Miscarriage Causes: Immune Mechanisms

The fetus contains foreign genetic material coming from the father, but in normal circumstances it does not get rejected. However, in some women the immune system may reject the fetus and cause a miscarriage either by being high in numbers or by abnormal hostile activity. There are several immune disorders:-

NK cells

What are NK cells?

There is a special class of NK cells (CD16-, CD56+) in the placenta that promotes fetus survival. Opposing is another group of NK cells (CD16+, CD56+), which, if active, are toxic to the placenta and hence may cause a miscarriage. The same cells secrete tumor necrosis factor (TNF) which can destroy the placenta.

 Implantation of embryos into the mother’s womb is a complex process involving several factors including the local systemic immune responses. A pregnancy may fail when these events are not well synchronized.

Therapy aimed at calming these immune activating factors should, theoretically at least, encourage fetal viability.

CD69 is a functional triggering molecule on activated NK cells and is one of the earliest cell surface activation markers expressed and is capable of inducing toxicity.

CD94 is an inhibitory marker of NK cell function. In 1999, a study demonstrated that NK cell toxicity could be blocked by the CD94 inhibitory receptor. Previous studies have shown that imbalances in CD69 and CD94 expression could result in infertility of unknown aetiology or recurrent miscarriage.

The NK cell is the most abundant immune cell infiltrating the womb implantation site. In a previous study, an elevated percentage of peripheral blood NK cells were associated with recurrent failed IVF-ET treatment cycles. Another study showed that increased peripheral blood NK cell toxicity was associated with an increased rate of recurrent failed implantation after IVF-ET treatment. More recent studies have confirmed elevated NK cell CD69 expression as being associated with recurrent miscarriage and infertility of unknown aetiology. Finally, a recent small non-randomised study has also suggested elevated NK cell CD69 expression may be related to failed implantation of the embryo.

We recently conducted a study to evaluate the effect of steroid therapy in women (who have positive peripheral blood NK cells CD16/56) on implantation and miscarriage rates after IVF-ET treatment. Our results are very encouraging with a success rate exceeding 80%. We are currently finishing our data collection and evaluation.

We also recently conducted a study to evaluate the effect of the absolute count of the activation marker (CD69) and inhibitor marker (CD94) expression on peripheral blood NK cells on implantation and miscarriage rates after IVF-ET treatment. It was a randomised prospective observation study of 138 randomly selected women who underwent IVF-ET treatment from December 2002 to September 2003. Our data suggests that an elevated level of CD69+ peripheral blood NK cells is a detrimental factor for implantation of embryos in IVF-ET treatment. Those women who have an elevated peripheral blood CD69+ NK cell count achieve a positive pregnancy from IVF-ET have a significantly higher risk of miscarriage. The specificity and positive predictive value of predicting IVF-ET outcome for women who have a peripheral CD69+ NK cell count above 1.0 x10 6 /L are 92.1% and 92.3% respectively. This test may therefore be used in clinical practice to predict negative outcome of IVF-ET treatment. The good news however is that we can significantly improve your chances of success with our treatment programme.


This very new scientific research that enables us to establish a link between recurrent miscarriage and the abnormal behaviour of the mother’s immune system may sound unfamiliar and complicated to some women. Because it is such a cutting edge science, it is quite possible that your GP or even other specialist consultants may not have heard of such a connection, and be sceptical about its importance.

The good news, however, is that we can do the diagnostic tests here in our clinic, and if the results are positive for elevated NK cells, we can also offer you an extremely effective, safe and inexpensive treatment, after which the chances of a positive pregnancy outcome are increased to 80%. The main component of the treatment programme is immune therapy which may include Prednisolone, Intralipid Infusions and Intravenous Immunoglobulin (IVIG). These drugs are safe in the doses we prescribe and we will discuss any worries or possible side effects with you.