaction against bacteria, viruses or any substance or organ that is immunologically different. This is achieved by a combined humoral and cell medicated response. The humoral immune response is through immunoglobulins while the cell mediated response is through cells of the immune system, including lymphocytes, monocytes, macrophages & dendritic cells. These cells also act through chemicals known as cytokines & chemokines. The cytokines play a major role in the response towards the foreign substances.

RPL & Immune System

Fetus as semi-allograft

In ‘unexplained’ RPL, the underlying cause can be alloimmune rejection of pregnancy as previously mentioned. The pregnancy is 50% from father & 50% from mother. The part coming from father is immunologically totally different to the mother’s body. So the fetus is in fact a “semi-allograft” and should get rejected by the maternal immune system. However, this does not happen and this is known as the “Paradox of Pregnancy”. This is due to the complex interactions at the feto-maternal interface, between the trophoblastic HLA-G and immune cells in the decidua. This complex interaction leads to either acceptance or rejection of pregnancy through allo-recognition. The subsequent changes in the immune cells and the cytokines released by them help to maintain pregnancy or reject pregnancy.

Immune reaction at feto-maternal interface

There are 2 types of immune responses Inflammatory or Th1 and Anti-inflammatory or Th2. In presence of allo-recognition the Th2 (anti-inflammatory) response is predominant with rise in T-reg cells and release of Th2 cytokines (anti-inflammatory) like IFN gamma, IL10.

In absence of allorecognition, Th1 (inflammatory) response becomes predominant with rise in Th17 cells and release of Th1 cytokines (inflammatory) like TNF Alpha, IL6, leading to rejection of pregnancy.

Significance of cytokines in diagnosis of allo-immune factor of RPL

In unexplained RPL, certain immunological tests can be done to confirm the underlying alloimmune factor for RPL. Estimation of T-reg cells is useful. A falling level of T-reg cells is an indicator of failing pregnancy and treatment can in initiated in such a case. Estimation of cytokines is also useful. Test for Th1:Th2 cytokine activity ratio is helpful. A falling or low ratio indicates alloimmune problem. Estimation of individual cytokine (Sr. TNF α, IL6) OR TNF α / IL10 ratio are also useful. Raised Sr. TNF α or IL6 or high TNF α / IL10 ratios are suggested of allo-immune rejections as the cause.

Management of Alloimmune factor in RPL

As mentioned above there is a predominance of Th1, cytokines in case of alloimmune rejection pregnancy. Th1, type cells and Treg cells are also low. In fact, there is a “mini cytokine storm” at the feto-maternal interface with overactivity of inflammatory Th1 cytokines leading to destruction of pregnancy leading to miscarriage.

The treatment modalities that will increase the Treg cells or the anti-inflammatory cytokines will help in preventing the immune reaction against the pregnancy thus averting the miscarriage. This can be achieved by active immunomodulation with Lymphocyte Immunization Therapy (LIT), which leads to increased T-reg cells and reduces Sr. TNF Alpha levels. This can be followed by passive immunomodulation with Immunoglobulins Intralipids, steroids or other immunomodulatory medications.


In “unexplained” RPL, the immune system plays an important role and allo – immune rejection of pregnancy can be a causative factor. The “cytokine storm” at the feto-maternal interface is the event responsible for rejection and destruction of pregnancy leading to miscarriage.

Estimation of Treg cells (anti-inflammatory) and estimation of cytokines activity (TNF Alpha & IL 6 levels TNF Alpha / 1L to ratio. Th1/Thcytokines ratio) along with antipaternal antibody estimation can help to diagnose the allo-immune problem. It helps to predict whether immunomodulation will be beneficial.

Use of active immunomodulation (LIT) or passive immunomodulatory medications can help to prevent the ‘cytokine storm’ helping in continuation of pregnancy.

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