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In preterm premature rupture of membranes (PPROM), a decision between early delivery with prematurity complications and pregnancy prolongation bearing the risk of chorioamnionitis has to be made. To define disadvantages of delayed prolongation, latency duration of PPROM in expectantly managed pregnancies was investigated. We included those PPROMs > 48 h leading to preterm birth prior 37 weeks’ gestation and retrospectively analyzed 84 preterm infants fulfilling these criteria. The association between latency duration/appearance of PPROM and respiratory outcome (primary outcomes) and neurological outcome (secondary outcomes) was investigated. The study showed that latency duration of PPROM is not associated with clinical or histological chorioamnionitis (p = 0.275; p = 0.332). As the numerous clinical parameters show multicollinearity between each other, we performed a multiple regression analysis to consider this fact. Respiratory distress syndrome is significantly associated with gestational age at PPROM (p p = 0.014). The other respiratory parameters including steroids and diuretics therapy, bronchopulmonary dysplasia, and the neurological parameters (intraventricular hemorrhage, Bayley II testing at a corrected age of 24 months) were not significantly associated with PPROM duration or gestational age at PPROM diagnosis.Conclusion: Latency duration of PPROM was not associated with adverse neonatal outcome in expectantly and carefully managed pregnancies, but respiratory distress syndrome was pronounced. The observed effect of pronounced respiratory distress syndrome can be treated with surfactant preparations and was not followed by increased rate of bronchopulmonary dysplasia. What is Known:• In case of preterm premature rupture of membranes, a decision between pregnancy prolongation with the risk of chorioamnionitis and early delivery with prematurity complications has to be made.• Chorioamnionitis is a dangerous situation for the pregnant woman and the fetus.• Impaired neurodevelopmental outcome is strongly correlated with pronounced prematurity due to the increased rate of serious complications. What is New:• Respiratory distress syndrome is significantly associated with gestational age at PPROM, and surfactant application is significantly associated with PPROM duration.• Latency duration of PPROM is not associated with adverse respiratory neonatal outcome (therapy with continuous positive airway pressure, therapy with diuretics and/or steroids, bronchopulmonary dysplasia) in expectantly and carefully managed pregnancies.• Intraventricular hemorrhage and Bayley II testing at a corrected age of 24 months are not associated with latency duration of PPROM when pregnancies are carefully observed.

Supplemental Digital Content is available in the text., One driving factor for developing preeclampsia—a pregnancy disorder, often associated with poor spiral artery (SpA)-remodeling and fetal growth restriction—is the anti-angiogenic sFLT1 (soluble fms-like tyrosine kinase-1), which is found to be highly upregulated in preeclampsia patients. The sFLT1-mediated endothelial dysfunction is a common theory for the manifestation of maternal preeclampsia symptoms. However, the influence of sFLT1 on SpA-remodeling and the link between placental and maternal preeclampsia symptoms is less understood. To dissect the hsFLT1 (human sFLT1) effects on maternal and/or fetoplacental physiology in preeclampsia, sFLT1-transgenic mice with systemic hsFLT1 overexpression from midgestation onwards were used. SpA-remodeling was analyzed on histological and molecular level in placental/mesometrial triangle tissues. Maternal kidney and aorta morphology was investigated, combined with blood pressure measurements via telemetry. hsFLT1 overexpression resulted in maternal hypertension, aortic wall thickening, and elastin breakdown. Furthermore, maternal kidneys showed glomerular endotheliosis, podocyte damage, and proteinuria. preeclampsia symptoms were combined with fetal growth restriction already at the end of the second trimester and SpA-remodeling was strongly impaired as shown by persisted vascular smooth muscle cells. This phenotype was associated with shallow trophoblast invasion, delayed presence of uterine natural killer cells, and altered lymphatic angiogenesis. Overall, this study showed that circulating maternal hsFLT1 is sufficient to induce typical maternal preeclampsia-like symptoms in mice and impair the SpA-remodeling independent from the fetoplacental compartment, revealing new insights into the interaction between the placental and maternal contribution of preeclampsia.

An abnormally invasive placenta is an increasing and potentially life-threatening pregnancy complication. The case presented herein is a heterotopic dichorial pregnancy with implantation of 1 placenta within the isthmocervical area, which caused vaginal bleeding during the 20th week of pregnancy, requiring a blood transfusion. To stop the bleeding, a bilateral embolization of the cervical branches of the uterine arteries was performed. The embolization was well tolerated and resulted in the abrupt and lasting cessation of bleeding for more than 10 weeks, resulting in the live birth of 1 child.

CD8+ T cells are the most frequent T cell population in the immune cell compartment at the feto-maternal interface. Due to their cytotoxic potential, the presence of CD8+ T cells in the immune privileged pregnant uterus has raised considerable interest. Here, we review our current understanding of CD8+ T cell biology in the uterus of pregnant women and discuss this knowledge in relation to a recently published immune cell Atlas of human decidua. We describe how the expansion of CD8+ T cells with an effector memory phenotype often presenting markers of exhaustion is critical for a successful pregnancy, and host defense towards pathogens. Moreover, we review new evidence on the presence of long-lasting immunological memory to former pregnancies and discuss its impact on prospective pregnancy outcomes. The formation of fetal-specific memory CD8+ T cell subests in the uterus, in particular of tissue resident, and stem cell memory cells requires further investigation, but promises interesting results to come. Advancing the knowledge of CD8+ T cell biology in the pregnant uterus will be pivotal for understanding not only tissue-specific immune tolerance but also the etiology of complications during pregnancy, thus enabling preventive or therapeutic interventions in the future.

Defect healing of the uterotomy at ceasarean section (CS) results in a morphological und probably functional disruption of the anterior uterine wall. Clinical sequelae concern subsequent pregnancies with a broad range of complications before and during pregnancy as well as at birth. In the following chapter, we provide an overview about the definition, diagnosis, symptoms and pathogenetical mechanisms of CS scar defects. Keeping in mind the pathogenesis allows to introduce preventative approaches.

Background B7-H4, a checkpoint molecule of the B7 family, regulates a broad spectrum such as T-cell activation, cytokine secretion, tumour progression and invasion capacities. Our previous data revealed that soluble B7-H4 (sB7-H4) blood serum levels are elevated in women at high risk for the hypertensive pregnancy disorder preeclampsia (PE) in the first trimester, as well as in patients with confirmed early/ late-onset PE. Aim We here aim to investigate the expression pattern of B7-H4 in placental tissues of PE and HELLP Syndrome versus control group. Methods B7-H4 protein expression and localization were investigated by immunoblotting as well as co-immunohistochemistry in placental chorionic villous and decidual basalis tissues. Results B7-H4 protein was prominently expressed at the cell membrane, in the cytoplasm of the syncytiotrophoblast (STB) and interstitial extravillous trophoblast (EVT). B7-H4 protein levels in placental chorionic villous tissue was significantly higher in women with early-onset/late-onset PE and HELLP, while it was decreased in decidual basalis tissues of early-onset PE and HELLP compared to controls. Conclusion B7-H4 was inversely expressed in placental chorionic villous and decidual basalis tissues of PE and HELLP patients. The increase of B7-H4 in the STB in PE and HELLP may lead to excessive apical expression and release of soluble B7-H4 in the maternal circulation. In contrast, the decrease of B7-H4 in decidual basalis tissues could be related to the decrease in invasion ability of the EVT in PE. Thus, the current results strongly suggest that B7-H4 is involved in the pathogenesis of PE and HELLP.

Background The prevalence of food allergies (FA) in children increased rapidly at the turn of the century. The EuroPrevall study identified Germany as a country with very high prevalence of FA at that time. Using two large German birth cohorts we provide an update of the status quo ten years later. Methods KUNO Kids and Ulm SPATZ Health studies are two ongoing prospective birth cohorts. Information on FA was obtained by questionnaires at birth and after 6, 12 and 24 months. Univariable and multivariable logistic regression analyses were performed to investigate risk factors during pregnancy, birth and early childhood. Results In 1139 and 1006 children from KUNO Kids and SPATZ the point prevalence of parent-reported FA symptoms at the ages of 1 and 2 years was 13.2% (95% CI: 11.2-15.2) and 13.9% (95% CI: 11.5-17.2) in KUNO Kids. Doctor's diagnosed FA at 1 and 2 years was 2.4% (95% CI: 1.6-3.4) and 2.7% (95% CI: 1.2-4.3) in KUNO Kids and 2.3% (95% CI: 1.3-3.6) and 3% (95% CI: 2.0-4.5) in SPATZ. Cow's milk and citrus fruits were most frequently suspected by parents to cause FA symptoms. Atopy in the child was associated with a higher frequency of FA at any time, whereas atopy in first degree relatives was only associated with FA at year 1. Smoke exposure during pregnancy was a risk for FA at age 2. Conclusion The prevalence of food allergy seems to have plateaued in the last 10 years in Germany. FA is often suspected by parents but only rarely diagnosed by oral food challenge. Risk factor analysis may help to establish personalized health approaches.

Problem The aim of this study was to evaluate the sCEACAM1 concentrations in serum from patients in the first trimester who have a high risk for developing PE during pregnancy. Method of the study Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) levels were determined with ELISA. The patients (n = 109) were divided into two groups: patients who have a high risk of developing PE early-onset and a control group. Patients who have a high risk of developing PE were then divided into two subgroups depending on PE development in third trimester of pregnancy: PE in third trimester versus no PE in third trimester. Results sCEACAM1 concentrations in patients who were screened as having a high risk for developing PE were significantly higher than in healthy pregnant women in the first trimester (p = .03). The highest sCEACAM1 concentration was found in the high-risk group with PE development compared to the control group (p = .004). Conclusion Elevated sCEACAM1 blood serum levels in women with PE suggest that there is immune dysregulation in early pregnancy, which may be helpful in PE prediction and therapy.

Objectives Midregional pro atrial natriuretic peptide (MR-proANP) is a cardiac biomarker and the maternal serum levels could be different in preeclampsia (PE) or intrauterine growth restriction (IUGR) at third trimester of pregnancy. Methods This prospective study measured serum levels of MR-proANP between 32 and 37 weeks of pregnancy: 32 patients suffered from PE and 22 developed IUGR. 676 patients exhibited no pregnancy complications. Results The median level of MR-proANP was significantly higher in PE (64.9 pmol/l (interquartile range (IQR) 36.3-105.2) and IUGR (59.7 pmol/l (IQR 39.7- 163.0) groups compared to controls (38.7 pmol/l (IQR 29.7-49.2). Linear regression analysis showed association between PE and MR-proANP levels (Exp(s)= 1.56; 95% CI: 1.34-1.81). Area under the curve (AUC) estimates showed a predictive value for PE (AUC: 0.72) and IUGR (AUC: 0.71). Conclusions Measuring MR-proANP in maternal serum at third trimester could predict PE and IUGR presenting after 34 weeks of pregnancy. Thus, we assume that MR-proANP may be an additional biomarker which mirrors the maternal cardiosvascular status next to sFlt-1/PLGF representing the angiogenic status.

Background The reason for increased serum creatinine levels in preterm infants often remains unclear. We aimed to determine whether postnatal serum creatinine in preterm infants correlates with intake of amniotic fluid, represented by the amount of amniotic fluid after preterm premature rupture of membranes (PPROM). Methods 74 preterm infants with PPROM > 48 h duration were retrospectively studied. Postnatal creatinine concentration was determined at day 2–5, 10–17 and 26–33 of life and compared between infants with normal intrauterine amniotic volumes, oligohydramnios and anhydramnios. Results Mean gestational age of included patients was 29.7 weeks (range: 24.0–36.1 weeks) and mean birth weight was 1452 g (range: 560–2940 g). Serum creatinine concentration was similar at day 2–5 and day 10–17 of life between the three groups. We observed a significant decrease in creatinine concentration from day 2–5 to day 26–33 in infants with normal amniotic fluid volume and oligohydramnios (p = 0.0001 and p = 0.0071, respectively), but not in anhydramnios. On day 26–33 of life, infants with anhydramnios showed significantly higher creatinine levels compared to infants with normal amniotic fluid volume and oligohydramnios (p = 0.0211). Conclusion Postnatal serum creatinine of preterm infants at day 26–33 of life is elevated in infants with PPROM-induced anhydramnios, but not in oligohydramnios.

Objective: Preterm premature rupture of membranes (PPROM) is a risk factor for chorioamnionitis (CA) and injury to the fetal brain. However, prolongation of gestation prevents morbidity and decreas...

Objectives The aim of this study was to investigate, whether maternal serum levels of sFlt-1, PlGF and PAPP-A at third trimester of pregnancy are associated with late-onset PE and intrauterine growth retardation (IUGR) after 34 weeks of pregnancy. Methods This was a prospective study measuring the maternal serum levels of soluble tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF) and pregnancy-associated plasma protein-A (PAPP-A) at 32–37 weeks of pregnancy: 730 patients were enrolled and 676 had neither intrauterine growth restriction (IUGR) nor preeclampsia (PE) or pregnancy induced hypertension (PIH) throughout the pregnancy. 22 patients developed IUGR, 32 PE and 24 PIH. Results Linear regression analyses after adjusting for maternal age, gestational age at the blood sampling and maternal BMI showed associations between PE and serum sFlt-1 levels (Exp(s) = 3.29; 95% CI: 2.69–4.04), serum PlGF levels (Exp(s) = 0.18; 95% CI: 0.13–0.24), sFlt-1/PlGF ratio (Exp(s) = 15.59; 95% CI: 10.64–22.84) and serum PAPP-A (Exp(s) = 1.48; 95% CI 1.15–1.89). sFlt-1, PlGF and sFlt-1/PlGF-Ratio showed comparable area under the curve (AUC) estimates with a predictive ability to discriminate pregnancies developing PE and IUGR from controls. The predictive ability of PAPP-A for PE was only slightly better than chance. Conclusions This study supported the ability of a single measurement of sFlt-1/PlGF ratio at third trimester to predict PE and IUGR occurring after 34 weeks of pregnancy. However, larger multicentre studies are needed to replicate our results.

Follistatin levels increase during the course of pregnancy and may play a role in ovarian arrest, reflected by the simultaneous decrease of anti-mullerian-hormone (AMH) levels. The aim of the study was to investigate AMH and follistatin levels during the hormonal window at the beginning of pregnancy. Since both parameters are described as deregulated in polycystic ovarian syndrome (PCOS), subgroup analysis of PCOS patients may additionally elucidate their interplay and effects on ovarian activity. Serum samples were retrospectively analyzed using the AMH Gen II ELISA and the Human Follistatin Quantikine ELISA Kit. Samples were collected longitudinally from 57 patients (32 with PCOS and 25 controls) before conception and during the first trimester. In 18 patients, measurements from the early and the late first trimester were available. Potential associations of AMH and follistatin levels with PCOS-related parameters were compared between the subgroups as well as longitudinally before and in the first trimester of pregnancy. For statistical analysis, the Spearman’s correlation, Wilcoxon test, t test, Friedman test and multiple linear regression analysis was performed. In contrast to AMH, follistatin levels differed not between controls and PCOS patients before and in pregnancy. In both subgroups, AMH levels significantly decreased and follistatin levels significantly increased in longitudinally performed measurements before conceiving and in the first trimester of pregnancy. Follistatin levels are not suited as a biomarker for PCOS, but could be involved in suppressing ovarian activity, as reflected by AMH levels at the beginning of pregnancy.

Das Rendu-Osler-Weber-Syndrom Typ 1 (hereditare hamorrhagische Teleangiektasie 1, HHT1) und die Praeklampsie basieren beide auf einer pathologischen Funktion des Endoglins. Patienten mit HHT1 haben einen heterozygoten Endoglingendefekt, der zu einer systemischen vaskularen Dysplasie fuhrt. Bei der Praeklampsie produziert der Trophoblast losliches Endoglin (sEng). sEng wirkt wie ein „Antikorper“, der das mutterliche Endoglinrezeptorsubstrat hemmt und antagonisiert. Dies fuhrt zu einer endothelialen Dysfunktion. Im Beitrag werden 2 verschiedene endoglinbedingte Erkrankungen miteinander verglichen, um eine fundiertere Einsicht in die spezifischen klinischen Merkmale zu gewinnen. Diskutiert werden ferner Managementoptionen fur schwangere Patientinnen mit HHT.

Investigating potential value of maternal serum Visfatin, sFlt-1, PlGF, AFP, PAPP-A levels at first trimester for prediction of small for gestational age (SGA) at birth.Measurements were performed in 20 SGA and 65 control cases. Logistic regression analysis adjusted for age and weeks of pregnancy at data collection was performed to estimate odds ratios (OR), 95% confidence intervals (95% CI) and p values separately for each potential predictor. A multiple regression model was used to assess the impact of all the promising predictors adjusted for each other. Receiver operating characteristic (ROC) analysis was used to indicate the ability to discriminate between SGA cases and controls.There was an association of serum PlGF levels (OR 0.53 per interquartile range [IQR] increase in PlGF; 95% CI 0.24-1.16), sFlt-1/PlGF ratio (OR 1.42 per IQR increase in sFlt-1/PlGF; 95% CI 1.03-1.96), serum Visfatin levels (OR 0.31 per IQR increase in Visfatin; 95% CI 0.10-0.95) and smoking (OR 4.24; 95% CI 1.10-16.37) with SGA at birth.Associations between SGA and lower PlGF, Visfatin levels as well as increased sFlt-1/PlGF ratio and smoking status were detected which may contribute to predict SGA.

Objective: \ud\udX-linked hypohidrotic ectodermal dysplasia (XLHED), a developmental disorder characterized by malformation of hair, teeth, and sweat glands, results from defective ectodysplasin A1 (EDA1) caused by EDA mutations. Inability to sweat, the major problem of XLHED which can lead to life-threatening hyperthermia, has been shown to be amenable to intrauterine therapy with recombinant EDA1. The aim of this retrospective study was to evaluate the diagnostic accuracy of tooth germ sonography to identify affected fetuses in pregnant women with EDA mutations.\ud\udMethods: \ud\udTooth germ sonography was performed in 38 cases at 10 study sites between gestational weeks 18 and 28. XLHED was diagnosed if fewer than six tooth germs were detected in mandible and/or maxilla. In all subjects, diagnoses were verified postnatally by EDA sequencing and/or clinical findings (standardized clinical assessments of hair, sweating, and dentition; orthopantomograms). Estimated weights of 12 affected male fetuses and postnatal weight gain of 12 boys with XLHED were assessed using appropriate growth charts.\ud\udResults: \ud\udIn 19 of 38 sonografic examinations of 23 male and 13 female fetuses, a prenatal diagnosis of XLHED was made. The diagnosis proved to be correct in 37 cases; one affected male fetus was missed. Specificity and positive predictive value were both 100%. Tooth counting by clinical assessment corresponded well with radiografic findings. We observed no weight deficits of subjects with XLHED in utero but occasionally during infancy.\ud\udConclusions: \ud\udTooth germ sonography is highly specific and reliable in establishing a prenatal diagnosis of XLHED.

Objective\ud \ud In X‐linked hypohidrotic ectodermal dysplasia (XLHED), dysfunction of ectodysplasin A1 (EDA1) due to EDA mutations results in malformation of hair, teeth, and sweat glands. Hypohidrosis, which can cause life‐threatening hyperthermia, is amenable to intrauterine therapy with recombinant EDA1. This study aimed at evaluating tooth germ sonography as a noninvasive means to identify affected fetuses in pregnant carrier women. \ud \ud \ud Methods\ud \ud Sonography, performed at 10 study sites between gestational weeks 18 and 28, led to the diagnosis of XLHED if fewer than six tooth germs were detected in mandible or maxilla. The assessment was verified postnatally by EDA sequencing and/or clinical findings. Estimated fetal weights and postnatal weight gain of boys with XLHED were assessed using appropriate growth charts. \ud \ud \ud Results\ud \ud In 19 of 38 sonographic examinations (23 male and 13 female fetuses), XLHED was detected prenatally. The prenatal diagnosis proved to be correct in 37 cases; one affected male fetus was missed. Specificity and positive predictive value were both 100%. Tooth counts obtained by clinical examination corresponded well with findings on panoramic radiographs. We observed no weight deficits of subjects with XLHED in utero but occasionally during infancy.\ud \ud \ud Conclusion\ud \ud Tooth germ sonography is highly specific and reliable in detecting XLHED prenatally.

Purpose: Oxidative stress is involved in the pathogenesis of hypertensive disorders such as preeclampsia (PE) and associated with the human vitamin E-binding protein afamin. The aim of this study was, therefore, to analyse afamin in the first trimester of patients developing PE later in pregnancy and in control subjects without pregnancy complications. Methods: In this retrospective study, 137 serum samples from the first trimester of pregnancy were analysed in a case–control study design. 39 patients developed PE (10 patients with early-onset and 29 patients with late onset disease) and 98 women had an uncomplicated pregnancy. Mann–Whitney U test, t test, logistic regression and ROC analyses were performed for statistical evaluation. Results: Pregnant women developing PE presented with higher afamin concentrations in the first trimester [median 101.81 mg/L; interquartile range (IQR) 88.94–113.26] compared to subjects with uncomplicated pregnancy (median 86.40; IQR 75.26–96.92; p < 0.001). After adjusting for confounders, the odds ratio per afamin standard deviation was 1.60 (95% CI: 1.04–2.58; p = 0.04). An afamin threshold concentration of 87.8 mg/L exhibited the best sensitivity (79.5%) and specificity (57.1%) in predicting PE. Subgroup analysis of early- and late-onset disease resulted in substantially higher afamin concentrations in women with developing late-onset PE compared to controls (p < 0.001) with an odds ratio per afamin standard deviation of 1.62 (95% CI: 0.98–2.70; p = 0.06). Conclusions: Serum afamin concentrations are elevated in the first trimester among patients developing PE compared to controls. Substantial differences were observed mainly among patients with late-onset PE.

Background In search of potential early biomarkers for timely prediction of gestational diabetes mellitus (GDM), we focused on afamin, a vitamin E–binding protein in human plasma.. Afamin plays a role in anti-apoptotic cellular processes related to oxidative stress and is associated with insulin resistance and other features of metabolic syndrome. During uncomplicated pregnancy its serum concentrations increase linearly. The aim of this study was to investigate the suitability of afamin as early marker for predicting GDM. Methods In a first-trimester cohort from a prospective observational study of adverse pregnancy outcomes we secondarily analyzed afamin concentrations in 59 patients diagnosed with GDM and 51 controls. Additionally, afamin concentrations were cross-sectionally examined in a mid-trimester cohort of 105 women and compared with results from a simultaneously performed oral glucose tolerance test (OGTT). Subgroup analysis comparing patients treated with either insulin (iGDM) or dietary intervention (dGDM) was performed in both cohorts. Patients were recruited at the University Hospital Essen, Germany, between 2003 and 2016. Results Results were adjusted for body-mass-index (BMI) and gestational age. First and mid-trimester cohorts yielded significantly elevated afamin concentrations in patients with pathological OGTT compared to patients without GDM (first trimester cohort: mean, 113.4 mg/l; 95% CI, 106.4–120.5 mg/l and 87.2 mg/l; 95% CI, 79.7–94.7 mg/l; mid-trimester cohort: mean, 182.9 mg/l; 95% CI, 169.6–196.2 mg/l and 157.3 mg/l; 95% CI, 149.1–165.4 mg/l, respectively). In the first-trimester cohort, patients developing iGDM later in pregnancy presented with significantly higher afamin concentrations compared to patients developing dGDM and compared to patients without GDM. In the mid-trimester cohort, mean concentrations of afamin differed significantly between patients with dGDM compared to controls and between patients with iGDM and controls. Patients with iGDM showed only slightly higher afamin levels compared to patients with dGDM. Conclusion Afamin may serve as a new early biomarker for pathological glucose metabolism during pregnancy. Further research is needed to determine afamin’s concentrations during pregnancy, its predictive value for early detection of pregnancies at high risk to develop GDM and its diagnostic role during the second trimester.

Outcome of aneurysmal subarachnoid hemorrhage (SAH) depends strongly on occurrence of symptomatic vasospasm (SV) leading to delayed cerebral ischemia (DCI). Various demographic, radiographic, and clinical predictors of SV have been reported so far, partially with conflicting results. The aim of this study was to analyze the role of patients’ age and sex on SV/DCI risk, especially to identify age and sex-specific risk groups. All patients admitted with acute SAH during a 14-year-period ending in 2016 were eligible for this study. The study endpoints were the following: SV requiring spasmolysis, occurrence of DCI in follow-up computed tomography scans and unfavorable outcome at 6 months (modified Rankin scale > 2). Nine hundred ninety-four patients were included in this study. The majority was female (666; 67%). SV, DCI, and unfavorable outcomes were observed in 21.5, 21.8, and 43.6% of the patients, respectively. Younger age (p

What are the trends in anti-Müllerian hormone (AMH) concentrations from pre-conception to the third trimester of pregnancy in women with polycystic ovary syndrome (PCOS)?Observational study including cross-sectional and longitudinal data analysis. The Beckman Coulter AMH Gen II Assay was used to determine AMH levels longitudinally before pregnancy from 52 women with PCOS and 51 controls during all trimesters. Differences in AMH levels across successive stages of pregnancy were examined with the Wilcoxon signed-rank test for paired values. Linear regression models, adjusted for body-mass index (BMI), gestational and maternal age were used to compare AMH levels of PCOS and controls.AMH levels decreased significantly (all P0.05) from pre-pregnancy level throughout each trimester in women with PCOS and healthy controls. After adjusting for maternal age, gestational age and maternal BMI, AMH levels before pregnancy were 1.89 (95% CI 1.46 to 2.44; P0.0001) times higher among women with PCOS compared with controls (median 7.66 versus 2.67 ng/ml). During the first trimester, AMH levels were 1.61 (95% CI 1.22 to 2.13; P = 0.001) times higher among women with PCOS compared with controls (median 5.33 versus 2.48 ng/ml). Differences in AMH levels between women with PCOS and controls in the second trimester (1.68 times higher; 95% CI 0.94 to 3.01; median: 5.50 versus 2.20 ng/ml) and the third trimester (1.45 times higher; 95% CI 1.01 to 2.07; median: 1.36 versus 1.06 ng/ml) were not statistically significant.These findings indicate a pregnancy-associated AMH-decline independent of pre-pregnancy elevated AMH levels.

Die Insulinresistenz (IR) stellt einen bedeutenden Faktor in der Pathogenese des PCOS dar. Sie scheint Mitverursacher der erhohten Komplikationsraten in der Schwangerschaft zu sein. Der differenzierte Einsatz des Insulinsensitizers Metformin zur Ovulationsinduktion wird durch die Deutschen Gesellschaft fur Gynakologie und Geburtshilfe (DGGG) empfohlen. Eine Therapie in der Schwangerschaft zur Verbesserung des geburtshilflichen Outcomes bei Risikopatientinnen wird den aktuellen Leitlinien aufgrund fehlender Evidenzlage nicht empfohlen, erscheint jedoch unter kritischem Studium der verfugbaren Literatur vielversprechend.

Die Geburtseinleitung ist eine haufige geburtshilfliche Masnahme, die bei angemessener Indikationsstellung Vorteile fur Mutter und Kind erbringen kann. Zur Verfugung stehen sowohl medikamentose als auch mechanische Methoden: PGE1/PGE2 in unterschiedlicher Verabreichungsform und Oxytocin sowie mechanische Instrumente wie der Zervixreifungsballon (CRB Cook®) und Foley-Katheter (Off-label-Use). Ein kombiniertes Einleitungsschema, das mechanische Methoden wie den Zervixreifungsballon impliziert, erscheint effektiv, sicher und fur die Patientinnen sehr zufriedenstellend.

Problem CEACAM1 and CEACAM6 belong to the carcinoembryonic antigen (CEA) family and may play an immune-modulatory role during pregnancy. The aim of the study was to determine the blood serum levels of soluble CEACAM1 and CEACAM6 over the course of pregnancy and postpartum. Method of study CEACAM1 and CEACAM6 levels were determined with customized in-house Sandwich-enzyme-linked immunosorbent assay (ELISA) systems. The study population (n=125) was divided into four groups according to the pregnancy trimester and postpartum. Additionally, samples of non-pregnant women (n=14) were analyzed. Results Serum levels of CEACAM1 in healthy pregnant women were much lower than in non-pregnant women, a difference not seen for CEACAM6. Comparison between the trimesters and postpartum revealed a significant difference in CEACAM1 serum levels. The highest CEACAM1 levels were detected in third trimester. These levels were statistically significantly different from the CEACAM1 levels in first trimester and second trimester. The lowest levels were observed in the second trimester. Postpartum CEACAM1 serum concentrations were slightly lower than in the third trimester, but higher than in the first trimester and significantly higher compared to levels in the second trimester. Conclusion Decreased concentration of CEACAM1 during the pregnancy suggests its regulatory role in the immune tolerance during the course of pregnancy.

Sonographic features of polycystic ovaries consist of elevated antral follicle count or ovarian volume of at least one ovary. The aim of this prospective cross-sectional study was to estimate intraindividual differences in sonographic measurements between the both ovaries of PCOS patients and controls and clinical consequences.Both ovaries of 85 PCOS patients and 48 controls were scanned transvaginally and agreement of sonographic measurements was analyzed using the Bland-Altman method. Concordance correlation coefficients (CCC) were computed.Mean differences between right and left ovaries were 0.24 (95% confidence interval [95% CI]: -0.32-0.80) follicles for AFC and 1.14 (95% CI: 0.34-1.92)ml for OV in the whole study population, 0.14 (95% CI: -0.68-0.96) follicles for AFC and 1.48 (95% CI: 0.39-2.58)ml for OV in PCOS patients, 0.42 (95% CI: -0.19-1.02) follicles for AFC and 0.53 (95% CI: -0.50-1.56)ml for OV in controls. Rather wide limits of agreement and low CCCs (0.7 for all estimates) indicated poor agreement between the ovaries for both sonographic measurements. Width between lower and upper limits of agreement was higher for PCOS patients than for controls. 23.5% of the PCOS patients showed polycystic ovarian morphology (PCOM) only in one ovary, resulting in 9.4% potentially missed PCOS diagnosis according to the Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group.Substantial differences in antral follicle count and ovarian volume between the right and left ovary were observed. In approximately 10% of the PCOS patients in our study only the examination of both ovaries has led to a reliable diagnosis of PCOS. In clinical practice it is recommended to scan both ovaries for a reliable diagnosis of abnormal sonographic findings in PCOM and PCOS diagnosis.

Anti-Mullerian-hormone (AMH) does not seem to fluctuate significantly during the menstrual cycle in healthy women. However, little is known about cycle fluctuations of AMH levels in patients with polycystic ovarian syndrome (PCOS). The purpose of this study was to examine AMH fluctuations during the follicular phase in PCOS patients receiving antiestrogens or recombinant follicle-stimulating hormone (FSH). About 40 PCOS patients diagnosed according to Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group 2003 and 19 controls were prospectively enrolled. PCOS patients received either antiestrogens or recombinant FSH for monoovulation induction and controls received antiestrogens. AMH levels were determined (1) between the 2nd and the 5th day of follicular phase and (2) when a single large dominant follicle ≥18 mm had appeared. Our study shows that AMH levels do not change during follicular development in controls as well as in PCOS patients with AMH levels 5 ng/ml, irrespective of antiestrogen or FSH therapy. However, in PCOS patients with AMH levels ≥5 ng/ml, AMH declines significantly during follicular development (p 0.01). We conclude that AMH levels should be determined in the early follicular phase in PCOS patients without the influence of antiestrogens or exogenous FSH, because these interventions may lower AMH values in patients with high levels.

Oxidative stress seems to be present in patients with polycystic ovary syndrome (PCOS). The aim of this study was to evaluate the correlation between characteristics of PCOS and serum concentrations of afamin, a novel binding protein for the antioxidant vitamin E. A total of 85 patients with PCOS and 76 control subjects were investigated in a pilot cross-sectional study design between 2009 and 2013 in the University Hospital of Essen, Germany. Patients with PCOS were diagnosed according to the Rotterdam ESHRE/ASRM-sponsored PCOS Consensus Workshop Group. Afamin and diagnostic parameters of PCOS were determined at early follicular phase. Afamin concentrations were significantly higher in patients with PCOS than in controls (odds ratio (OR) for a 10 mg/ml increase in afamin=1.3, 95% CI=1.08–1.58). This difference vanished in a model adjusting for age, BMI, free testosterone index (FTI), and sex hormone-binding globulin (SHBG) (OR=1.05, 95% CI=0.80–1.38). In patients with PCOS, afamin correlated significantly with homeostatic model assessment-insulin resistance (HOMA-IR), fasting glucose, BMI, FTI, and SHBG (PP=0.001). No correlation was observed between afamin and androgens, LH, FSH, LH/FSH ratio, antral follicle count, ovarian volume, or anti-Müllerian hormone. In conclusion, elevated afamin values may indicate a state of oxidative stress and inflammation, strongly associated with IR and offering an indicator of impaired glucose tolerance in patients with PCOS irrespective of obesity.

Features of polycystic ovarian syndrome (PCOS) including sonographic aspects, androgens, LH and LH/FSH ratio as well as Anti-Mullerian Hormone (AMH) were evaluated according to their diagnostic potency in detecting different degrees of PCOS severity. 80 women with PCOS diagnosed according to the Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group 2003 and 48 controls were enrolled between 2011 and 2013. PCOS patients fulfilling all Rotterdam criteria were defined as having severe PCOS (n = 59), while patients showing oligo-/amenorrhoea and polycystic ovaries but without hyperandrogenemia were defined as having mild PCOS (n = 21). All patients were treated at the University Hospital of Essen, Germany. The strongest group difference between controls and severe PCOS patients was observed for AMH showing an age-adjusted odds ratio of 2.56 [95 % confidence interval (CI) 2.00–3.27; p

Objective Ovarian quiescence is a common condition during pregnancy. In vitro, follistatin, an antagonist of follicle-stimulating hormone, blocks follicular development at early stages, and its serum levels increase during pregnancy. A possible surrogate biomarker of ovarian arrest during pregnancy is a decrease in anti-mullerian hormone (AMH) levels followed by an increase in these levels on the second day after labor. The purpose of this study was to determine whether follistatin could act as an ovarian-suppressing agent during pregnancy. Follistatin levels and AMH levels were determined at various stages of pregnancy and postpartum. Study design The follistatin and AMH levels of 69 patients were retrospectively determined with the AMH Gen II ELISA and with the Human Follistatin Quantikine ELISA Kit. For 49 patients, samples were available from various trimesters for cross-sectional analysis; for the other 20, samples were available longitudinally from day one before labor and then daily on days 1 through 4 after labor. Statistical significance was determined with linear regression, the Friedman rank sum test and the Wilcoxon–Nemenyi–McDonald–Thompson post hoc test. Results The behavior of follistatin levels was exactly opposite that of AMH levels: Follistatin levels increased significantly during pregnancy and on the first day after parturition but declined afterwards, whereas AMH levels decreased significantly during pregnancy and increased after labor. Conclusion Follistatin can induce ovarian arrest during pregnancy.

Introduction The successful outcome of pregnancy requires adequate immune tolerance. A lack of appropriate tolerance might cause placental dysfunction and pregnancy complications such as preeclampsia (PE). Members of the B7 family play an essential role in maintaining immune tolerance in pregnancy by effecting T cells. Objectives B7-H4 is responsible for the negative regulation of T-cell-mediated immune response and might play an important role in PE. We currently revealed that sB7-H4 is involved in the spontaneous onset of labor and is elevated in early pregnancy in women with a preterm premature rupture of the amniotic membranes (pPROM). Thus, here we investigated the association between PE and sB7-H4 levels. Material and methods Maternal serum levels of sB7-H4 were determined by enzyme-linked immunosorbent assay in first trimester with elevated risk for PE Results In women at elevated risk for PE in first trimester significantly higher levels of sB7-H4 were detected compared to controls (p Conclusion sB7-H4 is involved in the regulation of immune tolerance in women with PE in the third trimester. In the first trimester, sB7-H4 might serve as a predictive immunological biomarker for women who are at elevated risk of developing PE.

Problem To determine the association between maternal soluble B7-H4 (sB7-H4) and the preterm premature rupture of the amniotic membranes (pPROM), the blood serum concentration levels of sB7-H4 were studied. Method of study Maternal serum levels of sB7-H4 were determined with enzyme-linked immunosorbent assay (ELISA) in patients between 11 and 13 weeks’ gestation who later on in the pregnancy developed pPROM (n=21), premature rupture of the amniotic membranes at term (n=18), and in control group (n=27). Results The highest serum levels of sB7-H4 were found in patients who developed pPROM. An OR of 1.39 (95%-CI: 1.17–1.77; P=.002) per ng/mL sB7-H4 indicated an increased risk for developing pPROM, with some predictive ability to discriminate between pPROM cases and controls (AUC=.81). Conclusion Increased serum levels of sB7-H4 in early pregnancy in pPROM cases may indicate the dynamics of the immune response at the feto-maternal interface and, thus, may serve as a predictive marker for this pregnancy complication.

Bei Frauen jenseits der Menopause ist eine genitale Blutung immer ein alarmierendes Zeichen. In jedem vierten Fall liegt ein Malignom zugrunde. Aber vor allem auch die altersbedingte Atrophie, eine Zystitis, eine Endometriumhyperplasie, die Einnahme von Hormonpraparaten oder eine Tamoxifentherapie kommen als Ursache infrage.

PROBLEM: B7-H4 negatively regulates T-cell-mediated immunity and might play an important role in preeclampsia (PE). Here, we have investigated the association between PE and maternal soluble B7-H4 (sB7-H4) serum levels and B7-H4 mRNA expression in the placenta. METHOD OF STUDY: Maternal serum levels of sB7-H4 were determined by enzyme-linked immunosorbent assay in women between 11 and 13 weeks' gestation with elevated risk for PE (n = 48) and women without elevated risk for PE (n = 47). In the third trimester, sB7-H4 serum levels (n = 166) and B7-H4 mRNA expression in the placenta (n = 54) were determined in women with early-onset PE, late-onset PE, fetal growth restriction (FGR), and in healthy controls. RESULTS: In the first trimester, significant higher levels of sB7-H4 were detected in women at elevated risk for PE compared to women without risk for PE (P

Ostrogenabhangige Endometriumkarzinome und die Prakanzerosen betreffen zunehmend junge Frauen mit relativer oder absoluter Hyperostrogenamie. Adipositas und chronische Anovulation stellen nicht nur wichtige Risikofaktoren dar, sondern demarkieren auch ein Kollektiv mit Sterilitatsanamnese und Wunsch nach Organerhalt. Gestagene als potente antiproliferative Agentien an Endometriumzellen werden erfolgreich bei Hyperplasien eingesetzt. Liegen Atypien oder ein Karzinom vor, stellt die Hysterektomie – ggf. nach Entbindung – bei hoher Progressionstendenz der Lasionen das kurative Mittel der Wahl dar. Retro- und prospektive Daten zeigen, dass Organerhalt bei Kinderwunsch unter engmaschiger Kontrolle und hoch dosierter Gestagentherapie moglich ist. Assistierte Reproduktionsverfahren sind oft a priori im betroffenen Kollektiv erforderlich und ermoglichen eine Verkurzung des therapiefreien Intervalls zwischen Komplettremission und Schwangerschaftseintritt. Die medikamentose Therapie ist auch in der palliativen Situation indiziert. Neben Gestagenen und Tamoxifen stehen mit Fulvestrant und GnRH-Analoga-gekoppelten Zytostatika vielversprechende und nebenwirkungsarme Optionen zur Verfugung.

Ziel: Evaluation der diagnostischen Wertigkeit der hochauflösenden B-Mode-Sonographie zum Nachweis von Mikrokalk und mikrokalkassoziierten Herdbefunden bei Patientinnen mit BI-RADS-4a-Läsionen. Patientinnen und Methode: Bei 40 Patientinnen wurden eine Röntgenmammographie und eine B-Mode-Sonographie mit 13 MHz durchgeführt. Untersucht wurden: mit Röntgenmammographie: Ausdehnung der Mikrokalkareale und Darstellbarkeit assoziierter Herdbefunde; mit Ultraschall: Sensitivität des Mikrokalknachweises, Qualität der Darstellung, Ausdehnung der Mikrokalkareale, Darstellbarkeit assoziierter Herdbefunde und Durchführbarkeit einer ultraschallgestützten Biopsie. Ergebnisse: In der Röntgenmammographie betrug die mittlere Ausdehnung von Mikrokalkarealen 28 ± 21 mm. Sensitivität, Spezifität, positiver (PPV) und negativer prädiktiver Wert (NPV) und die Nachweisgenauigkeit mikrokalkassoziierter Herdbefunde betrugen 61,5, 57,9, 50, 45,8 und 47,5%. Die B-Mode-Sonographie erreichte eine Sensitivität von 100%. Die mittlere Ausdehnung der Mikrokalkareale betrug sonographisch 7 ± 3 mm und war damit signifikant geringer (p < 0,01). Es ergaben sich für Sensitivität, Spezifität, PPV, NPV und die Nachweisgenauigkeit 14,3, 84,2, 50, 47,1 und 47,5%. Die Durchführung einer ultraschallgestützten Biopsie erschien bei 22 (55%) Patientinnen möglich. Schlussfolgerung: Die Hochfrequenz-B-Mode-Sonographie ermöglicht einen hoch sensitiven Nachweis von Mikrokalk bei BI-RADS-4a-Läsionen und lässt eine ultraschallgestützte Biopsie bei etwa der Hälfte der Patientinnen durchführbar erscheinen.

Background In the last few years, the therapy of cervical carcinoma has progressed substantially due to the use of simultaneous platinum- containing radiochemotherapy. However, there are no data which evaluate an individualized treatment adapted to tumor biology, in spite of the fact that patients show remarkably different responses to chemotherapy. Therefore this preclinical phase I study aims at finding therapeutic alternatives to the current cytostatic drugs to treat cervical carcinoma. Material and methods In a tumor chemosensitivity assay, 8 drugs were tested on freshly isolated tumor cells of 16 patients [carbo- and cisplatin, topotecan, paclitaxel as well as the 2 tyrosine kinase inhibitors imatinib (Glivec) and gefitinib (Iressa (R) ) and the 2 monoclonal antibodies cetuximab (Erbitux) and trastuzumab (Herceptin (R) )]. Results Overall the test was evaluable for 16 specimens (100%). Ten of 15 tumor samples (66.6%) were sensitive to imatinib. A sensitive therapeutic response could be demonstrated in all tested FIGO stages. An interindividual comparison could establish sensitivity to cetuximab in 12.5% of cases, to gefitinib in 6.25%, to trastuzumab in 6.6%, to cisplatin in 13.3%, to carboplatin in 7.6%, to paclitaxel in 93.8% and to topotecan in 25%. Conclusion Imatinib seems to be an efficacious therapeutic option for patients with cervical carcinoma, independently of tumor subtype.