DEGUM Recommendations on Diagnostic Puncture in Prenatal Medicine. / Empfehlungen der DEGUM zu diagnostischen Punktionen in der Pränatalmedizin.

Diagnostic puncture (amniocentesis, chorionic villus sampling, and fetal blood sampling) is an essential part of prenatal diagnostics and the only established and sufficiently scientifically evaluated possibility of diagnosing genetic diseases from pregnancy-specific cells. The number of diagnostic punctures in Germany, as in other countries, has fallen significantly. This is largely due to the introduction of first-trimester screening with further detailed ultrasound examination of the fetus and the analysis of cf-DNA (cell-free DNA) from maternal blood (noninvasive prenatal test - NIPT). On the other hand, knowledge about the incidence and appearance of genetic diseases has increased. The development of modern molecular genetic techniques (microarray and exome analysis) makes a differentiated investigation of these diseases increasingly possible. The requirements for education and counseling regarding these complex correlations have thus increased. The studies performed in recent years make it clear that diagnostic puncture performed in expert centers is associated with a low risk of complications. In particular, the procedure-related miscarriage risk hardly differs from the background risk for spontaneous abortion. In 2013, the Section of Gynecology and Obstetrics of the German Society for Ultrasound in Medicine (DEGUM) published recommendations on diagnostic puncture in prenatal medicine 1. The developments described above and new findings in recent years make it necessary to revise and reformulate these recommendations. The aim of this review is to compile important and current facts regarding prenatal medical puncture (including technique, complications, genetic examinations). It is intended to provide basic, comprehensive, and up-to-date information on diagnostic puncture in prenatal medicine. It replaces the publication from 2013 1.

Basic Gynecologic Ultrasound Examination (Level I): DEGUM, ÖGUM, and SGUM Recommendations. / Qualitätsanforderungen an gynäkologische Ultraschall-Untersuchungen der DEGUM-Stufe I: Empfehlungen der DEGUM, ÖGUM und SGUM.

Ultrasound has become an essential diagnostic tool in gynecology, and every practicing gynecologist must be able to differentiate normal from pathologic findings, such as benign or malignant pelvic masses, adnexal torsion, pelvic inflammation disease, endometriosis, ectopic pregnancies, and congenital uterine malformations at least on a basic level. A standardized approach to the correct settings of the ultrasound system, the indications for gynecologic ultrasound investigations, and the sonographic appearance of normal anatomy and common pathologic findings in the standard planes are important prerequisites for safe and confident clinical management of gynecologic patients. Based on current publications and different national and international guidelines, updated DEGUM, ÖGUM, and SGUM recommendations for the performance of basic gynecologic ultrasound examinations were established.

Updated DEGUM Quality Requirements for the Basic Prenatal Screening Ultrasound Examination (DEGUM Level I) between 18 + 0 and 21 + 6 weeks of gestation. / Aktualisierte Qualitätsanforderungen an die Ultraschall- Screeninguntersuchung in der pränatalen Basisdiagnostik (=DEGUM-Stufe I) im Zeitraum 18 + 0 bis 21 + 6 Schwangerschaftswochen.

A precondition for the early detection of fetal abnormalities is the high quality of prenatal basic ultrasound (screening examination). The objective of ultrasound screening is the recognition of abnormal fetal growth and fetal anatomical anomalies. The prenatal detection of fetal abnormalities enables detailed prenatal counselling of parents, improved care at birth and potentially a reduction in morbidity and mortality. In the guidelines for maternity care in Germany ("Mutterschaftsrichtlinien"), the performance of basic ultrasound in pregnancy is not clearly defined. The required image documentation includes a few biometric measurements only. Therefore, adherence to a standard technique and the possibility of audit are limited, thus not necessarily resulting in high screening quality. In this update of the DEGUM quality requirements for level I screening ultrasound examination between 18 + 0 and 21 + 6 weeks of gestation, the required parameters, standard planes and required documentation are described in detail. The greater experience of gynecologists in the field of sonographic screening examinations and the use of a modern ultrasound technique allow improvement of the screening quality. This will improve the standard of basic ultrasound screening. Due to the enhanced standard of the DEGUM I examination, more pregnant women may benefit from a detailed ultrasound examination and specialized therapy in DEGUM level II and III centers. The required fetal structures are described in detail. This update of the requirements for level I DEGUM basic ultrasound examination between 18 + 0 and 21 + 6 weeks of gestation goes far beyond the guidelines for maternity care in Germany (the "Mutterschaftsrichtlinien") thereby elevating standards.

DEGUM, ÖGUM, SGUM and FMF Germany Recommendations for the Implementation of First-Trimester Screening, Detailed Ultrasound, Cell-Free DNA Screening and Diagnostic Procedures. / Empfehlungen der DEGUM, der ÖGUM, der SGUM und der FMF Deutschland zum Einsatz von Ersttrimester-Screening, früher Fehlbildungsdiagnostik, Screening an zellfreier DNA (NIPT) und diagnostischen Punktionen.

First-trimester screening between 11 + 0 and 13 + 6 weeks with qualified prenatal counseling, detailed ultrasound, biochemical markers and maternal factors has become the basis for decisions about further examinations. It detects numerous structural and genetic anomalies. The inclusion of uterine artery Doppler and PlGF screens for preeclampsia and fetal growth restriction. Low-dose aspirin significantly reduces the prevalence of severe preterm eclampsia. Cut-off values define groups of high, intermediate and low probability. Prenatal counseling uses detection and false-positive rates to work out the individual need profile and the corresponding decision: no further diagnosis/screening - cell-free DNA screening - diagnostic procedure and genetic analysis. In pre-test counseling it must be recognized that the prevalence of trisomy 21, 18 or 13 is low in younger women, as in submicroscopic anomalies in every maternal age. Even with high specificities, the positive predictive values of screening tests for rare anomalies are low. In the general population trisomies and sex chromosome aneuploidies account for approximately 70 % of anomalies recognizable by conventional genetic analysis. Screen positive results of cfDNA tests have to be proven by diagnostic procedure and genetic diagnosis. In cases of inconclusive results a higher rate of genetic anomalies is detected. Procedure-related fetal loss rates after chorionic biopsy and amniocentesis performed by experts are lower than 1 to 2 in 1000. Counseling should include the possible detection of submicroscopic anomalies by comparative genomic hybridization (array-CGH). At present, existing studies about screening for microdeletions and duplications do not provide reliable data to calculate sensitivities, false-positive rates and positive predictive values.

Pentaerythrityltetranitrate (PETN) improves utero- and feto-placental Doppler parameters in pregnancies with impaired utero-placental perfusion in mid-gestation - a secondary analysis of the PETN-pilot trial.

AIM: In pregnancies complicated by impaired utero-placental perfusion, pentaeritrithyltetranitrate (PETN) has been shown to reduce the risk of severe fetal growth restriction (FGR) and perinatal death by 39%. The effect is most likely related to the vasodilatative influence of PETN. To assess its impact on utero-placental and fetal perfusion, we analyzed the Doppler parameters measured during the PETN pilot-trial. METHODS: One hundred and eleven pregnancies presenting impaired utero-placental resistance at mid-gestation were included in the trial. Fifty-four women received PETN, while 57 received a placebo. Doppler velocimetry measurements were monitored biweekly. Statistical analysis was performed using a mixed linear model. RESULTS: Within the first week of treatment, the mean pulsatility index (PI) of the uterine artery (UtA) dropped more prominently in the PETN group [-0.20, 95% confidence interval (CI): -0.34 to -0.05, P=0.007). The adjusted relative risk (RR) for abnormal cerebro-placental ratio (CPR) was significantly reduced by PETN [RR 0.412 (95% CI: 0.181-0.941)]. Kaplan-Meier analysis demonstrates the postponement of absent end-diastolic flow (AED), absent or reverse end-diastolic flow (ARED), brain sparing and abnormal cerebroplacental ratio (CPR) in the PETN group. CONCLUSION: The demonstrated effect of PETN on utero-placental and feto-placental perfusion strengthens the evidence for a positive impact in pregnancies complicated by impaired placental perfusion and might explain the effect on neonatal outcome, as shown in the PETN-pilot trial.

Erratum to: Impact of the nitric oxide-donor pentaerythrityl-tetranitrate on perinatal outcome in risk pregnancies: a prospective, randomized, double-blinded trial.

On page 1 "adjusted relative risk (RR)" should be changed to "adjusted odds ratio (OR)". On page 1, 3 and in the table head of table 2 "adjusted RR" should be changed to "adjusted OR". On page 3 "Mantel-Haenszel estimates of relative risk" should be changed to "Mantel-Haenszel estimates of odds ratios". In Table 2, caption b "Mantel-Haenszel estimate of relative risk" should be changed to "Mantel-Haenszel estimate of odds ratio".

Impact of the nitric oxide-donor pentaerythrityl-tetranitrate on perinatal outcome in risk pregnancies: a prospective, randomized, double-blinded trial.

Intrauterine growth restriction (IUGR) and preeclampsia (PE) are associated with impaired placentation. Patients who are at risk of developing both these disorders can be identified by abnormal uterine artery Doppler at mid-trimester pregnancy. Nitric oxide (NO)-donors like pentaerithrityl-tetranitrate (PETN) reduce the impedance in the uteroplacental vessels and possess protecting effects on the endothelium. We tested the effectiveness of the NO-donor PETN for secondary prevention of IUGR, PE, and preterm birth in pregnancies at risk. Some 111 women who presented with abnormal placental perfusion at 19-24 weeks of gestation (w.o.g.) were included into a prospective, randomized, placebo-controlled, double-blinded study. The primary endpoint was IUGR and/or perinatal death. Secondary endpoints were preterm birth, PE, and placental abruption. Pentaerithrityl-tetranitrate significantly decreased the risk for IUGR and/or perinatal death [adjusted odds ratio (OR) 0.410; 95% confidence interval, CI, 0.184-0.914] and for IUGR (adjusted OR 0.436; 95% CI 0.196-0.970). Preterm birth before 32 w.o.g. (adjusted OR 0.204; 95% CI 0.052-0.801) was reduced, but not the risk for PE. No placental abruption occurred in the PETN, but five occurred in the placebo group [corrected]. These results suggest that secondary prophylaxis of adverse pregnancy outcome might be feasible in pregnancies exhibiting abnormal placentation using PETN.

Fetal heart rate variability in growth restricted fetuses.

Intrauterine growth restriction (IUGR) remains a major problem in perinatal medicine because of the variety of its underlying causes and the prediction of its outcome. Characteristics of heartbeat interval patterns are associated with neuro-vegetative and humoral regulatory processes. Fetal magnetocardiography allows non-invasive assessment of these processes with high precision throughout the second half of gestation. The aim of our study was the analysis of linear and non-linear parameters of fetal heart rate fluctuations to distinguish between IUGR fetuses and a cohort of normal subjects, both pre-selected from heart-rate traces representing a quiet state of activity in the third trimester of gestation.

The impact of fetal renal pelvic diameter on postnatal outcome.

OBJECTIVES: To determine thresholds for the fetal renal pelvic anterior-posterior diameter (APD) predicting postnatal clinically relevant pelvicaliceal dilatation. METHODS: One hundred and forty-eight infants whose prenatal sonography had identified an isolated uni- or bilateral fetal APD of > or = 4 mm before 33 and/or > or = 7 mm after 33 weeks' gestational age were investigated postnatally. On the basis of postnatal ultrasound examination, these infants were grouped according to the Society for Fetal Urology Grading System: no pelvic dilatation (n = 38); only pelvic dilatation (n = 59); pelvicaliceal dilatation (n = 33); pelvicaliceal and ureter dilatation (n = 18). RESULTS: Fetal pyelectasis of 7 mm was 89.3% sensitive and 78.9% specific < 33 weeks, and > or = 33 weeks pyelectasis of 10 mm was 88.4% and 78.6% in predicting subsequent postnatal pelvicaliectasis, respectively. Using a threshold of 4 mm < 33 weeks and 7 mm > or = 33 weeks yielded a sensitivity of 100% and a specificity of 18.7% and 47.8%, respectively. The median APD (range) at > or = 33 weeks was 19 mm (9-36 mm) in patients requiring surgery and 13 mm (7-21 mm) in conservatively treated patients (p = 0.001). Thirteen of fourteen patients with APD > or = 19 mm underwent surgery. CONCLUSION: Women with ultrasonographically detected prenatal fetal pelvic dilatation of > or = 4 mm before 33 weeks and of > or = 7 mm from 33 weeks onwards of gestation should have repeated prenatal ultrasound scans and a detailed postnatal evaluation. The dilatations of an APD > 4 mm before 33 weeks, which have disappeared at the post-33-week scan need no further investigation in the postnatal period.

Prenatal evidence of left-right asymmetries in auditory evoked responses using fetal magnetoencephalography.

Auditory evoked responses between right- and left-hemispheric derivations were investigated in 53 recordings from fetuses in the third trimester using fetal magnetoencephalography (fMEG). The side-different latency development of the component P2pm suggests an earlier maturation of certain right than homologous left hemispheric brain areas during fetal brain development.

A case report of body stalk anomaly complicating a twin pregnancy.

The body stalk anomaly is described as a maldevelopment during embryonic folding in the third week after conception, resulting in a severe defect of the fetal abdominal wall. The extra-embryonic coelom fails to obliterate and parts of the fetal body remain in an exo-coelomic situation. Reports on its occurrence in multiple pregnancies have in the past focused on concordance between monozygotic twins. We report on a case of a twin pregnancy after fertility treatment that was complicated by a Body Stalk Anomaly in one of the fetuses with a positive neonatal outcome of the unaffected twin.

Maternal and fetal side effects of tocolysis using transdermal nitroglycerin or intravenous fenoterol combined with magnesium sulfate.

OBJECTIVE: To compare the maternal and fetal side effects of transdermal nitroglycerin and intravenous fenoterol combined with magnesium sulfate in a prospective randomised study. STUDY DESIGN: Fifty pregnant women between 27 and 35 weeks of gestation with preterm labour were treated with either nitroglycerin (0.4-0.8 mg/h) or fenoterol (60 - 120 microg/h). Outcome parameters were (1) the effects on fetal and maternal heart frequency (FHF/MHF) and blood pressure, and (2) subjective experiences of adverse effects assessed by utilising a questionnaire. RESULTS: In the fenoterol group, elevated mean MHF, FHF and systolic blood pressure were recorded compared to nitroglycerin. Fewer maternal side effects were reported in the nitroglycerin group. Palpitations (82%), tremor (68%) and restlessness (64%) were most common in the fenoterol group (two drop-outs), whereas nitroglycerin caused headaches in 71% of the cases (four drop-outs). CONCLUSION: Transdermal nitroglycerin appears to be a safe therapy for the mother and fetus and is a promising new option for the treatment of preterm labour.

Fetal magnetocardiography in the investigation of congenital heart defects.

OBJECTIVES: To investigate the changes of the fetal magnetocardiography (FMCG), a new noninvasive diagnostic tool in the analysis of electrophysiologic changes of the heart, in cases of congenital heart defect (CHD). METHODS: The FMCG was analysed and compared to the postnatal ECG in eight cases of CHD: atrial septal defect ASDII (three cases), a combination of atrioventricular-septal-defect (AVSD) and Tetralogy of Fallot (TOF) (one case ), complete transposition of great arteries (d-TGA) (two cases), coarctation of aorta (COA) (one case), stenosis of the pulmonary artery (PS) and right ventricular hypoplasia (one case). RESULTS: (1) The following FMCG changes were observed: a split R-wave (AVSD/TOF, ASDII), prolongation of QRS complex (COA, PS). (2) The notch of the R-wave could not be observed in the newborn with AVSD/TOF. (3) Neither the fetal FMCG nor the neonatal ECG revealed any changes in the cases of d-TGA. (4) All other neonatal ECGs were corresponding to the FMCG. CONCLUSIONS: The FMCG can unearth changes of the cardiac electrophysiologic activity in the case of CHD. The method provides additional information concerning the effect of a CHD on the cardiac conductory system. As in the neonate, the FMCG changes do not reflect the severity of the CHD. FMCG cannot serve as a primary diagnostic tool in the case of CHD as compared to echocardiography.

Cultivation of fetal erythroid precursors from maternal blood: isolation and characterization by PCR and FISH.

Cultivation of fetal progenitor cells from maternal blood offers the opportunity to produce sufficient fetal cells for prenatal molecular genetic and cytogenetic analysis. For in vitro cultivation, 10 ml of blood was collected from 22 women carrying a male fetus. After triple-density gradient centrifugation, the mononucleated cells were cultivated for 10 to 14 days in special hematopoietic growth medium. Red and white colored cell colonies were individually collected by micromanipulation. A representative sample from each colony was characterized by chromosome Y-specific polymerase chain reaction (PCR) systems. The remaining cells of the Y-positive colonies were used to perform chromosome preparations and fluorescence in situ hybridization (FISH) to detect XY-positive interphase nuclei and metaphases. Y-positive signals could be detected in 15 (68%) of the 22 analyzed blood samples. With SRY PCR 10.5% (40/379) of the collected red colonies were determined to be of fetal origin and 6.1% (32/522) of the colonies analyzed by amelogenin PCR were Y-positive. All collected white cell colonies were Y-negative. FISH analyses of PCR-positive colonies revealed that less than 30% of the cells within a colony are of fetal origin and reflect more precisely the actual situation within a single colony. Moreover the successful preparation of fetal metaphases in non-invasive prenatal diagnosis is presented.

Fetal magnetocardiography: development of the fetal cardiac time intervals.

OBJECTIVES: To analyse the physiologic development of fetal cardiac time intervals throughout gestation using fetal magnetocardiography (FMCG). METHODS: FMCG data of 163 uncomplicated pregnancies (19th and 42nd gestational week) were analysed. Mean value, standard deviation, minimum and maximum of the duration of the P-wave, the QRS-complex, the PR and the QT-interval were plotted against gestational age. RESULTS: QRS-complex, P wave and QT-interval showed a significant lengthening between the 20th and 42nd gestational week. The mean of the QRS complex raised from 36+/-4.7 ms (week 21-24) up to 48+/-5.2 ms (> or =37th week), (p=0.0001). The mean of the P-wave was between 47+/-5.9 ms (week 21-24) and 53+/-9.5 ms (> or =37th week), (p=0.05) and the mean of the QT-interval was 198+/-18 ms (week 21-24) and increased up to 244+/-23.9 ms (> or =37th week), (p=0.009). The PR-interval did not show a correlation with gestational age. CONCLUSION: FMCG provides sufficient information about all parts of the fetal cardiac conduction system from the 19th gestational week on. It offers the possibility to analyse the shape and the duration of the PQRST-complex.