RU2295132C1 - Method for earlier predicting the syndrome of delayed fetal development - Google Patents

Abstract

FIELD: medicine, obstetrics.

SUBSTANCE: it is necessary to investigate peripheral venous blood of a pregnant woman, moreover, during the period of 6-12-wk-long gestation one should determine the value of vasculoendothelial growth factor (VEGF) content and at its values being equal or below 20 pg/ml it is possible to predict the onset of the syndrome of delayed fetal development.

EFFECT: increased sensitivity and specificity of the technique applied.

3 ex, 1 tbl

Description

The invention relates to medicine, namely to obstetrics, and can be used for early, in 6-12 weeks of pregnancy, prediction of fetal growth retardation syndrome (FPS).

The relevance of the development of the method is determined by the relatively high frequency of SZRP (5-17.6%), identified in the analysis of the results of population studies in various countries [1]. This necessitates the search for objective methods for early prediction of fetal pathology in order to develop adequate treatment tactics and correct the revealed deviations.

A modern method of ultrasound diagnosis of SZRP is the study of the uterus, including Doppler mapping of the uterine vessels and determining the state of their blood supply based on the pulsation index. To do this, Doppler mapping and determination of the nature of blood flow in radial and spiral uterine-placental arteries and with an increase in pulsation indices in these arteries compared with the same data in healthy pregnant women are referred to the risk group for delayed fetal development later in pregnancy ( Patent No. 2204329. A method for diagnosing fetal growth retardation / A. A. Orazmuradov, V. A. Sobolev, V. E. Radzinsky, T. A. Dukhina, T. V. Galina, N. M. Starceva, Ch. G. Gagaev, B.S. Demidov (Russia) // Inventions. second models. - 2003. - No. 14, Part 2. - C.321).

This method has several disadvantages:

- the gestational age is not determined at which the use of this method is possible, while it is advisable to conduct a dopplerometric study not earlier than 16-18 weeks of pregnancy, because only by this time the vascular membrane becomes insensitive to the action of endogenous pressor agents [1];

- similar violations of the uteroplacental blood flow are observed with the development of SZRP, and with gestosis [1];

- the sensitivity of the dopplerometric method for diagnosing SZRP according to different authors varies from 32 to 100%, specificity - from 53 to 94%, which indicates the lack of reproducibility of this method for diagnosing SZRP [1].

There is a laboratory method for identifying the risk of fetal development disorders by determining in the blood serum deviations of its immunoreactivity from the level of normal values with respect to the main myelin protein, S 100 protein, anionic tightly bound chromatin protein ACBP 14/18, MP 65 membrane protein, characterized in that it additionally deviations of immunoreactivity with respect to chorionic gonadotropin, total fraction of phospholipids, DNA, rheumatoid factor, collagen and anionic neutrophil cytoplasmic antigens are determined ov. If immunoreactivity deviates from normal values, the risk level of fetal developmental disorders is established (Patent No. 2208791. Method for assessing fetal developmental disorders / A.B. Poletaev, T. S. Budynina (Russia) // Inventions. Utility models. - 2003. - №20 , Ch.3. - P.737).

This method has several disadvantages:

- to identify the risk of fetal development disorders, a laboratory examination is required for 10 different indicators;

- the nature of fetal development disorders is not determined;

- the timing of the examination is not indicated, but as you know, the level of chorionic gonadotropin significantly changes in the dynamics of pregnancy [2];

- indicators of the content of the main myelin protein and S100 protein increase with any damage to the nervous tissue, and are used in perinatology to predict perinatal hypoxic brain lesions [3];

- production of antiphospholipid and antinuclear antibodies accompanies not only fetal growth retardation, but also habitual miscarriage, antenatal fetal death, chronic fetal hypoxia, premature birth, severe gestosis, and may also be present outside pregnancy in the presence of autoimmune diseases [4].

Closest to the claimed method according to the technical solution is a method for predicting fetal growth retardation syndrome in women in the second trimester of pregnancy complicated by gestosis (Patent No. 2221253. A method for predicting fetal growth retardation syndrome in women in the second trimester of pregnancy complicated by gestosis / I.V. Chirkova , O.Yu.Sevostyanova, O.I.Yakubovich, A.D. Mazurov (Russia) // Inventions. Useful models. - 2004. - No. 1, Part 4. - S.865). To do this, determine the number of platelets in the peripheral blood, the activated partial thromboplastin time, the level of fibrinogen and calculate the prognostic index S by the formula: S = AK1 + BK2 + CK3 + const, where A is the number of platelets in 10 ⁹ / l; B - activated partial thromboplastin time (APTT); C - fibrinogen level, g / l; K1, K2, K3 - coefficients equal to 0.02, respectively; 0.046; -0.06; const = -4.39, and if the value of the S index is less than 0, then the threat of SZRP is predicted, if the value of S is more than 0, then the proportional development of the fetus is predicted.

The specified method is selected as a prototype.

The disadvantages of the prototype method are:

- studies are conducted at the end of the second trimester of pregnancy in women with advanced gestosis, which is not timely enough to start the prevention of SZRP, as pathogenetic changes leading to this pathology have already occurred;

- the ability to change these indicators of hemostasis not only in women with SZRP, but also in the presence of pathology of the hemostasis system in women (including thrombocytopathy, thrombocytopenia, gestosis) in the absence of SZRP;

- the need to use a cumbersome formula for forecasting.

These disadvantages are proposed to eliminate in the present method.

The claimed technical result is achieved by the fact that in the serum of the peripheral blood of pregnant women at 6-12 weeks of gestation, an indicator of the content of vasculoendothelial growth factor (VEGF) is determined and, with values of this indicator equal to or less than 20 pg / ml, the development of intrauterine growth retardation syndrome is predicted with an accuracy of 81 , 25%.

The novelty of the proposed method lies in the fact that for the first time it is proposed to predict the syndrome of intrauterine growth retardation of the fetus at 6-12 weeks of gestation by determining the content of vasculoendothelial growth factor in the peripheral blood serum of a pregnant woman. It is generally accepted that the development of SZRP is associated with inadequate perfusion of the placenta due to a violation of angiogenesis. VEGF is one of the factors regulating angiogenesis, and its deficiency in the early stages of gestation probably reduces the growth rate of placental vessels and leads to a violation of its trophic function [5]. Earlier, Khaliq A. et al., Noted an increase in the content of VEGF in the mature placenta with SZRP [6], which may be due to a local inflammatory reaction [7] with the development of thrombosis and ischemic necrosis [8].

The method is as follows:

one). 1 ml of peripheral venous blood was collected in a dry tube. After the formation of a clot, the blood is centrifuged for 5-10 min at 1500 rpm and 100 μl of serum are taken for the reaction.

2). The determination of the content of vasculoendothelial growth factor is carried out in accordance with the methodological recommendations of the manufacturer of the used test system (Cytimmune, USA).

Using the proposed method allows with high accuracy 81.25% at 6-12 weeks of gestation to predict the development of SZRP.

Distinctive features of the method are: a prognostic parameter for the content of vasculoendothelial growth factor in the peripheral blood of women at 6-12 weeks of gestation is established, with a value of which 20 pg / ml or less, fetal growth retardation syndrome is predicted.

The essence of the proposed method is illustrated by the following examples.

Example 1

Pregnant F., 26 years old. Real pregnancy is the second. The first pregnancy ended in medical abortion at 6 weeks gestation. A woman had a history of chronic pyelonephritis. In the first trimester of pregnancy, a woman was observed in a antenatal clinic about the threat of miscarriage, manifested by pulling pains in the lower abdomen and uterine hypertonicity in an ultrasound study. When examining the inventive method in the period of 7 weeks of pregnancy in the peripheral blood revealed a content of vasculoendothelial growth factor equal to 16.5 pg / ml, which corresponds to the claimed criterion for the development of SZRP. According to an ultrasound scan at 24 weeks of gestation, fetal size corresponded to 22 weeks of gestation. According to the conclusion of the ultrasound scan: threatened by FFP. At 24-27 weeks, FPI was treated in the day hospital of an obstetric clinic. Upon repeated examination of the ultrasound at 35 weeks, the size of the fetus corresponded to 33-34 weeks of pregnancy. The woman was hospitalized in a hospital with a diagnosis of SZRP. Conducted appropriate treatment. Pregnancy ended in timely delivery at 38 weeks and the birth of a live full-term baby weighing 2700 g, height 49 cm and an Apgar score of 8-9 points. The diagnosis of the child at birth: SZRP 1 degree. Conclusion: the forecast for the claimed method was confirmed.

Example 2

Pregnant D., 36 years old. This is the fifth pregnancy. Four previous pregnancies ended in medical abortions. A woman is obese 1 degree. In the first trimester of pregnancy, the woman was monitored in a antenatal clinic about the threat of miscarriage. The woman had uterine fibroids of small sizes. When examining the inventive method at 8 weeks of pregnancy in the peripheral blood, the content of vasculoendothelial growth factor was found to be 20 pg / ml, which corresponds to the claimed criterion for the development of SZRP. The further course of pregnancy was complicated by the threat of miscarriage at 25-27 and 37 weeks of gestation, dropsy of the 1st degree and anemia at 37 weeks. During these periods, the woman was treated in a hospital. Ultrasound examination at 25 weeks showed fetal size consistent with gestational age. With ultrasound at 37 weeks, the size of the fetus corresponded to 35-36 weeks of pregnancy. Conclusion of ultrasound: threatened by FFP. Treatment for fetoplacental insufficiency and gestosis was carried out. Pregnancy ended in timely delivery and the birth of a full-term newborn weighing 2750 g, height 51 cm, rating on the Apgar scale of 7-8 points. Diagnosis of a child at birth: SZRP 2 degrees, chronic fetal hypoxia. Conclusion: the forecast for the claimed method was confirmed.

Example 3

Pregnant M., 38 years old. This is the eleventh pregnancy. A history of one timely delivery, one spontaneous miscarriage and eight medical abortions. In the first trimester of pregnancy was observed in the antenatal clinic about the threat of miscarriage. Uterine hypertonicity was noted. When examining the inventive method at 8 weeks of pregnancy, the content of vasculoendothelial growth factor in the peripheral blood was found to be 86.2 pg / ml. Conclusion: the development of SZRP is not predicted. At 34 weeks, pregnancy was complicated by mild gestosis (dropsy 1), about which a woman was treated in a hospital at 34-35 weeks. With ultrasound at 34 weeks, the size of the fetus corresponded to a gestational period. Pregnancy ended in a timely delivery of 40 weeks and the birth of a full-term baby. The mass of the child was 3450 g, height - 52 cm, Apgar score of 8-9 points. Diagnosis of a child at birth: full-term newborn, chronic fetal hypoxia. Conclusion: the forecast for the claimed method was confirmed.

This method examined 32 pregnant women at 6-12 weeks of gestation, the research data are shown in table 1.

Table 1 Indicator The number of examined Total women 32 true positive result 12 false positive result 2 true negative result 7 false negative four Total: the accuracy of the proposed method is 81.25% the sensitivity of the proposed method is 75.00% the specificity of the proposed method is 87.50%

The advantages of the proposed method:

1. a study of the content of VEGF in the peripheral blood is carried out at 6-12 weeks of pregnancy, which allows for early preclinical prediction of SZRP, to carry out a set of preventive measures, to reduce the risk of having a baby with this pathology;

2. high accuracy - 81.25%, sensitivity - 75.00%, specificity - 87.50%;

3. the possibility of a screening examination of pregnant women in the first trimester of pregnancy to predict SZRP;

4. simplicity and accessibility of the implementation of the methodology.

Information sources

1. Medvedev M.V., Yudina E.V. Intrauterine growth retardation. - 2nd ed. - M .: RAVUZDPG, 1998 .-- 208 p.

2. Savelyeva G.M., Fedorova M.V., Klimenko P.A., Sichinava L.G. Placental insufficiency. - M.: Medicine, 1991 .-- 276 p.

3. Monoclonal antibodies in neurobiology / Ed. M.B.Starka, M.V. Starostina. - Novosibirsk: Offset JSC, 1995. - 228 p.

4. Genius M.G., Makatsaria A.D. Antibodies to phospholipids and miscarriage // Bulletin of the Russian Association of Obstetricians and Gynecologists. - No. 1. - 2000. - P.44-50.

5. Kovalchuk L.V., Gankovskaya L.V., Khoreva M.V., Sokolova E.V. System of cytokines, complement and modern methods of immune analysis. - M .: RSMU, 2001. - P.20.

6. Khaliq A., Dunk C., Jiang J., Shams M., Li XF, Acevedo C., Welch H., Whittle M., Ahmed A. Hypoxia down-regulates placenta growth factor, whereas fetal growth restriction up- regulates placenta growth factor expression: Molecular evidence for "placental hyperoxia" in intrauterine growth restriction // Lab. Invest. - 1999. - V.79. - P.151-170.

7. Bretelle F., Sabatier F., Shojai R., Agostini A., Dignat-George P., Blanc B., d'Ercole C. New insight in physiopathology of preeclampsia and intrauterine growth retardation: role of inflammation // Gynecol Obstet Fertil. - 2004 .-- V.32. - p. 482-489.

8. Kujovich J.L. Thrombophilia and pregnancy complications // Am J Obstet Gynecol. - 2004 .-- V.191. - p. 412-424.

Claims (1)

A method for early prediction of fetal growth retardation syndrome by examining the peripheral venous blood of a pregnant woman, characterized in that at 6-12 weeks of gestation an indicator of the content of vasculoendothelial growth factor (VEGF) is determined and, with its values equal to or less than 20 pg / ml, the development of the syndrome is predicted fetal growth retardation.