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:-

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.

Treatment

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.

Natural Killer Cytotoxicity

What are Natural Killer Cytotoxicity Assay and Drug Assays?

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 51 chromium 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.

Treatment

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 infusion.

Raised TH1/TH2 Cytokines

What are Raised TH1/TH2 Cytokines?

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 an important role in the promotion of Th2 response, regulation of placentation process, defence against infections and initiation of delivery. Together with Th2 activity it is a 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 to stimulate the 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 the 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.

Treatment

Most immune drugs such as steroids, hydroxychloroquine, IVIG and others can help suppress an overactive TNF alpha. However, Humira has been shown to very effective in these circumstances.

Antinuclear Antibodies

What are Antinuclear Antibodies?

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

If your results revealed that you have positive ANA, I will offer you treatment with Prednisolone.

Antithyroid Antibodies

What are Antithyroid Antibodies?

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.

Gliadin antibodies

What are Gliadin antibodies?

The incidence of miscarriage, birth weight babies, is higher among women with coeliac disease. This is effectively corrected by gluten-free diet in this group of women. Coeliac disease has been associated  with  numerous  unfavourable  health  outcomes, including pregnancy complications such as miscarriages, infertility, preterm birth, and preeclampsia. In one study  positive results  for IgA gliadin antibodies  were  different  in  women  with  and  without recurrent miscarriages.

In the case-control study, comparison of 94 untreated with 31 treated celiac women indicated that the relative risk of miscarriages 8.90 times higher, the relative risk of low birth weight baby was 5.84 times higher, and duration of breast feeding was 2.54 times shorter in untreated mothers. Abortion, low birth weight of baby, and duration of breast feeding did not significantly relate to the severity of celiac disease among untreated women. In the before-after study, 12 pregnant celiac women in either treated or untreated condition were compared. Results indicated that the gluten-free diet reduced the relative risk of miscarriage by 9.18 times, reduced the number of low birth weight babies from 29.4% down to zero, and increased duration of breast feeding 2.38 times. Both case-control and before-after studies indicated that threatened abortion and premature delivery did not significantly relate to treatment of celiac disease. CONCLUSIONS: The high incidence of abortion, of low birth weight babies, and of short breast-feeding periods is effectively corrected by gluten-free diet in women with celiac disease.

http://www.ncbi.nlm.nih.gov/pubmed/8677936

The study included 132 women (average age 38.5 years) with celiac disease observed in the period from 2000 to 2010. Comparison group consisted 105 women (average age 38.7 years) with predominantly functional bowel disorders (irritable bowel syndrome, functional constipation, functional bloating, inert colon). RESULTS: The average age of onset of menses was 14.3 years, and in the control group 13.0 years. In 61.3% of patients with celiac disease was irregular menstrual cycle while in the comparison group such violations were noted in 13.3%. Prolonged periods of amenorrhea we observed in women with newly diagnosed celiac disease 3 times more likely than the comparison group: 43.9% and 11.4% respectively. They also had nearly 3 times more likely to occur spontaneous miscarriage: at 46.9% and 14.3% respectively. The frequency of reproductive disorders increased with the growth of the severity of malabsorption syndrome. In 43% of women after 6-8 months of strict adherence to a gluten free diet had disappeared amenorrhea and there were regular menses. Three women of childbearing age, strictly abided the gluten free diet and had a history of repeated spontaneous abortion during the year managed to get pregnant and give birth to healthy full-term baby.

http://www.ncbi.nlm.nih.gov/pubmed/21695947

Gluten free diet normalizes miscarriage risk in celiac disease

The mean number of children born to patients with celiac disease was significantly less at 1.9 compared to 2.5 in controls. Beforediagnosis the mean number of children born to patients was 1.4 and 1.8 in controls. After diagnosis and treatment, patients had 0.5 children compared to 0.7 in controls. It seems likely that the overall difference in fertility is due to relative infertility prior to diagnosis and its correction by a gluten-free diet. Significantly more conceptions amongst women with celiac disease (15%) ended in miscarriage prior to diagnosis than amongst controls (6%). After diagnosis and treatment the rate of miscarriage was similar. There were 120 live babies and 7 stillbirths to patients compared with 161 live babies and 1 stillbirth to controls. CONCLUSIONS: Patients with celiac disease are subfertile and have an increased incidence of stillbirths and perinatal deaths.

http://www.ncbi.nlm.nih.gov/pubmed/8783766

Gluten free diet improves pregnancy outcome in coeliacs

Available literature data show that celiac disease is a frequent cause of recurrent miscarriage. However, data are lacking for pregnancy outcome when the patient is on a gluten free diet. A case-control study about the effect of gluten free diet on pregnancy was conducted from 1995 to 2006. A cohort of 13 women (mean age 32 years, range 22-38 years) affected by celiac disease with recurrent miscarriages was observed. In all of them several causes of miscarriage (gynaecological, endocrine, haematological, etc.) were excluded. All patients were started on a gluten free diet and were reassessed throughout a long-term follow-up period to evaluate the outcome of pregnancy. RESULTS: Six of 13 became pregnant as follows: 1 patient 1 year after gluten free diet was started, 3 patients 2 years after gluten free diet was started, 1 patient after 3 years, and finally 1 4 years after GFD was started. Moreover, two patients had multiple pregnancies (one had had two childbirths and another had undergone three births within a 7-year follow-up period under gluten free diet). CONCLUSIONS: Gluten free diet seems to favour a positive outcome of pregnancy in most celiac disease patients with recurrent miscarriage.

http://www.ncbi.nlm.nih.gov/pubmed/18368491

Seventy-six adult celiac patients were analysed according to nutritional status and to gluten-free diet adherence. As controls, 84 adults and 22 adolescents with irritable bowel syndrome were used. The significant findings were observed as follow: adult celiac patients, irrespective of the nutritional status, were younger than controls, presented delayed menarche, secondary amenorrhea, a higher percentage of spontaneous abortions, anaemia and hypoalbuminemia. No differences were observed regarding the number of pregnancies, age at menopause and duration of the reproductive period. After treatment, patients presented with normal pregnancies and one patient presented spontaneous abortion. The adolescents who were not adherent to gluten-free diet presented delayed menarche and secondary amenorrhea. In conclusion, gluten per se could explain the disturbances and malnutrition would worsen the disease in a consequent vicious cycle. Therefore, celiac disease should be included in the screening of reproductive disorders.

http://www.ncbi.nlm.nih.gov/pubmed/15232359

The effect of celiac disease and its treatment on fertility and pregnancy in 74 patients is reported. Those on a normal diet had a shorter reproductive period, were relatively infertile, and had a higher incidence of miscarriage than those on a gluten free diet. Although maternal health did not appear to be seriously impaired by pregnancy in undiagnosed coeliacs, those on a gluten free diet had significantly fewer symptoms and had heavier babies.

http://www.ncbi.nlm.nih.gov/pubmed/7134839

Celiac disease more common in recurrent miscarriage

To determine the presence or absence of subclinical autoimmunity in Caucasian Argentine healthy women with first trimester recurrent miscarriage, the sera of healthy women with a history of three or more consecutive abortions and fertile control women without abortions and two children were analysed for the presence of autoantibodies. RESULTS: There was no significant difference between controls and patients with antinuclear, antismooth muscle, antimitocondrial, antiliver-kidney-microsomal fraction, antineutrophil cytoplasmatic and antigastric parietal cells. The prevalence of anticardiolipin antibodies in recurrent miscarriage was significantly higher than controls and the prevalence of positive antibodies for antigliadina type IgA and IgG and IgA antitransglutaminase in recurrent miscarriage was significantly higher than controls. CONCLUSION: We show that Caucasian Argentine women with recurrent miscarriage showed significantly higher incidence of anticardiolipin antibodies than normal controls and finally we recommended the screening of IgA and IgG antigliadina and IgA antitransglutaminase antibodies in pregnancy, because of the high prevalence of subclinical celiac disease in recurrent miscarriage and the chance of reversibility through consumption of a gluten free diet.

http://www.ncbi.nlm.nih.gov/pubmed/16451354

Treatment

Antiphospholipid Antibodies

What are Antiphospholipid Antibodies?

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

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 with 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 a stomach ulcer you need to inform me prior to commencement of the programme.

Clinic Fees

  • Initial consultation – £350 (a deductible £100 deposit is required to secure this appointment)
  • Follow up consultation – £200
  • Immune tests- tests range from £150 to £700 each
  • Wellbeing tests- tests range from £60 to £155 each
  • Hormonal tests – tests range from £87 to £105 each
  • Non-invasive Fetal DNA testing- £450
  • Initial scan – £235
  • 3D saline scan – £450
  • HyFosy – £475
  • 3D saline scan + Hyfosy – £625
  • Early pregnancy scans (includes consultation) – £290
  • Nuchal scan (includes blood tests) – £360
  • Anomaly scan- £360
  • Growth scans package (28, 32 and 36 weeks) – £760

    Fetal Medicine scan packages are available on request.
  • Manual Vacuum Aspiration (MVA) – from £1893
  • Hysteroscopy – from £1300
  • Initial consultation –  £285
  • Nurse consultation – £200
  • IVF cycle-  From £3950 (excludes initial and nurse consultations medications,  pre-IVF investigation tests)

    IVF packages are available on request.
  • Initial consultation –  £285
  • Nurse consultation – £200
  • IUI cycle-  From £1200 (excludes initial and nurse consultations medications,  pre-IUI investigation tests)

    IUI packages are available on request
  • Sperm DNA Integrity- £490
  • Semen Analysis- £225
We accept insurance policies from BUPA at CRP Clinic.

Consultations are billed under Professor Shehata’s provider number: 04346007

Tests and investigations are billed under The Miscarriage Clinic’s provider number: 60012322

Please Note:
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  • Contact your insurer before your initial consultation to verify coverage.
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