[Clinical and morphological characteristics of the atypical placentation spectrum in the uterus]. / Kliniko-morfologicheskaya kharakteristika spektra atipichnoi platsentatsii v matke.

BACKGROUND: The concern of the global community of gynecologists and obstetricians (FIGO) regarding the increase in the number of caesarean sections has resulted in the creation of a new classification, Placenta Accreta Spectrum (PAS), which presents degrees of villus invasion into the uterine wall. OBJECTIVE: Compare the main types of atypical placentation (AP) with the stages of PAS, to supplement and unify the clinical and morphological criteria AP. MATERIAL AND METHODS: Surgical material was examined from 73 women after metroplasty (n=61) and hysterectomies (n=12) from the regions of Russia, Moscow and the Moscow region for ingrown villi and from 10 women with a typical placenta location during the first cesarean section. A targeted cutting of material from the uteroplacental region was used, at least 10-12 pieces, with further H&E and Mallory staining. RESULTS: In the classification of AP, the terms «placenta accreta¼, «increta¼, «percreta¼ should be retained. It is necessary to single out pl. previa as a separate type. Attention is focused on the need to assess the depth of villi invasion accompanied by a layer of fibrinoid, the volume of scar tissue and the degree of disorganization of the myometrial bundles, the state of the vessels in the serous membrane. A new type of AP has been proposed - a sharp thinning of the lower segment of the uterus, due to the scar failure and the pressure of the growing amniotic sac, leading to atrophy and necrosis of the myometrium. CONCLUSION: An integrated approach should be used to classify atypical placentation, taking into account not only the depth of villus invasion, but also anatomical and pathogenic factors in order to develop targeted methods of surgical treatment.

Analysis of Healing of Rat Uterine Wall After Full-Thickness Surgical Incision.

We studied the dynamics of morphological changes in the operated segment of the uterine horn of Sprague-Dawley rats during the first 2 weeks of the wound-healing process after a full-thickness surgical incision with regard to the estrous cycle phase. Morphometric parameters of injured uterine right horn were compared with those in the intact left horn of the same animal as a control of changes determined by the hormonal background. It was found that the uterine epithelium in the focus of injury was restored as soon as on day 2 after surgery under the influence of estrous cycle hormones. By day 4, the wound space was completely filled with the endometrial tissue on the side of the uterine lumen and coved by the attached adipose tissue of the mesentery on the side of the abdominal cavity. The thickness of the uterine wall and the uterine lumen differed most strongly between the operated and intact uterine horns during the first 3 days and on day 6 after surgery. The size of the healing area increased during the first three days and reached the peak value by day 3, but then decreased to minimum by day 6.

Role of Immune Distribution of Tissue Factor in the Development of Hemostasis during the First Trimester of Normal Pregnancy.

Immunohistochemistry of tissue factor, vimentin, and cytokeratin-8 was studied in the medical abortion material at gestation week 5-10 in 20 healthy women. No expression of tissue factor was found in vimentin-positive decidual cells of the parietal endometrium. By contrast, intensive immunostaining of the TF/FVIIα complex was detected in the marginal layer of Rohr fibrinoid and less intense staining was found in vimentin-positive decidual cells adjacent to the walls of modified spiral arteries in the utero-placental region under conditions of invasion of the interstitial and intravascular cytotrophoblast (marker: cytokeratin-8). In the villi, tissue factor was expressed only in the fibrinoid lumps at sites of the syncytiotrophoblast defects. We demonstrated the formation of local hemostasis system in the uteroplacental region at weeks 5-8. This system creates optimal conditions for external thrombogenesis aimed at realization of the cytotrophoblast invasion and subsequent flow of arterial blood between the villi at the end of the first trimester.

[Cytotrophoblastic invasion is the most important mechanism of placentation and pregnancy progression]. / Tsitotrofoblasticheskaia invaziia - vazhneishii mekhanizm platsentatsii i progressii beremennosti.

The paper presents new Russian and foreign materials on cytotrophoblastic invasion, the most important mechanism of interaction between the placenta, fetus, and mother during the progression of physiological pregnancy. The original classification of placental cell development has been published; the initial wave of invasion, the main and additional ways of its implementation in the second trimester, and the formation of cytotrophoblastic plugs in the spiral arteries, and the fate of multinucleated giant cells have been characterized. Additional sources of invasive cells in the second trimester are presented. A general concept of cytotrophoblastic invasion as a regulator and main mechanism of transition from the histotrophic to more effective hemochorial type of fetal nutrition has been made. The modern definition of an invasive process is given. This information is important for obstetricians and pathologists who analyze the causes of obstetric complications.

[The decisive importance of constitutional interferons in human and animal ontogenesis]. / Opredeliaiushchee znachenie konstitutsional'nykh interferonov v ontogeneze cheloveka i zhivotnykh.

Biomedical publications contain little information on the constitutional (endogenous) interferons (IFNs) produced by different cells without prior exposure to viruses and oncogenic factors. Literature analysis has provided a generalized concept that these interferons play different functional roles according to ontogenetic stages. The maximum production of high-molecular- weight immature forms of IFNα/ß was detected in the embryos of mice, Syrian hamsters, and humans and in the syncytiotrophoblast of placental villi. This is due to the direct involvement of IFNs in embryogenesis and fetogenesis. They also afford first-line antiviral and anti-oncogenic protection. In the late fetal and neonatal periods, IFN levels fall, rising slightly during the second year of life. In human adults, the organs consist of a branched network of cell producers of low concentrations of constitutional IFNs that carry out autocrine priming of cells for rapid and adequate volume synthesis of IFN during viral infection. Main publications on the ontogenesis of the IFN system came out in the 1980-1990; in recent years their number has decreased dramatically. It is necessary to increase the number of such studies, because they are fundamental to many branches of medicine.

[The increasing importance of extragenital pathology in the structure of maternal mortality in Russia]. / Vozrastaiushchee znachenie ékstragenital'noi patologii v strukture materinskoi smertnosti v Rossii.

OBJECTIVE: to determine the proportion of direct obstetric and indirect extragenital causes of maternal deaths in Russia in recent years. MATERIAL AND METHODS: Official statistical data on maternal mortality in Russia were analyzed according to the criteria of the 10th revision of the International Classification of Diseases and compared with those in European countries and the USA. RESULTS: In the past 10 years, Russia has registered a gradual decline in the single maternal mortality rate: 27.7 in 2005, 18.6 in 2010, 12.9 in 2013, 11.9 in 2014, 10.7 in 2015, and 8.3 in 2016 per 100,000 live births. This was mainly due to a substantial decrease in obstetric losses and to the expansion of a network of well-equipped perinatal centers. Stabilization of the proportion of extragenital causes was simultaneously found. Among them in 2014, cardiovascular diseases were a dominant cause of death (51.7%), followed by respiratory diseases (29.8%) and digestive diseases and other conditions (18.2%). The demographic, socioeconomic, and medical conditions for extragenital causes were analyzed and compared with those in European countries and the USA. Recommendations were given to improve the postmortem analysis of maternal deaths in Russia. CONCLUSION: It is necessary to improve the postmortem diagnosis of the direct and indirect causes of maternal deaths and to ensure the quality and completeness of autopsies in deceased women.

[Deported syncytiotrophoblast and placental microparticles in the mother's body during normal pregnancy and preeclampsia (28 years later)]. / Deportirovannyi sintsitiotrofoblast i platsentarnye mikrochastitsy v organizme materi pri normal'noi beremennosti i preeklampsii (28 let spustya).

Over the last 25 years, there has been new evidence for the need to systematize deported placental cells, by identifying 3 groups according to their size, blocking or passing the pulmonary capillaries. In group 1, deported syncytiotrophoblast is a viable multinucleated complexes 100 to 20 µm in diameter. Their common cytoplasm displays ß-hCG immunoexpression. After apoptosis of these cells in the lung capillaries, placental bioproducts directly interact with endothelial cell receptors, by contributing to the gestational rearrangement of the woman's body. In Group 2, placental microparticles are necrotized parts of syncytiotrophoblast microvilli and organelles 1000 to 100 nm in size: they freely pass the lung capillaries, activate the production of proinflammatory cytokines by maternal macrophages, and cause a systemic inflammatory response. In excess they become triggers of extensive endotheliosis and vasospasm. In Group 3, placental nanoparticles (or exosomes) are the smallest structures 120 to 20 nm in size; their numbers in the blood are increased in preeclampsia. The given materials call for further investigation of deported placental cells by standardized studies.

[Features of cytotrophoblast invasion in complete placenta previa and increta]. / Osobennosti tsitotrofoblasticheskoi invazii pri polnom predlezhanii i vrastanii platsenty.

AIM: to investigate the characteristics of cytotrophoblast invasion in complete placenta previa and increta. MATERIAL AND METHODS: Three groups of placentas and amputated uteri were examined. These were: 1) 10 placentas at 20-22 weeks' gestation after drug-induced abortion; 2) 4 uteri with typical placentation at 34-36 weeks and wall ruptures; 3) 12 uteri with ultrasound-confirmed complete placenta previa and subsequent hysterectomy (at 34-36 weeks.) due to massive bleeding. In all cases, the sections were stained with hematoxylin and eosin, azan by the Mallory's method; immunovisualization of invasive cells with the marker cytokeratin 8 was also used. In Groups 2 and 3, the uterine distribution density of invasive cells was compared in a standard slice area (×200) separately, within the endometrium and myometrium. RESULTS: Complete placenta previa was found to have the following characteristics: 1) all the uteri exhibited focal or diffuse friable, or thick scars after cesarean section; 2) multiple active anchor villi with villous cytotrophoblast layers, which were characteristic of Group 1 placentas and absent in the uteri women of Group 2; 3) bays diagnosed in the basal endometrium with ingrown villi (placenta increta); 4) a morphometrically significant increase in the distribution density of interstitial cytotrophoblast in the endometrium and only a similar trend in the myometrium. Invasive cells did not penetrate into the area of scars. Failure of the second wave of cytotrophoblast invasion was confirmed by incomplete gestational restructuring and partial obliteration of the myometrial radial arteries. CONCLUSION: Real risks for severe clinical forms of abnormal placentation declare more stringent indications for surgical delivery.

[The morphology, typical combinations of polymorphic genes of hemostasis, and specific features of the pathogenesis of retrochorial hematoma in missed abortion]. / Morfologiya, kharakternye sochetaniya polimorfnykh genov gemostaza i osobennosti patogeneza retrokhorial'noi gematomy pri nerazvivayushcheisya beremennosti.

AIM: to identify mutations and hemostatic gene polymorphisms typical for retrochorial hematoma (RCH) and to study its pathogenesis in missed abortion. SUBJECTS AND METHODS: A PCR assay was used to detect the genetic forms of thrombophilia in 270 patients with ultrasonographically verified RCH. Logistic regression analysis revealed that with the F7 (proconvertin, coagulation factor (CF) VII G10976A polymorphism or with the F13 (fibrinase, CF XIII) G>T, or FGB (fibrinogen ß-chain) G455A polymorphism, the risk of RCH was 2.72, 2.16, and 1.92 times higher, respectively. First trimester missed abortion was found in 42 (15.5%) cases; among them there were 24 (8.8%) women with different polymorphism combinations: F7 (G10976A), F13 (fibrinase, G>T), FGB (G455A). A total of 18 cases of missed abortion due to morphologically verified endometritis, endocrinopathies, and antiphospholipid syndrome were excluded from the sample. RESULTS: Compared to the morphology of medical abortions of the same period (16 women), patients with polymorphic genes of hemostasis were found to have statistically significant incomplete endometrial decidualization, thinning or absence of a Rohr's fibrinoid layer, a smaller number and shortening of syncytiotrophoblast microvilli, and the maximum amount of dissecting hemorrhage and RCH in the utero-chorionic region. The stages of RCH pathogenesis were determined; these included penetration of maternal erythrocytes deep into the decidua ~ dissociation of a layer of decidual cells with impairment of a «hemostatic envelope¼ ~ formation of RCH with a dense network of fibrin threads ~ final necrosis of surrounding cells and tissues. CONCLUSION: The investigators identified for the first time the typical combinations of polymorphic genes of predisposition to a high risk for RCH; its complete formation requires additional changes in maternal and placental components that provide local hemostasis.

[Embryochorionic insufficiency: anatomic and physiologic prerequisites, rationale, definitions and pathogenetic mechanisms].

The paper provides a rationale for the new concept--embryochorionic insufficiency as a combined pathological response of extraembryonic structures and an embryo to different maternal exo- and endogenous disorders; it gives rise to early spontaneous abortions and non-developing pregnancies. The main pathogenetic mechanisms of embryochorionic insufficiency are: 1) endometrial structural incompetence; 2) dyschronism in the development of the extraembryonic coelom, amniotic cavity, yolk sac, and early placenta; 3) insufficient cytotrophoblast invasion; 4) discordant hemodynamic relationships; 5) blood rheological disorders; 6) local inflammation (endometritis); 7) oxidative stress; 8) secondary changes in the placental villi; 9) compensatory responses.

[The intensity of expression of matrix metalloproteinases type 2 and type 9 by invasive trophoblast cells in uncomplicated pregnancy and preeclampsia].

OBJECTIVE: To estimate the intensity of immunoexpression of matrix metalloproteinases type 2 and type 9 (MMP-2 and MMP-9) during cytotrophoblast invasion (CTI) in the uteroplacental region. MATERIALS AND METHODS: There were 6 groups: 1) medical abortions at 7 to 8 weeks' gestation; 2) amputated uteri at 9 to 12 weeks; 3) late medical abortions at 18 to 24 weeks' gestation and amputated uteri at 25 weeks; 4) amputated uteri and biopsies of the placental bed, performed during cesarean section at 38-40 weeks. Two more groups included biopsies from women with preeclampsia: biopsy at 28-33 weeks (Group 5) and 34-38 weeks (Group 6). A total of 49 women were examined. An immunohistochemical method performed using the standard procedure revealed the expression of MMP-2, MMP-9, and cytokeratin in three invasive elements: interstitial cytotrophoblast (IC), multinucleated giant cells (MGCs), and intravascular cytotrophoblast (IVC). RESULTS: The expression of MMP-2 is intensive in all the invasive cells in the first and second trimesters and then decreases in IC and MGCs. The immunoexpression of MMP-9 with its minimal values in the first trimester successively increases in IVC and IC by a full-term gestation. CONCLUSION: MMP-2 hyperproduction in IVC and IC is of the greatest value for the first wave of CTI and high MMP-9 immunoexpression in all the invasive cells is more important for the second wave. In cases of preeclampsia, the least expression of MMP-2 and MMP-9 is recorded in IC and MGCs in the complete absence of IVC.

[Morphometric evaluation of the frequency distribution and diameter of extravillous trophoblast cells in apparently uncomplicated pregnancy].

Special materials were collected from medical abortions at 6 to 11 weeks' gestation (19 cases + 5 amputated uteri), late abortions at 24 to 25 weeks' gestation (n = 5) + 4 uteri and biopsies of the placental bed and uterus during the third trimester for the morphometric evaluation of the cell composition of cytotrophoblast invasion into the uteroplacental area. The interstitial cytotrophoblast (IC) and multinucleated giant cells (MGCs) immunovisualized by cytokeratin 8 were determined in the standard field of view (area 785,000 microm). The maximum IC distribution frequency that was 15-17 times greater than that for MGCs was found during the first trimester of apparently normal pregnancy. These cells' diameters measured in the nuclear cross section were 12-20 microm for IC and 22-28 microm for MGCs. In the mid-gestation (22-25 weeks), the distribution frequency of IC remained high (200-208 cells); it drastically fell to 86-100 cells at 31 weeks and to 27 cells with a tendency for increasing the diameter up to 24 pm in the full-term period. On the contrary, MGCs gradually increased their distribution frequency (from 14 cells at the end of the first trimester to 52 cells in the full-term period). These data characterize the cellular ratios of cytotrophoblast invasion during apparently uncomplicated pregnancy. They are important as the first step for the morphometry of an invasive process in different obstetric abnormalities.

[Human placenta structure in II and III trimesters of physiological pregnancy].

The placenta of 20 women with normal pregnancy was studied during II and III trimesters to obtain the complex characteristic of the structures participating in the formation of syncytio-capillary membranes. Immunocytochemical endothelial cell marker CD34 and morphometry were used for the assessment of some villous parameters: villous area, villous stromal area, villous epithelial area and vascular endothelium area. The main attention was given to the remodeling of the villous epithelium and capillary network. The significant reduction of the epithelial area and that of the villous stroma was detected simultaneously with intensive their vascularization. Morpho-functionally, most of the terminal villi were specialized, containing sinusoid-type capillaries which were in close contact with attenuated, anuclea regions of syncytiotrophoblast. The proportion of terminal villous endothelium in respect to the stroma was significantly increased. Thus, in II and III trimesters of physiological pregnancy the structural changes take place in the placenta, in particular, the capillaries are transformed into thin-walled sinusoids, that approach and closely interact with syncytiotrophoblast resulting in the formation of the syncytio-capillary membranes necessary for an adequate diffusion and meeting the growing needs of the fetus.

[Anchoring villi are sources of cytotrophoblastic invasion in the second trimester of physiologic pregnancy].

The basal laminas and fixed on them anchoring villi after late abortion on 18-28 weeks of pregnancy have been studied. The pregnancies were without complication and abortions were activated by "Enzaprost" injection. 4 types of anchoring villi were studied: without cytotrophoblastic invasion, with maximal, medium and minimal density of cytotrophoblastic distribution and depth of its invasion into endometrium from villi's base. The maximum of its migration activity was in 18-20 and 22-23 weeks of pregnancy. The activity decay of cytotrophoblastic invasion was been found in the end of the second trimester Anatomic contact of villi's base with endometrium increased by them parallel attachment or horseshoe-shaped form. The estimation of villi's quantity and density of cytotrophoblastic distribution in their base can use for definition of cytotrophoblastic invasion rate in the adjacent myometrium of pregnant women on the second trimester.

[Morphogenesis of human placenta in the first trimester of gestation].

On the basis of morphometric and immunohistochemical study of placental villi obtained from 45 cases of medicinal and medical abortions in healthy women, the new data on placentation are presented with the discrimination of three stages of placental morphogenesis. The first stage (weeks 4 and 5 after fertilization) included a differentiation of villous chorion (chorion frondosum). It was characterized by high mitotic activity of villous cytotrophoblast and intensive vasculogenesis in the villous stroma. The second stage (weeks 6 and 7) included capillary development (angiogenesis) and formation of vascular communications within a "placenta-embryo" subsystem functioning in low-oxygen level environment. The third stage (weeks 8 and 9-10) was characterized by vascular bed formation in "mother-placenta" subsystem and by the beginning of more effective hemochorial embryo and fetal metabolism. As a result of placentation, hemodynamics formation in "mother-placenta-embryo" system was completed, which is a necessary condition for further fetal development.

[Correlations between placental morphological and functional parameters and neonatal status after normal full-term, prolonged pregnancy, and truly protracted pregnancy].

To solve the problem of differentiating protracted pregnancy, a special morphometric study was undertaken to examine three placental groups: 1) after normal full-term pregnancy (n = 35); 2) after prolonged pregnancy (n = 40); 3) after truly protracted pregnancy with partial or complete Clifford's syndrome (n = 30). A semiquantitative score (14 most important placental indicators), placenta and birth weights, Apgar scores, the infant's weight and height at the end of the first year of life were used so as to estimate the mild, moderate, and severe degree at 0.5, 1.5, and 3 points, respectively. One hundred and twenty-six possible pairs of structural and functional parameters were made up in all the groups. Pearson's correlation coefficient (r > 0.4) was applied to graphically display the pairs. Normal full-term pregnancy was characterized by few positive correlations mainly between the terminal villi and weight-height indices without associations with the Apgar scale. Prolonged pregnancy with the multiple placental tissue structural parameters along with organometric indices being involved was intermediate. The total scores permitted grades 1 and 2 chronic placental insufficiency (CPI) to be diagnosed in 27.5 and 2.5%, respectively. The severest form was truly protracted pregnancy that was distinguished by the maximum positive and negative correlations between all the parameters and the highest rate of diagnosis of CPI of grades 1 (45%) and 2 (15%). The findings strongly suggest that it is essential to identify prolonged and truly protracted pregnancy as important risk factors, by following up the infants for a year.

[Disputable problems of the pathogenesis of implantation of the placenta into the uterine wall].

The review analyzes publications on the clinical and pathomorphological diagnosis of implantation of the placenta (placenta accreta) (500 references). It characterizes the prevalence of placenta accreta in different countries of the world and a rapid increase in this indicator because of a rise in cesarean sections with further uterine scars. The clinical variants, major pathomorphological types, risk factors of this severe puerperal obstetric complication and the existing hypotheses of its pathogenesis are given. Promises for further studies of the mechanisms for implantation of villi and surrounding components of the uterine placental bed are denoted.

[Macro- and microscopic systematization of cerebral cortex malformations in children].

For the first time in pediatric pathologicoanatomic practice the complete systematization of cerebral cortex malformations is represented. Organ, macroscopic forms: microencephaly, macroencephaly, micropolygyria, pachygyria, schizencephaly, porencephaly, lissencephaly. Histic microdysgenesis of cortex: type I includes isolated abnormalities such as radial (IA) and tangential (I B) subtypes of cortical dislamination; type II includes sublocal cortical dislamination with immature dysmorphic neurons (II A) and balloon cells (II B); type III are the combination focal cortical dysplasia with tuberous sclerosis of the hippocampus (III A), tumors (III B) and malformations of vessels, traumatic and hypoxic disorders (III C). Band heterotopias. Subependimal nodular heterotopias. Tuberous sclerosis. Cellular typification of cortical dysplasia: immature neurons and balloon cells.

[Investigation of uterine scraping after non-progressive pregnancy due to HLA compatibility in married couples].

Non-progressive pregnancy in the first trimester is one of the common and little studied causes of early habitual miscarriage. Pathohistological and immunohistochemical investigations of uterine scrapings were first carried out during laboratorily verified observations of HLA compatibility of two (12 patients) or more (12 patients) similar alleles. Stepwise degradation of decidual cells in the uteroplacental area and parietal endometrium was revealed as their pathomorphological equivalents due to the activation of local large granular lymphocytes and macrophages. These cells are characterized by a strong release of proteolytic enzymes and by cytolysis of surrounding decidual cells. Moreover, there was superficial cytotrophoblastic invasion, atrophy, and numerous villous epithelial defects with villous cytotrophoblast reduction. These pathological markers in the uterine scrapings are proposed to use for a further goal-oriented study of a married couple-HLA system.

[Morphological characteristics of a second wave of cytotrophoblast invasion].

In the morphological studies of cytotrophoblast invasion into the uteroplacental area, the final activity of interstitial and intravascular cytotrophoblasts is usually limited to 18-20 weeks of pregnancy. The activity of cytotrophoblast invasion from 15 weeks to the end of pregnancy is morphologically and semiquantitatively assessed on the basis of a collection of scrapes from the uterine cavity and uteri amputated for myomas, early bleedings and iatrogenias (the conditional standard of pregnancy). The second wave of cytotrophoblast migration is first shown to peak at 17-24 weeks in the central zone of the uteroplacental area due to the simultaneously high activity of interstitial and intravascular cytotrophoblasts attacking the myometrial radial arteries. Then both components of cytotrophoblast invasion move to the marginal sites of the uteroplacental area where they are highly active up to 33-36 weeks. The gestational rearrangement of adjacent myometrial radial arteries in the center and around the periphery of the uteroplacental area results in a continuous rise in the volume of the uterine arterial blood entering the intervillous lacuna and hemochoreal exchange leads to adequate fetal nutrition and development. Impairments in the course of the second wave of a cytotrophoblast wave are of importance in interpreting the pathogenesis of severe obstetric complications, such as preeclampsia, eclampsia, intrauterine growth retardation, miscarriage, and many others.