RU2595884C1 - Method for choosing management approach to pregnant women with placental insufficiency and foetal growth retardation syndrome (fgrs) - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to choosing management approach to pregnant women with placental insufficiency and foetal growth retardation syndrome (FGRS). For this purpose, in patients with placental insufficiency and GRS immunoassay of blood serum is examined for activity of superoxide dismutase, content of placental growth factor, endoglin and melatonin are determined. Based on these values prognostic coefficient P is calculated by formula: P=(0.0001*COD+0.0255*Mel+0.1636*CD105+(-0.0487*PGF)-8.5389, where COD is superoxide dismutase, pg/ml, Mel-melatonin, pg/ml, CD 105 is endoglin, pg/ml, PGF is placental growth factor, pg/ml. If value P is equal to 0.64 and more, high risk of developing antenatal foetal critical state that requires termination of pregnancy by Cesarean section surgery in emergency order for sake of foetus.

EFFECT: method provides higher prediction accuracy of critical condition of fetus antenatal that enables well-timed adequate therapeutic approach to patient.

1 cl, 2 ex

Description

The invention relates to medicine, namely to obstetrics, is intended to predict the critical condition of the fetus and will be widely used for an objective choice of obstetric tactics.

The invention relates to medicine, namely to obstetrics, and is intended to choose the tactics of managing pregnant women with placental insufficiency and fetal growth retardation syndrome (PN and SZRP).

Chronic placental insufficiency (PN) is one of the most important problems of modern obstetrics and perinatology (Dvoryansky S.A., Putinsky E.M., 2009; Serov V.N., Tyutyunnik V.L., Mikhailova O.I., 2010) . The number of observations of this pathology varies, according to different authors (Strizhakov A.N., I.N. Voloshchuk, Macharashvili E.T., 2010; Sharygin SA, Sryeva O.R., Peretiatko LP, Posiseeva LV, 2008), from 22 to 45% of all pregnancies, significantly increasing with concomitant extragenital pathology, preeclampsia and chronic intrauterine infection.

About 10% of newborns who underwent perinatal hypoxia constitute a risk group for mortality in the acute period, and among survivors, 30% are at risk of developing neuropsychic functions, epilepsy, schizophrenia, autism (Khaibullina Z.R. et al., 2014; Mwaniki M .K. Et al., 2012). About 0.2-0.4% of all live births suffer from perinatal ischemia - hypoxia (Clemente Apumayta H.M., 2011), which causes the development of neurological deficit and school failure in children. According to the authors, these complications include delayed fetal growth syndrome, acute and chronic hypoxia.

Fetal growth retardation, the frequency of which, according to Vasiliev V.E. et al. (2012), ranged from 4 to 40%, and is a high risk factor for adverse perinatal outcomes. So, the share of PSA in the structure of perinatal mortality accounts for more than 10%, and among stillborn more than 50% (Pavlov K.A., 2011).

According to V.V. Vetrova et al. (2013) the frequency of the syndrome of intrauterine growth retardation is observed in 5-17% of pregnant women and the causes of complications are chronic somatic diseases and occupational hazards.

The ability to identify early diagnostic markers of the development of chronic placental insufficiency and fetal growth retardation, especially severe forms, necessitates expanding the arsenal of methods for the prevention and treatment of this pathology, by choosing an adequate obstetric tactic, which will reduce perinatal morbidity and mortality.

A known method for predicting obstetric pathology (2339954, November 27, 2008) by examining a pregnant woman, characterized in that in the blood serum of a woman in the first trimester of pregnancy, the content of the growth factor of the placenta and vascular endothelial growth factor is determined with the subsequent calculation of their ratio and its value equal 2 predict fetal growth retardation syndrome (SAR); with a value of 3, gestosis is predicted; equal to 4 - premature birth.

The disadvantages of this method are the inability to determine the gestational age when there is a pronounced decompensation in the placenta, and timely delivery of the patient. In addition, the indicators obtained in the first trimester of pregnancy can vary by the second and third trimesters, which can also increase the number of both false-negative and false-positive results.

There is a method of determining the tactics of managing patients with PN according to the results of measuring the amniotic fluid index (IAI), since it reflects violations of the excretory function of the placenta. With severe oligohydramnios and critical index numbers (IAI <5), early delivery is indicated.

The disadvantage of this method is also the low information content, since IAI is a variable value that reflects only the excretory function of the placenta. And with a long-lasting fluctuation of the IAI, either towards normovodia, or toward low water, there is a risk of missing the decompensation of the fetus.

There is a method of choosing management tactics for pregnant women with placental insufficiency (PN) and fetal growth retardation syndrome (SZRP) (RF patent No. 2517374, 05.27.2014), which includes determining in the blood of a pregnant woman with PN and SZRP angiogenic factors sFlt-1 - soluble fms-like tyrosine kinases and PIGF - placental growth factor, calculation of the angiogenic coefficient (Ka) according to the formula: Ka = sFlt-1 / PlGF × 10 and the choice of tactics for further pregnancy management by the value of the angiogenic coefficient; at the same time, if Ka is less than or equal to 10, the pregnant woman does not need hospitalization, does not require dynamic observation, visits to the doctor of the antenatal clinic are carried out according to the plan; in the event that more than 10, but less than 50, the pregnant woman is hospitalized in a hospital; conduct cardiotocography (CTG), dopplerometry, determination of the amniotic fluid index (IAI); carry out treatment aimed at improving the uteroplacental blood flow within 10 days, while the infusion volume is 400 ml per day, the drugs of choice are actovegin, trental, instenon, carnitine chloride; after 2 weeks, control ultrasound, Doppler examination, CTG, IAH, control of the angiogenic coefficient are carried out; in the absence of negative dynamics, a pregnant woman is prescribed; in the event that Ka is greater than or equal to 50, but less than 100, the pregnant woman is hospitalized in a hospital, CTG, dopplerometry, IAH are performed; carry out treatment aimed at improving the uteroplacental blood flow within 14 days, while the infusion volume is 800 ml per day, the drugs of choice are actovegin, trental, instenon, carnitine chloride; carry out control dopplerometry and CTG once every 3 days, after 2 weeks - control Ka; with positive dynamics, discharge is possible, in the absence of dynamics - continued treatment for 2 weeks; in the event that Ka is greater than or equal to 100, but less than 150, the pregnant woman is hospitalized in a hospital, CTG, dopplerometry, IAH are performed; carry out treatment aimed at improving the uteroplacental blood flow within 14 days, the amount of infusion is at least 800 ml per day, the drugs of choice are the same; additionally injected drugs aimed at correcting hemostasis - fraksiparin, fragmentin, clexane to choose from; Dopplerometry and CTG monitoring daily, with oligohydramnios daily IAI control; up to 34 weeks, prophylaxis of RDS of the fetus is carried out - Dexon 24 mg according to the scheme: 6 mg every 12 hours No. 4; after 2 weeks of treatment - mandatory control of Ka; with positive dynamics, discharge is possible, in the absence of dynamics - continued treatment for 2 weeks; in the event that Ka is greater than or equal to 150 - with a gestational age of up to 34 weeks, the treatment tactics are the same as with Ka from 100 to 150, but control Dopplerometry, CTG, IAH 2 times a day; in the absence of dynamics of fetal weight gain within 2 weeks of treatment or with a deterioration in the functional state of the fetus, caesarean section; with a gestational age of 34-36 weeks - the treatment and observation tactics are the same as with a term of up to 34 weeks, except for the prevention of fetal RDS, but with a deterioration in the nature of fetal movements or a deterioration in the functional state of the fetus according to CTG or dopplerometry - cesarean section; with a gestational age of more than 36 weeks and Ka values greater than or equal to 150 - early delivery.

The disadvantages of this method is the multifactorial nature of the studied parameters, complexity.

This method is accepted by us as a prototype.

Thus, there are still no reliable methods for predicting the critical state of the fetus. In this regard, it is important to search for informative and accessible prognostic criteria based on knowledge of the physiological mechanisms of preparation, the development of normal and the causes of discoordinated labor.

The objective of the invention is the development of a method that allows even at the preclinical stage to predict with high accuracy the critical condition of the fetus, which will be widely used in practical obstetrics for an objective choice of obstetric tactics.

The problem is solved in that in women with fetoplacental insufficiency of the blood serum of women, the content of the placenta growth factor (PGF), endoglin (CD 105), melatonin (Mel), superoxide dismutase (COD) is determined by the enzyme immunoassay and the prognostic coefficient P is calculated by the formula:

P = (0.0001 * COD + 0.0255 * Mel + 0.1636 * CD105 + (- 0.0487 * PGF)) - 8.5389,

Where

COD - superoxide dismutase, pg / ml;

Mel - melatonin, pg / ml;

CD 105 - endoglin, pg / ml;

PGF - placental growth factor, PG / ml,

and when the coefficient P is greater than or equal to 0.64, a high risk of developing a critical condition of the fetus in the antenatal period is predicted, which requires the completion of pregnancy by cesarean section on an emergency basis in the interest of the fetus.

The technical result obtained during the use of the claimed invention consists in increasing the accuracy of prediction, which allows you to timely form a high risk group, thereby choosing the appropriate patient management tactics, timing and method of delivery.

When studying the main mechanisms of placental insufficiency formation and fetal growth retardation, the question of the role of melatonin (Mel) in the formation of the functional system "mother-placenta-fetus" remained outside the field of view of researchers. Melatonin (5-methoxy-Atacetyltryptamine) is an endogenous soluble lipid hormone produced in the pineal gland that synchronizes circadian and seasonal processes in the body. It is also a powerful antioxidant that stimulates endogenous antioxidant systems, such as glutathione peroxidase and glutathione reductase 18, and inhibits the prooxidative enzyme nitric oxide, NO synthase (Miller SL, Wallace E. M. // Effect of antenatal steroids on haemodynamics in the normally grown and growth restricted fetus. Curr Pediatr Rev 2013; 9: 67-74). According to the authors, melatonin also stabilizes cell membranes, improving their resistance to oxidative damage, melatonin protects villous trophoblast from hypoxia, oxidative stress and apoptosis. Due to its strong antioxidant factor and its ability to cross the placenta and the blood-brain barrier, melatonin is considered a powerful neuroprotector, due to which melatonin inhibits norepinephrine-stimulated spasm of the middle cerebral artery and promotes dilation of the umbilical artery (Lanoix D, Lacasse A-A, Reiter RJ et al. : The watchdog of villous trophoblast homeostasis against hypoxia / reoxygenation-induced oxidative stress and apoptosis. Mol Cell Endocrinol 2013; 381: 35-45).

Many scientists emphasize the importance of the participation of endoglin, also called CD 105, a soluble cofactor for the transforming growth factor-1β receptor (TGF-1β), produced in the placenta and plays an important role in the pathogenesis of preeclampsia (Maynard SE, Karumanchi SA. Angiogenic factors and preeclampsia. Seminin Nephrol 2011; 31 (1): 33-46.). According to the authors, the expression of endoglin was high at 4–9 weeks of pregnancy, when the oxygen concentration was low, and decreased after 10 weeks, when the oxygen concentration in the syncytiotrophoblast increased. These data indicate that reduced placental perfusion, leading to placental hypoxia, contributes to increased expression of endoglin in pregnancy with fetal growth retardation.

In recent years, much attention has been paid to studying the role of the placental growth factor, the production of which during physiological pregnancy rises from 8-10 weeks and is characterized by a sharp increase in it (Alwasel SH, Abotalib Z, Aljarallah JS, Osmond C, Al Omar SY, Harrath A, et al. The breadth of the placental surface but not the length is associated with body size at birth. Placenta 2012; 33 (8): 619-22). In women, with a complicated course of the gestational process, in 92.5% of cases there is a violation of the production of FRP, which occurs with the onset of pregnancy and is characterized by its significantly lower level during the entire period of pregnancy. Inadequate formation and dysfunction of placental vessels lead to the development of placental insufficiency and fetal growth retardation (Cotechini T, Komisarenko M, Sperou A, Macdonald-Goodfellow S, Adams MA, Graham CH. Inlammation in rat pregnancy inhibits spiral artery remodeling leading to fetal growth restriction and features of preeclampsia. J Exp Med 2014; 211 (1): 165-79).

Many authors consider oxidative stress as the “universal basis” for the development of all complications caused, in particular, by impaired endothelial function and increased oxidative stress (Prentki M., 2006). Under normal conditions, almost all oxygen is used in the mitochondria of cells for the synthesis of adenosine triphosphoric acid (ATP), and only 1-2% go to the synthesis of reactive oxygen species. Under hypoxic conditions, this ratio shifts toward the synthesis of superoxide (Brand MD, 2006). Normally, superoxide dismutase (SOD) and catalase are involved in the removal of the superoxide radical by cleavage to H ₂ O and O ₂ in the mitochondria (NS Shishkin, 2005). SOD and catalase are enzymatic antioxidants with high specificity, retain high intracellular activity and play an important role under oxidative stress. Currently, there is no doubt that placental insufficiency and PSA are formed under conditions of prolonged hypoxia, and from this point of view, this pathological process can be considered endotheliosis, in the development and course of which an imbalance of the oxidative systems of the body plays a significant role.

A detailed description of the method and examples of its clinical application

The main generally accepted examination methods were used: medical history, complaints, examination of pregnant women, laboratory tests, ultrasound with dopplerometry. When detecting signs of pathology, the volume of examinations and therapy, respectively, expanded to the necessary.

Determination of placental insufficiency with the formation of fetal growth retardation was carried out on the basis of a comprehensive examination and ultrasound examination to determine whether the fetal size corresponded to gestational age (with a mismatch of more than 5 percentile, PSA was observed). Dopplerography of the fetal-placental vessels assessed the status of fetoplacental hemodynamics, the degree of compensation and decompensation.

Blood sampling of women was carried out during hospitalization, followed by determination by the method of enzyme immunoassay of the content of biologically active substances: superoxide dismutase (COD), melatonin (Mel), endoglin (CD 105), placental growth factor (PGF).

Determination of superoxide dismutase (SOD) activity

Superoxide dismutase (SOD) catalyzes the dismutation reaction of superoxide anions, turning them into hydrogen peroxide and oxygen. The determination was carried out by a method based on the ability of SOD to inhibit the auto-oxidation of adrenaline at a pH of 10.2. For analysis, 0.1 ml of venous blood was taken and diluted with 5 mM Tris-HCl buffer in a 1: 9 ratio. Hemoglobin was precipitated from the obtained hemolysis by adding 0.25 ml of ethanol and 0.15 chloroform. The contents of the tubes were centrifuged at 200 rpm for 15 minutes to remove hemoglobin and chloroform. The supernatant was used to determine the activity of SOD.

- 1 ml of 0.15 M sodium carbonate buffer with the addition of EDTA, pH 10.2;

- 0.5 supernatant of the test blood (or water, if a control sample was measured);

- 1.7 ml of 0.005 M potassium phosphorus buffer with the addition of EDTA, pH 7.8;

- 0.4 ml of 2.25 · 10 ^-3 M aqueous solution of adrenaline, pH 2.5.

The reaction was started by adding adrenaline and rapidly stirring the contents of the cuvette.

SOD activity was measured on a spectrophotometer at a wavelength of 540 nm. First, the rate of autoxidation of adrenaline in adrenochrome was determined (control sample E I), then the autooxidation of adrenaline in the presence of SOD (test sample E II). The true initial rate of oxidation of adrenaline (E III) in the presence of SOD was calculated by the formula

E III = E I - E II (opt. Units / min).

The amount of SOD required for inhibiting the initial adrenaline rate of 50% was taken as the unit of activity. The percentage of inhibition of the reaction of autooxidation (T%) was calculated by the formula:

Determination of melatonin activity

The level of melatonin in the blood serum of patients by enzyme-linked immunosorbent assay kits from BACHEMGROUP (USA). The preparation of standard solutions, antisera, conjugate, wash buffer was carried out according to the instructions for the set.

50 μl of standard solutions or test samples were added to the appropriate wells of the plate. 25 μl of antiserum and 25 μl of biotin conjugate were added to all wells of the plate, after which they were incubated for 1 hour at room temperature.

At the end of the incubation, the wells of the plate were washed three times with washing buffer on an ELISAWASHEPHUMAN microplate washer (USA). 100 μl of streptavidin-peroxidase conjugate solution was added to all wells of the plate and re-incubated for 1 hour at room temperature. The plate was washed 5 times, as described above, after which 100 μl of TMB solution was added to all wells of the tablet, the next incubation was carried out in the dark for 30 minutes, the color reaction was stopped by adding 100 μl of 2 NHCl solution to each well.

The optical density was measured at 450 nm and the results were calculated using a MULTILABELCOUNTER 1420 photometer (Finland).

Numerical values of melatonin concentrations in standard solutions were introduced into the computer software of the device, and after measurement, the concentration of melatonin in experimental samples in pg / ml was obtained.

Determination of the level of placental growth factor (PFR).

The level of placental growth factor (PFR) in blood serum was determined by enzyme-linked immunosorbent assay kits from R&D Systems (USA).

Wash buffer, standard solutions, substrate solution were prepared according to the instructions for the set.

100 μl of working buffer were added to all wells of the plate coated with murine polyclonal antibodies to human PFR. 100 μl of the standard dilution solution was added to the blank well, 100 μl of the prepared standard samples were added to the wells for constructing the standard curve, and 100 μl of the studied samples to the remaining wells. The plate was covered with film and incubated for 2 hours at room temperature.

At the end of the incubation, the wells of the plate were washed with washing buffer 4 times on an ELISA WASHNER HUMAN microplate washer (USA).

Then, 200 μl of a solution of a conjugate of polyclonal antibodies to human PFR with horseradish peroxidase were added to all wells. The plate was incubated at room temperature for 2 hours.

Wash the plate 4 times with wash buffer as described above.

200 μl of a freshly prepared substrate solution was added to all wells and incubated for 30 minutes, protecting from direct sunlight.

The color reaction was stopped by adding 50 μl of stop reagent to each well.

The optical density was measured at 450 nm and the results were calculated using a MULTILABEL COUNTER 1420 photometer (Finland).

Numerical values of the concentrations of PFR in standard solutions were introduced into the computer software of the device, and after measurement, the concentration of PFR in the experimental samples in pg / ml was obtained.

Determination of the level of endoglin (CD 105)

The level of endogline in blood serum was determined by enzyme-linked immunosorbent assay kits from BIOSOURSE (USA).

Wash buffer, standard solutions were prepared according to the instructions for the device.

50 μl of incubation buffer was added to all wells of the plate coated with polyclonal antibodies to human endogline. 100 μl of the standard dilution solution was added to the blank well, 100 μl of prepared standard samples were added to the wells for constructing the standard curve, 50 μl of the dilution buffer and 50 μl of the studied samples were added to the remaining wells. The plate was covered with film and incubated for 2 hours at room temperature. At the end of the incubation, the wells of the plate were washed with washing buffer 4 times on an ELISA WASHNER HUMAN microplate washer (USA).

The optical density was measured at 450 nm and the results were calculated using a MULTILABEL COUNTER 1420 photometer (Finland).

Numerical values of endoglin concentrations in standard solutions were introduced into the computer software of the device, and after measurement, the concentration of endoglin in the experimental samples was obtained. The results were multiplied by a dilution factor (2) and expressed endoglin in the patient's blood serum in pg / ml.

The results obtained as a result of the study were substituted into the formula:

P = 0.0001 * COD + 0.0255 * Mel + 0.1636 * CD105 + (- 0.0487 * PGF) -8.5389,

Where

COD - superoxide dismutase, pg / ml,

Mel - melatonin, pg / ml,

CD 105 - endoglin, pg / ml,

PGF - placental growth factor, PG / ml,

and with a value of P equal to or greater than 0.64, the development of a critical condition of the fetus requiring surgical delivery was predicted.

The performance of the claimed method is confirmed by the following clinical examples.

Example 1

Pregnant Class N.V., 34 years old. Diagnosis at admission: Pregnancy 29-30 weeks. Chronic placental insufficiency, compensation. Fetal growth retardation II-III degree (according to ultrasound). Burdened obstetric history. Scar on the uterus.

On the first day of hospitalization, the patient underwent ultrasound and Dopplerometric examination. Before treatment, blood was taken to determine the activity of superoxide dismutase, the content in the blood serum of the growth factor of the placenta, endoglin, melatonin.

superoxide dismutase COD - 12281.60 pg / ml pg / ml,

Melatonin Mel - 266.10 pg / ml,

endoglin CD 105 - 6.06 pg / ml,

PGF placenta growth factor - 189.37 pg / ml.

The results of the study were used by the formula for calculating:

P = (0.0001 * 12281.60 + 0.0255 * 266.10 + 0.1636 * 6.06 + (- 0.0487 * 189.37)) - 8.5389 = 0.629469.

The resulting P value of 0.629469 pg / ml made it possible to predict a favorable course of pregnancy. This pregnancy ended in operative delivery at the time of full-term pregnancy, as planned, with a living full-term, healthy baby weighing 2700.0 g. Final diagnosis: Childbirth II, operative at 38 weeks 2 days. Chronic placental insufficiency, compensation. Fetal growth retardation I-II degree. Burdened obstetric history. Uterus scar (2).

Example 2

Pregnant V-va M.Kh., 24 years old.

Received in the Obstetric Department of Pregnancy Pathology with a diagnosis of Pregnancy in the period of 28-29 weeks. Chronic placental insufficiency, compensation. Fetal growth retardation III degree. Burdened obstetric history. Scar on the uterus.

On the day of hospitalization in the pregnant ward, an ultrasound and dopplerometric examination was performed. Before treatment, blood was taken to determine the activity of superoxide dismutase, the content of placental growth factor, endoglin, and melatonin in the blood.

superoxide dismutase COD - 5402.60 pg / ml,

Melatonin Mel - 260.31 pg / ml,

endoglin CD 105 - 10.73 pg / ml,

PGF placenta growth factor 98.63 pg / ml.

The results of the study were used by the formula for calculating:

P = (0.0001 * 5402.60 + 0.0255 * 260.31 + 0.1636 * 10.73 + (- 0.0487 * 98.63)) - 8.5389 = 0.641747.

The resulting P value of 0.641747 pg / ml made it possible to predict the development of a critical condition of the fetus with a zero diastolic component of blood flow in the umbilical artery, which requires surgical delivery. According to a Doppler study, a critical condition of the fetus with a zero diastolic component of blood flow in the umbilical artery was revealed. An emergency caesarean section was performed with a favorable outcome. A lively, premature baby was born, with a body weight of 700 grams and treatment in the Department of Anesthesiology and Resuscitation.

According to the claimed method were examined 65 patients in the period 24-34 weeks of pregnancy. The criterion for the formation of clinical groups was the course of this pregnancy, the presence of placental insufficiency with the formation of fetal growth retardation or absence.

The first clinical group included patients whose average age was 26.5 ± 0.5 years, in the period of 24-34 weeks of pregnancy. P indicators (according to the formula) were less than 0.64, which was indicated by the data of special research methods in the framework of this scientific work on the physiological course of pregnancy. This group consisted of 40 women.

The second clinical group consisted of 25 pregnant women, also in the period of 24-34 weeks of pregnancy. The average age of the patients was 25.8 ± 0.5 years. Their P values (according to the formula) were equal to 0.64 and higher, with a progressive course of placental insufficiency, which led to the development of decompensation and a critical condition of the fetus - operative delivery on an emergency basis in 100% of cases.

The data presented allow us to say with confidence that the implementation of a critical condition of the fetus is in utero related to the content and action of various biologically active substances in the patient's blood serum on fetoplacental blood flow. Peculiarities of development, the nature of the course and outcome of pregnancy in case of placental insufficiency and PSR depend not only on the absolute values of biological substrates in the blood serum, but also on their ratio, described by a special formula for calculating the prognostic coefficient.

The inventive method allows us to choose the tactics of delivery, taking into account the differentiated approach to assessing the condition of the fetus, as well as taking into account the anamnesis of a pregnant woman who is undergoing therapy at different gestational periods, which significantly increases the accuracy of the method.

Thus, the claimed method is specific and sensitive in comparison with the known. The method is specific, because it allows, using a fairly simple technique, to accurately predict the critical state of the fetus.

1. Has a high sensitivity. False negative results received only 3.

2. Clinical application of the method will allow timely implementation of adequate obstetric tactics.

3. The prognostic coefficient P is determined long before the decompensation of the fetoplacental hemodynamics with zero diastolic component of blood flow in the umbilical artery is detected according to the Dopplerometric study, which indicates a critical condition of the fetus.

The inventive method for predicting the condition of the fetus has been tested on sufficient clinical material and can be recommended for use in obstetric hospitals.

Claims (1)

A method for choosing the management tactics for pregnant women with placental insufficiency and fetal growth retardation syndrome (FDS) by examining blood serum, characterized in that the levels of superoxide dismutase, placental growth factor, endoglin and melatonin are determined, and the prognostic coefficient P is calculated by the formula:
P = (0.0001 * COD + 0.0255 * Mel + 0.1636 * CD105 + (- 0.0487 * PGF) -8.5389,
Where
COD - superoxide dismutase, pg / ml,
Mel - melatonin, pg / ml,
CD105 - endoglin, pg / ml,
PGF - placental growth factor, PG / ml,
and with a value of P equal to 0.64 or more, the development of a critical state of the fetus requiring surgical delivery is predicted.