Management of pregnancy with antiphospholipid syndrome

During the first trimester, the most important period for autoimmune pathology, hemostasis is monitored every 2 weeks. From the 2nd day after ovulation in the conception cycle, the patient receives 1 t (5 mg) of prednisolone or metipre-alpha. Vitamins for pregnant women or metabolic complexes, folic acid and, if necessary, add antiplatelet agents and/or anticoagulants. Of the antiplatelet agents, it is preferable to use curantil N in a dose of 25 mg 3 times a day in the first trimester. If signs of hypercoagulation or RKMF appear, heparin is added to the treatment at 5,000 IU 3 times subcutaneously or LMWH (fraxiparin) 0.3 ml subcutaneously once a day or fragmin 0.2 ml (2.500 IU) 2 times subcutaneously until hemostasis parameters are normalized.

An alternative to anticoagulant and antiplatelet therapy is the use of rheopolyglucin 400.0 and 10,000 U of heparin intravenously by drip every other day - 2-3 drips. This therapy option can be used almost throughout the entire pregnancy to avoid long-term use of a combination of glucocorticoids and heparin.

Based on our own extensive experience and good clinical results in the treatment of this category of patients, we should dwell on some controversial issues of the treatment of antiphospholipid syndrome during pregnancy.

Monotherapy with unfractionated heparin or even in combination with aspirin does not provide such therapeutic success as desired. Monotherapy with LMWH (fraxiparin, fragmin) is preferable to heparin. According to Shehota H. et al. (2001), where the main type of therapy for antiphospholipid syndrome is aspirin and LMWH, the incidence of preeclampsia is 18%, intrauterine growth retardation is 31%, and premature birth is 43%, perinatal mortality is 7%.

According to research data, the frequency of complications for the fetus with different anticoagulant therapy regimens is different. Thus, when using warfarin with or without heparin, pregnancy loss was 33.6%, fetal defects 6.4%; heparin during the entire pregnancy from 6 weeks - no developmental defects were detected, the frequency of pregnancy loss was 26.5%.

Another debatable issue is the use of immunoglobulin in the treatment of pregnant women with antiphospholipid syndrome. All patients with antiphospholipid syndrome have a chronic viral infection. Due to the peculiarities of the course of pregnancy, the use of glucocorticoids even in minimal doses may reactivate the viral infection. Therefore, during pregnancy, it is recommended to conduct 3 courses of preventive therapy, which consists of intravenous administration of immunoglobulin at a dose of 25 ml (1.25 g) every other day for a total of 3 doses, simultaneously prescribing suppositories with Viferon. Small doses of immunoglobulin do not suppress the body's own production of immunoglobulins, but stimulate the body's defenses.

Re-administration of immunoglobulin is carried out at 24 weeks of pregnancy and before delivery. This is one side of the issue - the introduction of immunoglobulin to prevent the activation of a viral infection.

There is also a second side, the use of large doses of immunoglobulin to suppress the production of autoantibodies.

There is evidence that large doses of immunoglobulin suppress the production of autoantibodies and this method can be used instead of glucocorticoid therapy. There is a whole series of works on the effectiveness of using immunoglobulin. Thus, according to research data, the combination of using small doses of aspirin, heparin and intravenous administration of immunoglobulin at a dose of 1 g / 1 kg of weight for 2 days of each month of pregnancy up to 36 weeks, gave very good results - all patients successfully completed their pregnancy. The introduction of immunoglobulin began before 12 weeks of pregnancy, and these groups included patients who had the same therapy without immunoglobulin in previous pregnancies, which ended unfavorably for the fetus. However, there are many opponents of immunoglobulin therapy and their main provisions are that:

• Immunoglobulin is a very expensive drug, it is necessary to use large doses, and the cost of treatment ranges from 7,000 to 14,000 US dollars;
• there is a possibility of transmission of some viruses if the immunoglobulin is not prepared properly;
• there are complications from the administration of immunoglobulin in the form of headache, nausea, hypotension;
• The use of immunoglobulin does not significantly improve the outcome of treatment with heparin and aspirin.

Despite the objections, interest in immunoglobulin therapy is extremely high. Only the excessive high cost of this drug for our patients and the impossibility of using domestically produced immunoglobulin in large doses due to possible anaphylactic complications limit the use of this extremely effective method of therapy. When administering immunoglobulin, there may be complications in the form of allergic reactions, headaches, and often minor symptoms of acute respiratory disease. To prevent these complications, it is necessary to analyze the total levels of immunoglobulins in the blood of the IgG, IgM, and IgA classes. With a low IgA level, it is dangerous to administer immunoglobulin due to possible anaphylactic reactions. It is possible to recommend the administration of antihistamines before and after the administration of immunoglobulins, prescribe plenty of fluids, tea, coffee, juices, and antipyretic drugs for acute respiratory infections. As a rule, all complications disappear in a day or two. An integral part of pregnancy management in patients with antiphospholipid syndrome is the prevention of placental insufficiency.

The state of the fetoplacental system in antiphospholipid syndrome

The pathogenetic action of antiphospholipid antibodies is associated with thrombosis in the placental vessels with the formation of infarctions in the placenta and impaired blood microcirculation. The consequence of these disorders is the development of placental insufficiency. According to ultrasound examination, placental insufficiency is diagnosed when signs of fetal hypotrophy appear. However, a careful examination of the placenta allows us to identify the presence of infarctions, cysts, thinning, reduction of the placenta, placentitis and other changes that indicate a violation of the normal functioning of the placenta. Cardiotocography data are also informative in assessing the condition of the fetus in patients with antiphospholipid syndrome. In 70% of pregnant women, despite the therapy, one or another degree of chronic fetal hypoxia is detected. However, CTG data are informative only after 34 weeks of pregnancy. Ultrasound Doppler of fetoplacental blood flow has a great prognostic value in assessing the condition of the fetus. Ultrasound Doppler in various basins of the fetoplacental system is a valuable diagnostic method for assessing the condition of the fetus, can serve as a criterion for the effectiveness of the therapy and be one of the indicators determining the timing and methods of delivery. The study is conducted from 16-20 weeks with intervals of 3-4 weeks before delivery. If the hemostasiogram indicators worsen, Doppler is performed weekly to assess the effectiveness of the therapy.

The conducted studies of Doppler blood flow in the umbilical artery in dynamics in case of miscarriage have shown that "zero" and "negative" blood flow at any gestational age are extremely unfavorable signs in assessing the condition of the fetus, the therapy does not give an effect, which corresponds to the literature data. In such cases, if the gestational age allows, urgent delivery is necessary. The discrepancy between the blood flow indicators and the gestational age (both "advancement" and "lag") are also unfavorable signs requiring more intensive therapy to normalize blood flow, improve placental function and combat chronic fetal hypoxia. "Advancement" is considered significant with a difference of 8 weeks or more.

Thus, Doppler ultrasound of fetal-placental blood flow, carried out during pregnancy dynamics, allows us to evaluate the effectiveness of the therapy and more accurately determine the timing of delivery.

Prevention and treatment of placental insufficiency in patients with antiphospholipid syndrome should be carried out from the first trimester of pregnancy. The complex of preventive measures, in addition to antiplatelet and, if necessary, anticoagulant therapy, includes courses of metabolic therapy, carried out regularly throughout the pregnancy with two-week breaks.

For the treatment of placental insufficiency in patients with antiphospholipid syndrome, it is advisable to use such agents as intravenous administration of actovegin at a dose of 5 ml in 250.0 ml of physiological sodium chloride solution (course - 5 droppers every other day), alternating with instenon at a dose of 2.0 ml in 200.0 ml of physiological sodium chloride solution, also 5 droppers. It is advisable to use essentiale-forte intravenously by drip or jet slowly, or in capsules, troxevasin intravenously or in capsules.

Treatment of placental insufficiency should be carried out under the control of Doppler ultrasound of fetal-placental blood flow, hemostasiogram in order to assess the effectiveness of the therapy, select the optimal timing of delivery and avoid iatrogenic complications.

In case of placental insufficiency and lack of effect from drug therapy, it is advisable to perform plasmapheresis.

This management tactic and therapy before and during pregnancy allows us to complete pregnancy without serious complications in 95-96.7% of women with habitual pregnancy loss due to antiphospholipid syndrome.

Thus, the combination of several drugs with different effects in a minimal but effective dose allows for a better effect with fewer iatrogenic complications.

In recent years, there have been reports of the use of fish oil capsules in the treatment of patients with antiphospholipid syndrome in a dosage equivalent to 5.1 g of eicosapentaenoic acid (EPA) and decosahexaenoic acid (DHA) at a ratio of 1:1.5. EPA and DHA are unsaturated fatty acids obtained from marine plankton. They are able to competitively suppress the saturation and elongation of the alpha chain of the precursor of arachidonic acid - minoleate. Due to their ability to inhibit the formation of thromboxane A and platelet aggregation, these acids have antithrombotic activity.

Little experience with its use does not allow us to assess the preventive significance of this method of therapy.

It is extremely important when treating patients with antiphospholipid syndrome to get not only a living but also a healthy child, since without therapy, almost 90% or more pregnancies die and only 10% are born alive. Therefore, an important aspect is the assessment of the course of the neonatal period of children in mothers with antiphospholipid syndrome. In mothers with antiphospholipid syndrome, using modern treatment and diagnostic technologies, 90.8% of children are born full-term and do not have gross violations in the functioning of vital organs and systems. The deviations detected during the early neonatal period are assessed as a strain on the adaptation mechanisms caused by the peculiarities of the intrauterine period of development, which allows us to classify these children as a high-risk category for adaptation failure. Features of the endocrine status in the form of hypocortisolemia at birth (46%) and thyroid insufficiency (24%) are transient, as a rule, do not require hormone replacement therapy and disappear during the first month of life. Changes in the immune status, such as an increase in the blood content of T-lymphocytes (CD3+), T-helpers (CD4+), B-lymphocytes (CD19+), the proportion of cells expressing adhesion molecules (CD11 p+), an increase in the level of serum interferon with reduced interferon-producing activity of cells, are compensatory and adaptive in nature and indicate a tense state of the immune system during early neonatal adaptation, which is consistent with the tendency to develop infectious and inflammatory pathology.

In newborns born to mothers with antiphospholipid syndrome, it is advisable to conduct control studies to assess the pituitary-thyroid-adrenal system in the complicated course of the early neonatal adaptation period for timely corrective therapy. Changes in the immune status detected during the neonatal period allow us to recommend dispensary observation of these children for timely prevention of infectious and inflammatory diseases.

Prevention of thromboembolic complications after childbirth

The postpartum period is the most dangerous for the health of a woman in labor with antiphospholipid syndrome, since thromboembolic complications are observed more often than during pregnancy. In our practice, we have had all cases of thrombophilic complications in the postpartum period.

In order to prevent thromboembolic complications, it is necessary to continue taking prednisolone for two weeks at a dose of 5-10 mg. The hemostasis system is assessed on the 3rd-5th day after delivery. In case of severe hypercoagulation, it is advisable to conduct a short course of heparin therapy at a dose of 10 thousand or 20 thousand units per day subcutaneously for 10-12 days (fraxiparin, fragmin are preferable) and prescribe aspirin at 100 mg for a month.

It is necessary to recommend the mother a diet with restrictions on foods that increase the clotting potential of the blood, and a hemostasis test once every six months.

If joint pain, fever, proteinuria and other symptoms of autoimmune diseases occur, it is recommended to undergo examination by rheumatologists, since subclinical autoimmune disorders often precede manifest forms of autoimmune diseases.

"Catastrophic" antiphospholipid syndrome

Currently, along with the usual and secondary antiphospholipid syndrome, clinical and serological variants of antiphospholipid syndrome are distinguished (Asherman RA, 1997).

• "Catastrophic" antiphospholipid syndrome.
• Other microangiopathic syndromes:
  • thrombotic thrombocytopenic purpura;
  • hemolytic uremic syndrome;
  • HELLP syndrome (hemolysis, elevated liver enzymes, thrombocytopenia)
• Hypothrombinemia syndrome;
• Disseminated intravascular coagulation;
• Antiphospholipid syndrome combined with vasculitis.

"Catastrophic" antiphospholipid syndrome - a term proposed by Asherman RA in 1992, previously known as "devastating noninflammatory vasculopathy" (Ingram S. et al., 1987), is characterized by the development of multiple organ failure due to recurrent thromboses in various organs over a short period of time.

The combination of this syndrome with the development of DIC worsens the prognosis. The genesis of the "catastrophic" antiphospholipid syndrome is more complex compared to what occurs with antiphospholipid syndrome. It is believed that various cellular mediators (cytokines) responsible for the "explosion" of the clinically manifested inflammatory response with the development of multiple organ failure take part in its development.