Method for predicting cerebral disorders in neonatals in mothers from high-risk group

FIELD: medicine, perinatology.

SUBSTANCE: one should sample the waters during the period of delivery in pregnant women from the risk group at verified urogenital infection and/or the presence of fetoplacental insufficiency to detect the value of TNF-α and neopterin. At TNF-α being above 88.1±7.9 pg/ml and neopterin being above 17.3±1.6 ng/ml one should predict hypoxic-ischemic lesion of neonatals' CNS. The innovation enables to indicate earlier curative procedures.

EFFECT: higher accuracy of prediction.

3 ex, 1 tbl

 

The invention relates to medicine, namely to Perinatology and can be used for prediction of perinatal hypoxic-ischemic lesion of the Central nervous system in newborns from mothers with infectious pathology and placental insufficiency.

The problem of perinatal hypoxic-ischemic lesion of the nervous system in newborns retains its relevance because of the high morbidity and mortality among newborns and children of early age (Zaitseva NS, Dolgin E., Nepokulchitsky NV Some parameters of immunity in newborns with perinatal hypoxia. Pediatrics, No. 4, 1994, p.20).

The most common cause of hypoxia is a chronic fetoplacental insufficiency. A special place in the etiology of chronic placental insufficiency belongs acute and chronic urogenital infections. Easy and even asymptomatic infection pregnant can lead to severe placental insufficiency until death and severe disability of the child. This phenomenon is largely due to the tropism of pathogens (especially viral) to embryonic tissues, and cells of the fetus are the ideal breeding ground for microorganisms (Bubnov NI, Zaidieva SS, Tyutyunnik V.L. Morphological changes in the placenta, caused the mixed infection. - Sat. Current issues of diagnosis, treatment and prevention of preeclampsia. - M., 1998, p.222).

The combination of chronic placental insufficiency and infection burdens gestational process, increases the risk of diseases of the fetus and newborn.

Infection in the reproductive tract of pregnant women the stimulation of proinflammatory cytokines, which are intermediaries in the development of inflammatory and immune reactions in the system mother - placenta - fetus. Maternal infection increases the risk of miscarriage, which in turn is associated with impaired placental blood flow and increased risk of intraventricular haemorrhage, damage to the white matter of the brain. (Dammann o, Leviton A. Maternal intrauterine infection, cytokines, and brain damage in the preterm newbonr. - Pediatr Res, No. 42, 1997, p.1).

Despite the large number of studies on this issue in the spotlight obstetricians and neurologists are issues such as the risk of perinatal damage of the Central nervous system of the fetus in pregnant women with urogenital infection and placental insufficiency. The identification of reliable markers predict the development of perinatal CNS damage will allow us to highlight the newborns of these mothers at risk for early treatment and preventive measures is s, that will help to reduce the frequency of neurological morbidity in children of early age.

At the present time in modern literature widely discusses the various methods of diagnosing and predicting the condition of the fetus and placental system. Some of them directly register hypoxic lesions of the Central nervous system of the fetus (dopplerometrical study of utero-placental and fetal-placental blood flow, ultrasonic Feto - and placentalia) (Savelyeva G.M., Fedorov M.V., Klimenko P.A. Placental insufficiency. - M.: Medicine, 1991, pp.272). Others identify functional and biochemical markers of developmental disorders of the Central nervous system of the fetus and determining their values for prediction of the degree of neurological disorders in newborns (Is functional and biochemical markers in the development of the Central nervous system in the antenatal period to forecast the severity of neurological disorders in the newborn. - Pavlova N.G., Fomenko B.A.,. She E.I., 2002).

There is a method of forecasting the health of infants born to mothers with urogenital infection (Patent No. 2232394 from 07.10.2004 g) by determining the level of phospholipids in the peripheral blood of pregnant women. When the level of phosphatidylethanolamine less than 22%, phosphatidylcholine more than 4%, phosphatidylserine less than 4% predict the formation of PA the sociology of the respiratory system, the occurrence of autoimmune processes in children. However, the method does not allow to predict neurological disorders in children before their birth.

There is a method of screening examinations of women of childbearing age using the test system ELI-P to forecast the development of the embryo/fetus and the birth of healthy or abnormal child (Patent No. 2107913 from 27.03.1998 g) by determining the immunoreactivity of serum antibodies of the woman's body, has a significant impact on normal embryologist and directed to antigens that are involved in the development of organs and tissues of the fetus.

There is a method of predicting the course of pregnancy and risk assessment development of the embryo/fetus and the birth of a child with various disabilities (Patent No. 2233121 from 27.07.2004,) using the test system for ELISA. If the intensity of the reactions is beyond the norm, it belongs to the group variances and predict the risk of adverse pregnancy and abnormal development of the embryo/fetus. The disadvantage of these methods is the identification of the already formed organic pathology of the fetus.

A known method for the diagnosis of complications of pregnancy and prediction of the state of the fetus and newborn (Patent No. 2120636 from 20.10.1998, by determining the concentration of immune serum proteins is Atari, associated alpha 2-globulin (SBAG) and USSR of betaglobin (TBG), which is judged on the presence of complications of pregnancy and subsequent forecasting of a condition of the newborn (preeclampsia, fetal hypoxia, disadaptation syndrome of the newborn).

There is a method of determining the status of the fetus (Application No. 93036133/14 from 20.05.97, by definition in the blood concentration of creatinine and by increasing its 51 Ámol/l and above define a violation of the condition of the fetus. However, the disadvantage of this method are large individual variations in the concentration of creatinine, which does not allow to judge about fetal development, and insufficient information of the method.

The prototype of the invention, the selected method of risk assessment prenatal brain damage described (Yoon B.N., Park C.W., Chaiworapongsa T., "Intrauterine infection and the development of cerebral palcy". - BJOG, 2003, v.110, p.122). The authors investigated the level of tumor necrosis factor alpha, IL-6, IL-8 in amniotic fluid of pregnant women with symptoms of threatened abortion and laboratory markers of infection. Their correlation was found in the concentration levels of Pro-inflammatory cytokines in the amniotic fluid, obtained by transabdominal amniocentesis and increased risk of cerebral damage in newborns.

He has a number of disadvantages:

1) Way Tr is required sampling of amniotic fluid by amniocentesis, what is traumatic, accompanied by high risk of complications.

2) determination of the concentration of only cytokines cannot be considered an adequate approach to the assessment of activation of cellular immunity, this is due to the short half-life of cytokines. In this regard, the optimum is an additional dimension more inert product, such as neopterin concentrations.

3) the study did not provide information on the definition of specific indicators neopterin concentrations and TNF in the amniotic fluid, which allows the obstetrician-gynecologist to make a conclusion about the selection of newborns at risk.

These drawbacks are eliminated in this present method.

The objective of the invention: improving the accuracy of prediction of cerebral disorders, namely perinatal hypoxic-ischemic lesions of the Central nervous system in newborns from mothers with urogenital infection and placental insufficiency for most early medical treatment and preventive measures.

The problem is solved by the fact that pregnant women risk group with verified urogenital infection and/or the presence of placental insufficiency in childbirth conduct simultaneous determination of TNF-α and neopterin concentrations in the amniotic fluid and the importance of TNF-α above 88,1±to 7.9 PG/ml and neopterin concentrations above the 17.3±1.6 ng/ml predict the ISU is cichecki-ischemic lesion of the Central nervous system of the newborn.

This method allows you to determine with high accuracy, sensitivity and specificity of the risk of cerebral disorders, namely hypoxic-ischemic lesions of the Central nervous system in newborns in order to conduct early adequate therapy that will help greatly reduce the frequency of neurological morbidity in children of early age.

It is known that microbial invasion activates the synthesis of TNF-α cells of the amnion, chorionic and decidual fruit tissues, which leads to disorders of the hemostatic system, dysfunction of the endothelial cells of the placenta, changes in uteroplacental blood flow, increased permeability of the placenta and, therefore, to the prenatal suffering of the fetus. Increased levels of TNF-α in the amniotic fluid reflects the dysfunction of the placenta. High levels of TNF-α may be a triggering factor destructive inflammatory reactions in the placenta, leading to ischemic areas. In addition, increased levels of proinflammatory cytokines in the environment surrounding the embryo, can have a significant impact on the developing brain (Uracubo A., Jarskog, L.F., Lieberman J.A., "Prenatal exposure to maternal infection alters cytokine exspression in the placenta, amniotic fluid, and fetal brain. - Schizofrhr Res, 2001, No. 47, p.27), to disrupt the blood-brain barrier permeability and neurological symptoms in the early period of the new is codenotti (Degtyareva MV, Degtyarev D.N., Volodin N.N., Kovalchuk L.V. "the Role of interleukin-1 and tumor necrosis factor in newborn infants in norm and pathology". - Pediatrics, No. 1, 1996, p.93).

Neopterin is a marker of the activation of cellular immunity. The increase of its concentration is associated with the intensity of the inflammatory process. The combined effect of TNF-α and neopterin concentrations enhances apoptosis of placental cells due to the action of active oxygen (Baier-Bitterlich g, Fuchs D., "Effect of neopterin and 7, 8 dihidroneopterin on tumor necrosis factor induced programmed cell death". - FEBS Lett, No. 2, 1995. p.234). Neopterin plays a significant role in the mechanisms of cytotoxic action of activated macrophages. The concentration of neopterin concentrations plays a predictive role in autoimmune, infectious diseases, however, in literature examples of the use of this indicator to predict the degree of severity of the pathology of the placenta and, therefore, hypoxic disorders of the Central nervous system of the fetus. The level of neopterin concentrations according to (Yudina S.M., Stepanenko IV, Popobawa O.N. Diagnosis and prediction of intrauterine infection of the fetus. - Russian journal of immunology, v.9, No. 2, 2005, s) in pregnant women with urogenital infections significantly increased in serum and amniotic fluid that the authors used for the prediction of intrauterine infection.

Everything ieuconoe was the basis for our studying changes in the level of TNF-α and neopterin concentrations in the amniotic fluid for prediction of hypoxic-ischemic lesions of the Central nervous system in newborns from mothers with urogenital infection and placental insufficiency. Our research has enabled us to establish a very important quantity, TNF-α and neopterin concentrations, which are indicative of the selection of infants at risk for development of cerebral disorders.

The technical result obtained by the implementation of the proposed method is that the inventive method is non-invasive, allows to predict the risk of perinatal hypoxic-ischemic lesion of the Central nervous system of the newborn. The combination of tests TNF-α and neopterin in the amniotic fluid will improve the accuracy and efficiency of the prediction of perinatal hypoxic-ischemic injury in the brain of a newborn.

The method is as follows:

Logistics method.

1) MultiScan ORGANON TECHNIKA, Finland.

2) a Diagnostic test system for the determination of TNF-α-company "Protein component", St. Petersburg.

3) a Diagnostic test system for the determination of neopterin concentrations firm IBL, Germany.

4) Centrifuge (reg. No. 93/199-262).

A pregnant woman in childbirth explore the amniotic fluid. Amniotic fluid is collected in a dry centres is uinuu tube centrifuged at 1500 rpm for 20 minutes. Adosados taken in a test tube type Ependorf. Determining the level of TNF-α conduct enzyme-linked immunosorbent assay using test systems "Protein component", St. Petersburg. Determining the level of neopterin concentrations spend enzyme-linked immunosorbent assay using a test system IBL (Germany). The reaction accounting is performed on multiscale at a wavelength of 450 nm. Upon receipt of the level of TNF-α in the amniotic fluid above 88,1±to 7.9 PG/ml and the level of neopterin concentrations in the amniotic fluid above the 17.3±1.6 ng/ml predict perinatal hypoxic brain damage a newborn.

Example 1.

Pregnant D-K, 26 years. Entered the maternity ward NIIAP 18.05.04 with a diagnosis of pregnancy 38-39 weeks, fetoplacental insufficiency, large fruit, endocervicitis, colpitis, chronic pyelonephritis in remission. Parvovirinae. History before pregnancy treatment of a ureaplasmosis, trichomoniasis and genital herpes. In the early stages of pregnancy was noted the threat of abortion, the risk of a low placentation by ultrasound, therapy was not given. In the 21st week was marked polyhydramnios, vaginal dysbiosis, exacerbation of chronic pyelonephritis. A pregnant woman was hospitalized at the place of residence for antibacterial therapy. With a 29-0 weeks pregnant ultrasound signs of placental insufficiency. When PCR-diagnostics revealed micoplasma hominis, Trichomonas vaginalis, held antibacterial therapy, vaginal cleansing. Delivery made through the birth canal with prenatal rupture Econoline stained amniotic fluid. The boy was born weighing 4400, length 56 cm, with double tight entanglement of the umbilical cord around neck, with rating on a scale of Apgar 6-8 points, events cephalohematoma. In childbirth extracted amniotic fluid, which detected the levels of TNF-α 88,1 PG/ml and neopterin concentrations of 17.3 ng/ml, that has allowed to carry a newborn at high risk of developing perinatal hypoxic-ischemic lesion of the Central nervous system. On the first day, the condition of the newborn evaluated by a neonatologist as moderately heavy. On the 2nd day the child was examined by a neurologist: diagnosis - cerebral ischemia, grade II hypertensive-hydrocephalic syndrome and recommendations for further treatment, he was transferred to the neonatal care unit. In the Department, the child was examined. Neurosonogram: brain size 90,8 mm Lateral ventricles S:D=3,4:4,4 (elongated shape). 3 ventricle 3.9 mm, ventricular index of 37%. Selview the water is open, the cavity 3 and 4 ventricular free. Choroid plexus normal ahopelto, heterogeneous, the contours of the left rough. In parasagittal projection on the left choroid plexus (anterior)lazerous two pseudocyst size of 3.3 and 2.8 mm. Right on the vascular plexus pancreatic pseudocyst size to 2.0 mm, moderate signs of intracranial hypertension. When USDG cerebral hemodynamics showed signs of amiodarone with symptoms of venous degenii I-II degree. Thus, according to the clinical observation of the dynamic and additional studies of the diagnosis was confirmed. The forecast for the proposed method was confirmed.

Example 2.

Pregnant D-co, 25 years old, was admitted to the maternity ward NIIAP 11.11.03 with a diagnosis of pregnancy 38-39 weeks, colpitis, fetoplacental insufficiency, concomitant late gestosis on the background gestational pyelonephritis in remission, hypothalamic syndrome, symptomatic hypertension. Parvovirinae. History prior to pregnancy treatment of chlamydia, Trichomonas and herpes infection. In the period of 7-8 weeks observed phenomena threat of termination of pregnancy (abdominal pain, bloody discharge from the genital tract, according to the ultrasound area of the detachment of the chorion), the phenomenon of early preeclampsia, received comprehensive care in the Department of pathology of pregnancy NIIAP. In 29-30 weeks of gestation re-hospitalization in the Department of pathology of pregnant women with signs of placental insufficiency by ultrasonography and diplomaticheskogo research. When PCR and ELISA diagnostics detected Mar the career of reactivation of chlamydia and herpes infection. Delivery made through Estestvennye vaginally in a planned manner. Born live, full-term baby weighing 3250 g, length 50 cm In childbirth extracted amniotic fluid, which detected the level of neopterin concentrations - a 24.3 ng/ml, TNF-α - 100,2 PG/ml, that has allowed to carry this newborn is at risk of clinical manifestation of hypoxic-ischemic lesion of the Central nervous system. When viewed by a neonatologist and a neurologist in the maternity Department of pathology it is not revealed. However, at the age of 20 days was observed symptoms of neurological disorders and diagnosed with cerebral ischemia II extent syndrome vegetovisceral dysfunction with the assignment of appropriate medical therapy. Outpatient with additional research on neurosonogram identified: brain size 82 mm Lateral ventricles S:D 2,4:2.7 mm, 3 ventricle 3.5 mm, ventricular index of 26.5%. In the parenchyma of the brain fine-grained vascular plexus normal ecoprotect. A homogeneous, clear contours. In parasagittal projection right lazerette echopositive education (up to 2 mm closer to the posterior horn in the thickness of the choroid plexus echopositive education to 3.4 mm When USDG cerebral hemodynamics were determined by indirect signs of intracranial hypertension in the stage of subcompensation, which helped confirm the prediction of the proposed method.

Example 3.

Pregnant-F., 35 years old, was admitted to the maternity ward NIIAP diagnosed with pregnancy 38-39 weeks, JAA, colpitis, chronic tonsillitis, remission, Avtomobilnaya, powerseraya. History of cervical erosion, chronic salpingo-oophoritis. In the period 13-14 weeks was detected chlamydial and urea-mycoplasmal infection conducted antibacterial therapy. At 23-24 weeks of pregnancy was complicated by violation of uteroplacental hemodynamics, concerning which received metabolic therapy. At 38 weeks of pregnancy in PCR diagnostics revealed a Ureaplasma urealiticum. Birth programmed. Born live, full-term baby weighing 3500 g, length 53 see childbirth extracted amniotic fluid, which detected the levels of TNF-α 48,1 PG/ml, the level of neopterin concentrations of 10.0 ng/ml, which allowed to predict the absence of neurological disorders in the newborn. Early neonatal period proceeded without features. The child was discharged on the 5th day in a satisfactory condition under the supervision of the district pediatrician. Further clinical follow-up revealed no neurological disorders in the newborn. The forecast for the claimed method was confirmed.

The reliability of the method is confirmed by clinical and laboratory research. By the present method were examined in 50 pregnant women in the period of 38-40 weeks ber is mennoti with markers urogenital infections and/or placental insufficiency. In 33 of them, the level of neopterin concentrations in the amniotic fluid was 17.3±1.6 ng/ml and above, the level of TNF-α 88,1±to 7.9 PG/ml and above, indicating that the risk of hypoxic-ischemic lesion of the Central nervous system in newborns, which was confirmed in further clinical and laboratory observations. 17 pregnant these indicators were lower in babies born from them, CNS lesions not identified. Survey data are shown in table 1.

As a result of the statistical analysis using the criterion of Mann-Whitny in the environment of the application package STATISTIKA 6, it was found that there is strong statistical difference in the groups of pregnant women with various perinatal outcomes indicators TNF-α with certainty P=0,000003 and neopterin concentrations with certainty P=0,000021. This result was the basis for the development of prognostic rules for forming groups of risk newborns in the development of hypoxic-ischemic lesion of the Central nervous system using the method of logitrans (Rebrov O.Y Statistical analysis of medical data, M: Media field, 2003). The resulting rule provides high accuracy, sensitivity and specificity of the method.

The advantage of the inventive method is that in pregnant women the C high-risk groups on the basis of highly sensitive modern laboratory markers are predictive of cerebral abnormalities in their babies, namely perinatal hypoxic-ischemic lesion of the Central nervous system, for early appointment of adequate therapy. In clinical practice, this will reduce the frequency of neurological disorders and disabling conditions in children of early age. The method can be recommended for wide use in clinical practice.

A method for predicting cerebral disorders in newborns from mothers at risk with verified urogenital infection and/or placental insufficiency by studies of cytokines in the amniotic fluid, characterized in that the taking of amniotic fluid at birth, investigate the level of neopterin concentrations and TNF-α method of enzyme-linked immunosorbent assay and the concentration of neopterin concentrations of 17.3±1.6 ng/ml or higher, and concentrations of TNF-α 88,1±to 7.9 PG/ml and above predict perinatal hypoxic-ischemic lesion of the Central nervous system of the newborn.



 

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3 ex, 3 tbl

FIELD: immunology.

SUBSTANCE: through a flow microcell of 15-20 mcl volume one should pass the flow of phosphate buffer solution-carrier at the rate of about 30-90 mcl/min which should be supplemented with analyzed serumal sample at the volume of 200 mcl. The flow cell is supplied with a horizontally fixed piezogravimetric immunosensor at fluctuation frequency fm and receptor covering based upon one of the LPC Yersinia enterocolitica of serovars O:3, O:5 or O:6.30. Then it is necessary to register the binding LPC Yersinia enterocolitica of serovars O:3, O:5 or O:6.30 with antibodies according to the decrease of sensor's fluctuation frequency from fm up to f to detect the concentration of antibodies according to calibration graph being directly proportional against ▵f being equal to fm-f. Application of the present innovation enables to decrease the procedure of analysis up to 10 min and, also, carry out a re-usable analysis after regeneration of sorbed LPC at sensitivity being 1.3 mcg/ml and detect concentration of antibodies ranged 10-100 mcg/ml.

EFFECT: higher accuracy and efficiency of detection.

8 ex, 1 tbl

FIELD: medicine, laboratory diagnostics.

SUBSTANCE: the present innovation deals with detecting the concentration of antibodies to neurospecific enolase (NSE) and gliofibrillo-acid protein (GFAP) in blood serum of pregnant women. The development of gestosis should be predicted at the level of anti-NSE-antibodies being above 0.6 mcg/ml or anti-GFAP-antibodies being above 0.9 mcg/ml. The innovation provides high information value and specificity of the method suggested to predict the development of gestosis.

EFFECT: higher efficiency.

3 ex, 1 tbl

FIELD: medicine, ophthalmology.

SUBSTANCE: in lacrimal liquid one should detect the content of interleukin 8 (IL-8) and that of interleukin 1 beta (IL-1β) to calculate prognostic coefficient (PC) due to dividing the first value by the second one by the following formula: At PC value being below 10.0 one should predict favorable disease flow, and at PC value being above 10.0 - unfavorable flow.

EFFECT: higher accuracy of prediction.

2 ex

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