Placental insufficiency - Diagnosis

It is not difficult to establish a diagnosis of placental insufficiency in cases of severe intrauterine growth retardation of the fetus; it is much more difficult to identify its initial manifestations when placental insufficiency is realized at the level of metabolic disorders in the mother and fetus. That is why the diagnosis should be established based on a comprehensive examination of pregnant women, data from a carefully collected anamnesis taking into account living and working conditions, bad habits, extragenital diseases, features of the course and outcomes of previous pregnancies, as well as the results of laboratory research methods.

A comprehensive examination of the fetoplacental complex should include:

• Evaluation of fetal growth and development by carefully measuring the height of the uterine fundus, taking into account the abdominal circumference and body weight of the pregnant woman.
• Ultrasound biometry of the fetus.
• Assessment of the condition of the fetus by studying its motor activity and cardiac activity (cardiotocography, echocardiography, determination of the biophysical profile of the fetus, in some cases - cordocentesis).
• Ultrasound assessment of the condition of the placenta (location, thickness, area, volume of the maternal surface, degree of maturity, presence of cysts, calcification).

History and physical examination

Currently, various methods are used to diagnose placental insufficiency. Clinical methods include identifying anamnestic risk factors, objective examination of the pregnant woman and fetus by measuring the abdominal circumference and the height of the fundus, determining the tone of the myometrium, the position of the fetus, and calculating its estimated weight. It is known that a lag in the height of the fundus of the uterus by 2 cm or more compared to the required value for a specific gestational age or the absence of an increase over 2–3 weeks indicates the likelihood of developing IUGR. Clinical assessment of the state of the cardiovascular system is carried out by auscultation. For antenatal clinics, the point system for determining the risk of placental insufficiency developed by O.G. Frolova and E.N. Nikolaeva (1976, 1980) is acceptable.

Important information about the functional reserves of the fetus during labor comes from the assessment of the quality of the amniotic fluid. Currently, prognostic criteria for severe complications of placental insufficiency have been identified - meconium aspiration of the fetus and newborn (based on the nature of the amniotic fluid in combination with data on its cardiac and respiratory activity). A point scale has been created that takes into account the color of the water, the consistency of meconium, the gestational age, and the presence of signs of hypoxia based on the assessment of the cardiac activity of the fetus. With 12 points, the probability of meconium aspiration in the fetus is 50%, 15 or more - 100%. However, a significant limitation of clinical diagnostic methods is the individual variability of the size of the abdomen and uterus of a pregnant woman, depending on anthropometric features, the severity of the subcutaneous fat layer, the amount of amniotic fluid, the position and number of fetuses. Changes in the auscultatory picture occur only in the late stages of fetal distress and are more often manifested already during labor. In practice, assessing the condition of the amniotic fluid is possible only after its discharge, since amnioscopy is uninformative, and amniocentesis is classified as an invasive method, which has a number of limitations and requires special conditions. Almost 60% of pregnant women do not detect placental insufficiency by clinical methods. On the other hand, only one out of three pregnant women with suspected IUGR, referred for ultrasound, has the clinical diagnosis confirmed.

Laboratory and instrumental studies

Among the laboratory methods used in recent years are determination of the hormonal and protein-synthesizing function of the fetoplacental complex (placental lactogen, progesterone, estriol, cortisol, a-fetoprotein, SP1, PP12, etc.), biochemical study of its enzymatic activity (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, etc.). Laboratory diagnostics of placental insufficiency based on determination of hormone concentration has its own characteristic signs that precede clinical manifestations of placental insufficiency by 2-3 weeks. Placental insufficiency in early pregnancy mainly depends on insufficient hormonal activity of the corpus luteum and is accompanied by low levels of progesterone and hCG. Later, in the II and III trimesters of pregnancy, the development of placental insufficiency is accompanied by morphological disorders, which gradually causes the development of insufficiency of the hormone-producing function of the placenta.

An early preclinical sign of placental insufficiency is a decrease in the synthesis of all hormones of the fetoplacental system (estrogens, progesterone, placental lactogen). The greatest practical significance has been acquired by determining the concentration of estriol as a method of monitoring the condition of the fetus during pregnancy. In complicated pregnancy, a decrease in the concentration of estriol is an early diagnostic sign of fetal developmental disorders. A decrease in the excretion of estriol in the urine to 12 mg / day or less indicates a significant deterioration in the condition of the fetus and the fetoplacental system. However, significant fluctuations in this indicator in the norm and in fetal hypotrophy make it necessary to conduct dynamic studies. A sign of placental insufficiency is a decrease in the concentration of estriol in the amniotic fluid. For diagnosis, the estriol index is determined - the ratio of the amount of hormone in the blood and in the urine. As the insufficiency progresses, the index value decreases. One of the most common causes of low estriol content in the blood of pregnant women is fetal growth retardation. A sharp decrease in estriol (less than 2 mg/day) is observed in fetal anencephaly, adrenal hypoplasia, Down syndrome, intrauterine infection (toxoplasmosis, rubella, cytomegalovirus infection). High estriol levels are observed in multiple pregnancies or in large fetuses. In addition to the fetal condition, there are a number of exogenous and endogenous factors that affect the biosynthesis, metabolism, and excretion of estriol. Thus, treatment of a pregnant woman with glucocorticoids causes temporary suppression of fetal adrenal function, which leads to a decrease in estriol concentration. When treating a pregnant woman with betamethasone or antibiotics, estriol synthesis also decreases. Severe liver disease in the mother can lead to impaired conjugation of estrogens and their excretion with bile. Changes in renal function in a pregnant woman lead to a decrease in estriol clearance, as a result of which the hormone content in the urine decreases, its concentration in the blood increases inadequately to the condition of the fetus. In rarer cases, congenital enzymatic defects of the placenta occur, which are the cause of extremely low estriol values, while the condition of the fetus will not be disturbed. Similar patterns are observed when determining the estriol content in the blood of pregnant women. Of particular interest is the study of the content of neuron-specific enolase in the mother's blood and the creatine kinase isoenzyme in the amniotic fluid as antenatal markers of impaired brain development, the concentration of which increases with fetal hypoxia. At the same time, it should be taken into account that most hormonal and biochemical tests have wide limits of individual fluctuations and low specificity; to obtain reliable data, it is necessary to determine the content of the hormone or enzyme in dynamics. The general disadvantage of these tests is the inability to interpret the result at the time of the fetal examination.

In the early stages of pregnancy, the most informative indicator is the concentration of human chorionic gonadotropin, a decrease in which is usually accompanied by a delay or cessation of embryo development. This test is used when examining pregnant women in case of suspicion of a non-developing pregnancy and the threat of its termination. In this case, a significant decrease in the level of human chorionic gonadotropin and its beta-subunit is noted, which is usually combined with a decrease in the concentration of progesterone in the blood.

In the first trimester of pregnancy, with the development of placental insufficiency, the level of placental lactogen may also decrease significantly. Extremely low values of placental lactogen in the blood are detected in pregnant women on the eve of the death of the embryo or fetus and 1-3 days before a spontaneous miscarriage. The greatest informative value in predicting the development of placental insufficiency in the first trimester of pregnancy is a decrease in the level of placental lactogen by 50% or more compared to the physiological level.

The state of the fetoplacental system is also reflected by the concentration of estriol (E3), since when the fetus suffers due to placental insufficiency, the production of this hormone by the fetal liver decreases.

However, unlike placental insufficiency, a 40-50% decrease in the E3 level is most informative in predicting placental insufficiency after 17-20 weeks of pregnancy.

Cortisol also belongs to the fetoplacental system hormones, produced with the participation of the fetus. Despite the fact that its content in the blood serum of a pregnant woman is subject to large fluctuations, in placental insufficiency a low concentration is determined and a persistent tendency to decrease its production in case of fetal hypotrophy.

Trophoblastic beta-globulin (TBG) is considered a specific marker of the fetal part of the placenta and is synthesized by cyto- and syncytiotrophoblast cells. In the dynamics of physiological pregnancy, its content progressively increases in periods from 5-8 to 37 weeks. The most unfavorable for the prognosis of placental insufficiency and perinatal pathology in case of miscarriage are low levels of TBG secretion (5-10 times or more compared to the norm) from the first trimester of pregnancy and not having a pronounced tendency to increase in the second and third trimesters. Most often, a decrease in the TBG level from the first trimester of pregnancy is determined in cases of low placentation (according to ultrasound data) or chorionic abruption, when pregnancy proceeds with a threat of interruption of a recurrent nature.

Placenta-specific alpha-microglobulin (PAMG) is secreted by the decidua and is a marker of the maternal part of the placenta, unlike TBG. During physiological pregnancy, the PAMG level in the blood does not exceed 30 g / l, while in the case of primarily developing placental insufficiency, the concentration of this protein is initially high and does not tend to decrease with the development of the gestational process. The results of PAMG determination in the II and III trimesters have the greatest prognostic and diagnostic value, while a sharp increase in its level (up to 200 g / l) allows predicting perinatal pathology up to antenatal death of the fetus with high reliability (up to 95%).

• Assessment of the state of metabolism and hemostasis in the body of a pregnant woman (CBS, SRO, enzymes aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), alpha-hydroxybutyrate dehydrogenase (a-HBDH), creatine phosphokinase (CPK), γ-glutamyl transpeptidase (γ-GTP), volumetric oxygen transport, hemostasiogram parameters). Placental insufficiency of any etiology is based on placental circulation disorders, including microcirculation and metabolic processes, which are interconnected and often interdependent. They are accompanied by changes in blood flow not only in the placenta, but also in the body of the mother and fetus. Particularly pronounced disturbances of rheological and coagulation properties of blood are observed in cases of intrauterine growth retardation in the presence of autoimmune causes of miscarriage. However, it is possible to identify signs of microcirculation disturbances at early stages of placental insufficiency formation by analyzing the parameters of the hemostasiogram (pronounced hypercoagulation, decrease in the number of platelets, increase in their aggregation, development of chronic DIC syndrome).

In diagnostics of fetal disorders in placental insufficiency, the determination of the concentration of alpha-fetoprotein (AFP), which clearly correlates with the gestational age and body weight of the fetus, is of great value. Changes in the physiological level of AFP during pregnancy, both upward and downward, indicate not only developmental defects, including genetic ones, but also pronounced disturbances of metabolic reactions in the fetus.

The above-mentioned shortcomings are absent in the methods of echography and functional assessment of the fetus (cardiotocography, cardiointervalography, Doppler blood flow study), which are currently the leading methods in the diagnosis of placental insufficiency. The main significance of echography for the diagnosis of placental insufficiency is to identify IUGR and determine its form and severity. Ultrasound diagnostics of IUGR is based on a comparison of the fetometric parameters obtained as a result of the study with the standard parameters for a given gestational age. The most widely used method for diagnosing intrauterine fetal growth retardation is measuring the biparietal diameter of the head, average diameters of the chest and abdomen, circumferences and cross-sectional areas, and femur length. In order to monitor fetal development, a percentile approach is used, which allows for each specific gestational age to accurately determine the correspondence of the fetus size to the gestational age, as well as the degree of their deviation from the standard values. The diagnosis of intrauterine growth restriction is made if the fetal size is below the 10th percentile or more than 2 standard deviations below the average for a given gestational age. Based on the ultrasound results, it is possible to determine the form of intrauterine growth restriction (symmetrical, asymmetrical), characterized by different ratios of fetometry parameters (femur length/abdominal circumference, femur length/head circumference). It is possible to develop a "mixed" form of intrauterine growth restriction of the fetus, characterized by a disproportionate lag in all fetometry parameters with the most pronounced lag in abdominal size. Based on the fetometry data, it is possible to determine the degree of fetal growth restriction. At degree I, a difference in fetometry parameters from the norm is noted and their correspondence to the parameters typical of pregnancy 2 weeks earlier (34.2%), at degree II - 3-4 weeks earlier (56.6%), at degree III - more than 4 weeks earlier (9.2%). The severity of intrauterine growth retardation correlates with the severity of fetoplacental insufficiency and adverse perinatal outcomes.

Recently, echographic examination has also been used to assess the condition of the umbilical cord as a criterion for intrauterine fetal distress. With an umbilical cord diameter of no more than 15 mm (thin umbilical cord) at 28–41 weeks of pregnancy, and vein and artery diameters of 8 and 4 mm, respectively, there are signs of fetal hypoxia in 66% of observations and IUGR in 48%. The authors consider hyperdevelopment of the umbilical cord to be an additional criterion for intrauterine fetal distress and a prognostic sign of newborn distress.

Important information about the fetus's condition is provided by its motor and respiratory activity. The presence of regularly repeated respiratory movements of the fetus in the presence of meconium in the amniotic fluid is considered a risk factor for the development of aspiration syndrome. A particularly unfavorable prognostic factor is a long period of "gasping" type movements (suffocation).

In the last decade, three-dimensional ultrasound has been used to perform fetometry, including in cases of placental insufficiency and IUGR. This technique has greater accuracy in measuring the biparietal diameter, fetal head and abdominal circumference, and femur length compared to two-dimensional ultrasound, especially in cases of oligohydramnios or abnormal fetal positions in the uterus. This provides a significantly smaller error in calculating the estimated fetal body weight (6.2–6.7% versus 20.8% with two-dimensional ultrasound).

Ultrasound placentography plays an important role in the diagnosis of placental insufficiency, allowing, in addition to determining the location of the placenta, to assess its structure and size. The appearance of stage II before 32 weeks, and stage III of placental maturity before 36 weeks of pregnancy indicates its premature maturation. In some cases, ultrasound examination reveals cystic changes in the placenta. Placental cysts are defined as echo-negative formations of various shapes and sizes. They occur more often on the fetal side of the placenta and are formed due to hemorrhages, softening, infarctions and other degenerative changes. Depending on the pathology of pregnancy, insufficiency of placental functions is manifested by a decrease or increase in the thickness of the placenta. Thus, a characteristic sign of gestosis, threatened miscarriage, and IUGR is considered to be a "thin" placenta (up to 20 mm in the third trimester of pregnancy), while in hemolytic disease and diabetes mellitus, a "thick" placenta (up to 50 mm or more) indicates placental insufficiency. One of the most widely used methods of functional assessment of the fetus's condition is cardiotocography. Along with fetal cardiac activity indicators, this method allows recording fetal motor activity and uterine contractility. The most widely used is a non-stress test that assesses the nature of fetal cardiac activity in natural conditions. Less commonly, the fetus's reaction to certain "external" effects (sound, uterine contractions under the influence of exogenous oxytocin, etc.) is studied. In the presence of IUGR, the non-stress test reveals fetal tachycardia in 12% of observations, decreased basal rhythm variability in 28%, variable decelerations in 28%, and late decelerations in 13%. At the same time, it should be taken into account that due to the timing of the formation of the myocardial reflex (by 32 weeks of pregnancy), a visual assessment of cardiotocograms is possible only in the third trimester of pregnancy. In addition, as the results of expert assessments show, the frequency of discrepancies in the visual assessment of cardiotocograms by several specialists can reach 37–78%. The nature of the cardiotocographic curve depends not only on the gestational age, but also on the sex of the fetus, body weight, and the characteristics of labor management (pain relief, labor induction, labor stimulation). In recent years, the definition of the so-called biophysical profile of the fetus during an echographic study has become widespread. This test includes a comprehensive scoring (scale from 0 to 2 points) of the amount of amniotic fluid, motor activity and muscle tone of the fetus, respiratory movements, as well as the results of the non-stress cardiotocographic test.

A score of 8–10 points indicates a normal fetal condition. A repeat examination should be performed only in high-risk pregnant women after 1–2 weeks. With a score of 4–6 points, obstetric tactics are determined taking into account signs of fetal maturity and readiness of the birth canal. In cases of insufficient fetal maturity and unreadiness of the birth canal, the examination is repeated after 24 hours. If a repeated unfavorable result is obtained, glucocorticoid therapy must be administered, followed by delivery no earlier than 48 hours later. If there are signs of fetal maturity, delivery is indicated. A score of 0–2 points is an indication for urgent and gentle delivery. In the absence of signs of fetal maturity, delivery must be performed after 48 hours of glucocorticoid preparation of the pregnant woman.

The Doppler method of studying blood flow in the fetoplacental system, which has been intensively developing in recent years, is considered safe, relatively simple and at the same time highly informative for assessing its functional reserves. In the early stages, Doppler provides information not only on the formation of uteroplacental and fetoplacental blood flow, but also reveals hemodynamic markers of chromosomal pathology. Intraplacental blood flow (blood flow in the spiral arteries and terminal branches of the umbilical artery) in uncomplicated pregnancy is characterized by a progressive decrease in vascular resistance, reflecting the main stages of placental morphogenesis. The most pronounced decrease in vascular resistance is in the spiral arteries at 13–15 weeks, and in the terminal branches of the umbilical artery at 24–26 weeks, which is 3–4 weeks ahead of the peak of the decrease in vascular resistance in the uterine arteries and terminal branches of the umbilical artery. When studying blood flow in the uterine arteries, umbilical artery and intraplacental circulation, the fact that disturbances in intraplacental blood flow are detected 3–4 weeks earlier than those in the main links is fundamentally important for predicting the development of gestosis and placental insufficiency, starting from 14–16 weeks of pregnancy.

The most important study of the uteroplacental and fetoplacental circulation for the purpose of predicting the development and early diagnosis of gestosis and placental insufficiency becomes in the second trimester of pregnancy. In addition to the increase in vascular resistance indices in the uterine arteries, the appearance of a dicrotic notch in the early diastole phase is possible. If pathological hemodynamic indices are detected in the mother-placenta-fetus system, the patient is classified as a high-risk group for the development of gestosis and placental insufficiency, and she requires differentiated drug correction of the detected hemodynamic disorders. In case of disorders in the uteroplacental link of blood circulation, the drugs of choice are agents that improve the rheological properties of blood (acetylsalicylic acid, pentoxifylline), in case of disorders in the fetoplacental link, it is advisable to use actovegin. In the overwhelming majority of cases of complicated pregnancy and extragenital diseases, the initial stage of the development of the pathological process is a disturbance of the uteroplacental blood flow with gradual involvement of the fetoplacental circulatory system and the cardiovascular system of the fetus in the pathological process. The specified sequence of pathogenetic mechanisms for the development of hemodynamic disturbances is presented in the classification of blood flow disturbances in the mother-placenta-fetus system developed by A.N. Strizhakov et al. (1986).

• Grade IA - disruption of uteroplacental blood flow with preserved fetoplacental blood flow.
• Grade IB - violation of fetoplacental blood flow with preserved uteroplacental blood flow.
• Grade II - simultaneous disruption of uteroplacental and fetoplacental blood flow, not reaching critical values (preservation of positively directed diastolic blood flow in the umbilical artery).
• Grade III - critical disturbance of fetoplacental blood flow (absence or retrograde direction of end-diastolic blood flow) with preserved or impaired uteroplacental blood flow.

A decrease in umbilical artery blood flow velocity in diastole to zero values or the appearance of retrograde blood flow indicates a significant increase in vascular resistance in the placenta, which is usually combined with a critically high level of lactate accumulation, hypercapnia, hypoxemia, and acidemia in the fetus.

During a comprehensive study of the arterial circulation of the fetus in placental insufficiency, the following changes are noted:

• increased vascular resistance indices in the umbilical artery (VRI > 3.0);
• increased vascular resistance indices in the fetal aorta (VRI > 8.0);
• decrease in vascular resistance indices in the middle cerebral artery (SDO < 2.8);
• decreased blood flow in the renal arteries;
• violation of intracardiac hemodynamics (the appearance of reverse blood flow through the tricuspid valve).

In fetoplacental insufficiency, intracardiac hemodynamic disturbances of the fetus occur, consisting of a change in the ratio of maximum blood flow rates through the valves in favor of the left sections of the heart, as well as the presence of regurgitant flow through the tricuspid valve. In critical fetal condition, the following changes in fetal hemodynamics are detected:

• zero or negative blood flow in the umbilical artery;
• tricuspid valve regurgitation;
• absence of diastolic component of blood flow in the fetal aorta;
• increase in the diastolic component of blood flow in the middle cerebral artery;
• impaired blood flow in the venous duct and inferior vena cava. In this case, the Doppler criterion for impaired blood flow in the venous duct is a decrease in blood flow velocity in the late diastole phase, down to zero or negative values. In critical fetal condition, the pulsatility index in the venous duct exceeds 0.7. Doppler criteria for impaired blood flow in the inferior vena cava include: an increase in the velocity of reverse blood flow by more than 27.5–29% and the appearance of zero/reverse blood flow between systolic and early diastolic flows.

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Differential diagnosis of placental insufficiency and intrauterine growth retardation syndrome

A number of criteria have been proposed to allow differential diagnosis between IUGR and a constitutionally small fetus ("small for gestational age"). Some of the criteria are:

1. The use of a set of indicators in the diagnosis of IUGR (calculation of the estimated fetal weight, assessment of the amount of amniotic fluid, the presence of arterial hypertension in the mother) allows increasing the accuracy of IUGR diagnosis to 85%.
2. Doppler study of blood flow in the umbilical artery and uterine arteries.
3. Calculation of the ponderal index [body weight (g) x 100/length (cm) ³ ].
4. An increase in the number of nuclear forms of erythrocytes in the blood of the fetus obtained by cordocentesis (caused by hypoxia in the presence of PN and IUGR).
5. Features of weight gain after birth (25% of newborns with severe (III) degree of IUGR up to 24 months of life maintain a lag in weight and height indicators below the 3rd percentile).

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Screening for placental insufficiency and intrauterine growth retardation syndrome

Routine prenatal screening for the diagnosis of placental insufficiency and the resulting IUGR includes:

• identification of pregnant women at high risk of placental insufficiency and IUGR;
• assessment of the height of the fundus of the uterus during pregnancy;
• biochemical screening (double and triple tests);
• Ultrasound at 10–14 weeks, 20–24 weeks, 30–34 weeks of gestation with assessment of fetal anatomy, detection of markers of chromosomal abnormalities, intrauterine infection, fetal malformations;
• ultrasound fetometry at the specified time with diagnosis of symmetrical and asymmetrical IUGR, assessment of the severity of the syndrome;
• assessment of the amount of amniotic fluid;
• assessment of the degree of maturity of the placenta;
• Doppler ultrasound of blood flow in the uterine, spiral arteries, umbilical artery and its terminal branches at 16–19 weeks, 24–28 weeks and 32–36 weeks of gestation;
• assessment of fetal hemodynamics (middle cerebral artery, aorta, renal arteries, venous duct, inferior vena cava);
• cardiotocography (if the gestation period is more than 28 weeks).

In addition, invasive research methods (amniocentesis, chorionic villus biopsy, placentocentesis, cordocentesis) can be used according to indications, followed by karyotyping if there is a high risk of chromosomal abnormalities and gene defects in the fetus.

Thus, the diagnosis of placental insufficiency is established on the basis of a dynamic, comprehensive examination, including clinical and laboratory data, studies of the hormonal, transport, protein-synthesizing functions of the placenta, and an assessment of the condition of the fetus using functional methods.