Obstetric Syndrome Research Articles

Профилактика больших акушерских синдромов у беременных с резистентностью к биодоступному прогестерону

The article presents modern literature data on the role of defective deep placentation in the development of great obstetrical syndromes, bioavailable progesterone and its receptors in the formation of the placenta and the development of pregnancy, mechanisms of development of resistance to bioavailable progesterone, and a scheme of the pathogenesis of progesterone deficiency during pregnancy as one of the main causes of great obstetrical syndromes. Modern data on the development of resistance to bioavailable progesterone in adolescence, in patients with endometrioid disease, polycystic ovary syndrome and idiopathic recurrent pregnancy loss are presented. The therapeutic possibilities of prophylaxis of great obstetrical syndromes with resistance to bioavailable progesterone are described. Research data on the use of highly selective progestogen with increased affinity for progesterone receptors dydrogesterone for the prevention of great obstetrical in pregnant women with resistance to bioavailable progesterone are presented. Key words: great obstetrical syndromes, defective deep placentation, progesterone, progesterone receptors, bioavailable progesterone resistance, adolescence, endometrioid disease, polycystic ovary syndrome, idiopathic recurrent pregnancy loss, prevention, dydrogesterone.

ANTIPHOSPHOLIPID SYNDROME AND PREGNANCY

The main issues of etiopathogenesis, clinical manifestations, diagnosis of antiphospholipid syndrome are considered. This syndrome is a state of the body whereat a thrombosis can occur, especially during pregnancy. This syndrome pathogenesis is characterized with an interaction of antiphospholipid antibodies with negatively charged phospholipids. They are the part of membranes of platelets, endotheliocytes, prothrombin−activating complex, beta−2−glycoprotein and nerve cells with impaired functions. Joining to phospholipids, the antiphospholipid antibodies lead to a sharp decrease in platelet count and impaired endothelial cell function. In nerve tissue disorders according to the structural and functional type occur, the formation and function of the humoral agents responsible for hemostasis are disrupted. The antiphospholipid syndrome in obstetrics and gynecology often manifests as spontaneous miscarriages, the effect of the "empty fetal egg", fetal growth retardation and even its antenatal death, as well as preeclampsia. In the treatment of pregnant women with antiphospholipid syndrome, mainly several protocols have been used, i.e. anticoagulants and antiplatelet agents in combination with glucocorticoids; combination of glucocorticoids with acetylsalicylic acid; monotherapy with sodium heparin or acetylsalicylic acid; anticoagulants and antiplatelet agents for hemostasis correction. The treatment protocols during pregnancy, childbirth and postpartum period have been presented. It is emphasized that the patients with antiphospholipid syndrome and vascular thrombosis should be monitored by rheumatologist, surgeon, obstetrician and gynecologist after successful child delivery. Duration of receiving antiplatelet and anticoagulant therapy has to be solved individually. Key words: antiphospholipid syndrome, antiphospholipid antibodies, cardiolipin antibodies, lupus anticoagulant, pregnancy, postpartum period.

The Placental Roots of Intrauterine Growth Restriction Are in the Central and Contractile Regions of the Villous Tree

Background: Intrauterine growth restriction (IUGR) is an obstetric syndrome with a high incidence and severe health burden. The restricted placental growth in IUGR reflects a weight restriction for the placental villous tree. It is unknown whether the whole villous tree or only specific parts of it show restricted growth in IUGR. Clarifying this would have a significant impact on the development of innovative therapeutic approaches for compensating placental dysfunction in IUGR since in the case of uniform growth restriction of the villous tree, IUGR placentas would primarily be smaller than normal placentas. However, if only specific parts of the villous tree are growth restricted, then IUGR placentas would be morphologically, developmentally and, therefore, functionally different from normal placentas. Methods: We investigated ten normal placentas and eleven IUGR placentas with quantitative microscopic techniques (design-based stereology). Using immunohistochemical detection of placental myofibroblasts (γ-sm-actin) and foetoplacental endothelium (CD34), we distinguished between more centrally located villi showing the presence of myofibroblasts (contractile villi; C-villi) and more peripherally located villi showing the absence of myofibroblasts (noncontractile villi; NC-villi). Findings: Compared to normal placentas, IUGR placentas showed significantly reduced mean volumes of C-villi and vessels in C-villi but not of NC-villi. Additional stereologic estimates confirmed the known alterations in the morphology of NC-villi in IUGR. Interpretation: Our results suggest that IUGR placentas are not just smaller but morphologically (and therefore functionally) different from normal placentas. We hypothesize that the reduced volume of C-villi and vessels in C-villi reflects a developmental disturbance in the formation of C-villi (most of them being stem villi). As such, key pathological alterations in IUGR placentas could begin before the formation of intermediate and terminal villi, possibly already in the late first trimester of pregnancy. Funding Statement: Supported by the German Research Council (DFG Fr1245/9-1, to HGF). Declaration of Interests: The authors declare no conflicts of interest. Ethics Approval Statement: The ethics board of Ludwig-Maximilians-University of Munich (LMU Munich) approved all investigations under the numbers 084-11 and 478-12.

Abnormal uterine inflammation in obstetric syndromes: molecular insights into the role of chemokine decoy receptor D6 and inflammasome NLRP3.

The adaptation of the uterine environment into a favorable immunological and inflammatory milieu is a physiological process needed in normal pregnancy. A uterine hyperinflammatory state, whether idiopathic or secondary to hormonal or organic uterine disorders (polycystic ovary syndromes, endometriosis/adenomyosis and fibroids), negatively influences the interactions between decidua and trophoblast, early in gestation, and between chorion and decidua later in pregnancy. Abnormal activation of uterine inflammatory pathways not only contributes to the pathogenesis of the obstetric syndromes, i.e. recurrent pregnancy loss (RPL), pre-term delivery (PTD) and pre-eclampsia (PE), but also to correlates with severity. In this review, we summarize recent advances in the knowledge of uterine molecular mechanisms of inflammatory modulation in normal pregnancy and obstetric syndromes (RPL, PTD and PE). In particular, we focus on two regulators of uterine/placental inflammation: the NLRP3 inflammasome and the chemokines decoy receptor D6. We performed comprehensive review of the literature in PubMed and Google Scholar databases from 1994 to 2018. The available evidence suggests that: (i) the expression of inflammasome NLRP3 is increased in the endometrium of women with unexplained RPL, in the chorioamniotic membranes of women with PTL and in the placenta of women with PE; (ii) there is a role for abnormal expression and function of D6 decoy receptor at the feto-maternal interface in cases of RPL and PTD and (iii) the function of placental D6 decoy receptor is impaired in PE. A wider comprehension of the inflammatory molecular mechanisms involved in the pathogenesis of the obstetric syndromes might lead to the identification of new potential therapeutic targets.

HMOX1 is partly responsible for phenotypic and functional abnormalities in mesenchymal stem cells/stromal cells from placenta of preeclampsia (PE) patients

BackgroundPreeclampsia is a common obstetric syndrome affecting women in their first pregnancy and characterized by hypertension and proteinuria, which appears after 20 weeks of gestation. It is characterized by high blood pressure and occasional damage to another organ system most often the liver and kidneys. Currently, the etiology and pathogenesis of this syndrome are not fully understood. Since mesenchymal stem cells/stromal cells (MSCs) are intimately associated with endothelial cells that line vessel walls in the decidua they may play some role in the pathogenesis of this syndrome. In this study, we have partly, unveiled the mechanism of preeclampsia pathogenesis at the stem cells level.MethodsWe have isolated and characterized MSCs from decidua basalis of preeclampsia placenta (PE-DBMSCs) and showed their decreased functionality in terms of proliferation, migration, adhesion and clone formation potential as compared to MSCs isolated from decidua region of normal placentae (DBMSCs). The cells were preconditioned with H2O2 and the functional characteristics were evaluated. Differentially expressed genes were analyzed using mass spectrometry. Immunoblotting confirmed the expression of these proteins.ResultsPre-conditioning with H2O2 restored the functional outcome of PE-DBMSCs. Mass spectrometry (MS) analysis of differentially expressed proteins revealed HMOX1 as one of the major candidates missing in PE-DBMSCs. HMOX1 inhibition by tin protoporphyrin (SnPP) in normal DBMSCs resulted in a reduction in proliferation, migration, adhesion, and clone formation processes as compared to the untreated controls. mRNA and protein analyses of PE-DBMSCs preconditioned with H2O2 at lower doses showed upregulation of HMOX1 expression.ConclusionsWe hereby show for the first time that loss of function of stem cells/stromal cells isolated from the patients with preeclampsia may contribute towards the disease exacerbation. Our results suggest that HMOX1 may be partially responsible for the loss of functionality in PE-DBMSCs and contribute significantly towards the pathophysiology of preeclampsia. However, further investigation is required to decipher its exact role in the development and onset of the disorder.

Placenta-Specific Genes, Their Regulation During Villous Trophoblast Differentiation and Dysregulation in Preterm Preeclampsia

The human placenta maintains pregnancy and supports the developing fetus by providing nutrition, gas-waste exchange, hormonal regulation, and an immunological barrier from the maternal immune system. The villous syncytiotrophoblast carries most of these functions and provides the interface between the maternal and fetal circulatory systems. The syncytiotrophoblast is generated by the biochemical and morphological differentiation of underlying cytotrophoblast progenitor cells. The dysfunction of the villous trophoblast development is implicated in placenta-mediated pregnancy complications. Herein, we describe gene modules and clusters involved in the dynamic differentiation of villous cytotrophoblasts into the syncytiotrophoblast. During this process, the immune defense functions are first established, followed by structural and metabolic changes, and then by peptide hormone synthesis. We describe key transcription regulatory molecules that regulate gene modules involved in placental functions. Based on transcriptomic evidence, we infer how villous trophoblast differentiation and functions are dysregulated in preterm preeclampsia, a life-threatening placenta-mediated obstetrical syndrome for the mother and fetus. In the conclusion, we uncover the blueprint for villous trophoblast development and its impairment in preterm preeclampsia, which may aid in the future development of non-invasive biomarkers for placental functions and early identification of women at risk for preterm preeclampsia as well as other placenta-mediated pregnancy complications.

Obstetric APLA syndrome: Catastrophe hidden in iceberg

Obstetric Antiphopholipid Syndrome (OAPS) is a serious threat in pregnancy leading to, either or both, maternal and fetal morbidity / mortality. We present here a case of young primigravida, pre-eclamptic female with intrauterine fetal death and subsequent postpartum renal cortical necrosis. Association with antiphospholipid antibodies (APLA) as a causative factor for these catastrophic events was established only during workup of renal biopsy reporting. This case highlights the importance of including APLA as a screening investigation during antenatal care especially in developing and underdeveloped countries.

«Поздние» осложнения беременности как триггеры акушерского атипичного гемолитико-уремического синдрома

«Поздние» осложнения беременности как триггеры акушерского атипичного гемолитико-уремического синдрома

Placental bed research: II. Functional and immunological investigations of the placental bed

Research on the placenta as the interface between the mother and the fetus has been undertaken for some 150 years, and in 2 subsequent reviews, we attempted to summarize the situation. In the first part, we described the discovery of unique physiological modifications of the uteroplacental spiral arteries, enabling them to cope with a major increase in blood flow necessary to ensure proper growth of the fetus. These consist of an invasion of the arterial walls by trophoblast and a progressive disappearance of its normal structure. Researchers then turned to the pathophysiology of the placental bed and in particular to its maternal vascular tree. This yielded vital information for a better understanding of the so-called great obstetrical syndromes (preeclampsia, fetal growth restriction, premature labor and delivery, placenta accreta). Systematic morphological investigations of the uteroplacental vasculature showed that preeclampsia is associated with decreased or failed transformation of spiral arteries and the persistence of endothelial and smooth muscle cells in segments of their myometrial portion. Here we report on recent functional investigations of the placental bed, including in situ biophysical studies of uteroplacental blood flow and vascular resistance, and manipulation of uteroplacental perfusion. These new methodologies have provided a novel way of identifying pregnancies in which remodeling is impaired. In animals it is now possible to manipulate uteroplacental blood flow, leading to an enhancement of fetal growth; this opens the way to trials in abnormal human pregnancies. In this second part, we explored a new, extremely important area of research that deals with the role of specific subsets of leukocytes and macrophages in the placental bed. The human first-trimester decidua is rich in leukocytes called uterine natural killer cells. Both macrophages and uterine natural killer cells increase in number from the secretory endometrium to early pregnancy and play a critical role in mediating the process of spiral artery transformation by inducing initial structural changes. It seems therefore that vascular remodeling of spiral arteries is initiated independently of trophoblast invasion. Dysregulation of the immune system may lead to reproductive failure or pregnancy complications, and in this respect, recent studies have advanced our understanding of the mechanisms regulating immunological tolerance during pregnancy, with several mechanisms being proposed for the development of tolerance to the semiallogeneic fetus. In particular, these include several strategies by which the trophoblast avoids maternal recognition. Finally, an important new dimension is being explored: the likelihood that pregnancy syndromes and impaired uteroplacental vascular remodeling may be linked to future maternal and even the child's cardiovascular disease risk. The functional evidence underlying these observations will be discussed.

Galectin 13 (PP13) Facilitates Remodeling and Structural Stabilization of Maternal Vessels during Pregnancy.

Galectins regulate cell growth, proliferation, differentiation, apoptosis, signal transduction, mRNA splicing, and interactions with the extracellular matrix. Here we focus on the galectins in the reproductive system, particularly on a group of six galectins that first appears in anthropoid primates in conjunction with the evolution of highly invasive placentation and long gestation. Of these six, placental protein 13 (PP13, galectin 13) interacts with glycoproteins and glycolipids to enable successful pregnancy. PP13 is related to the development of a major obstetric syndrome, preeclampsia, a life-threatening complication of pregnancy which affects ten million pregnant women globally. Preeclampsia is characterized by hypertension, proteinuria, and organ failure, and is often accompanied by fetal loss and major newborn disabilities. PP13 facilitates the expansion of uterine arteries and veins during pregnancy in an endothelial cell-dependent manner, via the eNOS and prostaglandin signaling pathways. PP13 acts through its carbohydrate recognition domain that binds to sugar residues of extracellular and connective tissue molecules, thus inducing structural stabilization of vessel expansion. Further, decidual PP13 aggregates may serve as a decoy that induces white blood cell apoptosis, contributing to the mother’s immune tolerance to pregnancy. Lower first trimester PP13 level is one of the biomarkers to predict the subsequent risk to develop preeclampsia, while its molecular mutations/polymorphisms that are associated with reduced PP13 expression are accompanied by higher rates of preeclampsia We propose a targeted PP13 replenishing therapy to fight preeclampsia in carriers of these mutations.

Placental Galectins Are Key Players in Regulating the Maternal Adaptive Immune Response.

Galectins are potent immunomodulators that regulate maternal immune responses in pregnancy and prevent the rejection of the semi-allogeneic fetus that also occurs in miscarriages. We previously identified a gene cluster on Chromosome 19 that expresses a subfamily of galectins, including galectin-13 (Gal-13) and galectin-14 (Gal-14), which emerged in anthropoid primates. These galectins are expressed only by the placenta and induce the apoptosis of activated T lymphocytes, possibly contributing to a shifted maternal immune balance in pregnancy. The placental expression of Gal-13 and Gal-14 is decreased in preeclampsia, a life-threatening obstetrical syndrome partly attributed to maternal anti-fetal rejection. This study is aimed at revealing the effects of Gal-13 and Gal-14 on T cell functions and comparing the expression of these galectins in placentas from healthy pregnancies and miscarriages. First-trimester placentas were collected from miscarriages and elective termination of pregnancies, tissue microarrays were constructed, and then the expression of Gal-13 and Gal-14 was analyzed by immunohistochemistry and immunoscoring. Recombinant Gal-13 and Gal-14 were expressed and purified, and their effects were investigated on primary peripheral blood T cells. The binding of Gal-13 and Gal-14 to T cells and the effects of these galectins on apoptosis, activation marker (CD25, CD71, CD95, HLA-DR) expression and cytokine (IL-1β, IL-6, IL-8, IL-10, IFNγ) production of T cells were examined by flow cytometry. Gal-13 and Gal-14 are primarily expressed by the syncytiotrophoblast at the maternal-fetal interface in the first trimester, and their placental expression is decreased in miscarriages compared to first-trimester controls. Recombinant Gal-13 and Gal-14 bind to T cells in a population- and activation-dependent manner. Gal-13 and Gal-14 induce apoptosis of Th and Tc cell populations, regardless of their activation status. Out of the investigated activation markers, Gal-14 decreases the cell surface expression of CD71, Gal-13 increases the expression of CD25, and both galectins increase the expression of CD95 on T cells. Non-activated T cells produce larger amounts of IL-8 in the presence of Gal-13 or Gal-14. In conclusion, these results show that Gal-13 and Gal-14 already provide an immunoprivileged environment at the maternal-fetal interface during early pregnancy, and their reduced expression is related to miscarriages.

Placental bed research: I. The placental bed: from spiral arteries remodeling to the great obstetrical syndromes

The term placental bed was coined to describe the maternal-fetal interface (ie, the area in which the placenta attaches itself to the uterus). Appropriate vascularization of this area is of vital importance for the development of the fetus; this is why systematic investigations of this area have now been carried out. Initially, the challenge was the identification and classification of the various successive branching of uterine arteries in this area. These vessels have a unique importance because failure of their physiological transformation is considered to be the anatomical basis for reduced perfusion to the intervillous space in women with preeclampsia, fetal growth restriction, preterm labor, preterm premature rupture of membranes, abruptio placentae, and fetal death. To investigate in depth the pathophysiology of the placental bed, some 60 years ago, a large number of placental bed biopsies, as well as of cesarean hysterectomy specimens with placenta in situ, from both early and late normotensive and hypertensive pregnancies, were carefully dissected and analyzed. Thanks to the presence of a series of specific physiological changes, characterized by the invasion and substitution of the arterial intima by trophoblast, this material allowed the identification in the placental bed of normal pregnancies of the main vessels, the uteroplacental arteries. It was then discovered that preeclampsia is associated with defective or absent transformation of the myometrial segment of the uteroplacental arteries. In addition, in severe hypertensive disease, atherosclerotic lesions were also found in the defective myometrial segment. Finally, in the basal decidua, a unique vascular lesion, coined acute atherosis, was also identified This disorder of deep placentation, coined defective deep placentation, has been associated with the great obstetrical syndromes, grouping together preeclampsia, intrauterine growth restriction, preterm labor, preterm premature rupture of membranes, late spontaneous abortion, and abruptio placentae. More recently, simplified techniques of tissue sampling have been also introduced: decidual suction allows to obtain a large number of decidual arteries, although their origin in the placental bed cannot be determined. Biopsies parallel to the surface of the basal plate have been more interesting, making possible to identify the vessels' region (central, paracentral, or peripheral) of origin in the placental bed and providing decidual material for immunohistochemical studies. Finally, histochemical and electron microscopy investigations have now clarified the pathology and pathogenetic mechanisms underlying the impairment of the physiological vascular changes.

Epigenome-wide association data implicate fetal/maternal adaptations contributing to clinical outcomes in preeclampsia.

Aim: To investigate the changes of placental DNA methylome in preeclampsia (PE). Materials & methods: We performed an epigenome-wide association study in a Chinese cohort and six published datasets consisting of 335 samples in total. Results & conclusion: Numerous consistently hypomethylated probes were associated with early-onset PE in different populations, with 2125 reaching epigenome-wide significance. The validated probes were enriched for cytosine-phosphate-guanine dinucleotide (CpG) sites partially methylated and located in genes related to trophoblast fusion. The methylation levels of the validated probes were associated with clinical severity, while the intermediate samples showed antagonistic fetal/maternal outcomes. The DNA methylation patterns of PE and clinically relevant obstetrical syndromes suggested partially common pathophysiologies and complex maternal/fetal adaptive responses contributing to variable clinical outcomes.

Ante and Postnatal Ultrasound Contribution and Near-infrared Spectroscopy (NIRS) Monitoring in Preterm Newborns with Intrauterine Growth Restriction Under 32 Weeks of Gestation

IUGR remains an important health problem in developing countries around the world, being one of the major obstetrical syndromes associated with placental defects, but also one of the topical issues of neonatology, and in particular the association between IUGR and prematurity under 32 weeks of gestation. Neonatal morbidity and mortality remain significant and has an important economic impact. The need for more stringent diagnostic criteria remains a problem. The study proposes to follow the time of extraction of a premature pregnancy IUGR with gestation age �32 weeks, taking into account the centralization of bloodflow as well as IH (hypoxic index) during observation, following the immediate consequences on this new category - as well as their prognosis depending on the associated pathology using cerebral serial Doppler ultrasounds and near-infrared spectroscopy (NIRS).

Preeclampsia link to gestational hypoxia.

Complications of pregnancy remain key drivers of morbidity and mortality, affecting the health of both the mother and her offspring in the short and long term. There is lack of detailed understanding of the pathways involved in the pathology and pathogenesis of compromised pregnancy, as well as a shortfall of effective prognostic, diagnostic and treatment options. In many complications of pregnancy, such as in preeclampsia, there is an increase in uteroplacental vascular resistance. However, the cause and effect relationship between placental dysfunction and adverse outcomes in the mother and her offspring remains uncertain. In this review, we aim to highlight the value of gestational hypoxia-induced complications of pregnancy in elucidating underlying molecular pathways and in assessing candidate therapeutic options for these complex disorders. Chronic maternal hypoxia not only mimics the placental pathology associated with obstetric syndromes like gestational hypertension at morphological, molecular and functional levels, but also recapitulates key symptoms that occur as maternal and fetal clinical manifestations of these pregnancy disorders. We propose that gestational hypoxia provides a useful model to study the inter-relationship between placental dysfunction and adverse outcomes in the mother and her offspring in a wide array of examples of complicated pregnancy, such as in preeclampsia.

Атиповий гемолітико-уремічний синдром очима акушера (Огляд літератури)

The article presents an overview of native and foreign publications on atypical hemolytic-uremic syndrome. Modern terminology, classification is presented, questions about the causes and pathogenesis of this pathology are considered. The opinions of experts of obstetric and gynecological communities of the world on questions of clinics, diagnostics and treatment are given. Key words: pregnancy, obstetric atypical hemolytic-uremic syndrome, eculizumab.

Сучасний погляд на великі акушерські синдроми (Огляд іноземної літератури)

The literature review summarizes the data about etiology, pathogenesis and possible methods of prophylaxis of great obstetrical syndromes. It is proven that these syndromes are caused by defective deep placentation due to obstruction, absent or partial transformation of spiral arteries of deciduo-myometrial interface, that is caused by hormonal imbalance. The perspective method of prophylaxis of great obstetrical syndromes is intake of medications, that might have a modulating effect of the factors mentioned above. Key words: great obstetrical syndromes, defective deep placentation, deciduo-myometrial interface, spital arteries, oxidative stress, decidual immune cells, preimplantational factor, progesterone-induced blocking factor, progesterone, dydrogesterone.

Intensive care for disseminated intravascular coagulation syndrome (dic-syndrome, coagulopathy) in obstetrics

Intensive care for disseminated intravascular coagulation syndrome (dic-syndrome, coagulopathy) in obstetrics

Arteriolar injuries in clinical obstetric and gynecologic syndromes

Arteriolar injuries in clinical obstetric and gynecologic syndromes

MODERN METHODS OF GREAT OBSTETRICAL SYNDROMES PROGNOSTICATION (LITERATURE REVIEW)

Introduction: The term "Great Obstetrical Syndromes" (GOS) was widely implemented to clinical practice after 2009, due to publications of G. C. Di Renzo and R. Romero. The effective prognostical methods are still being searched for early correction of the disorders and decrease of negative consequences on mother and fetus. The aim: To analyze the up to date data concerning prognostication of Great obstetrical syndromes. Materials and methods: Used database Pubmed from 2004 up till 2019 to search clinical studies of great obstetrical syndromes. Conclusions: The literature review summarizes the data about existing methods of prognostication of GOS based on history of the patient and the results of additional clinical and laboratory investigations.