Thrombotic microangiopathy and pregnancy.

OBJECTIVE: The aim of this study is to draw attention to a nosological unit called thrombotic microangiopathy (TMA). This syndrome represents a serious pathological condition characterized by microangiopathic haemolytic anemia (MAHA), thrombocytopenia and various organ dysfunction. Patients are most often presented with symptoms of the HELLP syndrome but if the clinical picture is not restituted within 48-72 hours after delivery, other TMAs should be considered. SETTING: Department of Obstetrics and Gynecology, 1st Medical Faculty and General Teaching Hospital Prague; Clinic of Nephrology, 1st Medical Faculty and General Teaching Hospital Prague; Department of Obstetrics and Gynecology, Regional Hospital Kolín. DESIGN: Review article and case reports. METHODS: Review of the literature and description of two cases of TMA. CONCLUSION: The authors present a basic overview of the issue of TMA, which requires interdisciplinary cooperation of obstetricians, anesthesiologists, nephrologists and hematologists. In the second part of the article, we present two TMA case reports and finally show the differential diagnostic and therapeutic scheme as agreed by the authorities in the field.

Current options of prediction of preterm labour.

OBJECTIVE: A summary of current possibilities to adequately determine spontaneous preterm labour. DESIGN: Review. SETTING: Department of Obstetrics and Gynecology, 1st Faculty of Medicine and General Teaching Hospital, Charles University in Prague. METHODS: Research of literature and current studies. CONCLUSION: Based on the combination of personal medical history, clinical signs, biomarkers and transvaginal ultrasonographic measurement of cervical length, it is possible to predict preterm labour. To avoid a major prediction miscalculation, it is necessary to understand and correctly evaluate certain clinical findings. This approach decreases redundant medical intervention and therefore leads to amelioration of perinatal outcome.

Cervical cerclage - history and contemporary use.

OBJECTIVE: Contemporary role of cerclage as a preterm birth treatment. DESIGN: Review article. SETTING: Department of Obstetrics and Gynecology of the First Faculty of Medicine and General Teaching Hospital in Prague. METHODS: Research of existing literature, predominantly foreign journal articles, but also Czech literature and personal experience with the method. RESULTS: Cerclage is one of the well-known surgical procedures carried out during pregnancy. Its aim is to provide a mechanical support to the cervical canal and to keep the cervix closed. The cervical mucous plug serves as a mechanical barrier between the vagina and the uterine cavity, but it also contains many immune components which protect the fetal compartment from ascendent infections. Application of a cervical stitch can help to retain the mucous plug and thus increases the immunity of the cervical canal. Results of 15 randomised studies (Cochraine Database of Systematic R) suggest that in women with increased risk of preterm birth, cerclage decreases the occurrence of preterm birth relative to the expectant management. CONCLUSIONS: Despite the decreasing numbers of cerclage surgeries, it is still a useful method of preterm birth prevention for a specific group of women. More recently, a progesterone treatment has gained popularity. Its application, however, must begin before the 16th week of pregnancy.

Low maternal serum concentrations of mannose-binding lectin are associated with the risk of shorter duration of pregnancy and lower birthweight.

Chronic inflammation has been implicated as the underlying mechanism responsible for the pathophysiology of preterm labour. Mannose-binding lectin (MBL) plays a central role in the innate immune response and is thus an important component of the first line of defense. The aim of this study was to investigate whether serum concentrations of MBL correlated with the incidence of preterm birth and low birthweight in a cohort of women with signs of threatened preterm birth. A cohort of 60 patients who presented with regular contractions and/or short cervix (group A) between 24 and 32 weeks of gestation and 20 healthy controls (group B) who had no pregnancy complications and delivered at term were recruited into a prospective study. The following outcomes were recorded: presence of preterm labour and birthweight in all patients. MBL and high sensitivity C-reactive protein levels were measured in all serum samples. The serum concentrations of MBL were significantly reduced in patients with threatened preterm labour (Group A), compared to the control Group B. Furthermore, infants born to Group A mothers with MBL deficiency (n = 13, MBL ≤100 ng/mL) had significantly lower birthweights, compared to those born to Group A women with normal MBL serum concentrations (P < .0001). Our small cohort study demonstrated a strong association between MBL deficiency and preterm delivery, and associated low birthweight. MBL deficiency could thus be considered an important risk factor for preterm birth.

Fetal and neonatal alloimmune thrombocytopenia.

OBJECTIVE: This article shows our experience with fetal and neonatal alloimmune thrombocytopenia (FNAIT) on a particular patient and the difficulties we faced during the hospitalization. DESIGN: Case report. SETTING: Department of Obsterics and Gynecology 1st Faculty of Medicine, Charles University and General Faculty Hospital in Prague. METHODS: Our experience with FNAIT therapy. RESULTS: According to literature is recommended to use IVIG for FNAIT treatment. Women, who were treated by IVIG have better results, in comparison with women, who had no treatment at all. Our case is not confirming this statement, because first pregnancy of our patient terminated by IUFD, on the other hand second pregnancy was successful and she delivered healthy child. CONCLUSION: FNAIT is relatively rare disease, but if it appears, it can be dangerous for a fetus or for a new-born baby. In the worst case FNAIT can result in intracranial bleeding or prenatal death. There are limited preventive steps and available therapy produces uncertain results. The only partially accepted treatment substance is IVIG (intravenous immunoglobulins). Unfortunately, this therapy is very expensive and not accepted by some experts. This article shows our experience with FNAIT on a particular patient and the difficulties we faced during the hospitalization.

[The role of T-regulatory lymphocytes in pathogenesis of preterm delivery]. / Úloha T-regulacních lymfocytu v patogenezi predcasného porodu.

OBJECTIVE: To describe the role of T-regulatory lymphocytes in pathogenesis of preterm delivery. SETTING: Department of Obstetrics and Gynecology, General University Hospital and 1st Medical Faculty, Charles University, Prague. METHOD: T-regulatory lymphocytes modulate the immune system, secure the tolerance to own antigens and prevent autoimmune disease. During pregnancy is maternal immunity in contact with the semi-allogeneic fetus due to the fetomaternal crosstalk. It seems that maternal immunity and T-regulatory lymphocytes have an effect on premature birth and other pregnancy pathologies. According to the latest data, their role in the immunomodulation of pregnant women seems to be very significant, although we still do not understand many mechanisms.

[The role of maternal imunity and woman´s microbiome in the pathogenesis of preterm labor]. / Úloha materské imunity a mikrobiomu zeny v patogenezi predcasného porodu.

OBJECTIVE: To summarize available data concerning the role of maternal imunity and woman´s microbiome in the pathogenesis of preterm labor and their use in clinical practice. SETTING: Department of Obstetrics and Gynecology od the First Faculty of Medicine, Charles University in Prague, and General Teaching Hospital. DESIGN: Review article. METHODS: Compilation od published data from scientific literature. CONCLUSION: Preterm labor complicates approximately 10% of all pregnancies and represents a serious medical, social and economic problem. In the past, a lot of causes of preterm labor were discussed; infection, uteroplacental ischemia, decidual hemorrhage, uterine overdistension, cervical disease and maternal-fetal tolerance disorder were considered the most common. However, chronic inflammation seems to be the common pathogenic process underlying preterm labor, irrespective of the original stimulus. Currently, impaired maternal-fetal immunological tolerance represents most discussed topic. Growing scientific evidence suggests that the immune regulation of the maternal-fetal interface is the result of the coordinated interaction among maternal microbiota, trophoblast and maternal cellular components. From this view we understand preterm labor as a result of disruption of this process.

[Septic shock in pregnancy on the basis of an acute pyelonephritis]. / Septický sok v tehotenství na podklade akutní pyelonefritidy.

OBJECTIVE: According to the World Health Organisation, sepsis is one of the four main causes of pregnancy-related mortality worldwide, together with hemorrhage, hypertensive disease and abortion. The main goal of this paper is an analysis of one case of septic shock in pregnancy. DESIGN: A case report. SETTING: Department of Obstetrics and Gynaecology of the First Faculty of Medicine and General Teaching Hospital, Prague. METHODS AND RESULTS: Authors would like to draw attention to the pitfalls of diagnosis and treatment of septic shock which developed in 25th week of pregnancy on the basis of pyelonephritis due to E. coli. CONCLUSIONS: Early diagnosis of sepsis and an interdisciplinary co-operation are the main prerequisities for successful treatment.

[Intrahepatic cholestasis of pregnancy]. / Intrahepatální cholestáza v tehotenství

The review of intrahepatic cholestasis of pregnancy attempts to summarize the current knowledge of this disease by analysing available literary sources. Intrahepatic cholestasis of pregnancy is a disease that typically appears in the third trimester of pregnancy, sometimes already at the end of the second trimester of pregnancy. The main symptom of the disease is pruritus. In addition, the disease is characterized by increased levels of liver enzymes and bile acids. The symptoms of the disease disappear spontaneously after delivery. The disease is associated with high incidence of fetal distress, as well as with a high risk of premature labour. The most serious obstetric complication is antenatal sudden fetal death. Fetal complications are probably caused by elevated levels of bile acids. Therefore the aim of treatment should be to minimize negative effects of bile acids on the fetus, to prolong pregnancy and reduce maternal symptoms at the same time.

[Acute or expectant management in premature labour with preterm premature rupture of the membranes?]. / Akutní, nebo expektacní prístup u predcasného porodu s predcasne odteklou plodovou vodou?

OBJECTIVE: To evaluate current knowledge about the management of preterm premature rupture of the membranes (PPROM). DESIGN: Review article. SETTING: Perinatological center, Department of Gynecology and Obstetrics, General Faculty Hospital and 1st Medical School of Charles University, Prague. METHODS AND RESULTS: Expectant management in case of PPROM increases the incidence of infection/ inflammation but does not statistically increase mortality and serious morbidity of the infants. The incidence of infants morbidity corresponds with gestational age. The most serious complications occur in the lower gestational age. It is necessary to take an individual approach. The acute management increases the number of operative deliveries and respiratory distress syndrome (RDS) in the infants. The combination of RDS, extremely prematurity and hypoxia during the labour decreases the infants survival rate. CONCLUSIONS: The prolongation of the latency period in pregnancies above 28th week does not deteriorate the neonatal mortality or morbidity.

Pregnancy-associated plasma protein A polymorphisms in patients with risk pregnancies.

Pregnant women are often threatened by hypertension, symptoms of preterm labour, hepatopathy, and other. These complications might be the consequence of genetic factors together with involvement of environmental factors. We were searching for three polymorphisms Arg654Lys, Ala678Pro and Thr686Ala in exon 5, and two polymorphisms Phe802Leu, Ser827Ser/Leu in exon 7, and for the new mutations in exons 5 and 7 of the pregnancy-associated plasma protein A gene in the studied group consisting of 203 women - 79 pregnant women in time of preterm labour, 24 pregnant women suffering from preeclampsia, and 100 healthy pregnant and non-pregnant women serving as controls. We did not find any divergence from wild-type form of these polymorphisms in any of the studied groups, which led us to the hypothesis that these polymorphisms are not associated with our studied group of Caucasian origin. However, further studies with a larger group of subjects are needed to confirm our results.

[Spontaneous preterm birth in mother in an artificial sleep on ECMO with severe form of H1N1 infection]. / Spontánní predcasný porod u rodicky v umelém spánku na ECMO pri závazné forme infekce H1N1.

OBJECTIVE: The authors demonstrate a premature birth of a pregnant woman, who was for heavy Respiratory Distress Syndrome (ARDS), on the basis of pulmonary infection H1N1, connected to venovenous extracorporeal membrane oxygenation (ECMO). Patient spontaneously delivered after being connected to the ECMO for 30 hours. SETTING: Department of Obstetrics and Gynaecology, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Department of Anesthesiology and Intensive Care, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague. DESIGN: Case report. CONCLUSION: Preterm birth at 24 week of pregnancy. During pregnancy, the labor and postpartum was the pregnant woman connected to extracorporeal membrane oxygen therapy.

[Current perspective of treating hypertension in pregnancy]. / Soucasný pohled na lécbu hypertenze v tehotenství.

The author deals with the contemporary perspective on treatment hypertension in pregnancy. The article highlighted that hypertension treatment should be conducted not only with regard to the mother, but also to the possible negative impact on supply to the fetus. New information, particularly in the pathophysiology of pregnancy related hypertension show that in these diagnoses is vasoconstriction in placental microcirculation quite common. Inadequate treatment may have adverse effects on uteroplacental flow with potential risks to the fetus. The treatment of choice in pregnancy relatedy hypertension are methyldopa, calcium antagonists and labetalol.

Steroids, steroid associated substances and gestational diabetes mellitus.

As gestational diabetes mellitus (GDM) is both a frequent and serious complication, steroid levels in pregnancy are extremely elevated and their role in pregnancy is crucial, this review focuses on the role of steroids and related substances in the GDM pathophysiology. Low SHBG levels are associated with insulin resistance and hyperinsulinemia, while also predicting a predisposition to GDM. Other relevant agents are placental hormones such as kisspeptin and CRH, playing also an important role beyond pregnancy, but which are synthesized here in smaller amounts in the hypothalamus. These hormones affect both the course of pregnancy as well as the synthesis of pregnancy steroids and may also be involved in the GDM pathophysiology. Steroids, whose biosynthesis is mainly provided by the fetal adrenal glands, placenta, maternal adrenal glands, and both maternal and fetal livers, are also synthesized in limited amounts directly in the pancreas and may influence the development of GDM. These substances involve the sulfated ?5 steroids primarily acting via modulating different ion channels and influencing the development of GDM in different directions, mostly diabetogenic progesterone and predominantly anti-diabetic estradiol acting both in genomic and non-genomic way, androgens associated with IR and hyperinsulinemia, neuroactive steroids affecting the pituitary functioning, and cortisol whose production is stimulated by CRH but which suppresses its pro-inflammatory effects. Due to the complex actions of steroids, studies assessing their predominant effect and studies assessing their predictive values for estimating predisposition to GDM are needed.

Is maternal progesterone actually independent of the fetal steroids?

Progesterone and estradiol are the foremost steroid hormones in human pregnancy. However, the origin of maternal progesterone has still not been satisfactorily explained, despite the generally accepted opinion that maternal LDL-cholesterol is a single substrate for placental synthesis of maternal progesterone. The question remains why the levels of progesterone are substantially higher in fetal as opposed to maternal blood. Hence, the role of the fetal zone of fetal adrenal (FZFA) in the synthesis of progesterone precursors was addressed. The FZFA may be directly regulated by placental CRH inducing an excessive production of sulfated 3beta-hydroxy-5-ene steroids such as sulfates of dehydroepiandrosterone (DHEAS) and pregnenolone (PregS). Due to their excellent solubility in plasma these conjugates are easily transported in excessive amounts to the placenta for further conversion to the sex hormones. While the significance of C19 3beta-hydroxy-5-ene steroid sulfates originating in FZFA for placental estrogen formation is mostly recognized, the question "Which maternal and/or fetal functions may be served by excessive production of PregS in the FZFA?" - still remains open. Our hypothesis is that, besides the necessity to synthesize de novo all the maternal progesterone from cholesterol, it may be more convenient to utilize the fetal PregS. The activities of sulfatase and 3beta-hydroxysteroid dehydrogenase (3beta-HSD) are substantially higher than the activity of cytochrome P450scc, which is rate-limiting for the placental progesterone synthesis from LDL-cholesterol. However, as in the case of progesterone synthesis from maternal LDL-cholesterol, the relative independence of progesterone levels on FZFA activity may be a consequence of substrate saturation of enzymes converting PregS to progesterone. Some of the literature along with our current data (showing no correlation between fetal and maternal progesterone but significant partial correlations between fetal and maternal 20alpha-dihydroprogesterone (Prog20alpha) and between Prog20alpha and progesterone within the maternal blood) indicate that the localization of individual types of 17beta-hydroxysteroid dehydrogenase is responsible for a higher proportion of estrone and progesterone in the fetus, but also a higher proportion of estradiol and Prog20alpha in maternal blood. Type 2 17beta-hydroxysteroid dehydrogenase (17HSD2), which oxidizes estradiol to estrone and Prog20alpha to progesterone, is highly expressed in placental endothelial cells lining the fetal compartment. Alternatively, syncytium, which is directly in contact with maternal blood, produces high amounts of estradiol and Prog20alpha due to the effects of type 1, 5 and 7 17?-hydroxysteroid dehydrogenases (17HSD1, 17HSD5, and 17HSD7, respectively). The proposed mechanisms may serve the following functions: 1) providing substances which may influence the placental production of progesterone and synthesis of neuroprotective steroids in the fetus; and 2) creating hormonal milieu enabling control of the onset of labor.

[Progesterone neuroactive metabolites in human pregnancy]. / Progesteron a jeho neuroaktivní metabolity v mechanismu porodu.

OBJECTIVE: Review of the physiological role of neuroactive and neuroprotective steroids in human pregnancy. DESIGN: A review article. SETTING: Gynecological-Obstetrical Clinic, 1st Medical Faculty, Charles University and General Hospital, Prague. CONCLUSION: Human parturition is a multi-factorial process. Various mechanisms related to the onset of labor were suggested. Estrogens show accelerating increase in late pregnancy, which probably reflect the increasing activity of fetal zone of the fetal adrenal. This zone is stimulated by progressive increase of placental CRH resulting in excessive production of conjugated 3beta-hydroxy-5-en-steroids, which are transported by circulation to placenta and further metabolized to active hormones. Some progesterone metabolites probably participate in pregnancy sustaining via modulation of ligand-gated ion channels in the CNS and periphery. In this review, the question was addressed whether the catabolism of pregnancy sustaining progesterone metabolites accelerate like the estrogen formation.

[News in pathophysiology and management of preterm labour]. / Novinky v patofyziologii a managementu predcasného porodu.

OBJECTIVE: To summarize available data concerning pathophysiology and management of preterm labour and their use in clinical practice. SETTING: Department of Obstetrics and Gynecology od the First Faculty of Medicine, Charles University, and General Teaching Hospital, Prague. DESIGN: Review article. METHODS: Compilation od published data from scientific literature. CONCLUSION: Birth canal infections seem to play a key role in the ethiopathogenesis of premature delivery; the related biochemical changes significantly affect perinatal morbidity and mortality. Other potential causes, particularly hormone metabolism disorders or uteroplacental ischaemia have been intensively studied. The particular pathogenetic process of premature delivery is inflammation. This process is related to both mother and fetus. Fetal inflammatory response (FIRS)--can occur without maternal response--is connected with significant increase in perinatal morbidity. FIRS is characterised by defined laboratory, histological and clinical criteria. Effective primary prevention of premature delivery does not exist at present. The sensitivity and specificity of the laboratory markers having been used so far is low. Thus, the research is focused on finding new inflammation markers to allow early identification of pregnant women at a high risk of premature delivery and fetal inflammation. The screening of women at a high risk by means of new laboratory and ultrasound tests belongs to the most important steps in secondary and tertiary prevention of premature delivery. Intensive research of potential trigger mechanisms has been carried out, including a variety of gene types, which are potentially related to the process of premature delivery. We try to exercise new informations about pathophysiology of preterm labour in prenatal care, firstly about thrombophillias and gestagens. We also use a principles of "evidence based medicine" and revalue importance of steroids, tocolytics and antibiotics.

Pathophysiology of preterm labour.

A specific pathogenic process of premature delivery represents the inflammation. Birth canal infections seem to play a key role in the ethiopathogenesis of premature delivery; the related biochemical changes significantly affect perinatal morbidity and mortality. Other potential causes, particularly hormone metabolism disorders or uteroplacental ischaemia have been intensively studied. This process is related both to the mother and fetus. Fetal inflammatory response (FIRS)--can occur without maternal response--and it is related to a significant increase in perinatal morbidity. FIRS has definite laboratory, histological and clinical criteria. Effective primary prevention of premature delivery does not exist at present. The sensitivity and specificity of so far used laboratory markers is low. Thus, the research is focused on finding new inflammation markers allowing the early identification of pregnant women at a high risk of premature delivery and fetal inflammation. The screening of women at a high risk by means of new laboratory and ultrasound tests belongs to the most important steps in secondary and tertiary prevention of premature delivery. Intensive research of potential trigger mechanisms has been carried out, including a variety of gene types, which are potentially related to the process of premature delivery.

Prenatal and perinatal management of preterm labour.

New knowledge of the pathophysiology of premature birth enables us to introduce new approaches in prenatal care as well as the management of premature delivery. These apply for the patients with subclinical risk factors, particularly with thrombophilias, chronic infections or other latent chronic infections. The peri- and pre-conceptional dispensarisation of these women might help reduce the development of premature delivery. Secondary prevention with the administration of gestagens is highly important for women with anamnestic or existing risk of premature delivery. During the underlying premature delivery, it is advisable to re-evaluate the significance of the administration of antibiotics and tocolytics as well as timing of corticoid dosage in the induction of foetal lung maturity. Using new diagnostic and therapeutic methods, the aim of present premature delivery management is to prolong the duration of pregnancy to the maximum with the lowest risk of the development of foetal inflammatory response possible and, therefore, with a low risk of long-term handicaps in children.

A method for determination of one hundred endogenous steroids in human serum by gas chromatography-tandem mass spectrometry.

Steroid profiling helps various pathologies to be rapidly diagnosed. Results from analyses investigating steroidogenic pathways may be used as a tool for uncovering pathology causations and proposals of new therapeutic approaches. The purpose of this study was to address still underutilized application of the advanced GC-MS/MS platform for the multicomponent quantification of endogenous steroids. We developed and validated a GC-MS/MS method for the quantification of 58 unconjugated steroids and 42 polar conjugates of steroids (after hydrolysis) in human blood. The present method was validated not only for blood of men and non-pregnant women but also for blood of pregnant women and for mixed umbilical cord blood. The spectrum of analytes includes common hormones operating via nuclear receptors as well as other bioactive substances like immunomodulatory and neuroactive steroids. Our present results are comparable with those from our previously published GC-MS method as well as the results of others. The present method was extended for corticoids and 17alpha-hydroxylated 5alpha/ß-reduced pregnanes, which are useful for the investigation of alternative "backdoor" pathway. When comparing the analytical characteristics of the present and previous method, the first exhibit by far higher selectivity, and generally higher sensitivity and better precision particularly for 17alpha-hydroxysteroids.