Tactics of preparation for pregnancy of patients with antiphospholipid syndrome

If there is a suspicion of a primary antiphospholipid syndrome according to anamnesis: habitual miscarriage, episodes of thrombophilic complications, previous pregnancies with delayed fetal development, early onset of toxicosis of the second half of pregnancy, complications of pregnancy in the form of an abnormal placenta detachment, in early pregnancy with chorion detachment - a blood test is performed - a hemostasiogram and a definition of lupus anticoagulant. When determining lupus anticoagulant, a number of studies are conducted to confirm the immune or infectious nature of the lupus anticoagulant, since at present we do not have the technical capabilities of differential diagnosis. We conduct research to exclude infection, to identify the infectious causes of the appearance of antiphospholipid antibodies:

• Bacteriological study of mucus of the cervix;
• PCR-diagnostics from the cervical canal - herpes simplex viruses, cytomegaloviruses, chlamydia, mycoplasma, ureaplasma;
• Virusuria;
• Evaluation of the immune status;
• Evaluation of interferon status.

In addition to these studies, we make a determination of the spectrum of antibodies to phospholipids: anticardiolipin antibodies, antiphosphatidylserine, antiphosphatidylinositol, antiphosphatidylethanol, antiphosphatidylcholine, antibodies to phosphatidic acid. It is possible that for diagnostics this is not so important, but to determine the tactics of doing, it can be of considerable help. It is known that in the presence of antibodies to cardiolipin, pregnancy loss occurs later in pregnancy and through such complications as intrauterine growth retardation, toxicosis of the second half of pregnancy. And in the presence of antibodies to phosphotidylserine and phosphatidylcholine, early pregnancy loss is most often observed.

Given that virtually all patients with antiphospholipid syndrome have a persistent viral infection, the first stage of preparation for pregnancy is carrying out an antibacterial (if necessary according to the results of bacteriological research and PCR data), antiviral and immunomodulatory therapy.

Begin treatment from the complexes of metabolic therapy, systemic enzyme therapy for at least a month (vobenzim 5 dragees 3 times a day) is normalizing the parameters of the immunogram (use of T-activin, imunofana); normalization of interferon status by the use of individually selected inducers of interferon. It is advisable to use enterosorbents (enterosgel, ryacen RD, etc.).

After the therapy, we control the hemostasis and re-determine the lupus anticoagulant. Very often after immunomodulatory therapy, AFA activity decreases.

If the hemostasiogram changes after the therapy, antiplatelet agents and / or anticoagulants should be used , or a course of treatment with plasmapheresis should be performed . Of antiplatelet agents, aspirin, a prostaglandin synthetase inhibitor, is most often and most successfully used: it inhibits irreversible synthesis of thromboxane A, inhibits the release of platelets, and reduces the adhesion of platelets.

Contraindicated aspirin for peptic ulcer, hypertension, hypersensitivity to aspirin. The use of aspirin in the first trimester of pregnancy is debated, as its teratogenicity is not removed from the agenda, although most researchers believe that it can be used in small doses. In connection with the peculiarities of the accumulation of aspirin in the body, it should stop taking it 6-10 days before the expected delivery, sometimes there may be hemorrhagic complications in the mother and the fetus. But if, against the background of his admission, the threat of miscarriage begins, then such a patient may have hemorrhagic complications. Of the side effects of aspirin, nausea, pain in the epigastric region, erosive and ulcerative lesions of the stomach, allergic reactions (should be used with caution in bronchial obstructive syndrome), bleeding, thrombocytopenia.

The second class of antiplatelet agents are adenylate cyclase activators and phosphodiesterase inhibitors : curantyl, trental, nicotinic acid preparations, antispasmodics. Currantyl (dipyridamole) is one of the most commonly used antiplatelet agents after aspirin. Produced in the form of tablets or pills for 25 or 75 mg. Kurantil N differs from the usual curantil by more complete and rapid release of the active substance from the drug formula by reducing the content of hydrophobic substances in the shell, which accelerates its dissolution. The core is also supplemented with additives that enhance the breakdown of the tablet.

Curantil inhibits the activity of phosphodiesterase and adenosine deaminase, activates adenylate cyclase, which promotes the accumulation of cAMP and adenosine in platelets and smooth muscle cells of the vascular wall, preventing their inactivation. An increase in the content of cAMP in the smooth muscles of the vascular wall causes their relaxation. With the accumulation of cAMP in platelets, their aggregation, adhesion and release of aggregation activators, clotting factors and vasoconstrictors are prevented, while calcium is retained in membrane structures. In addition, quarantine affects the metabolism of arachidonic acid, increasing the synthesis of prostacyclin in the vascular wall and reducing the synthesis of thromboxane A2 in platelets by inhibiting thromboxane synthetase. This also reduces the adhesion of platelets to the vascular endothelium, subendothelium and collagen of the damaged vascular wall, increasing the life span of platelets, preventing their aggregation and blocking the release of bioactive substances. The drug also potentiates the antiplatelet and vasodilating effect of the endothelial factor, inhibits the aggregation of erythrocytes and, to a lesser extent, has a fibrinolytic effect due to the release of plasminogen from the vessel wall. Kurantil does not increase the tone of the uterus, increases renal blood flow, improves coronary and cerebral blood flow, normalizes CBS, reduces peripheral resistance, increases the contractile ability of the myocardium. An important property of curantyl is absence of embryotoxic effect.

Kurantil improves utero-placental and feto-placental blood flow, and also has an immunostimulating effect due to the induction of interferon biosynthesis.

Contraindications to the use of curantyl - acute myocardial infarction, unstable angina, heart failure, severe hypotension, hemorrhagic syndrome. Side effects of curantyl - nausea, vomiting, headache, tachycardia, diarrhea, lowering blood pressure, general weakness. When using the drug, you must exclude from the supply of coffee, strong tea and xanthine-containing products.

The third group of antiplatelet drugs include membrane stabilizing: rheopolyglucin and other low molecular weight dextrans, which, forming a monomolecular layer on the intima and formed elements of blood, reduce electrostatic tension, platelet aggregation capacity 2 hours after administration. The effect lasts a day. There is an increase in BCC, blood viscosity decreases, fibrin is inactivated by precipitation, fibrinolytic activity of blood is increased. When pregnancy significantly increases blood flow in the placenta.

Contraindications - allergy, thrombocytopenia, anuria.

Drugs do not penetrate the placenta and are therefore safe during pregnancy. Side effects are very rare, but the allergy to rheopolyglucin is occasionally observed.

Anticoagulants that can be used in obstetric practice are mostly unfractionated and low molecular weight heparin.

The unfractionated heparin is an anticoagulant of direct action, it blocks the biosynthesis of thrombin, reduces platelet aggregation, inhibits the activity of hyaluranidase, and, to some extent, activates the fibrinolytic properties of the blood. After administration of the drug subcutaneously, its peak action is observed after 3-4 hours. Heparin does not penetrate the placenta and has no effect on the embryo / fetus. Doses of the drug should be selected strictly individually. Possible intravenous and subcutaneous injection. Control of heparin efficiency can be performed by increasing the activated partial thromboplastin time (APTT) by 1.5-2.5 times compared with the norm. Of the side effects of heparin should be noted the development of osteoporosis, which is observed with prolonged use of heparin, even in small doses and in older persons. According to these authors, the incidence of symptomatic vertebral fractures was 2-3%. According to Monreal et al. (1994), in a small study, the incidence of spinal fractures was 15% with heparin at a dose of 10,000 units for 3-6 months.

Approximately 3% of patients (studies conducted outside of pregnancy), from those who received unfractionated, i.e. Normal, heparin had an immune, IgG-associated thrombocytopenia, which can sometimes be accompanied by extremely severe heparin-induced thromboses. The diagnosis of immune thrombocytopenia is difficult to put, but it can be suspected if the platelet count drops below> 100x10 ⁹ / or <50% of the baseline level 5-15 days after onset of heparin therapy. This complication arises due to the fact that heparin is susceptible to the influence of the anti-heparin factor of platelets - factor 4 (PF4). This is fraught with the formation of antibodies to the heparin + PF4 complex, which leads to immune thrombocytopenia and the development of thromboses.

One of the undesirable side effects of heparin is the depletion of antithrombin III with prolonged administration of heparin, which may also explain the lack of effect from the use of heparin, cause a state of hypercoagulation and thrombosis. An increase in the dose of heparin does not give an effect, and continuation of therapy can be dangerous.

In a large cohort study, the frequency of volume bleeding in pregnant women receiving heparin was 2%. The authors note that there may be a prolonged effect of heparin more than 28 hours after the last injection and the mechanism of this is not clear, because, as a rule, after 6-12 hours of heparin there. In this regard, it is recommended to stop taking heparin one day before the birth. In the event that labor occurs during the administration of heparin, it is necessary to have a 1% solution of protamine sulfate, which is injected slowly intravenously, and if the heparin content in the blood can not be determined, then more than one dose can not be administered at once. More than 1 ml. It should also be remembered that when heparin is monitored for activated partial thromboplastin time (APTT) in pregnancy, the response to heparin on the APTT is weakened due to the increased content of factor VIII and fibrinogen. The lack of action of heparin can mislead the doctor, because the level of APTT can be within normal limits with a significantly increased level of heparin.

Many complications can be avoided by using low molecular weight heparin. Low molecular weight heparin is obtained by depolymerization of heparin. The change in molecular weight has changed the pharmacodynamics and pharmacokinetics of the drug, they have a high bioavailability (98%, not 30% as heparin), a longer half-life, so they can be administered once a day outside of pregnancy. However, recent studies on the pharmacokinetics of low-molecular-weight heparin have shown that it is significantly different in the same women outside and during pregnancy, due to an increase in the volume of circulating plasma, an increase in the rate of glomerular filtration, and production in the placenta of heparinase. Low molecular weight heparin has a high clearance rate and a greater dilution volume, so the concentration of low molecular weight heparin reaching a peak decreases more rapidly, especially at the end of pregnancy. Therefore, it is more expedient to introduce low molecular weight heparin 2 times a day, after 12 hours. Low molecular weight heparin has a number of advantages over heparin: it does not possess an antithrombin property and does not cause hypocoagulation; the antithrombotic effect is mainly related to its effect on factor Xa and on the lipoprotein-associated inhibitor of coagulation; promotes the activation of fibrinolysis; less susceptible to platelet factor 4 and therefore does not cause immune-mediated thrombosis and, apparently, heparin-induced osteoporosis.

The control of the effectiveness of low-molecular heparin is carried out in the same way as with the use of heparin for APTT, ABP, TEG, anti-Xa, platelet count.

Out of pregnancy, patients with antiphospholipid syndrome use indirect anticoagulants and most often warfarin is a vitamin K antagonist. This drug can not be used in pregnancy, as it gives developmental defects (warfarin syndrome, ie, penetrates the placenta). The most dangerous warfarin for the embryo in the period of 6-12 weeks of pregnancy. Therefore, if a patient with history of episodes of thromboembolic complications has been taking warfarin, which has become pregnant, then there is not much danger for the embryo in the first weeks of pregnancy. The drug should be discontinued at the time of pregnancy and replaced with ordinary or low-molecular-weight heparin.

The greatest debate in the literature calls for the use of glucocorticoids in patients with antiphospholipid syndrome. Unambiguously, they should not be used outside pregnancy, as the cycle and ovulation are often disrupted. The first experience of the use of glucocorticides was published in 1983 (Lubbe, W., et al.), In 1985 (Branch D. Et al.). The use of prednisolone in a dose of 40-60 mg / day and aspirin at a dose of 70-80 mg / day gave good results - a favorable outcome of 20 women was in 60-80%. According to Pattison and Lubbe (1991), treatment in a larger group of women with prednisolone was successful in 87% of patients. However, the side effects of prednisolone were in all women in the form of a cushingoid syndrome, the appearance of acne, some had infectious, mild complications. This therapeutic regimen was used by many researchers and all noted the side effect of prednisolonotherapy, including gestational diabetes, hypertension, infectious complications. However, to cause such complications, doses of glucocorticoids should be more than 30 mg per day, used for a long time. At the same time, there are data on the absence of adverse effects of glucocorticoids on the mother and the newborn when using small doses of 5-10 mg of prednisolone. In pregnancy, there is an increased ability of the maternal plasma to bind glucocorticoids, which limits their transfer through the placenta, due to the high enzymatic activity of the placental barrier and active destruction in the liver, the effect on the fetus is negligible.

Glucocorticoids have a number of useful actions: anti-inflammatory, antiallergic, antishock, etc.

Antiphospholipid antibodies refer to IgG globulins, penetrate the placenta and exert the same effect on the embryo / fetus / placenta as on the mother's body - cause thrombosis, placental infarction, etc. Therapy with anticoagulants protects the mother from thromboembolism, but not the fetus, since they do not penetrate the placenta. Antiaggregants penetrate the placenta, but they can not always prevent hypercoagulation of the hemostasis plasma.

Therefore, it is considered expedient to use glucocorticoids in small doses, combining them with antiplatelet agents and anticoagulants, and when the effect of their combined use in optimal and safe doses is not sufficient to remove antiphospholipid antibodies, it is advisable to use plasmapheresis. Antibodies to phospholipids accumulate slowly, and one course of plasmapheresis is sufficient to remove the pathogenic effect of antiphospholipid antibodies by almost 3 months.

Plasmapheresis

Currently, efferent therapy methods, in particular, plasmapheresis have been widely used in the treatment of acute conditions and chronic diseases in surgical and therapeutic hospitals, and more recently in obstetric and gynecological practice.

Plasmapheresis was first proposed in 1914 by two independent groups of authors: Yurevich and Rosenberg and Abel et al. (USA), but the beginning of its clinical application only dates back to the mid-20th century due to the development of new technologies - centrifugation, plastic bags, highways, devices for continuous plasmapheresis. The term "plasmapheresis" is based on the Greek root apheresis, which means "deducing", "removing". Currently, therapeutic plasmapheresis is an operation for the selective removal of plasma from the peripheral blood of a patient with the aim of curative correction of its protein or cellular composition. For the first time, therapeutic plasmapheresis was used as a means of removing Y-globulin in order to treat increased blood viscosity in Waldenstrom disease. Currently, plasmapheresis is used for various pathological conditions - sepsis, syndrome of massive tissue dilatation, disseminated intravascular coagulation syndrome, exogenous toxicoses, autoimmune diseases, allergic conditions, atopic and infectious-dependent bronchial asthma, asthmatic status.

In total there are about 200 nosological forms, in which plasmapheresis is effective. Depending on the composition of the morphological substrate to be removed, the efferent methods of therapy can be divided into plasmapheresis - removal of plasma from peripheral blood, and cytapheresis - selective removal of various cellular elements from the peripheral blood. So, in a number of cases, granulocyteperesis (leukocytapheresis) - granulocyte removal, lymphocytapheresis - lymphocytes, blastocytapheresis - blast cell removal, myelocaryocytapheresis - separation of bone marrow suspension into cellular elements is used to correct the cellular blood composition in hemoblastosis, thrombocytosis.

The possibility of removing and reducing the rate of formation of immune complexes, circulating antibodies by the method of therapeutic plasmapheresis was a prerequisite for the application of the procedure in a number of pathological conditions characterized by immune disorders. For this purpose, therapeutic plasmapheresis was performed to reduce the content of isoantibodies in patients with bone marrow transplantation, with Rh and ABO incompatibilities, lymphocytotactic, anti-leukocyte antibodies, antibodies against renal transplantation. In gynecological practice, plasmapheresis has been used in the complex therapy of patients with pelvoperitonitis after septic abortion, gynecological operations. Studies of Abubakirova AM, Baranova II (1993) proved the effectiveness of plasmapheresis in the treatment of pregnant women with gestosis. Fedorova TA, successfully applied plasmapheresis for the treatment of patients with chronic recurrent salpingo-oophoritis. Tsagilova S.G. {1999) used plasmapheresis in the treatment of patients with recurrent viral infection during pregnancy. Single data in the foreign literature on the use of plasmapheresis during pregnancy relate mainly to the treatment of acute fatty liver disease, HELLP syndrome, thrombotic thrombocytopenic purpura.

The first work to correct immune disorders in pregnant women refers to the use of plasmapheresis in the treatment of Rh-sensitization for the prevention and treatment of hemolytic disease of the fetus and newborn. Based on the results obtained by different authors, one can judge the positive role of conducting plasmapheresis procedures for correcting hyperimmune disorders in women with a high degree of Rh-sensitization. Clinical experience shows that the number of operations of plasmapheresis, their systematic nature, as well as the total volume of plasma exfusion, is of some importance. It can be assumed that this results in some temporary depletion of the production of Rh-antibodies. Plasmapheresis can significantly reduce the titre of Rh antibodies in the blood of pregnant women, as a result of which the fetus reduces the severity of the hemolytic process. The prognosis for the fetus is most favorable when there are manifestations of Rh-sensitization after 30 weeks of pregnancy. However, during the subsequent rhesus-conflict pregnancy, the production of antigen-dependent antibodies can again increase, so it is advisable in these cases to systematically perform plasmapheresis during pregnancy, in order to correct the titer of Rh antibodies. Unlike Rh-sensitization, the rate of antibody formation in autoimmune processes is much lower, which creates prerequisites for the use of therapeutic plasmapheresis in pregnant women with antiphospholipid syndrome more successfully than with rhesus-sensitization.

The use of plasmapheresis can normalize the rheological properties of blood, reduce hypercoagulation, reduce the dose of corticosteroids and heparin, which is especially important for poor tolerance.

The following therapeutic effects of plasmapheresis are distinguished: specific, nonspecific and additional.

The specific effects of plasmapheresis are:

• detoxification (elimination of toxic substances, "deblocking" - natural detoxification systems, antioxidant effect - extracorporeal biotransformation of toxic substances);
• reocorrection (decrease of blood viscosity, increase of deformability of blood cells, reduction of aggregation characteristics of blood cells, reduction of total peripheral resistance);
• immunocorrection (elimination of antigens, antibodies, CEC, immunocompetent cells, "deblocking" of the immune system, change in the direction of the immune response);
• increased sensitivity to exogenous and medicamentous substances;
• diffusion - diffusion of metabolites from organs and tissues. Nonspecific effects of plasmapheresis include:
  • hemodynamic reactions;
  • redistribution of blood cells;
  • activation of the endocrine system;
  • stress reaction.

Additional effects are determined by the effects of infusion transfusion and medication required for the procedure of plasmapheresis. The use of transfusion and drug programs makes it possible to potentiate the therapeutic effect of plasmapheresis along with leveling out the negative impact of this procedure.

There are various modifications of plasmapheresis - cascade plasmafiltration, the principle of which is to isolate the primary filter of the plasma, from which high molecular substances (proteins, lipoproteins, circulating immune complexes - CIC) are removed on the secondary filter. In patients with neuroendocrinal disorders, diencephalic syndrome, obesity, specific sorption methods developed in recent years, in particular LDL-apheresis, which allow to remove atherogenic low-density lipoproteins, cholesterol, triglycerides, are of particular value. The difference between plasmapheresis and plasmafiltration consists in the simplicity of the necessary hardware, relative cheapness, the absence of the need for thorough heparinization of patients, and catheterization of large main veins.

For intermittent discrete plasmapheresis, refrigerated centrifuges "R-70", "R-80", "Juan" - France, plastic bags and containers "Hemakon-500", "Hemakon-500/300" with citrate preservative-glue, firm "Gemonetik", "Dideko", "Baxter", PF-01, based on the use of gravity.

Procedure for conducting plasmapheresis

Plasmapheresis can be performed by a discontinuous (discrete) or gravitational flow-continuous method.

The technique of intermittent plasmapheresis is as follows:

1. Puncture of the ulnar vein;
2. Introduction of plasma-substituting crystalloid and colloidal solutions. The ratio of the volume of the removed plasma to the volume of plasma-substituting solutions should be at least 1: 1,2- outside of pregnancy at pregnancy 1: 2. It is advisable in the program of plasma replacement in the II and III trimesters of pregnancy to introduce protein preparations - 100 ml of a 10% solution of albumin.
3. Exfusion of blood (400-500 ml) in plastic containers of the type "Hemakon-500/300".
4. Separation of blood elements from the plasma, carried out in a refrigerator centrifuge in soft centrifugation at a speed of 3500-5000 rpm.
5. Separation of plasma into a satellite bag;
6. Reinfusion of the blood cells, diluted with physiological solution.

It is advisable to repeat the procedure 2-3 times, which allows 600-900 ml of plasma to be removed in 1 session (without taking into account the hemoconvant). The course of treatment is 3 sessions of plasmapheresis. Indications for a second course of plasmapheresis are the results of clinical and laboratory studies of each patient.

Unlike intermittent, continuous plasmapheresis requires the catheterization of two veins. One venous access is necessary for the introduction of infusion media, the other for connection to a blood separator. The patient's blood enters the rotor of the centrifuge, in which its separation takes place, plasma is removed along one of the trunks, while others - the uniform elements are removed, which are mixed with plasma-substituting solutions, which through the second vein return to the bloodstream of the patient. Continuity of the procedure is ensured by constant operation of the rotor. During the procedure for the prevention of thrombosis, 5-10 thousand heparin are injected intravenously. With continuous plasmapheresis, a special system of trunks, collective bags (containers), an anticoagulant solution containing sodium citrate and dextrose, crystalloid, colloidal and protein solutions are used. In order to compensate for the deficit of BCC, infusion media of different directionality of action are introduced individually in each case taking into account the indications.

Contraindications to plasmapheresis

1. Expressed organic changes in the cardiovascular system;
2. Anemia (hemoglobin below 100 g / l);
3. Hypoproteinemia (protein level below 55 g / l);
4. Hypocoagulation;
5. Immunodeficiency conditions;
6. Allergic reactions to anticoagulants, colloidal and protein preparations.

Relative contraindications are absence of venous access, phlebitis of peripheral veins in the stage of exacerbation.

[1], [2], [3], [4], [5], [6], [7],

Complications associated with plasmapheresis

1. Collaptoid states, as a rule, are a consequence of inadequate plasma replacement of the volume of the removed plasma in patients with hypotension. In the event of collapse, the removal of plasma should be stopped and infusion therapy should be performed with crystalloid, colloidal and protein preparations.
2. Allergic reactions to the introduction of infusion media. In such situations, the administration of solutions is discontinued, the use of antihistamines and corticosteroids is indicated.
3. Anemia and symptoms of angina pectoris. It is necessary to carefully consider contraindications to conducting plasmapheresis in patients with anemia, in case of severe anemia - the introduction of a freshly prepared erythromass and the appointment of anti-anemic drugs.
4. Violations of electrolyte blood composition (hypocalcemia, hypokalemia), which can manifest cardiac arrhythmia. It is mandatory to control the levels of electrolytes and correct the violations.

The literature also describes such complications as pulmonary edema and acute heart failure in response to the introduction of large volumes of low molecular weight solutions in patients with extragenital pathology. The above complications dictate the need for a thorough examination of women before the procedure - determining the indications for its appointment, strict observance of rights, conducting plasmapheresis, the presence of trained and highly qualified personnel

The experience of using intermittent plasmapheresis in patients with antiphospholipid syndrome indicates normalization of hemostasiological, immunological, biochemical parameters, detoxification effect, which makes it possible to use for optimization of therapy in women with habitual miscarriage. Research in this direction will be carried out in the future, which, perhaps, will allow studying and expanding the possibilities of using efferent therapy methods in obstetric practice.

Thus, at the stage of preparation for pregnancy, antibacterial, antiviral, immunomodulatory therapy and normalization of the parameters of the hemostasiogram are carried out, after which pregnancy is resolved. From Phase II of the proposed fertile cycle, we prescribe 5 mg of prednisolone or 1 tablet of metipred taken in the morning after breakfast to reduce the influence of prednisolone on the adrenal glands.

2 days before the expected menstruation, please make a pregnancy test and, if the test is positive, conduct a study of the hemostasiogram and determine the level of lupus anticoagulant.

The basis for determining autosensitization to the chorionic gonadotropin is the habitual miscarriage of pregnancy, the presence in the anamnesis of abortions, the use of gonadotropic drugs in order to stimulate ovulation; infectious and allergic diseases and complications.

Preparation for pregnancy is carried out in the same way as it is carried out with sensitization to phospholipids. A distinctive feature is the need for correction of luteal phase insufficiency, which is observed more often with anti-HC sensitization. It is recommended to conduct courses of systemic enzyme therapy. Disturbances in the system of hemostasis in patients of this category outside of pregnancy are very rare, but if they are, it is advisable to prescribe antiaggregants and / or anticoagulants. Glucocorticoids (prednisolone, metipred) are assigned to the second phase of the cycle after ovulation. Determined by the rectal temperature schedule. The dose is selected individually, taking into account the level of antibodies, anamnesis burden, individual tolerance. Typically, 5 or 10 mg of prednisolone in the morning after breakfast. Doses of 15 mg were administered extremely rarely with very high levels of antibodies.

Preparation for pregnancy can reduce the percentage of complications in the first trimester: the threat of interruption, the development of a chronic form of ICE, the duration of antithrombotic therapy, reduce the dose of glucocorticoids.

[8], [9], [10], [11], [12]