Christel Eckmann-Scholz

DNA-Methylation Profiling of Fetal Tissues Reveals Marked Epigenetic Differences between Chorionic and Amniotic Samples

Epigenetic mechanisms including DNA methylation are supposed to play a key role in fetal development. Here we have investigated fetal DNA-methylation levels of 27,578 CpG loci in 47 chorionic villi (CVS) and 16 amniotic cell (AC) samples. Methylation levels differed significantly between karyotypically normal AC and CVS for 2,014 genes. AC showed more extreme DNA-methylation levels of these genes than CVS and the differentially methylated genes are significantly enriched for processes characteristic for the different cell types sampled. Furthermore, we identified 404 genes differentially methylated in CVS with trisomy 21. These genes were significantly enriched for high CG dinucleotid (CpG) content and developmental processes associated with Down syndrome. Our study points to major tissue-specific differences of fetal DNA-methylation and gives rise to the hypothesis that part of the Down syndrome phenotype is epigenetically programmed in the first trimester of pregnancy.

Adding folate to the contraceptive pill: a new concept for the prevention of neural tube defects

Although it is proven for a long time that folic acid supplementation in the periconceptional period can prevent neural tube defects (NTDs) effectively, all measures taken so far including food fortification and awareness campaigns so far had only limited success. Since more than 50% of the pregnant women in Europe get pregnant after they have used oral contraceptives (OCs) before, OCs are an ideal vehicle to increase not only the awareness for periconceptional folate application, but they can also help to bridge the gap between the recognition of a pregnancy and closure of the neural tube which is before day 26. In order to reach a truly protective folate level at the critical time period during pregnancy, now OCs are available which contain metafolin. The availability of this innovative type of OC will significantly reduce the number of NTDs.

Integration and Validation of Hysteroscopy Simulation in the Surgical Training Curriculum

OBJECTIVE The primary objective of our study was to test the construct validity of the HystSim hysteroscopic simulator to determine whether simulation training can improve the acquisition of hysteroscopic skills regardless of the previous levels of experience of the participants. The secondary objective was to analyze the performance of a selected task, using specially designed scoring charts to help reduce the learning curve for both novices and experienced surgeons. DESIGN The teaching of hysteroscopic intervention has received only scant attention, focusing mainly on the development of physical models and box simulators. This encouraged our working group to search for a suitable hysteroscopic simulator module and to test its validation. We decided to use the HystSim hysteroscopic simulator, which is one of the few such simulators that has already completed a validation process, with high ratings for both realism and training capacity. As a testing tool for our study, we selected the myoma resection task. We analyzed the results using the multimetric score system suggested by HystSim, allowing a more precise interpretation of the results. SETTING Between June 2014 and May 2015, our group collected data on 57 participants of minimally invasive surgical training courses at the Kiel School of Gynecological Endoscopy, Department of Gynecology and Obstetrics, University Hospitals Schleswig-Holstein, Campus Kiel. PARTICIPANTS The novice group consisted of 42 medical students and residents with no prior experience in hysteroscopy, whereas the expert group consisted of 15 participants with more than 2 years of experience of advanced hysteroscopy operations. RESULTS The overall results demonstrated that all participants attained significant improvements between their pretest and posttests, independent of their previous levels of experience (p < 0.002). Those in the expert group demonstrated statistically significant, superior scores in the pretest and posttests (p = 0.001, p = 0.006). Regarding visualization and ergonomics, the novices showed a better pretest value than the experts; however, the experts were able to improve significantly during the posttest. These precise findings demonstrated that the multimetric scoring system achieved several important objectives, including clinical relevance, critical relevance, and training motivation. CONCLUSION All participants demonstrated improvements in their hysteroscopic skills, proving an adequate construct validation of the HystSim. Using the multimetric scoring system enabled a more accurate analysis of the performance of the participants independent of their levels of experience which could be an important key for streamlining the learning curve. Future studies testing the predictive validation of the simulator and frequency of the training intervals are necessary before the introduction of the simulator into the standard surgical training curriculum.

3-D ultrasound imaging of a prenatally diagnosed Beckwith-Wiedemann syndrome.

Imprinting disorders resulting in different syndromes such as Beckwith–Wiedemann syndrome (BWS), Silver–Russel syndrome or Angelman syndrome should be of great interest in prenatal diagnosis with respect to counseling the patients. BWS is an overgrowth syndrome associated with congenital malformations such as macroglossia, abdominal wall defects and increased incidence of embryonic tumors. The disorder has been linked to the chromosomal region 11p15.5, a region that harbours two clusters of imprinted genes (IC1 and IC2). With the exception of CDKN1C gene mutations, all alterations result from defects of the epigenetic regulation of 11p15 gene expression [1]. We present a fetus where the prenatally suspected diagnosis of BWS was confirmed postnatally by karyotyping. The pregnancy of our patient was complicated by unclear maternal anaemia, polyhydramnios and gestational diabetes. Prenatal ultrasound at 28 weeks suggested the fetus to suffer from BWS. Postnatal molecular analysis showed hypomethylation of imprinting centre 2 in the chromosomal region 11p15 thereby confirming the prenatal diagnosis. Ultrasound findings with a 3-D ultrasound picture showing the characteristic features of the fetus at 28 weeks of gestation are presented. We report on a 30-year-old gravida VII para II. The proposita is mentally retarded. The family history is suspicious for a major problem with mental retardation through at least three generations. The patient has an 11-year-old daughter with mild mental retardation and an 11-month-old son who is reported to be healthy so far. All pregnancies result from different fathers, the recent father is slightly mentally retarded as well. Four abortions are documented. At 28 weeks of gestation, the patient was sent to our hospital with an unclear anaemia Ultrasound findings of the fetus revealed a hydropic placenta, large abdominal circumference [95th percentile, hepatomegaly, polyhydramnios (Fig. 1a, b) and normal ultrasound Doppler parameters without signs of anaemia in the mid cerebral artery. A 3-D image gave a typical aspect with macroglossia, thus a BWS was suspected (Fig. 2). Pregnancy was complicated by unclear maternal anemia and polyhydramnios (Hb 7, 4 g/dl). Gestational diabetes (BMI [30) and a Faktor V-Leiden mutation (heterozygous) were diagnosed. The persistent anaemia was treated with transfusions, diabetes needed treatment with insulin. At 34 ? 0 weeks of pregnancy early onset of labour could not be stopped resulting in a caesarean section. The birth weight of the male newborn was 4,200 g (1.2 kg above the 97 percentile), birth length was 55 cm (4 cm above the 97 percentile) and head circumference was 35 cm (97 percentile) revealing severe macrosomia. Apgar was 6/7/8 and umbilical cord pH was 7.26. Due to the family history a karyotyping of the patient was initiated already at 28 weeks with the idea that chromosome 11 might be abnormal. As the critical region for BWS is located on chromosome 11 and the patient revealed an unclear anaemia, a possible reason was suspected to be a mutation in this region. Chromosome banding analysis revealed the mother to carry regular female (46, XX) karyotype, postnatal clinical findings in the male newborn showed typical dysmorphic characteristics for BWS. Cytogenetic analysis on blood lymphocytes revealed a C. Eckmann-Scholz (&) W. Jonat Universitatsklinikum Schleswig-Holstein, Frauenklinik Campus Kiel, Arnold-Heller-Str.24, Haus 3, 24105 Kiel, Germany e-mail: christel.eckmann@uksh.de

Safety and economical innovations regarding surgical treatment of fibroids

Abstract Uterine leiomyomas are the most frequent benign tumors of the female genital tract. Fibroids are associated with a variety of clinical problems, e.g. bleeding disorders, bulk-related symptoms or infertility. For women wishing to preserve their uterus, fibroids can be surgically removed by hysteroscopy, laparoscopy or laparotomy. The purpose of our review is to show that hysterectomy offers the only definitive solution. The indication for treatment has to be taken carefully after weighing up alternative treatment methods, such as expectant management, medical treatment or interventional radiologic methods, and after obtaining informed consent. The optimal method of treatment takes into account the patient’s interests and wishes and the practical feasibility in the clinical setup. Surgical skills and experience play an important role as surgical procedures on the uterus are not without risk and can lead to severe complications. The decision to operate anticipates an improvement of the initial situation; therefore, the ideal surgical approach is of utmost importance.

Aurora kinase inhibitor AZD1152 has an additional effect of platinum on a sequential application at the human ovarian cancer cell line SKOV3

PurposeThe treatment of ovarian tumors is carried out with platinum medicine which can lead to incompatibilities or resistances. Thus, it is of great interest to check new medicine suitability for its application. AZD1152 is an Aurora kinase inhibitor predominantly works against Aurora kinase B involved in the chromosome segregation. Cells become polyploidy and reduce the proliferation by this impairment. To investigate whether AZD1152, may play a role in the treatment of ovarian carcinoma we serving it to the cisplatinum-resistant cell line SKOV3 alone and in combination with platinum.MethodsWe look at the proliferation, the ploidy, the phases of cell cycle and the apoptosis activity of the cells.Results and conclusionWe could show that the combination of both medicines in the preclinical experiment produces a working advantage.

Pathologic ultrasound findings and risk for congenital anomalies in teenage pregnancies

Objective: To detect the number and diagnosis of fetal malformations in teenage pregnancies and to evaluate whether low maternal age or epigenetic factors have an influence on this issue. Materials and methods: We performed a retrospective analysis in a single center for prenatal diagnostics in Northern Germany. We searched our electronic databank for all pregnancies with maternal age under 20 years. Pregnancy outcome and fetal malformations are described. Results: The incidence of teenage pregnancies in our study was 638 patients (4.4%). The total of fetal malformations in teenage pregnancies was 51(8.3%). Chromosomal aberrations were found in 5 cases (0.9%). 9 cases of fetal gastroschisis as one of the most frequent malformations were followed up and neonatal outcome was uneventful. Furthermore we found 16 cases with different heart defects and 30 cases with other malformations. Patients’ body mass indices showed an increase over the years and nicotine consumption was testified in more than 50% of the patients. Conclusions: Teenage pregnancies are at risk for fetal non-chromosomal and chromosomal abnormalities. As these might be detected by first-trimester-screening prenatal care in teenage pregnancies should include at least early ultrasound examination. Epigenetic factors may play a key role in certain fetal malformations.

Normal prenatal ultrasound findings in a case with de novo mosaic small supernumerary marker chromosome 18 - how to counsel?

Introduction. We report on a prenatally diagnosed de novo small supernumerary marker chromosome (sSMC) derived form chromosome 18. Molecular cytogenetic studies led to information about the clinical relevance of the sSMC-induced chromosomal imbalance. As prenatal ultrasound was normal, detailed information with respect to prenatal counseling of the parents was necessary. In general, detection of an sSMC requires as much information on the exact genetic content with its possible impact on the phenotype as achievable. Material and methods. Amniocentesis was performed in a 37-year-old Gravida IV Para II with a history of an induced abortion due to a prenatally diagnosed trisomy 21. Fluorescence in situ hybridization quick test gave hint on a possible mosaic trisomy 18, whereas the conventional banding cytogenetic analysis revealed an sSMC. The amount of euchromatin was estimated to be less than 5 MB. Conclusions. sSMC are rare, being present in less than 0.08% of all pregnancies. Going together with an abnormal ultrasound, counseling of the parents is relatively easy to perform. In cases of normal prenatal ultrasound, profound knowledge about the surplus genetic content is necessary for the estimation of the fetal outcome prognosis. In the present case, detailed molecular cytogenetics techniques led the parents to continue the pregnancy.

Chromosomal mosaicisms in prenatal diagnosis: correlation with first trimester screening and clinical outcome.

Abstract Objective: To investigate the outcome of pregnancy after detection of chromosomal mosaicism and to determine the correlation between human chorionic gonadotropin (free β-HCG) and pregnancy-associated plasma protein-A (PAPP-A) levels from first-trimester-screening with pregnancy outcome. Methods: In a single-center, retrospective survey of the results of prenatal diagnostics performed between January 2000 and March 2011, we identified a total of 40 pregnancies with chromosomal mosaicism. Clinical characteristics and results of first-trimester screening, as well as the outcome of these cases, are described. Results: Out of 40 cases, 21 were defined as confined placental mosaicism, 10 classified as true mosaicism and nine were not classifiable cases. Nuchal translucency (NT) was ≥2.5 mm in 8/30 cases with respective measurements. PAPP-A levels were ≤0.4 MoM in 9/26 cases, with respective measurements, two of them being newborns with growth restriction. Remarkably, in pregnancies of all four children born with severe growth retardation, <3rd percentile PAPP-A levels were below 0.52 MoM. Conclusions: Our observations show mosaic pregnancy outcomes to be very heterogeneous. Nevertheless, a combination of low PAPP-A and interpretation of chromosomal mosaicism might identify pregnancies at particular risk for fetal growth restriction.

Perinatal management of pregnancies with severe fetal heart defects and epigenetic aspects

Objective: To describe pregnancies with severe fetal heart defects (CHD) with respect to perinatal complications and management. To discuss epigenetic factors with respect to maternal body mass index (BMI) and assisted reproduction treatment (ART). Methods: We performed a retrospective analysis in a single centre for prenatal diagnostics. Data were collected with respect to pre- and postnatal diagnoses of CHD, preterm labour and deliveries, maternal risk factors and postnatal outcome. Results: Between 2009 and 2011 we treated 116 patients with severe fetal heart defects. Prenatal diagnoses were: Hypoplastic left heart syndrome (HLHS) in 50 fetuses (43.1%), conotruncal heart defects (CTM) in 43 (37.1%), atrial ventricular septal defects in eight cases (7.8%).There were 11 (9.9%) twin pregnancies. Premature labour occurred in 11.2%, premature deliveries 12.9%. Nine pregnancies (7.8%) were achieved by assisted reproduction treatment (ART). A body mass index (BMI) > 25 occurred in 54.3% with 3% morbid obesity. Advanced maternal age >35 was found in 33.5%. Accuracy of the prenatal diagnosis was 97%. Conclusions: Patients with ART pregnancies may be referred to fetal echocardiography. Maternal obesity poses a diagnostic problem, the incidence of CTM may be higher due to epigenetic factors. This requires further studies. As premature labour and delivery is a frequent complication, perinatal management of these pregnancies must be reserved to specialized centers.