Causes & Side Effects
At our clinic we can do a whole range of investigations working through your physiology, hormones and finally your immune system. The tests will enable us to establish exactly what is causing you to miscarry and what treatment we can best provide you with.
It is useful if you bring any test results and documentation that you may have had already.
Miscarriage some of the possible causes...
Immune Mechanisms - 50% (Causes & Treatments)
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:-
- Natural Killer cells CD16/56 and 69 activity
- Natural killer cytotoxicity assay and drug assay
- Natural Killer cytokines (TH1/TH2)
- Antiphospholipid antibodies
- Antinuclear antibodies
- Antithyroid antibodies
- Gliadin antibodies
• 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 mother’s 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, 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 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.
Treatment of NK cells
• 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 it’s 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 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.
Safety of drugs and possible sideeffects
Prednisolone : does not pass through the placenta easily and is also broken down by enzymes in the placenta so that the fetus is exposed to only trace amounts.
Additionally, the body produces the equivalent of 8 mg per day of this corticosteroid. When indicated, Prednisone should be started prior to conception.
Maternal side effects are mostly reversible and include weight gain, mood swings, hair fall or growth, increase in blood pressure and blood sugars, sleeping difficulties and energy and skin problems.
• Antiphospholipid syndrome (APS) predominantly affects young women and there has been a growing awareness of this condition amongst obstetricians and gynaecologists over the last few years.
• Pregnancy makes the blood stickier and women with APS are at increased risk of blood clots unless blood-thinning medication is adequate.
• APS is associated with both early and late pregnancy morbidity and loss. Pregnancy loss can be a miscarriage, intrauterine death, stillbirth or neonatal death.
• Early pregnancy failure may result from impaired development of the placenta.
Treatment for Antiphospholipid Antibodies
• It is essential that women with APS who are considering embarking on a pregnancy are aware of the risks involved so that they can make an informed decision about conception whenever possible.
• I will offer you to start low dose Aspirin pre-pregnancy. I 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.
Safety of drugs and possible side effects
Heparin : it is a large molecule and therefore does not cross the placenta and is harmless to the fetus. It is a daily injection which may cause slight bruising, but otherwise safe to the mother. Rarely, as any other drug you may develop a drug allergy, which may lead to change of brand.
Aspirin : is safe for the fetus. If you have asthma or stomach ulcer you need to inform me prior commencement of the programme.
• Antinuclear Antibodies (ANA) are associated with several diseases such as Systemic Lupus Erythematosus (SLE).
• The miscarriage rate in SLE patients is much higher than that of the general population. Although most women who suffer recurrent miscarriages 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.
Treatment of Antinuclear Antibodies (ANA)
• If your results revealed that you have positive ANA, I will offer you treatment with prednisolone.
• Thyroid antibodies have been associated with first trimester miscarriages.
• In one study 70% of women with recurrent first trimester losses had thyroid antibodies, compared to 17% of controls.
Treatment for thyroid antibodies
• If your results revealed that you have positive thyroid antibodies, I will offer you treatment with prednisolone.
Natural killer (NK) cells are a major component of innate immunity and are responsible for immune surveillance. They induce direct cytotoxicity or secretion of cytokine/chemokine (chemicals) without recognising a specific antigen (foreign threat) as B and T cell, hence the name NK. NK cytotoxicity plays an important role in immune response against infected cells, malignancy, and stressed cells, and involves in pathologic process in various diseases. These cytotoxic functions are markedly variable among individuals, and NK function analysis has become a more routine practice in many diseases.
In clinical laboratory, several methods have been used to define the NK function in different diseases. The 51chromium release assay has been considered as the gold standard method for measuring NK activity.
In our laboratory we have introduced flow cytometry to measure NK cytotoxicity using labelled target cells to assess the function of these cells and their role in a pregnancy environment.
We also introduced an assessment of the killer effect of 3 different drugs on the activity of these cells in a pregnancy environment. The drugs include Prednisolone, IVIG and Intralipid.
For years conception of Th2 overbalance during pregnancy has been a paradigm for immunology of reproduction, while Th1 activity has been presented as unwanted component. Studies concerning Th1/Th2 balance in physiological and complicated pregnancy have been reviewed. Th1 activity during early peri-implantation period, premature and term labour not only accompanies but even predominates over Th2 activity.
Th1 activity plays important role in promotion of Th2 response, regulation of placentation process, defence against infections and initiation of delivery. Together with Th2 activity it is necessary component of immunological reactions during pregnancy.
Many miscarriages and failed assisted conception events are caused by or associated with abnormal levels of cytokines, which are proteins secreted by white blood cells to control the inflammatory process in the body. The activity of these cytokines can be broken down into two categories: pro-inflammatory (or TH1) and anti-inflammatory (TH2). Early exposure to pro-inflammatory cytokines is necessary in stimulating invasion of the blastocyst and the formation of new blood vessels during implantation. However, if the exposure to pro-inflammatory cytokines is excessive or prolonged, it can actually be severely detrimental to the pregnancy, and result in a failed implantation and early miscarriage.
New medical literature has also shown that an overbalance of TH17, another inflammatory cytokine, can result in recurrent pregnancy loss. There are many new cytokines in both TH1 and TH2 category that we at the Centre for Reproductive Immunology and Pregnancy now test for not only inside of the T-cells and NK cells but in the serum surrounding all of the blood cells.