RU2319489C2 - Method for treating anemia during pregnancy - Google Patents

Abstract

FIELD: medicine, obstetrics.

SUBSTANCE: additionally to iron preparations which should be prescribed by taking into consideration the values of serumal iron and those of ferritin of blood serum one should introduce ceruloplasmin, its daily dosage being 100 mg. It should be injected intravenously, by drops, for the period of 5 d. Due to applying ceruloplasmin at the dosages declared and at a certain mode of injection the present innovation provides the adequacy and safety of therapy both for mother and for fetus, at severe form of iron deficiency anemia and, also, anemia of redistributed genesis that leads to decreased frequency of pathology during pregnancy, in the course of delivery and perinatal pathology at the absence of side effects of therapy conducted.

EFFECT: higher efficiency of therapy.

1 ex, 4 tbl

Description

The present invention relates to medicine, namely to drug therapy, and can be used in obstetrics for the treatment of anemia during pregnancy.

In recent years, the problem of anemia during pregnancy continues to be relevant in obstetrics due to the high frequency of this pathology and the absence of a tendency to reduce it. A significant amount of scientific research has been devoted to the problem of anemia during pregnancy, addressing the issues of etiopathogenesis, diagnosis, treatment and prevention of this disease. There are new views on the pathogenesis of this pathological condition. In particular, a number of researchers have found that anemia clinically occurring as iron deficiency is often anemia of chronic diseases (Alper, BS Using ferritin levels to determine iron-deficiency anemia in pregnancy. / BSAlper, R. Kimber, AKReddy // J. Fam. Pract. - 2000. - Vol. 49, N 9. - P.829-832). ACh is characterized by a low content of serum iron and transferrin, a decrease in transferrin saturation, an increase in serum ferritin, an increase in the accumulation of iron in the reticuloendothelial system (RES) (Besa, E.S. Treatment of primary defective iron-reutilization syndrome: revisited. / ECBesa, PW Kim, FIHaurani // Ann. Hematol. - 2000. - Vol. 79. - P.465-468). In recent decades, new methods have been developed for correcting the pathological processes accompanying anemia of pregnant women, and methods of alternative treatment of anemia are being increasingly used in practice, since traditional therapeutic tactics are long and not effective enough (Dvoretsky L.I. Iron deficiency anemia // Russian Medical Journal, Volume 5, No. 19, p. 1234-1241). Nevertheless, despite the success in studying certain aspects of this pathology, one of the tasks of obstetrics at the present stage remains the search for new, highly effective means and methods for correcting anemia during pregnancy.

There is a method of treating anemia during pregnancy by the use of recombinant erythropoietin preparations (Pavlov, AD Erythropoietin: achievements and prospects // Hematology and transfusiology. - 1997. - No. 1. - P.25-29). The development of a domestic test system for determining the level of endogenous erythropoietin and the development of recombinant erythropoietin (REPO) preparations have expanded the possibilities for studying this new link in the regulation of hematopoiesis. To date, some experience has been gained with the use of REPO drugs for the correction of anemic conditions in pregnant women, puerperas and premature babies.

However, the known method has several disadvantages.

Firstly, the known method is effective only in case of anemia caused by inadequate production of erythropoietin in the body and a violation of its metabolism. In addition, the problem of using this drug is its high cost, since the production of REPO is associated with a complex technological process, including the stages of biosynthesis, purification and quality control of the drug. In accordance with this, the optimal doses and regimen of REPO administration, the criteria for predicting a positive response to treatment and priority groups of patients with the best prognosis regarding the response to therapy, quality and life expectancy require clarification, that is, the technique for widespread use of this drug in practical medicine is still under development (Efficacy and Satety of intravenously administered iron sucrose with and without adjuvant recombinant human erythropoietin for the treatment of resistant iron-deficiency anemia during pregnancy. / C. Breymann, E. Visca, R. Much, A. Huch // Am .Y. Obstet. Gynecol. - 2001. - Vol. 184, N 4. - P.662-667).

For the prototype of the invention, a well-known method of treating anemia during pregnancy, including the appointment of iron preparations (Shekhtman, MM Anemia in pregnant women // Gynecology. - 2004. - T.6, No. 2. - P.69-72).

The known method of treatment is as follows. The patient is prescribed sufficient doses of iron preparations, depending on the severity of anemia for a long time. The most physiological are prolonged salt preparations containing ferrous iron (fenules, sorbifer durules, tardiferon, ferrogradumet, etc.) and a ferric hydroxide-polymaltose complex of ferric iron (ferrum lek). The daily dose for the treatment of mild anemia is 60-100 mg of elemental iron (2 capsules of fenyuls or 1 tablet of ferrum lek per day), in case of severe anemia - 200 mg of elemental iron (2 tablets of ferrum lek per day or ferrous iron in a similar dose).

However, the known method has the following disadvantages.

As a rule, iron preparations are taken for a long time (over several months) and in some cases are unsuccessful (Iron deficiency anemia and pregnancy. / Zh. A. Sopoeva [et al.] // Probl. Pregnancy. - 2002. - No. 6 . - S.13-18). With ferrotherapy, a number of undesirable side effects and complications are possible: a metallic taste in the mouth, decreased appetite, darkening of the teeth and gums, dyspeptic symptoms, pain in the epigastric region, and in rare cases, necrosis of the intestinal mucosa. Unreasonable intake of iron-containing drugs, especially against the background of hypovitaminosis, helps to reduce the concentration of copper and disrupt the functioning of superoxide dismutase, ceruloplasmin, cytochrome oxidase and other copper-containing enzymes. Excess iron causes a decrease in the concentration of manganese, molybdenum, aluminum, magnesium and phosphorus, catalyzes the lipid peroxidation and contributes to an increase in the concentration of hydroxyl radicals. Excessive saturation of apolactoferrin with iron leads to a decrease in its bactericidal properties (Iskritsky, AM On the pathogenesis of pregnant anemia in modern conditions. / AMIskritsky, S.E. Sorokina // Materials of the 5th Mother and Child Russian Forum, Moscow, October 6-10, 2003 g. - M., 2003 .-- P.78-79).

It is now recognized that existing recommendations for dosing iron supplements during pregnancy are overestimated and exceed the required amount of iron (Daily and weekly and reference-dose iron absorption in Berkeley, Ca. and Dakar, Senegal. / FEViteri, C. Mendoza, A .Guiro, S. Hercberg // FASEB J. - 1999. - Vol.13. - P.A536.4).

As a result, we can conclude that the appointment of iron supplements to pregnant women does not solve the problems associated with anemia - the injected iron may not be absorbed by the body, and there is a danger of increased oxidative stress.

The task of the invention is to reduce complications, increase efficiency and shorten the treatment of anemia in pregnant women.

The problem is solved in that in the known method of treating anemia during pregnancy, including the appointment of iron preparations, ceruloplasmin 100 mg is additionally prescribed daily intravenously dropwise for 5 days, iron preparations are prescribed taking into account the indicators of serum iron and serum ferritin.

The proposed method of treatment includes the introduction of ceruloplasmin (CP) - intravenous infusion of 100 mg of the drug in 200 ml of sterile 0.9% sodium chloride. During treatment, each patient received 5 intravenous infusions of the solution every day. The applied single dosage was justified in experimental and clinical studies carried out earlier on the basis of the FSUE NPO Microgen at the Nizhny Novgorod plant for the production of bacterial preparations ImBio, which proved its adequacy and safety. The duration of the course of the proposed therapy was justified by us experimentally. The criterion for choosing this number of infusions was the significant decrease in the intensity of lipid peroxidation processes and activation of the antioxidant defense system in blood samples that we found. The effect of stabilization of lipid peroxidation proved by us (decrease in the content of primary and final products of lipid peroxidation and an increase in the total antioxidant activity of blood serum) in vitro served as the basis for using the proposed course duration in a clinical setting.

The present invention meets the criterion of "novelty", since in the process of patent information research, no sources of patent and scientific and technical information were found discrediting the novelty of the proposed method.

The present invention meets the criteria of the invention of "inventive step", since in the literature there are no methods for treating anemia with the essential features of the present invention.

In recent years, a number of works have appeared that show that CP significantly accelerates the oxidation of ferrous iron and the formation of transferrin. Thus, this protein contributes to hematopoiesis due to ferrooxidase activity. In addition, its antianemic effect is realized through the stimulation of erythropoiesis and the protection of erythrocyte membranes; CP enhances the proliferation and differentiation of erythroid elements in the bone marrow. The erythropoietic effect of CPA is independent or little dependent on the level of erythropoietin in the blood (Klimova, E.V. Mechanism of the erythropoietic effect of ceruloplasmin: Abstract of thesis ... Candidate of Medical Sciences / E.V. Klimova. - Chelyabinsk, 2001). In studies of both domestic and foreign authors, the fact that CP is the main blood antioxidant, binds superoxide radicals and prevents lipid peroxidation of cell membranes (Krainova, T.A. Tseruloplasmin. Biological properties and clinical use. / T.A. Kraynova, L.M. Efremova. - N. Novgorod: Publishing House NGMA, 2002. - 32 p.).

CP is the only physiological factor that promotes the removal of iron from tissues and oxidizes it to a safe form (Role of ceraloplasmin in macrophage iron efflux during hypoxia. / J. Sarkar [et al.] // J. Biol. Chem. - 2003. - Vol .278. - P.44018-44024). Today, in addition to CPU, there are very few tools that promote the removal and neutralization of iron. Such drugs are only deferroxamine and phlebotomy (the bloodletting procedure known since ancient times). CP differs from them in that it is the only physiological factor.

The proposed method for the treatment of anemia during pregnancy allows you to get the following positive effect.

A total of 120 pregnant women with anemia were monitored, which were divided into groups depending on the method of treatment of this pathology. The first (main) group consisted of 80 pregnant women with anemia, the complex therapy of which, in addition to iron preparations, included CP, and the second (control) group included 40 patients with anemia who underwent only ferrotherapy (Galitskaya, SA Diagnosis and correction of iron deficiency states in women in the third trimester of pregnancy: Abstract of thesis ... Candidate of Medical Sciences / S.A. Galitskaya. - Ivanovo, 2004. - 23 p.).

Depending on the severity of anemia, all patients were divided into subgroups. In the main group, the first subgroup of pregnant women with mild anemia was 40 patients, the second (with moderate anemia) was 30 pregnant women and 10 people with severe anemia. In the control group, pregnant women were divided as follows: 24 patients with mild anemia and 16 patients with moderate anemia.

Under the influence of therapy by the proposed method, a positive dynamics was observed during anemia, namely: 55% of the examined women with mild anemia showed normalization of hemoglobin indices, i.e. in fact, we observed a complete clinical and laboratory recovery. Also, 13.33% of pregnant women with moderate anemia experienced a normalization of hemogram values. It should be noted that the proposed method facilitated in 80% of cases of moderate anemia its transition to a mild degree and also in 80% of cases of severe anemia, its transition to moderate anemia.

When analyzing the course of the gestational process, it was found that the use of the proposed method for the treatment of anemia plays a positive role in reducing the risk of developing gestosis, the threat of termination of pregnancy: in pregnant women who received CP, these pregnancy complications were observed 1.75 times less than in patients who were prescribed traditional anemia therapy.

Also, the pattern of the protective action of CP in relation to chronic foci of infection is traced, due to the fact that this enzyme is the main plasma antioxidant, whose therapeutic effectiveness has been repeatedly confirmed by clinical practice.

As a result of the study, it was found that the frequency of preterm birth in the group of women receiving therapy by the proposed method was significantly less (3.6 times) than in patients who underwent only ferrotherapy.

Surgical delivery in the group using only iron preparations was carried out according to indications associated with complication of the birth process, and the most frequent indication was the weakness of labor, not amenable to drug correction. When using the proposed method of treatment, indications for surgical delivery were mainly not associated with complications of pregnancy and childbirth.

An analysis of the course of the birth act revealed that in pregnant women of the main group, labor weakness was observed 2.31 times less often and in childbirth per vias naturalis than in patients receiving only iron preparations (p <0.001). The early discharge of amniotic fluid in pregnant women, in the treatment of which the proposed method was used, was encountered 3.11 times less than in the first group (p <0.001), which, apparently, indicates the activation of antioxidant enzymes and stabilization of cell membranes under the influence of CP , including in the fetal membranes. 4.59 times more often in the second group there was an excessively violent labor (rapid and quick birth) (p <0.05). Ruptures of soft generic tissues were 3.28 times less common in the main group.

The proposed method for the treatment of anemia was also effective against perinatal outcomes. So, mild asphyxia was 2 times less common in the group of children whose mothers were prescribed CP, compared with newborns in the control group.

When comparing the state of newborns, it turned out that perinatal encephalopathy of hypoxic genesis in newborns of the main group was detected 3.12 times less often than in children of the control group (p <0.001). Jaundice and respiratory distress syndrome were also significantly less common in the main group compared with the control. Intrauterine infection of the fetus was confirmed only in newborns from women who received ferrotherapy. Thus, the use of the proposed method for the treatment of anemia creates the most optimal conditions for the adaptation of newborns in the perinatal period.

As a result of the assessment of the development of children in the first months of life, a tendency towards a more harmonious development in the main group was revealed. So, the lag in the physical development of children born to mothers treated with the proposed method was noted less frequently than in the control. Perinatal encephalopathy with various syndromes was detected in the main group 1.7 times less than in the control group, and also 1.6 times less on the background of CP there was a lag in the psychomotor development of children. Our data are consistent with studies conducted on the basis of the State Institution of the Nizhny Novgorod Regional Children's Clinical Hospital under the leadership of the head. Department of Pediatrics and Neonatology CPC and PPS GU NGMA Doctor of Medical Sciences, prof. Vorobevoy V.A. and candidate of medical sciences Ovsyannikova O.B., who used CP in newborns with severe central nervous system damage of hypoxic-ischemic origin. Against the background of the use of the drug, newborns experienced a relative improvement, intoxication phenomena decreased in 60% of the children, liver sizes returned to normal, diuresis recovered, gastrointestinal syndrome stopped, the activity of the infectious-inflammatory process decreased, and bilirubin levels decreased.

Thus, a comparative analysis of the clinical course of pregnancy, childbirth and the condition of the newborn in patients with anemia in both groups convincingly demonstrated the feasibility of using the proposed method for the treatment of anemia.

We have studied the effect of the proposed method of treatment on hemogram indices and iron metabolism in the body. The use of CP in combination with iron preparations for anemia led to a significant increase in hemoglobin at all degrees of severity of this pathology. The study also revealed a significant increase in hematocrit and the number of red blood cells in response to the use of the proposed method of treatment.

As a result of the study, it turned out that the use of CP in conjunction with ferrotherapy led to a positive trend in iron metabolism. In the main group, a fairly pronounced increase in serum iron was observed. The transferrin saturation coefficient with iron also increased significantly more under the influence of the proposed method of treatment.

In a study of serum ferritin, it turned out that among patients with mild anemia in 45.31%, ferritin was below normal values (<10 ng / ml). In the subgroup of pregnant women with moderate anemia, 52.17% of patients had low ferritin values. In the group of patients with severe anemia, in 70% of the examined patients the values of ferritin were also reduced. The data obtained by us are consistent with modern studies devoted to the study of this problem, in which, as was noted earlier, it has been established that anemia, clinically proceeding as iron deficiency, is often anemia of chronic diseases.

Our studies have shown that with true iron deficiency anemia (initially low rates of ferritin), the use of the proposed method of treatment leads to a more pronounced increase in ferritin in comparison with ferrotherapy. Thus, in patients with mild iron deficiency anemia in the main group, an increase in serum ferritin occurred by 19.19%, in the group using only iron preparations - by 11.54%, with moderate anemia, the increase in ferritin in the main group was 21.33 %, in the control - 6.49%.

As a result of our study, we found a positive correlation between the level of ferritin before treatment and an increase in hemoglobin concentration as a result of the application of the proposed method of treatment (r = 0.60, p = 0.05), Table 1.

Dependence of the increase in hemoglobin on the initial level of serum ferritin in pregnant women with anemia.

Table 1. Patient groups The increase in hemoglobin, g / l Normal Ferritin Anemia True Iron Deficiency Anemia Mild Anemia The main group (n = 40) 16.1 ± 1.7 * 6.3 ± 1.9 Control Group (n = 24) 3.64 ± 1.3 3.54 ± 1.7 Moderate anemia The main group (n = 30) 17.5 ± 2.1 * 7.2 ± 1.8 Control Group (n = 16) 4.6 ± 1.5 4.4 ± 1.7 Severe anemia The main group (n = 10) 17.8 ± 1.9 * 7.3 ± 2.1

It is obvious that the higher the level of ferritin, the more significantly increased hemoglobin under the influence of the proposed method of treatment. With true iron deficiency (initially low ferritin levels), the hemoglobin level did not increase so significantly. It is characteristic that no similar correlative relationships were established in the control group. The data obtained indicate that the mechanism of action of CP in pregnant anemia consists not only in stimulating the development of hematopoietic stem elements, but also in the regulation of impaired iron metabolism.

Thus, our studies have proved that the use of the proposed method for the treatment of pregnant anemia can not only increase hemoglobin levels, but also saturate the depot with iron in a shorter time with true iron deficiency anemia, and with the redistributive nature of anemia, restore impaired iron metabolism, with a more pronounced effect in with respect to the increase in hemoglobin, it was possible to achieve precisely in patients with anemia proceeding according to the type of AChP.

Our own studies have demonstrated a pronounced positive effect of the proposed method of treatment on the processes of lipid peroxidation and the antioxidant defense system. So, against the background of the therapy, there was a significant decrease in Imax, the level of diene and triene conjugates, and the concentration of Schiff bases. Normalization of the total antioxidant activity of blood serum occurred in 99.5% of patients with mild anemia and in 77.5% of pregnant women with moderate anemia in the main group. Thus, the use of CP in combination with iron preparations in the treatment of pregnant anemia helps to restore the normal relationship between LPO and AOS protection, prevents the catalytic effect of administering large doses of ferrous iron, and normalizes the permeability of erythrocyte membranes, breaking the leading link in the pathogenesis of anemia during pregnancy.

A comparative analysis of the effects of the anemia therapy methods used by us revealed a pronounced positive effect of the proposed method of treatment on the ultrasound parameters of the fetus. So, in all pregnant women in the main group, a sufficient increase in coolant was observed. The increase in the average increase in BDP of the fetal head under the influence of the proposed method for the treatment of pregnant anemia occurred significantly more.

Our studies have shown that the use of the proposed method for the treatment of anemia led to the prevention of the development of VZRP and intrauterine infection of the fetus. Under the influence of ferrotherapy, indirect signs of FSF progressed, and in a number of cases, ZVRP and markers of intrauterine infection of the fetus were diagnosed. The above indicates the appropriateness of the proposed method for the treatment of anemia of pregnant women.

We also found that an improvement in the utero-fetal-placental blood flow was observed with the use of the proposed method for the treatment of anemia significantly more often than when using only iron preparations. It is necessary to dwell on the fact that normalization of blood flow in one of the affected uterine arteries was observed significantly more often in the main group, which indicates a positive effect of CP on utero-placental blood flow.

By our studies, we proved that the use of CP in combination with iron preparations helps to reduce the incidence of placental insufficiency, has a prolonged protective effect on hemodynamics in the mother-placenta-fetus system, and is an effective preventive measure in relation to the development of FPI.

The pathomorphological assessment of the placenta conducted by us showed that the use of the proposed method for the treatment of anemia allows maintaining the protective mechanisms of the mother-placenta-fetus system at the proper level, prevents their breakdown, thereby creating favorable conditions for the growth and development of the fetus.

Thus, the proposed method for the treatment of pregnant anemia can increase the effectiveness of therapy, and is also able to provide a therapeutic effect with the redistributive nature of anemia, when taking only iron preparations does not give a clinical effect.

The proposed method for the treatment of anemia is as follows. The patient is tested for serum iron, ferritin. Depending on the values of the specified parameters, certain doses of iron-containing preparations are prescribed (fenyls 1-2 tons per day, ferrum Lek 1-2 tons per day, sorbifer 1-2 - tons per day, etc.). Simultaneously with ferrotherapy, daily intravenous infusions of CP are prescribed for 5 days.

Clinical example:

Nizhny Novgorod perinatal center, maternity hospital №7

Examination card for anemia patient

Card number 17

FULL NAME. Yurchenko Irina Nikolaevna

32 years old

Specialized secondary education

Place of work housewife

House. Address N.Novgorod, st. Smirnova, 35, apt. 49

Story number 3968

Department of Pregnancy Pathology

Chamber No. 604

Diagnosis:

Pregnancy 23 weeks. Severe anemia. OASA. Scar on the uterus. Chronic pyelonephritis in senior remission. Chronic hepatitis B. Lues in history.

Pregnancy outcome: Urgent operative delivery in the head presentation about uterine scar failure.

Date received 04.16.03

Date of discharge 30.04.03

Complaints at admission: Weakness, fatigue, decreased performance, brittle nails, taste perversion.

Anamnesis of life

Born full-term

Menarche age 13 years

Menses established from 14 years old

The nature of the menstrual cycle is regular

Age of onset of sexual activity 17 years

Contraception: VMK 1998-2000

Fertile history

Real Pregnancy 7th

Childbirth is coming 3

Previous pregnancies ended: 1 - urgent delivery, 2 - spontaneous miscarriage in the period of 8 weeks. pregnancy with curettage of the uterine cavity, 3 - urgent surgical delivery due to premature detachment of the normally located placenta, 4 - spontaneous miscarriage in the period of 8-9 weeks. pregnancy with curettage of the uterine cavity, 5, 6 - medical abortion for up to 12 weeks. pregnancy, 7 - a real pregnancy.

Heredity is not burdened.

No occupational hazards.

Gynecological diseases: DMK with curettage of the uterine cavity, adenomyosis, colpitis.

Extragenital diseases: Chronic pyelonephritis, chronic hepatitis B, diffuse thyroid hyperplasia.

While the patient was in the hospital, 5 intravenous infusions of 100 mg of the drug “CP” in 200.0 ml of 0.9% sodium chloride solution were carried out daily.

Against the background of the treatment, there was a positive dynamics regarding the severity of the clinical symptoms of anemia, namely, the disappearance of sideropenic syndrome was observed, there was an improvement in well-being, increased exercise tolerance, normalization of performance, and physiological coloration of the skin and mucous membranes appeared.

Laboratory data

General blood analysis

Parameter Before treatment After treatment Norm during pregnancy Hb, g / l 68 90 > 110 Red blood cells, * 10 2,3 3.0 <3,5 Hematocrit% 19 26 <30

Indicators of iron metabolism

Parameter Before treatment After treatment Norm Whey, μmol / L 5.7 9.0 <11.5 Plasma saturation with iron,% 9.7 15,5 <25 Ferritin, ng / ml 7.1 9.5 <10

Parameters characterizing the processes of lipid peroxidation and the state of the antioxidant defense system.

Test indicator Indicator value Norm during pregnancy DC before treatment, units opt. S / mg total lipids 0.45 0.23 ± 0.07 DC after treatment, units opt. S / mg total lipids 0.32 OS before treatment, conventional units / mg of total lipids 4.85 2.5 ± 1.0 OS after treatment, conventional units / mg of total lipids 3.26 TK before treatment, units opt. S / mg total lipids 0,079 0.025 ± 0.01 TK after treatment, units opt. S / mg total lipids 0,052 Imax before treatment, mv 5.55 2 ± 0.5 Imax after treatment, mv 3.74 OJSCA before treatment, rel. 0,112 0.146 ± 0.02 AOA after treatment, rel. 0.125

Pregnancy Outcome: Surgery.

Indications for operation Cesarean section: Insufficient scar on the uterus.

The postoperative period is correct.

Discharged on the 8th day.

Macroscopy of the placenta:

The mass of the placenta is 490.0 g, dimensions 16 · 16 · 2.5 cm. The umbilical cord 48 · 1.5 cm, the attachment is central. Shell pink. Maternal surface with smoothed slices of dark red color. Placental-fetal coefficient = 0.16.

Histological examination of the placenta:

Knitting plate without inflammatory changes. The villi are small and medium in size, their vessels are dilated, full-blooded. There is a sufficient number of syntial growths.

Conclusion: Mature placenta with diffuse hyperemia of villi.

Information about the newborn:

Height 53 cm

Weight 3060

Apgar score 7/8 points

Extract for 8 days in satisfactory condition.

During the first year of a child’s life, there was no lag in his physical development.

Claims (1)

A method of treating anemia during pregnancy, including the introduction of iron preparations, characterized in that ceruloplasmin 100 mg is additionally prescribed, intravenously, drip for 5 days, iron preparations are prescribed taking into account the indicators of serum iron and serum ferritin.