RU2740852C1 - Method for prediction of preeclampsia in pregnant women with gestational diabetes mellitus - Google Patents

Abstract

FIELD: medicine.SUBSTANCE: invention refers to medicine, particularly to obstetrics and gynecology, and discloses a method for prediction of preeclampsia in pregnant women with gestational diabetes mellitus. Method involves blood testing of pregnant woman and determination of glycated fibronectin level and, in case, if pregnancy is accompanied by left-sided location of the placenta and the sex of the fetus is male, and the fibronectin level is 315 pmol/ml, the development of preeclampsia during pregnancy is predicted. Declared method enables timely preventive therapy that will have a favorable effect on perinatal outcomes and reduced incidence of newborns.EFFECT: invention can be used in prediction of preeclampsia in pregnant women with gestational diabetes mellitus in the second-third trimester.1 cl, 4 ex

Description

The invention relates to medicine, in particular to obstetrics and gynecology, and can be used in predicting preeclampsia in pregnant women with gestational diabetes mellitus in the second or third trimesters.

Gestational diabetes mellitus (GDM) accounts for 85.1% of all cases of hyperglycemia during pregnancy. Today GDM is an important medical and social problem, as it significantly increases the risk of obstetric complications, adversely affects the intrauterine state of the fetus, as well as the health and development of the newborn in the future [Dedov I.I., Krasnopolsky V.I., Sukhikh G.T. Russian National Consensus "Gestational Diabetes Mellitus: Diagnosis, Treatment, Postpartum Care". Diabetes. 2012. 4.]. Despite the advances in obstetric diabetology, the overall incidence of pregnancy complications and morbidity in newborns with GDM remains high. The course of pregnancy is complicated by the development of preeclampsia, placental insufficiency with the formation of severe forms, deterioration of the condition of the pregnant woman / fetus, which requires early delivery; the number of preterm births, perinatal morbidity and mortality is increasing [Coustan, D. Diagnosis and Management of Diabetes Mellitus in Pregnancy. Glob. libr. women'smed. 2016. DOI 10.3843 / GLOWM. 10162].

Preeclampsia still remains one of the most serious complications of pregnancy. Approximately 2-8% of pregnant women suffer from preeclampsia, which is the second leading cause of maternal mortality worldwide [Alves E., 2013; Amin S.V., 2014]. According to the results of the latest analysis of data from the surveillance system of the Center for Pregnancy Control and Disease Prevention, about 9% of maternal deaths are associated with preeclampsia and eclampsia [Anderson U.D., 2015].

The main treatment for preeclampsia is delivery. As such, it is the main cause of induced preterm labor and, as a consequence, low birth weight. Studies in this area show that with preeclampsia, 6% of the total number of births are premature, and 19% of the noted cases are premature births with fetal pathology [Jillian T. Henderson, 2017]. Most cases of preeclampsia are observed after 34 weeks of pregnancy, but morbidity and mortality are higher with an early onset of the disease [Baschat AA, 2014; Bateman W. T., 2012]. The concept of early (≥20 - ≤34 weeks of pregnancy) or late (≥34 weeks of pregnancy) onset reflects differences in the pathophysiology of preeclampsia [Steegers EA, 2010].

Early preeclampsia is characterized by a high incidence of placental insufficiency [Metcalfe A., 2013; Nanda S., 2013], abnormal blood flow of the umbilical and uterine arteries [Liang S., 2012; Poon L.C., 2010], abnormal angiogenic / antiangiogenic profile [Blankley R., 2009; Takeuchi F., 2012], limiting fetal growth [Jelin AS, 2010; Lisonkova S., 2013].

Late preeclampsia is believed to be the result of a discrepancy between the intake of nutrients from the mother and the metabolic requirements of the fetus at the end of pregnancy [Valensise N., 2008]. With late preeclampsia, usually both the placenta [van der Merwe J.L., 2010] and the fetus [Eskild A., 2009; Espinoza J., 2014] have a normal weight, the Doppler of the uterine and umbilical arteries in most cases is within the normal range [Valensise N., 2008]. Late preeclampsia is more common in obese patients [Durst J.K., 2016; Ornaghi S., 2013].

In order to reduce the complications of maternal and fetal health associated with preterm birth, it is important that the doctor has at his disposal markers that can help make decisions about prolonging pregnancy at an early onset of preeclampsia.

The search for biochemical markers of preclinical diagnosis of preeclampsia is still one of the important scientific and practical problems of modern obstetrics.

There is a known method for assessing the severity of preeclampsia by studying the platelet count in venous blood, when the level of thrombocytopenia is judged on the severity of preeclampsia (Report of the Working Group on Hypertension in Pregnancy (US National Institutes of Health, National Institute of Heart, Lung and Blood, 2000). Intermedinfo . Siberian Medical Agency. Volume Obstetrics and Gynecology, No. 1, 2001, pp. 5-16).

The disadvantage of this method is its low specificity due to the presence of numerous mechanisms of thrombocytopenia (autoimmune, associated with disseminated intravascular coagulation, anemia, changes in BCC and others), including those not typical for pregnancy, as well as the absence of a clear relationship between the severity of preeclampsia and the severity of thrombocytopenia (Shifman EM Preeclampsia, eclampsia, HELLP-syndrome. - Petrozavodsk: Publishing house "IntelTek", 2002, pp. 142-158).

A known immunological method is used to determine the cytotoxicity index of endothelial antibodies and the activity of paired glycolytic enzymes in peripheral blood monocytes. Their increase in the second and third trimesters of pregnancy by 2-3 times in relation to physiological occurs 1-2 weeks before the clinical manifestations of severe gestosis (V.A.Melnikov et al. Act. Questions of obstetric and gynecological problems. T 1, 1, 2001-2002, p. 93).

As another method, severe forms of gestosis are predicted by studying the state of cell membranes, where in pregnant women with high rates of Na + - Li +, the risk of developing gestosis increases 2.5 times (IF Fatkullin et al. Akush. And Gynek. 4 , 2007, pp. 19-23).

There is a known method for assessing the severity of preeclampsia in pregnant women (RF patent No. 2250468, 20.04.2005.) By examining blood serum by enzyme immunoassay, characterized in that in pregnant women, the content of the circulating immune complex of the basic myelin protein with immunoglobulin G class during pregnancy is determined in the blood serum after 20 weeks and with its values less than 0.1 μg / ml, uncomplicated pregnancy is judged, at a level from 0.1 to 0.2 μg / ml - about mild preeclampsia, at a level from 0.2 to 0.5 μg / ml - about severe preeclampsia.

The disadvantage of this method is that forecasting is not provided, but only the severity of the state of gestosis during pregnancy at the preclinical stage and at a fairly late date - after 20 weeks is assessed.

There is a known method for preclinical diagnosis of preeclampsia (RF patent No. 2408259, 01/10/2011) by measuring blood flow parameters at different stages of pregnancy, characterized in that a sphygmogram is recorded, the speed of propagation of a pulse wave in m / s (a) is calculated by the formula: where lotr is the length aorta from the subclavian or carotid arteries to the aortic bifurcation or to the femoral artery, m; P - heart rate per minute; distance between two maxima of anacrotic and dicrotic waves along the time axis, mm; T 'is the distance between the maxima of anacrotic waves along the time axis, mm, and if the speed of the pulse wave propagation decreases with an increase in the gestational age, the physiological development of pregnancy is diagnosed, and in the absence of a decrease or with an increase in speed, the development of preeclampsia is predicted.

However, these methods are laborious, expensive, cannot always be used in general practice and are used only in the second half of pregnancy.

There is a known method for predicting the development of severe preeclampsia (RF patent No. 2481578, 05/10/2013) using a blood test, characterized in that the leukocyte index of intoxication is calculated in a pregnant woman in the second trimester, and if its value is higher than 1.6, the development of severe preeclampsia is predicted.

The disadvantage of this method is the late determination of the prognostic indicator only in the second trimester, an increase in which above the standard values during this period is considered as a risk of developing severe preeclampsia. The final diagnosis: severe preeclampsia is exposed only in the third trimester. In addition, this method predicts the development of only severe preeclampsia.

A known method for the diagnosis of severe preeclampsia in pregnant women (RF patent No. 25 87781, 20.06.2016), including an immunological study of peripheral venous blood at 22-37 weeks of gestation, characterized in that the relative content of CD62L + cells in the neutrophil population is determined and when its value is equal to or less than 57% are diagnosed with severe preeclampsia.

There is a known method for predicting preeclampsia in the second trimester of pregnancy (RF patent No. 2552931, 06/10/2015), by examining blood, characterized in that the activity of acidic and neutral proteinases is determined in the blood serum of women at 7-8 weeks of pregnancy, and when the activity of acidic proteinases is higher 5.6 μmol / L and the activity of neutral proteinases above 3.9 μmol / L predict the development of preeclampsia in the second trimester of pregnancy.

The disadvantage of this method is that it is expensive and only predicts early preeclampsia. Despite the fact that the frequency of complications in the development of preeclampsia in this period is 1.5-3.4 times higher, late preeclampsia occurs more often in 75-80% of all preeclampsia cases.

As a prototype of the claimed invention, we have chosen a method for predicting the development of preeclampsia in late pregnancy (RF patent No. 2691114, 06/11/2019), including a study of the blood of a pregnant woman, characterized in that the concentration levels of biochemical markers are determined in the blood serum of women at 12-13 weeks of pregnancy by ELISA method ADAM12 and RBP4 and with RBP4 levels above 87.90 μg / ml and ADAM12 above 2.33 ng / ml predict the development of moderate preeclampsia in the third trimester of pregnancy.

The disadvantage of this method is that it does not allow predicting the development of preeclampsia with high accuracy depending on the gender of the fetus

Thus, the main disadvantage of all of the above methods is the inability to predict the development of preeclampsia in the II-III trimesters of pregnancy.

These disadvantages are eliminated in the claimed technical solution.

The objective of the claimed invention: the development of a simpler and more reliable method for predicting the development of preeclampsia in pregnant women with gestational diabetes mellitus in the second or third trimester of pregnancy, which will facilitate the choice of adequate obstetric tactics and reduce complications of pregnancy and childbirth.

The set task of predicting preeclampsia in pregnant women with gestational diabetes mellitus is that in the II-III trimesters of gestation, using the ultrasound method, the sex of the pregnant fetus and placental lateralization are determined, and, in the case of the male fetus and the left-sided location of the placenta, additionally with the help of enzyme-linked immunosorbent assay determines the level of glycated fibronectin in the venous blood of women if the glycated fibronectin index of 315 pmol / ml or more predicts the development of preeclampsia.

The technical result obtained by using the method for predicting preeclampsia in the II-III trimester of pregnancy in pregnant women with gestational diabetes mellitus: high accuracy and reliability of the results, simplicity, availability. The possibility of forming a risk group in order to carry out timely preventive measures.

The placenta plays the role of a specific executive organ for the mother and fetus, which is their reflex zone and the main mediator. Functioning in the basin of one (right-sided or left-sided lateralization) or both (ambilateral location) of the uterine arteries, the placenta determines the formation of the gestational dominant in the contralateral hemisphere of the brain (Poroshenko A.B., 1985; Chernositov A.V., 2000; Botasheva T.L., 1999-2016), mediating the lateral specificity of the functional behavior of the "mother-placenta-fetus" system at all stages of pregnancy. The factor of placental lateralization significantly affects the processes of lateralization of uterine activity and uteroplacental hemodynamics, modulates the resistance of the female body and largely determines the likelihood of developing obstetric pathology (Poroshenko A.B., 1985; Orlov V.I., 1987; Botasheva T.L. , 1992; Orlov A.V., 1998; Chernositov A.V., 2000). The left-sided location of the placenta determines the ascending (afferent) flow of impulses into the right exchange-associated hemisphere, which is also responsible for the activity of the sympathetic part of the autonomic nervous system, which determines the increase in vascular tone underlying the pathogenesis of preeclampsia.

The adaptive-adaptive reactions of the maternal organism during pregnancy in the case of a female fetus are characterized by more pronounced production of sex steroids (estriol, progesterone B and placental lactogen), some vascular endothelial factors and interleukins (VEGF-A, endothelin-1 (in 2.5 times), EGF, as well as a higher expression of interleukins (IL-1, IL-10, IL-6), which indicates a greater functional activity of the mother's immune system.In the case of a male fetus, an increase in the activity of the coagulation link of hemostasis (an increase in the number of platelets , prothrombin time, D-dimer) in pregnant women, which potentiates in the maternal body a more frequent (1.8 times) development of coagulopathies, more pronounced stress in response to gestational changes (there are higher rates of adreno-corticotropic hormone and cortisol , increased situational and personal anxiety and lower values of the adaptive potential of pregnant women. (Agadzhanyan N.A., Smirnov V.M., 2009; Sidelnikova V.M., Sukhikh G.T., 2010; Agadzhanyan N.A., 2014; Savelyeva G.M. et al., 2016; Ailamazyan E.K. et al. 2009, 2017).

Within the framework of the functional system "mother-placenta-fetus" (FSMPP), it is customary to distinguish two subsystems that interact with each other at different levels: the functional system of the mother's body, which provides conditions for the normal development of the fetus, and the functional system of the fetus's body, whose activities are aimed at maintaining its normal homeostasis (Savenkov Yu.I., Lobyntsev K.S., 1980). The main link between the mother and the fetus is the placenta, which, together with the uterus, forms an additional communicative link of the FSMPP.

Meanwhile, the existing concept does not take into account an important aspect: the “fetus” subsystem in the FSMPP is the carrier of a genetically determined trait - the sex of the fetus. It has been established that the male sex of the fetus is an independent risk factor for the unfavorable outcome of pregnancy, and the favorable course of the perinatal period is more often recorded in female fetuses and preterm labor occurs less often (Di Renzo et al., 2007). To date, studies devoted to the course of the perinatal period, depending on the sex of the fetus, are of increased interest. It is generally known that the male sex of the fetus is an independent risk factor for an unfavorable outcome of pregnancy, and the favorable course of the perinatal period is much more often observed in female fetuses and premature births occur less often (Di Renzo G.C. et al., 2007).

Pregnant male fetuses have a greater predisposition to premature rupture of amniotic fluid caused by the presence of an infectious agent, while women carrying girls are characterized by premature labor accompanied by hypertension (Zeitlin J., Ancel PY, baroque B., Kaminski M., 2004). Chronic fetoplacental insufficiency significantly more often accompanies the course of pregnancies with male than female fetuses, which can be explained by a violation of trophoblast invasion as a result of an immune response from the maternal organism (Chidini A, Salafia S.M., 2005).

It is known that the optimal level of transplacental metabolism, growth and development of the fetus largely depends on the functioning of the blood system during pregnancy (Persianinov L.S., Demidov V.N., 1977; Arshavsky I.A., Zheleznyakova E.V., 2003 ), however, the existing literature data do not take into account the nature of changes in this system occurring against the background of gestation, from the standpoint of sexual dimorphism. Of considerable interest for practical obstetrics is the study of the function of the platelet hemostasis link in connection with its clinical significance for gestational complications (placental insufficiency, IGR, preeclampsia of the second half of pregnancy), as well as the increased titer of thrombocytopathies in recent years (Kashirina T.N., Makatsaria A. D., Mishchenko A.D., Nesterova S.G., 1982; Zazerskaya I.E., 1991; Aluyatdinova O.S., Smirnova L.M., Braginskaya S.G., 1999; Ascarelli M.N. , Emerson ES, Bigelow CL, Martin JN 1998).

Our studies have found that in pregnant women with a male fetus, left-sided placentation is more often determined. Type 2 diabetes mellitus also develops more often in mothers of boys (in 71.3% of women in the case of one child and in 85.7% of patients with two children, the first of which is a boy). Intersexual antagonism, which manifests itself in separate functional systems "mother-placenta-female fetus" and "mother-placenta-male fetus", which maintains the unity, hierarchical structure of each of them, ultimately turns into a factor that increases the risk of complications of pregnancy such as preeclampsia.

Glycated fibronectin is a protein determined in maternal blood serum using ELISA analysis, an increase in the level of which is recorded in microangiopathies that develop in all forms of diabetes and are also characteristic of preeclampsia.

A detailed description of the method and examples of its clinical implementation.

The method is carried out as follows. In pregnant women with gestational diabetes mellitus in the II-III trimesters of gestation, ultrasound determines the sex of the fetus and placental lateralization. Ultrasound examination (ultrasound) is performed in a horizontal position of the pregnant woman on her back. A special gel is applied to the surface of the skin of the abdomen and the side of fixation of the placenta and the sex of the fetus are determined. The study is carried out by the method of two-dimensional ultrasound scanning - the area of preferential localization of the placenta relative to the midline is determined according to the generally accepted method. All studies are performed on an ultrasonic device "Toshiba (Essosee) SSA-340" (Japan), 3.5 MHz, with color Doppler mapping (registration certificate FS No. 2005/1686).

When detecting left-sided lateralization and determining the male fetus, the level of glycated fibronectin is additionally determined by the enzyme-linked immunosorbent assay. For research in a pregnant woman in the morning on an empty stomach, blood is taken from the cubital vein. Determine the level of glycated fibronectin using sorption columns Amprer ("Amersham Lifesilence") and test systems Amersham Pharmacia Biotech (Great Britain). Studies are carried out on an ELISA analyzer Stat Fax-303 Plus (USA). If the glycated fibronectin value is 315 pmol / ml or more, the development of preeclampsia (PE) is predicted in the examined pregnant woman.

The efficiency of the method is confirmed by the following cynical examples.

Example 1.

Pregnant S-eva I.G., 21 years old, 28 weeks of gestation with gestational diabetes mellitus detected at 21 weeks. Ultrasound examination established the left-sided location of the placenta, the male sex of the fetus was determined. Fetometry indicators correspond to the gestational age. Additionally, ELISA analysis was performed - determination of the level of glycated fibronectin: 320 pmol / ml. According to the claimed method, the development of PE during pregnancy can be predicted.

At the 31st week of pregnancy, the woman developed complaints of tinnitus, headache, nausea and a feeling of heaviness in the back of the head. On physical examination: persistent edema in the lower extremities, an increase in blood pressure up to 147/95, which lasts for 6 hours, an increase in the protein content of up to 0.38 grams in the daily amount of urine. Diagnosed with preeclampsia, moderate course. Inpatient treatment of preeclampsia was carried out. At the end of the course of therapy, she was discharged in satisfactory condition. The pregnancy ended with delivery on time. Thus, the prognosis made by the claimed method was confirmed, and adequate obstetric tactics made it possible to reduce the risk to the mother and fetus.

Example 2.

Pregnant U-ich O.P., 20 years old, 30 weeks pregnant, with gestational diabetes mellitus diagnosed at 18 weeks. Ultrasound examination established the left-sided location of the placenta, the male sex of the fetus was determined. Fetometry indicators correspond to the gestational age. In the process of ELISA-analysis - the level of glycated fibronectin 315 pmol / ml. According to the claimed method, it is possible to predict the development of PE during pregnancy ..

At 34 weeks of pregnancy, the woman complained of headache and dizziness. On physical examination: an increase in blood pressure up to 156/100, which lasts for 7 hours, an increase in the protein content of up to 0.35 grams in the daily amount of urine. Diagnosed with preeclampsia, moderate course.

Example 3.

Pregnant I-ko S.N., 24 years old, 27 weeks pregnant with gestational diabetes mellitus detected at 23 weeks. Ultrasound examination established the left-sided location of the placenta, the male sex of the fetus was determined.

Fetometry indicators correspond to the gestational age. In the process of ELISA analysis - the level of glycated fibronectin 310 pmol / ml. According to the claimed method, a favorable course of pregnancy can be predicted. At all subsequent stages of pregnancy, including childbirth, there are no complaints. Physical examination blood pressure 116/78, protein in the daily amount of urine was not detected. Follow-up of the woman until the end of pregnancy, which ended in the birth of a full-term baby, confirmed the absence of preeclampsia.

Example 4.

Pregnant S-yan S.N., 29 years old, 30 weeks of pregnancy with gestational diabetes mellitus detected at 21 weeks. Ultrasound examination revealed the left-sided location of the placenta, the female sex of the fetus was determined. Fetometry indicators correspond to the gestational age. In the process of ELISA-analysis - the level of glycated fibronectin 315 pmol / ml. According to the claimed method, a favorable course of pregnancy can be predicted. At all subsequent stages of pregnancy, including childbirth, there are no complaints. On physical examination, blood pressure 120/73, protein in the daily amount of urine was not detected.

According to the claimed method, 70 women with gestational diabetes mellitus were examined, in whom the level of glycated fibronectin was determined in the blood serum in the II-III trimesters. In 27 pregnant women, this indicator was 315 pmol / ml or more. Of these, 21 were pregnant with a male fetus with left placental lateralization. In 19 women, pregnancy proceeded with a complication and diagnosis of preeclampsia, moderate course. The remaining 6 pregnant women showed either right-sided lateralization during pregnancy with a male fetus (1), or pregnancy with a female fetus with left and right lateralization of the placenta (5). In this group, observation until the end of pregnancy, which ended in the birth of full-term babies, confirmed the absence of preeclampsia.

Statistical processing of the data was carried out by methods of variation and descriptive statistics using a standard package for statistical calculation of data in Microsoft Excel. The significance of the differences in mean values was determined by the Student's t-test. The difference was considered significant when the p <0.05. Correlation analysis was performed using Pearson's coefficient.

The claimed method for predicting the development of preeclampsia allows timely preventive therapy of this obstetric pathology, which ultimately will have a beneficial effect on perinatal outcomes and a decrease in the incidence of newborns.

To do this, it is necessary to carefully monitor the pregnant woman in the antenatal clinic, to form a risk group in order to manage the pregnant woman rationally, carry out preventive and timely treatment measures aimed at reducing the frequency of preeclampsia, as well as timely hospitalization and delivery in the presence of uncontrollable risk factors.

The method has been tested on sufficient clinical material and can be recommended for widespread use in obstetric practice.

Claims (1)

A method for predicting preeclampsia in pregnant women with gestational diabetes mellitus, including the study of the blood of a pregnant woman, characterized in that in the II-III trimesters of gestation by ultrasound, placental lateralization and the sex of the pregnant fetus are determined by enzyme immunoassay determine the level of glycated fibronectin and, if it is 315 pmol / ml or more, predict the development of preeclampsia during pregnancy.