Plasmapheresis for miscarriage and infertility

The problem of miscarriage is one of the most urgent problems of obstetrics. Its frequency is 15-20% of all pregnancies, and the frequency of infertility – in 5-11% of marriages [Kon'kov D.G. et al., 2008]. 30-40% of these abortions are "unexplained» [Kutteh W.H. et al., 1999].

Among the etiological factors observed anatomical abnormalities of female genitalia, chromosomal pathology, infectious disease, neuroendocrine pathology, antiphospholipid syndrome. We shall mention only those in the elimination of which can be used apheresis therapy, especially using plasmapheresis.

Virtually all of the above complications of pregnancy to some extent also threaten miscarriage or premature birth. This is also characteristic of preeclampsia and revitalization hidden genital infections, and Rh-conflict. In all these cases the pathogenesis of disorders is reduced to the accumulation in the body of a pregnant pathological products and apheresis therapy that promotes their excretion, and provides the best conditions for the continuation of pregnancy.

Often threatened abortion occurs due to inadequate treatment as in the case of ovarian hyperstimulation syndrome, and this situation could also be eliminated with plasmapheresis.

Cause late miscarriages may be intrauterine "bullish" infection with the development of chorioamnionitis and exudative effusion in the placenta and umbilical cord, and then in the fetus itself. In placental hemorrhage occur with edge placental abruption with acute disorders of utero-placental and feto-placental circulation. Infection of amniotic fluid leads to rising microbial colonization of the airways of lungs with the development of bronchiolitis and perifocal desquamation interstitial pneumonia. Among the pathogens note Staphylococcus aureus, Enterobacter, yeast Candida, Klebsiella, Pseudomonas aeruginosa and Corynebacterium [Glukhovets N.G., 1998].

However, the causes of miscarriage may be autoimmune mechanisms. Sex hormones play a different role in the pathogenesis of autoimmune diseases. In animal experiments established that estrogens provoke some autoimmune processes affecting steroid receptors in specific CD8+ T-lymphocytes, and CD5+ B-lymphocytes. However, autoantibodies are present in sera of patients without symptomatic autoimmune disease also. Abnormal levels of autoantibodies may be accompanied by not only obvious, but also preclinical or subclinical autoimmune disorders.

This concept has been supported by the recent discovery of abnormal autoantibody levels in clinically healthy group of women who were, however, different forms of reproductive disorders. These women have the large number of different autoantibodies accompanied repeated "habitual" miscarriage, endometriosis, early ovarian function disorders, unexplained infertility, in vitro fertilization and embryo implantation failure [Geva E., et al., 1997].

Let us consider the most important autoimmune processes that contribute to infertility and miscarriage.

        Antiphospholipid autoantibodies (APA). Known for their relationship not only with recurrent venous and arterial thrombosis (pulmonary embolism, Budd-Chiari syndrome, thrombosis of the renal veins), but also with the usual spontaneous abortions, intrauterine fetal growth stop, "missed abortion", preeclampsia, thrombocytopenia [Hizroeva D.H. et al., 2003]. APA most often include two types of autoantibodies – anticardiolipin and lupus anticoagulant. 

They are found in about 2% of women with normal pregnancy [Lockwood C.J. et al., 1989]. At the same time, in pregnant women with preeclampsia frequency of antiphospholipid antibodies reaches 63.5% [Ponomareva I.V. et al., 2000], and the combination of intrauterine growth retardation with hypertensive disorders in pregnancy, this rate reaches 90% [Chaika V.K., Demina T.N., 2004].

Not organ-specific autoantibodies and, especially, APA, are one of the causes of recurrent miscarriage. Immunopathogenetic mechanism which leads to early miscarriage in patients with APA may be determined by the utero-placental thrombosis and vasoconstriction due binding antibodies with membrane phospholipid as well as endothelial cells and platelets. This reduces the production of prostacyclin by endothelial cells, increased platelet thromboxane production, reduced the activity of C-protein, which is a physiological anticoagulant inactivating procoagulants – factor Va and VIIIa [Kutteh W.H. et al., 1999]. This leads to instability of the membrane and increase platelet aggregation and inhibition of endothelial prostacyclin synthesis. In addition, the process can cause inhibition of prekallikrein and endothelial release of plasminogen. It may also affect the process of implantation of embryos at the endometrium.

N. Gleicher et al. (1989, 1994) studied the relationship between unexplained infertility and miscarriages with autoimmune disorders. Autoantibodies were detected such as lupus anticoagulant, antibodies to cardiolipin, phosphatidylserine, phosphatidylethanolamine, histones, to DNA and polyinosinic polydioxythymidylic acids – in 88% of patients with infertility and miscarriages with 70.8%. They reported and unusual frequency gamma-pathy (type IgM) in 38.5% and 45.8% of these patients, respectively. They concluded that some patients with unexplained infertility and miscarriages suffer polyclonal activation of B-lymphocytes and thus confirmed a causal relationship this autoimmune disorders with obstetric pathology. Even in cases where autoantibodies for some reason can not be determined, increased 1.5-2 times the level of the circulating immune complexes (CIC) may also indirectly indicate an autoimmune nature of "unexplained" infertility [Lubyanaya S.S. et al., 2006].

It is usually assumed that the spontaneous abortions in the first trimester of pregnancy are the result of chromosomal abnormalities. However, damage to the antiphospholipid antibody phospholipids of cell membranes trophoblast villous "opens" for their cytotoxic effects of maternal immune cells in the first trimester to the 8th week of pregnancy [Hasegava I. et al., 1990]. Circulation antiphospholipid antibodies even more often found in a group of early miscarriage in 43.1% of patients in the group, and even earlier pre-embryous loss (35.7%) than in the group of late miscarriage (22.4%). Characteristically, most of these women initially treated for infertility, while 15% of them have been repeated attempts in vitro fertilization [Makatsaria A.D. et al., 2005].

Clinical studies have shown that the causes of early miscarriages were not anticardiolipin and anti-phosphatidylserine and antip-hosphatidylethanolamine antibody. Phosphatidylethanolamine is one of the major components for both peripheral and inner layers of the cell membrane. However, these specific antibodies contribute not so much direct damage phosphatidylethanolamine much damage high molecular weight kininogen, factor XI or prekallikrein. In this kininogen-dependent antibodies stimulate antiphosphatidylethanolamine thrombin-induced platelet aggregation [Sugi T. et al., 1999].

Histologically revealed pronounced signs peri-villous thrombosis, vascular emptiness of terminal villi, their chronic inflammation [Salafia C.M. et al., 1997]. In addition to thrombosis and hemorrhage detected in inter-villous spaces retro-placental hematoma, extensive infarction and necrosis of placenta [Chaika V.K., Demina T.N., 2004]. This leads to early thrombosis of uteroplacental vessels with nutrition disorders and death of the embryo. Besides influence violations receptor function of endothelial cells and trophoblasts, as well as the impact of intrauterine autoantibodies affecting the embryonic development of the fetus and are the cause of repeated implantation failures that do not rightly interpreted as infertility [Taylor P.V. et al., 1989; Birkenfeld A., Mukaida T. et al., 1994]. In addition to blood supply disorders and fetal nutrition, it can happen also the direct effects of antiphospholipid autoantibodies. So, L.F.Akanli et al. (1998) described five cases of cerebral infarcts in newborns whose mothers showed increased concentration of anticardiolipin antibodies.

Antiphospholipid antibodies can bind to the cells of the trophoblast and hurt them in damage of the placental barrier, which becomes passable for CIC, viruses, bacteria, auto- and isoimmune antibodies. Antiphospholipid antibodies are a class of IgG-globulin and cross the placenta, giving the fetus the same effect as in the mother's body [Sidelnikova V.M., 2005]. Transplacental transfer of maternal antibodies to the fetus can cause vascular thrombosis of any location, including the aorta, renal arteries, cerebral arteries and the superior sagittal sinus, in the portal system. While antiphospholipid antibodies in the blood of the newborn may be delayed for a period of 3-6 months. On the other hand, in the "reverse" direction through impaired placental barrier can penetrate fetal antigens of fetus that promote sensitization with the development of fetal maternal antibodies, which further exacerbates the development of the fetus. [ChaikaV.K., DeminaT.N., 2004].

Surface of the apical membrane of placental villi facing the uterine intervillous circulation, normally covered by special anticoagulant protein – annexin-V. In studying these villi in the placenta at caesarean section extracted, J.H.Rand et al. (1997) found that in patients with antiphospholipid syndrome annexin-V content is significantly lower than in healthy women. During the incubation of tissue culture placental villi of normal placentas with antiphospholipid IgG for 24 hours showed a significant decrease of this apical annexin-V. Furthermore, there was founded the inhibition of cell proliferation of human umbilical vein endothelial cell culture containing anticardiolipin antibodies [Arakawa M. et al., 1999].

Available block of annexin-V specific anti-annexin-V antibodies are described in connection with recurrent miscarriage and systemic lupus erythematosus. These antibodies can facilitate the transition of anionic phospholipids on the inner and outer shell membranes promote apoptosis umbilical vein endothelial cells. When this happens there is also escape on membranes procoagulant phospholipid – phosphatidylserine [Cheng H.-M., 1997]. Such "externalizing" phosphatidylserine upon activation of platelets and macrophages leads to activation of their surface coagulation factors X and V, and also prothrombin [Vogt E. et al., 1997]. Removal of annexin V under the influence of antiphospholipid antibodies from the surface of trophoblast makes it procoagulant. In addition, they depress the formation of syncytia, hormone production and invasion of the decidua. The result is a placental insufficiency, leading to stop development of the fetus, preeclampsia and abortion [Rote N.S., 1997; Rogachevsky O.V. et al., 2005]. In antiphospholipid syndrome prematurity observed in 2.5 times more frequently, in 3 times more common an infants malnutrition and all cases of malnutrition III degree [Ponomareva I.V. et al., 2000].

Antiphospholipid syndrome predisposes also to severe preeclampsia [Romano G. et al., 2007]. In addition, there is possible development and the so-called catastrophic antiphospholipid syndrome with severe progressive multiorgan failure [Makatsaria A.D., et al., 2003]. Preeclampsia on the background of antiphospholipid syndrome in 71.5% of cases there were signs of placental insufficiency with intrauterine fetal development  retardation [El’skaya S.N., 2009].

Failure of implantation of embryos in vitro fertilization B.Fisch et al. (1991) explained the possible effect of ovarian hyperstimulation – stimulating effect of high doses of estrogen on the development of autoantibodies. They determined the level of APA during the early follicular phase, during the expected peak levels of E2 and 14 days after the egg retrieval. But these findings also show high initial level of APA before treatment still.

Because the pathogenesis of complications of pregnancy in antiphospholipid syndrome plays a leading role hypercoagulation, there are widely used anticoagulant and antiplatelet drugs on the background of corticosteroids [Sapina T.E., Mishchenko A.L., 1999]. Nevertheless, the conventional therapy with immunological reactivity suppression of corticosteroids and correction of hemostatic anticoagulants and antiplatelet agents are not always effective and fraught with acute exacerbation of chronic endometritis with the risk of intrauterine infection of the fetus. Moreover, there is evidence that glucocorticoids administered to a pregnant woman may help to delay the growth and development of the fetus, which was confirmed in special experiments on animals [Jobe A.H. et al., 1998].

Antiphospholipid syndrome, in addition to the danger of recurrent miscarriage, may also be accompanied by pulmonary vessels thromboembolism in the development of deep vein thrombophlebitis of the lower extremities and pelvis, the frequency of which is from 1.5 to 2.7 per 1,000 pregnant women and from 2.8 to 18.3% in of maternal mortality [Makarov O.V. et al., 1999].

S.A. Laskin et al. (1997) attempted to use prednisone and acetylsalicylic acid in pregnant women with APA and do not succeed, because the frequency of live births, not significantly increased, but premature in the main group was 62% compared with 17% in the control. In addition, there is information on the effects of aspirin on the fetus, causing hemorrhagic condition in newborns. Moreover, there are more likely develops hypertension (13% vs. 5%) and diabetes (15% versus 5% in control group). S. Cowchock (1997), leaving the possibility of the use of heparin in the presence of signs of thrombosis, urged caution with the appointment of prednisone and immunosuppressive therapy (including immunoglobulins) in pregnancy. Efforts were even attempts to use traditional Chinese therapy, which led to some reduction of antiphospholipid antibodies [Takakuwa K. et al., 1997].

It should be emphasized the dangers of hormone therapy during pregnancy. Thus, G. Celsi et al. (1998) have shown that the penetration of glucocorticoids across the placenta to slow fetal growth and the emergence of hypertension in them as adults. There was described dysfunction of the hypothalamic-pituitary-adrenal axis in children whose mothers received during pregnancy hormone therapy. This was confirmed in experiments in which the use of dexamethasone in pregnant animals led to a decrease in neonatal weight loss, malnutrition and reducing renal glomeruli compared to the control. It is believed that the number of nephrons decrease in glomerular filtration rate, reduces the area that contributes to the development of essential hypertension. Obviously this explains the higher blood pressure (130 vs. 107 mmHg in the control) in the experimental animals were born.

G. Framton et al in 1987 described a case of when, after 10 unsuccessful attempts to maintain the pregnancy only after the introduction of plasmapheresis in the range of therapeutic interventions it was managed to prolong pregnancy up to 34 weeks with the healthy delivery. Later D. Fulcher et al. (1989), also after repeated unsuccessful attempts to save the pregnancy and fetal life using prednisone and aspirin, have succeeded only with the help of six sessions of plasma exchange, which led to a significant reduction of anticardiolipin antibody levels and stabilized placental blood flow, followed by a live birth.

Experience of Moscow Scientific Center for Obstetrics, Gynecology and Perinatology [Serov V.N. et al., 1999; Aghajanova A.A., Abubakirova A.M., 2000; Rogachevsky O.V. et al., 2005] in the treatment of 147 patients using plasmapheresis showed the possibility to obtain a reduction of activity of the autoimmune process with a significant decrease until the complete disappearance of lupus anticoagulant, CIC levels (26%) and immunoglobulins E, F, G (for 16-21%), normalization coagulogram, paramecium-time, disappearance of markers of DIC. Normalized indicators of oxygen transport, PaO2 and hemoglobin oxygen saturation [Abubakirova A.M., et al., 1999]. 

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