Reproductive Immunology

Without giving patients any false hope, we believe we can offer patients with a history of recurrent IVF failure or miscarriage, a better chance of success by studying the role of their immune system in pregnancy. The late Dr Alan E. Beer, who is widely credited to be a pioneer in the field of Reproductive Immunology, believed that it is not simply due to bad luck that some women fail to conceive or have repeated pregnancy failure. We believe we have the experience to minimise recurrent miscarriage and IVF failure by investigating the immune system of the patient and offering immune therapy suited for each individual. The treatments offered may include Steriods, Intralipid and IVIg (Intravenous immunoglobulin) infusions and TNF-alpha blocking agents, Humira, amongst others. The embryo/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 embryo/fetus and cause a miscarriage either by being high in numbers or by abnormal hostile activity. There are several immune disorders:The tests we tend to focus on include: Natural Killer cells CD16/56 and 69 activity

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+), 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 mothers womb is a complex process involving several

factors including the local systemic immune responses. Pregnancy may fail when these events are not well synchronized.

Therapy aimed at calming these immune activating factors should, theoretically at least, CD69 is a functional triggering molecule on activated NK cells and is one of the earliest cell CD94 is an inhibitory marker of NK cell function. In 1999, a study demonstrated that NK cell

encourage fetal viability. surface activation markers expressed and is capable of inducing toxicity. 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 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 IVFET 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 programmes.

This very new scientific research that enables us to establish a link between recurrent

miscarriage and the abnormal behaviour of the mothers 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 a treatment programme is immune therapy which may include Prednisolone, Intralipid 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.

Antiphospholipid syndrome (APS)

possible.

Predominantly affects young women and there has been a growing awareness of this Pregnancy makes the blood stickier and women with APS are at increased risk of blood APS is associated with both early and late pregnancy morbidity and loss. Pregnancy loss Early pregnancy failure may result from impaired development of the placenta. It is essential that women with APS who are considering embarking on a pregnancy are

condition amongst obstetricians and gynaecologists over the last few years. clots unless blood-thinning medication is adequate. can be a miscarriage, intrauterine death, stillbirth or neonatal death.

aware of the risks involved so that they can make an informed decision about conception whenever

We will offer you to start low dose Aspirin pre-pregnancy. We may need to add Heparin

when you achieve a pregnancy and therefore you should present yourself as soon as you discover yourself pregnant, so that the Heparin can be started promptly.

Antinuclear Antibodies (ANA)

Are associated with several diseases such as Systemic Lupus Erythematosus (SLE).

The fertility rate may be reduced and the miscarriage rate in SLE patients is much higher

than that of the general population. Although most women who suffer recurrent miscarriages or recurrent IVF failure do not have clinical signs of SLE, many exhibit autoimmune phenomena similar to that seen in SLE patients.

The placentas in these women are sometimes found to be inflamed and weakened. If your results revealed that you have positive ANA, we will offer you treatment with

prednisolone.

Thyroid antibodies

Have been associated with fertility treatment failures and first trimester miscarriages. In one study 70% of women with recurrent first trimester losses had thyroid antibodies, If your results revealed that you have positive thyroid antibodies, we will offer you treatment

compared to 17% of controls. with prednisolone.