RU2313095C1 - Method for predicting perinatal hypoxia injuries of newborn central nervous system - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: method involves determining interleukine-1β concentration in peripheral venous blood of pregnant woman at 35 gestation week, in cases complicated with gestosis. The value being greater than 40 pkg/l, perinatal newborn central nervous system hypoxia injuries are to be predicted.

EFFECT: high accuracy and specificity of prognosis.

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Description

The invention relates to medicine, namely to perinatology and pediatric neurology, and can be used to predict the development of perinatal hypoxic lesions of the central nervous system in newborn children born to mothers with gestosis of varying severity.

Perinatal lesions of the central nervous system occupy a leading place (up to 80%) in the structure of the pathology of the nervous system (1, 2), among which 60.1% are hypoxic-ischemic lesions of the central nervous system in newborns (3). Gestosis is considered one of the significant factors contributing to the occurrence of perinatal lesions of the central nervous system in newborns (4).

Prediction of perinatal lesions of the central nervous system in newborns born to mothers with gestosis is a complex clinical problem.

A known method for predicting perinatal hypoxic-ischemic encephalopathy in newborns by studying the immunogenetic status of the body. In umbilical cord blood, antigens of loci A, B, DR of the HLA system are determined, and in the presence of one of the antigens A32, B8, B27, DR3 or a combination thereof, the development of perinatal hypoxic-ischemic encephalopathy in newborns is predicted. The accuracy of the method is unknown (patent No. 2157534 Russia, IPC 7 G01N 33/53. A method for predicting perinatal hypoxic-ischemic encephalopathy in newborns / Dzhumagaziev A.A., Rakhimova L.R., Goldenberg O.P. // Inventions, Utility models. - 2000. - No. 28, Part 2. - C.301).

The method has disadvantages:

- cord blood is examined, which means late prediction of perinatal hypoxic-ischemic encephalopathy in newborns and does not allow timely preventive measures;

- the method requires the determination of four parameters for predicting perinatal hypoxic-ischemic encephalopathy in newborns;

- Currently, the determination of HLA system antigens is carried out in a PCR reaction, which requires expensive equipment and reagents.

A known method for predicting neonatal encephalopathy by examining biological material - placental tissue, from which 10% homogenate is prepared, determines the activity of NADPH oxidase for the recovery of 2,6-dichlorophenylindophenol in the presence of NADPH, the reaction results are taken into account spectrophotometrically at a wavelength of 600 nm and with a value of NADPH activity -oxidase, equal to 13.5 optical density units and higher, predict the development of encephalopathy in a newborn (patent No. 2254573 Russia, IPC 7 G01N 33/52. A method for predicting encephalopa atii of the newborn / Krukier II // Inventions. Utility models. - 2005. - No. 17).

The accuracy of the method is unknown.

The method has disadvantages:

- the study is carried out after the birth of the child and does not allow the antenatal prognosis of perinatal CNS damage in the newborn;

- the manufacture of 10% placenta homogenate requires additional time;

- it is not indicated which parts of the placenta are used to prepare the homogenate, but, as you know, in the decidual membrane and trophoblast the level of NADPH oxidase can vary significantly;

- the examination is carried out by two different methods using highly toxic chemicals.

There is a method for predicting the development of hypoxic-ischemic encephalopathy in full-term newborns by clinical examination of a pregnant woman, with additional ultrasound of the uterine arteries, umbilical arteries and the middle cerebral artery of the fetus, risk factors are identified, their gradations and numerical values are determined, and prognostic factors F1 and F2 are calculated by the formulas and with the value of the prognostic coefficient F1≥F2, the development of hypoxic-ischemic encephalopathy is predicted in a full-term newborn who is given to an examined woman (patent No. 2167608 Russia, IPC 7 AB 8/00. A method for predicting the development of hypoxic-ischemic encephalopathy in full-term newborns / Sayutina SB, Shprakh V.V., Protopopova N.V. et al. // Inventions. Utility models. - 2001. - No. 15, Part 1. - P.224).

The accuracy of the method is unknown.

The method has disadvantages:

- calculations are made according to very complex formulas;

- this method is not without subjectivity, and the results of a Doppler study depend on the qualifications of the specialist conducting this study;

- it is impossible to tell in advance with accuracy whether a full-term baby will be born to the examined woman, and in the case of premature birth, the forecasting method is not applied.

The closest in technical solution is a method for predicting perinatal pathology in pregnant women with chronic infectious and inflammatory diseases by determining the ability of blood leukocytes in the venous blood of a pregnant woman to produce γ-interferon, the number of antibodies to γ-interferon, autoantibodies to the main myelin protein and S-100, and with a decrease in the production of γ-interferon less than 16 IU / ml, autoantibodies to the main myelin protein and S-100 less than (-) 40 conventional units for each indicator and an increase in antibodies to γ-interferon more than 2 0 conventional units predict perinatal pathology (patent No. 2256914 Russia, IPC 7 G01N 33/49, 33/53. A method for predicting perinatal pathology in pregnant women with chronic infectious and inflammatory diseases. / Tareeva T.G., Tkacheva I.I., Mikaelyan A.V. et al. // Inventions. Utility Models. - 2005. - No. 20).

This method is chosen by us as a prototype. The study of the content of autoantibodies to the main protein of myelin and S-100 indicates the prognosis, including perinatal pathology of the central nervous system. The main myelin protein and S-100 are specific markers of nerve tissue, and the appearance of autoantibodies to them in the peripheral blood indicates damage to the central nervous system (7). The accuracy of the method is unknown.

The method has disadvantages:

- the need to determine four parameters, each of which requires expensive reagents;

- to assess the production of ELISA, stimulation of blood leukocytes by viral macrophages is necessary (Ershov F.I. The interferon system is normal and with pathology. - Moscow: Medicine. - 1996. - 240 p.);

- the mechanism of the development of the central nervous system pathology in newborns is not clear with this combination of indicators, because the content of γ-interferon in the blood is less than 16 IU / ml, the reduced level of autoantibodies to the main myelin protein and S-100 corresponds to the uncomplicated pregnancy and normal development of the fetus, and an increase in the level of antibodies to γ-interferon can be a result of the development of an allergic reaction;

- a change in the production of γ-interferon in the venous blood may accompany the threat of premature birth.

- The gestational age at which this study is conducted is not indicated.

These disadvantages can be eliminated in the proposed method.

The claimed technical result is achieved by the fact that in the third trimester of gestation in the peripheral venous blood of a pregnant woman with gestosis, the content of interleukin-1β is determined and, with its value> 40 pcg / l, the development of perinatal hypoxic damage to the central nervous system in the newborn is predicted with an accuracy of 78.4%.

The novelty of the proposed method lies in the fact that for the first time it is proposed to predict the development of hypoxic perinatal CNS lesions in newborns born to mothers whose pregnancy was complicated by gestosis, by determining the content of interleukin-1β (IL-1β) in the mother’s peripheral venous blood in the third trimester of gestation.

Previously, the study of the content of IL-1β was carried out when examining women with external genital endometriosis in order to identify the inflammatory process. It was shown that an increase in the concentration of IL-1 in the peritoneal fluid, as well as an increase in its secretion by the cells of the ectopic and eutopic endometrium, indicate the presence of an inflammatory process (DI Sokolov, OV Pavlov, NG Solodovnikova. Imbalance of cytokines with external genital endometriosis // Immunology of reproduction: Republican scientific conference (April 11-14, 2005, Ivanovo) - Ivanovo, 2005. - p. 85). In obstetrics, an increase in the concentration of IL-1 in decidual tissue extracts testified to a virus-chlamydial infection of women with preeclampsia (Tsarkova R.Kh. Features of the immune response at the systemic and local levels in women with preeclampsia and chlamydial-viral infection // Abstract for a scientific degree Candidate of Medical Sciences. - Ivanovo. - 2003.) To predict perinatal hypoxic lesions of the central nervous system in newborns, this indicator is used for the first time.

However, IL-1β is produced by cells in any inflammatory process and is not a specific marker of central nervous system damage. Therefore, we believe that the relationship we established between the increase in the content of IL-1β in the peripheral blood of a pregnant woman and damage to the central nervous system of a child is determined by the production of IL-1β by brain neurons in hypoxic-ischemic lesions of the central nervous system. If the fetal blood-brain barriers are imperfect, IL-1β can enter the general system of uteroplacental circulation, while gestosis is accompanied by an increase in the permeability of placental barriers, which contributes to the penetration of IL-1β of the fetus into the systemic bloodstream of the mother (5).

The method is carried out according to the standard method as follows.

1. In a woman with gestosis in the third trimester of gestation, 1 ml of peripheral venous blood is taken.

2. Blood is centrifuged for 5 minutes at 1500 rpm, 200 μl of centrifuged serum is taken for examination.

3. Quantitative determination of human IL-1β in blood serum samples by enzyme-linked immunosorbent assay in accordance with the methodological recommendations of the manufacturer, the test system used (OOO "Cytokine").

4. The result of the analysis is calculated according to the calibration graph after measuring the optical density and is calculated in PCG / L.

Distinctive features of the method

A new prognostic parameter of the content of IL-1β in peripheral venous blood was established in the third trimester of pregnancy complicated by gestosis, with a quantitative value of> 40 pkg / l, the development of perinatal hypoxic lesions of the central nervous system is predicted.

The advantages of the proposed method

1. The study is carried out antenatally (before childbirth), which allows timely preventive measures.

2. Determination of one indicator of interleukin-1β.

3. The simplicity of the method, the method does not require large time expenditures.

4. High specificity of the method.

5. No need for a laboratory technician to work with viruses.

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

Example 1. Pregnant C., 33 years old. The first three pregnancies ended in medical abortion, without complications. This pregnancy is the fourth. She was registered for pregnancy in a antenatal clinic in the period of 7 weeks. At 28 weeks gestosis developed in the form of nephropathy. The woman was repeatedly hospitalized for the treatment of gestosis. In a period of 36 weeks, a woman was hospitalized in the clinic for worsening gestosis. Diagnosed with pregnancy 36 weeks. Combined severe gestosis in the form of nephropathy of the II degree against the background of vegetative-vascular dystonia of a hypertonic type. Delayed intrauterine development of the fetus I degree. Chronic intrauterine hypoxia of the fetus. When examining the inventive method in the period of 36 weeks of pregnancy, the concentration of interleukin-1β is 148.9 PCG / L; the development of perinatal hypoxic damage to the central nervous system in the newborn is predicted. At 38 weeks, the woman was delivered by cesarean section. A live full-term boy was born with a weight of 2600 grams, a height of 49 centimeters, with an Apgar score of 7/8 points. The child was observed in the early neonatal period by a neonatologist and pediatric neurologist, signs of hypertensive syndrome were detected. According to neurosonography, the pulsation of the intracerebral vessels was enhanced, the occipital horns of the lateral ventricles were dilated to 5 mm. Based on the clinical picture and the results of neurosonography, the diagnosis was made: perinatal damage to the central nervous system, cerebral ischemia of the II degree, hypertensive syndrome. On the 10th day of life, the child was transferred to aftercare. Conclusion: the forecast for the claimed method was confirmed.

Example 2. Pregnant R., 20 years. This pregnancy is the first. She registered for pregnancy in a antenatal clinic in the period of 20 weeks. At a period of 34 weeks, gestosis of moderate severity in the form of nephropathy developed, treatment was carried out on an outpatient basis in the conditions of a antenatal clinic. There was no effect from treatment, in connection with this, the pregnant woman was sent to inpatient treatment for a period of 39 weeks. During the examination, the clinic was diagnosed with a pregnancy of 39-40 weeks. Combined gestosis of moderate severity in the form of nephropathy of I degree against the background of anemia of I degree, chronic pyelonephritis, without exacerbation. Large fruit. When examining the inventive method in the period of 39-40 weeks of pregnancy, the concentration of interleukin-1β is 19.7 pcg / l; development of perinatal hypoxic damage to the central nervous system in the newborn is not predicted. In a period of 41 weeks, the first timely delivery occurred. A live full-term girl was born weighing 3750 grams, growing 55 centimeters, with an Apgar score of 8/9 points. In the early neonatal period, the child was observed by a neonatologist. When examining a newborn, pathology from the central nervous system was not detected. Conclusion: the forecast for the claimed method was confirmed.

Example 3. Pregnant X., 26 years old. The first pregnancy ended in medical abortion, without complications. This pregnancy is the second. She registered for pregnancy at the antenatal clinic in the period of 8 weeks. At 35 weeks gestosis developed in the form of dropsy, a woman was given a referral to inpatient treatment. During the examination, the clinic was diagnosed with a pregnancy of 37 weeks. Combined gestosis of mild severity in the form of dropsy on the background of chronic pyelonephritis without exacerbation. When examined in a period of 37 weeks by the claimed method, the concentration of interleukin-1β is 435.7 PCG / L; the development of perinatal hypoxic damage to the central nervous system in the newborn is predicted. At 39 weeks, the first timely delivery occurred. A live full-term girl was born, weighing 3750 grams, growing 53 centimeters, with an Apgar rating of 7/8 points. The child was observed in the early neonatal period by a neonatologist and pediatric neurologist, signs of hypertensive syndrome were detected. According to neurosonography, the pulsation of the intracerebral vessels was enhanced, the occipital horns of the lateral ventricles were dilated to 4 mm. Based on the clinical picture and the results of neurosonography, a diagnosis was made - perinatal damage to the central nervous system, cerebral ischemia of the first degree, moderate hypertensive syndrome. On the 5th day of life, the child was discharged home. Conclusion: the forecast for the claimed method was confirmed.

Example 4. Pregnant G., 33 years old. The first pregnancy ended in premature operative labor at the age of 35-36 weeks and the birth of a live premature baby girl weighing 2560 grams and growing 46 centimeters, with an Apgar score of 7/8 points, and Downes 3 points. The next two pregnancies ended in spontaneous miscarriages in the period of 7-8 weeks. This pregnancy is the fourth.

I registered for pregnancy in a antenatal clinic in the period of 5-6 weeks. At 32 weeks gestosis developed in the form of nephropathy, the woman was given a referral for inpatient treatment. The woman refused hospitalization. Outpatient treatment was performed. At the reception in the antenatal clinic for a period of 35 weeks, a deterioration is noted, and the ambulance woman is hospitalized in a hospital. During the examination, the clinic was diagnosed with a pregnancy of 35 weeks. Combined gestosis of moderate severity in the form of nephropathy against a background of obesity of 2 degrees. When examined in a period of 35 weeks by the claimed method, the concentration of interleukin-1β is 399.9 pkg / l; the development of perinatal hypoxic damage to the central nervous system in the newborn is predicted. In the period of 35-36 weeks, a second premature operative delivery occurred. A live premature girl was born weighing 3050 grams, growing 46 centimeters, with an Apgar scale rating of 6/7 points, Downs 3 points. The child was observed in the early neonatal period by a neonatologist and pediatric neurologist, signs of hypertensive syndrome were detected. According to neurosonography, the structure of the brain parenchyma is moderately reduced, the interhemispheric fissure is 1-2 mm, the lateral ventricles are S> D, the front horns are S = 2 mm, D is tightened. The left vascular plexus is dilated, moderately heterogeneous. Taking into account the clinical picture and the results of neurosonography, the diagnosis was made - perinatal damage to the central nervous system, cerebral ischemia of the II degree, intraventricular hemorrhage of the I-II degree, hypertensive syndrome. On the 9th day of life, the child was transferred to aftercare. Conclusion: the forecast for the claimed method was confirmed.

Example 5. Pregnant T., 29 years old. The first pregnancy ended in timely delivery and the birth of a live full-term girl weighing 3850 grams and a height of 53 centimeters, with an Apgar score of 8-9 points. The second pregnancy ended in medical abortion, without complications. This pregnancy is the third. She registered for pregnancy in a maternity welfare clinic at a period of 10 weeks. In a period of 36 weeks, mild gestosis developed in the form of dropsy, the treatment was carried out on an outpatient basis in a maternity ward. The pregnant woman is referred for prenatal hospitalization for a period of 39 weeks. During the examination, the clinic was diagnosed with a pregnancy of 39-40 weeks. Combined gestosis of mild severity in the form of nephropathy of I degree against the background of anemia of I degree. When examining the inventive method in the period of 39-40 weeks of pregnancy, the concentration of interleukin-1β is 40.0 pkg / l; development of perinatal hypoxic damage to the central nervous system in the newborn is not predicted. In the period of 39-40 weeks, a second timely delivery occurred. A live full-term girl was born weighing 3200 grams, growing 49 centimeters, with an Apgar score of 8/9 points. In the early neonatal period, the child was observed by a neonatologist. When examining a newborn, pathology from the central nervous system was not detected. Conclusion: the forecast for the claimed method was confirmed.

The research results are summarized in table.

Table Indicator The number of examined Total women examined 51 True positive result 28 False positive 3 True negative result 12 False negative result 8 Total: the accuracy of the proposed method 78.4%, the sensitivity of the proposed method 77.8%, the specificity of the proposed method 80%

Thus, the claimed method is simple in execution and allows us to accurately predict the development of hypoxic perinatal CNS lesions in newborns born to mothers with gestosis of various severity, which allows you to choose the right treatment tactics for pregnant women in the third trimester of gestation and the method of delivery. Timely taken measures will help reduce the frequency of perinatal CNS lesions in newborns and at the same time reduce the economic costs of their treatment.

Information sources

1. Shabalov N.P. Neonatology .: Textbook. In 2 volumes. T.1 - M .: MEDpress-inform, 2004 .-- 608 p.

2. Barashnev Yu.I., Bessonova Yu.V. Indicators of perinatal damage to the brain of the fetus and newborn // Obstetrics and gynecology. - 1997. - No. 2. - S. 28-33.

3. Barashnev Yu.I. Neonatal neurology: reality, illusions and hopes // Obstetrics and gynecology. - 1993. - No. 1. - S.14-19.

4. Kulakov V.I. Reproductive health of the population of Russia // Obstetrics and gynecology. - 2002. - No. 2. - S. 4-7.

5. Sargent I., Redcliffe J., Borzychowski A., Croy A.B., Redman C.W.J. The role of the innate immune system in type1 / type2 immunity shifts in normal pregnancy and pre-eclampsia // AJRI. - 2004. - v. 51. - P.460-461.

Claims (1)

A method for predicting perinatal hypoxic lesions of the central nervous system in newborns by immunological examination of a pregnant woman’s peripheral venous blood, characterized in that the content of interleukin-1β is determined from the 35th week of pregnancy complicated by gestosis, and with its value> 40 pcg / l, the development of perinatal hypoxic lesions is predicted CNS.