Systematic, noninvasive endometriosis diagnosis in transvaginal sonography by the Swiss Society of Ultrasound in Medicine.

We present a new systematic, comprehensive, checklist-based sonographic assessment of endometriosis in the female true pelvis. Emphasis is placed on practical skills teaching. The newly introduced White Sliding Line (WSL) is the core structure. The WSL separates five compartments (anterior, central, posterior, and lateral right and left) containing dedicated endometriosis signs of mobility and morphology to be checked. This approach relies on the 2016 IDEA Consensus and further developments. It directly connects to the 2021 #ENZIAN Classification Standard. In practice, evaluation follows the proposed checklist in all compartments, judging first sliding mobility between organs and structures in a highly dynamic investigation. A rigorous search for deep endometriosis (DE) is then performed. We treat adhesions due to their great clinical importance and possible, reliable diagnosis by TVS as the fifth endometriosis unit, next to endometrioma, DE, adenomyosis, and superficial endometriosis. Including superficial (peritoneal) endometriosis is a future goal.

The Predictive Value of Decisive and Soft Ultrasound Criteria for Ectopic Pregnancy Identification in 321 Preoperative Cases.

PURPOSE: To define the predictive value of morphological types (MTs) and further criteria in diagnosing ectopic pregnancy (ECP) by transvaginal sonography (TVS) prior to operative confirmation and treatment. MATERIALS AND METHODS: Retrospective cohort analysis of 321 consecutive patients with suspected ECP who were advised to undergo operation. RESULTS: ECP was investigated by TVS in all 321 patients. Application of the five selected MTs (blob sign, bagel sign, yolk sac, embryo, heart action) resulted in 85 % of cases receiving a conclusive diagnosis and 12 % receiving a presumed ECP diagnosis. 3 % remained nondiagnostic due to large or multiple ovarian cysts, large myoma, extended hemoperitoneum, or severe pain. ECP diagnosis was confirmed intraoperatively in 97 % of cases and was otherwise (3 %) immediately followed by curettage (CUR). The assessment of free fluid by TVS was achieved in most cases and correlated significantly with free blood. In the majority of cases, free blood was not bound to transmural ECP rupture. Histology confirmed the ECP diagnosis directly or by exclusion in 99 % of cases. Three cases of tubal ECP were diagnosed by TVS but not confirmed by LSC (1 %) and, finally, histology from CUR proved miscarriage (false-positive rate 1 %). CONCLUSION: We confirm the high accuracy of TVS diagnosis of ECP relying on five clearly different MTs, independent of its location. The blob and bagel sign emerged as important types (75 % of all ECPs). Histology from CUR was needed when ECP could not be visualized in LSC. Assessment of free fluid was essential and accurate in predicting free blood.

Judging Urgency in 343 Ectopic Pregnancies Prior to Surgery - The Importance of Transvaginal Sonographic Diagnosis of Intraabdominal Free Blood.

OBJECTIVES: Assessing urgency in ectopic pregnancies (ECP) remains controversial since the disorder covers a large clinical spectrum. Severe conditions such as acute abdomen or hemodynamic instability are mostly related to intra-abdominal blood loss diagnosed as free fluid (FF) on transvaginal sonography (TVS). The aims of the current study were to investigate the value of FF and to assess other potentially predictive parameters for judging urgency. METHODS: Retrospective cohort analysis on prospectively collected cases of proven ECP (n = 343). Demographics, clinical and laboratory parameters, and findings on TVS and laparoscopy (LSC) were extracted from the digital patient file. FF on TVS and free blood (FB) in LSC were evaluated. Low urgency was defined as FB (LSC) < 100 ml and high urgency as FB (LSC) ≥ 300 ml. The best subset of variables for the prediction of FB was selected and predictors of urgency were evaluated using receiver operator characteristic (ROC) curves. RESULTS: Clinical symptoms, age, ß-HCG, hemoglobin (HB) preoperative, and FF were examined in multivariate analysis for the cutoff values of 100 ml and 300 ml. FF was the only independent predictor for low and high urgency; HB preoperative was only significant for high urgency offering marginal improvement. ROC analysis revealed FF as an excellent discriminatory parameter for defining low (AUC 0.837, 95% CI 0.794-0.879) and high urgency (AUC 0.902, 95 % CI 0.860-0.945). CONCLUSION: Single assessment of FF on TVS is most valuable for judging urgency. However, the exact cutoff values for a low- and high-risk situation must still be defined.

Audit of the first > 7500 noninvasive prenatal aneuploidy tests in a Swiss genetics center.

OBJECTIVES: Noninvasive prenatal testing (NIPT) is actually the most accurate method of screening for fetal chromosomal aberration (FCA). We used pregnancy outcome record to evaluate a complete data set of single nucleotide polymorphism-based test results performed by a Swiss genetics center. MATERIALS AND METHODS: The Panorama® test assesses the risk of fetal trisomies (21, 18 and 13), gonosomal aneuploidy (GAN), triploidy or vanishing twins (VTT) and five different microdeletions (MD). We evaluated all 7549 test results meeting legal and quality requirements taken in women with nondonor singleton pregnancies between April 2013 and September 2016 classifying them as high or low risk. Follow-up ended after 9 months, data collection 7 months later. RESULTS: The Panorama® test provided conclusive results in 96.1% of cases, detecting 153 FCA: T21 n = 76, T18 n = 19, T13 n = 15, GAN n = 19, VTT n = 13 and MD n = 11 (overall prevalence 2.0%). Pregnancy outcome record was available for 68.6% of conclusive laboratory results, including 2.0% high-risk cases. In this cohort the Panorama® test exhibited 99.90% sensitivity for each trisomy; specificity was 99.90% for T21, 99.98% for T18 and 99.94% for T13. False positive rate was 0.10% for T21, 0.02% for T18 and 0.06% for T13. CONCLUSION: SNP-based testing by a Swiss genetics center confirms the expected accuracy of NIPT in FCA detection.

Pregnancy outcomes in women with a hemoglobinopathy trait: a multicenter, retrospective study.

PURPOSE: To determine the risk of adverse maternal and neonatal outcomes in pregnant women with a hemoglobinopathy trait. MATERIALS AND METHODS: Retrospective cohort study was conducted to compare adverse maternal and neonatal outcomes between pregnant women with a hemoglobinopathy trait (study group; n = 172), and without a hemoglobinopathy trait (control group; n = 360). The medical data were extracted from clinical records of pregnant women attending antenatal care and delivering at the University Hospital Basel or University Hospital Zurich between 2015 and 2018. RESULTS: A total of 172 pregnant women with a hemoglobinopathy trait and 360 controls were recruited. Apart from fetal acidosis, the groups did not differ significantly in any variables of adverse neonatal outcomes. Whereas, among the maternal outcomes the rate of abortion, gestational diabetes mellitus, bacteriuria or urinary tract infection, intrahepatic cholestasis, abnormal placentation and anemia postpartum were significantly increased in women with a hemoglobinopathy trait. CONCLUSION: In our study, a hemoglobinopathy trait increased the risk of adverse maternal outcomes but did not increase adverse neonatal outcomes.

Retained placenta and postpartum hemorrhage: time is not everything.

PURPOSE: Postpartum hemorrhage is the major cause of maternal mortality worldwide. Retained placenta accounts for nearly 20% of severe cases. We investigated the influence of the time factor and retained placenta etiology on postpartum hemorrhage dynamics. METHODS: Our retrospective study analyzed a single-center cohort of 296 women with retained placenta. Blood loss was measured using a validated and accurate technique based on calibrated blood collection bags, backed by the post- vs pre-partum decrease in hemoglobin. We evaluated the relationship between these two blood loss parameters and the duration of the third stage of labor using Spearman rank correlation, followed by subgroup analysis stratified by third stage duration and retained placenta etiology. RESULTS: Correlation analysis revealed no association between third stage duration and measured blood loss or decrease in hemoglobin. A shorter third stage (< 60 min) was associated with significantly increased uterine atony (p = 0.001) and need for blood transfusion (p = 0.006). Uterine atony was significantly associated with greater decrease in hemoglobin (p < 0.001), higher measured blood loss (p < 0.001), postpartum hemorrhage (p = 0.048), and need for blood transfusion (p < 0.001). CONCLUSION: Postpartum blood loss does not correlate with third stage duration in women with retained placenta. Our results suggest that there is neither a safe time window preceding postpartum hemorrhage, nor justification for an early cut-off for manual removal of the placenta. The prompt detection of uterine atony and immediate prerequisites for manual removal of the placenta are key factors in the management of postpartum hemorrhage.

Influence of newborn head circumference and birth weight on the delivery mode of primipara: what is more important?

Objectives Aim of the study was to analyze the impact of head circumference (HC) and birth weight (BW) on the delivery mode and delivery outcomes. Methods Study population consisted of pregnancy, delivery and newborn data from 1,762 women, who delivered between 2004 and 2016 at University Hospital of Zurich (UHZ). Odds ratio (OR) with 95% confidence intervals (CI) were calculated for mode of delivery. Newborns were sorted into four groups according HC or BW. To evaluate the association between HC and delivery outcome, a descriptive analysis was performed. In addition reference charts of newborn HC at term were constructed. Results OR for instrumental delivery (ID) was 2.37 (CI 95%, 1.63-3.46), for C-Section (CS) 3.74 (CI 95%, 1.49-9.37) when HC >36 cm. OR for ID was 1.59 (CI 95%, 1.02-2.50), for CS 3.18 (CI 95% 1.08-9.350) when BW was >4,000 g. OR for ID was 2.15 (95% CI, 1.69-2.73), for CS 1.93 (95% CI, 0.89-4.18) when HC ≥36 cm and BW <4000 g. OR for ID was 2.23 (95% CI, 1.35-3.67), for CS 4.39 (95% CI, 1.48-12.99) when HC ≥36 cm and BW ≥4,000 g. HC ≥36 cm was defined as large in our study. Mothers with higher age and body mass index delivered babies with larger HC (p<0.05). Blood loss and duration of expulsion period and BW was associated with larger HC (p<0.05). Conclusions The rate of ID and CS increased in case of a larger HC and greater BW. However, the main prognostic factor for ID was size of HC: ≥36 cm, but not macrosomia.

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.

[A Structured and Photographic Documentation of the Vacuum-Assisted Vaginal Delivery]. / Eine strukturierte und fotografische Dokumentation der Vakuumentbindung.

The correct placement of the vacuum cup is essential to reduce both maternal and neonatal morbidity after a vacuum-assisted vaginal delivery. Therefore, a checklist based report with all relevant clinical findings and a photo of the infant's head with the location of vacuum tag was introduced to make the exact application of the cup reproducible for. training/instruction purpose.

Detection of blood volumes and haemoglobin mass by means of CO re-breathing and indocyanine green and sodium fluorescein injections.

The main aim of the present study was to quantify the magnitude of differences introduced when estimating a given blood volume compartment (e.g. plasma volume) through the direct determination of another compartment (e.g. red cell volume) by multiplication of venous haematocrit and/or haemoglobin concentration. However, since whole body haematocrit is higher than venous haematocrit such an approach might comprise certain errors. To test this experimentally, four different methods for detecting blood volumes and haemoglobin mass (Hbmass) were compared, namely the carbon monoxide (CO) re-breathing (for Hbmass), the indocyanine green (ICG; for plasma volume [PV]) and the sodium fluorescein (SoF; for red blood cell volume [RBCV]) methods. No difference between ICG and CO re-breathing derived PV could be established when a whole body/venous haematocrit correction factor of 0.91 was applied (p = 0.11, r = 0.43, mean difference -340 ± 612 mL). In contrast, when comparing RBCV derived by the CO re-breathing and the SoF method, the SoF method revealed lower RBCV values as compared to the CO re-breathing method (p < 0.05, r = 0.95, mean difference -728 ± 184 mL). However, compared to the ICG and the SoF methods, the typical error (%TE) and hence reliability of the CO re-breathing method was lower for all measured parameters. Therefore, estimating blood volume compartments by the direct assessment of another compartment can be considered a suitable approach. The CO re-breathing method proved accurate in determining the induced phlebotomy and is at the same time judged easier to perform than any of the other methods.

Optimized Sonographic Weight Estimation of Fetuses over 3500 g Using Biometry-Guided Formula Selection.

Purpose The Hadlock et al. formula tends to underestimate fetal weight, in particular > 3500 g. At the high end of the range, the Merz et al. formula is more accurate, but becomes less so in smaller fetuses. This study was designed to improve fetal weight estimation in fetuses > 3500 g by identifying the fetal biometric parameter providing the most reliable guidance to optimal formula selection. Materials and Methods Regression analysis of 12 032 pregnancies showed that multiplication of abdominal circumference by femur length (AC × FL) gave the best choice of appropriate formula: Hadlock for AC × FL < 24 600, Merz for those ≥ 24 600. We then tested this rule, ('Zurich method'), prospectively in 4073 pregnancies, comparing it with the Hadlock, Merz and the Kehl formulas. Birth weights were merged into 7 categories (< 1500 to ≥ 4000 g, interval of 500 g). The percentage error (PE) and absolute percentage error (APE) were calculated. Results The PE using the Zurich method was lower in both > 3500 g groups than with the Hadlock formula alone (3500 - 3999 g: 0.9 % vs. - 5.3 %, > 4000 g: - 3.2 % vs. - 8.6 %), similar to that with the Merz formula alone, and lower than with the Kehl formulas (3500 - 3999 g: - 9.0 % vs. - 3.2 %, > 4000g: - 5.1 % vs. 0.9 %). The Zurich method and Hadlock formula also shared the lowest PE in the < 1500 g group: 0.2 % vs. 6.8 % (Kehl) vs. 9.6 % (Merz). In terms of APE the Zurich method performed almost as well as the Merz formula in the > 4000 g group, while sharing the lowest value with the Hadlock formula in the < 1500 g group (8.2 % vs. 10.5 % [Kehl], 23.6 % [Merz]). Conclusion The Zurich method uses a pivotal value of the biometry parameter AC × FL to switch between formulas and corrects for the errors of the Hadlock formula in fetuses ≥ 3500 g and those of the Merz formula in fetuses < 3500 g.

Position at birth as an important factor for the occurrence of anal sphincter tears: a retrospective cohort study.

OBJECTIVE: This work aimed to analyze the association between maternal position at birth in spontaneous deliveries and the occurrence of anal sphincter tears (AST) given the lack of evidence related to the least traumatic birth position. STUDY DESIGN: A total of 7832 vaginal deliveries were included. Vaginal-operative deliveries and deliveries with fundal pressure were excluded. Birth positions on bed, in water, kneeling, and in a squatting position on a low stool were compared. Birth position on bed was considered as the reference group, and a logistic regression analysis adjusting for important fetomaternal parameters was performed. RESULTS: The overall incidence of AST was 1.1%. AST rate was significantly increased in squatting (2.9%) and kneeling (2.1%) positions compared with birth position on bed (1.0%) or in water (0.9%). Logistic regression analysis revealed a significantly higher risk for ASTs in squatting (OR 2.92, CI 95% 1.04-8.18) and in kneeling positions (OR 2.14, CI 95% 1.05-4.37) compared with the reference group on bed. When adjusting for risk factors, birth in a kneeling position remained significantly associated with ASTs (adj. OR 2.21, CI 95% 1.07-4.54). CONCLUSIONS: Birth in squatting or in kneeling position is associated with an elevated risk for ASTs. Birth in water is not associated with an increased risk for AST. Based on the results, women should be informed about the association of certain birth positions with the occurrence of AST.

Diagnostic accuracy of random massively parallel sequencing for non-invasive prenatal detection of common autosomal aneuploidies: a collaborative study in Europe.

OBJECTIVE: The objective of this study is to validate the diagnostic accuracy of a non-invasive prenatal test for detecting trisomies 13, 18, and 21 for a population in Germany and Switzerland. METHODS: Random massively parallel sequencing was applied using Illumina sequencing platform HiSeq2000. Fetal aneuploidies were identified using a median absolute deviation based z-score equation. A bioinformatics algorithm based on guanine-cytosine normalization was applied after the data were unblinded. Results of massively parallel sequencing and invasive procedures were compared. RESULTS: Overall, 40/42 samples were correctly classified as trisomy 21-positive, including a translocation trisomy 21 [46,XY,der(13;21),+21] and a structural aberration of chromosome 21 [46,XX,rec(21)dup(21q)inv(21)(p12q21.1)] but not including a low percentage mosaic trisomy 21 [47,XY,+21/46,XY], [sensitivity: 95.2%; one-sided lower confidence limit: 85.8%]; 430/430 samples were correctly classified as trisomy 21-negative (specificity: 100%; one-sided lower CL: 99.3%). Using a new bioinformatics algorithm with guanine-cytosine normalization, detection of trisomy 21 was facilitated, and five of five trisomy 13 cases and eight of eight trisomy 18 cases were correctly identified. CONCLUSION: Our newly established non-invasive prenatal test allows detection of fetal trisomies 13, 18, and 21 with high accuracy in a population in Germany and Switzerland.

Cardiovascular biomarkers in preeclampsia at triage.

INTRODUCTION: To investigate the ability of cardiovascular plasma biomarkers to identify imminent preeclampsia (PE) among pregnant women at triage. MATERIAL AND METHODS: C-terminal pro-arginine vasopressin (copeptin), C-terminal pro-endothelin-1 (CT-proET-1), mid-regional pro-adrenomedullin (MR-proADM), and mid-regional pro-atrial natriuretic peptide (MR-proANP) were prospectively measured in pregnant women presenting at the obstetrical triage units of the University Hospitals of Basel and Zurich, Switzerland. Logistic regression and receiver operating characteristics (ROC) analysis was used to assess and quantify the predictive ability of cardiovascular biomarkers. RESULTS: Of the 147 included women, 27 (18.4%) were diagnosed at admission with PE. All biomarker levels were significantly higher in participants with PE as compared to controls. However, only MR-proANP, MR-proADM and CT-proET-1 were significant and independent predictors of PE, after taking into account the effect of various clinical confounders. The area under the ROC curve (AUC) was 0.62 (95% confidence interval 0.50-0.73) for copeptin, 0.64 (0.52-0.76) for MR-proADM, 0.71 (0.61-0.82) for CT-proET-1, and 0.83 (0.73-0.92) for MR-proANP. The combination of MR-proANP and MR-proADM resulted in the highest diagnostic performance (AUC 0.88; 0.79-0.96). DISCUSSION: Assessment of the cardiovascular plasma biomarkers MR-proANP and MR-proADM holds promise to support diagnosis of PE at triage.

Rectal paracetamol in newborn infants after assisted vaginal delivery may increase pain response.

OBJECTIVE: To assess the efficacy of paracetamol (acetaminophen) for neonatal pain relief. STUDY DESIGN: Randomized, double-blind placebo-controlled trial in 3 Swiss university hospitals. Term and near-term infants (n = 123) delivered by forceps or vacuum were randomized to receive 2 suppositories with paracetamol (60/80/100 mg in infants <3000 g/3000-4000 g/>4000 g birth weight) or placebo at 2 and 8 hours of life. Pain and discomfort during the first 24 hours was assessed by the échelle de douleur et d'inconfort du nouveau né [neonatal pain and discomfort scale] score. The response to the subsequent heel prick for metabolic screening at days 2-3 of life was investigated by the Bernese Pain Scale for Neonates (BPSN). RESULTS: The échelle de douleur et d'inconfort du nouveau né [neonatal pain and discomfort scale] pain scale ratings after assisted vaginal delivery were low and declined within 4 hours of life (P < .01) irrespective of paracetamol administration. At 2-3 days of life, BPSN scores after heel prick were significantly higher in infants who had received paracetamol, compared with controls, both when BPSN were scored by nurses at the bedside (median [IQR] 4 [2-7] vs 2 [0-5], P = .017) or off-site from videos (4 [2-8] vs 2 [1-7], P = .04). Thirty-five of 62 (57%) infants treated with paracetamol cried after heel prick, compared with 25 of 61 (41%) controls (P = .086). CONCLUSIONS: Infants born by assisted vaginal delivery have low pain scores in the immediate period after birth. Paracetamol given to newborns soon after birth may aggravate a subsequent stress response.

Copeptin: a marker for stress reaction in fetuses with intrauterine growth restriction.

OBJECTIVE: To compare venous cord plasma concentrations of 4 vasoactive peptide precursors: carboxy-terminal proarginine vasopressin, CT-prondothelin (ET)-1, midregional proadrenomedullin, and MR-proatrial natriuretic peptide, between fetuses with intrauterine growth restriction and appropriate for gestational age controls. STUDY DESIGN: Matched-pair analysis of 12 fetuses with significant intrauterine growth restriction and 42 healthy appropriate for gestational age control fetuses. All infants were singletons, delivered by elective section after 34 weeks and without chromosomal abnormalities. RESULTS: Umbilical cord plasma copeptin levels (median [range]) were 4-fold higher in intrauterine growth restriction infants than in matched appropriate for gestational age controls: 23.2 (6.7-449) vs 5.1 (2.5-53) pmol/L (P < .001). Multivariate regression analysis revealed an association between copeptin and umbilical artery resistance index z-score (P = .034). The 3 other precursor peptides showed no changes. CONCLUSION: High copeptin concentrations in the cord blood of intrauterine growth restriction newborns reflect a fetal stress response and support the fetal programming hypothesis.

Plasma midregional proadrenomedullin in newborn infants: impact of prematurity and perinatal infection.

INTRODUCTION: Adrenomedullin (ADM) is one of the strongest endogenous vasodilating hormones. Its stable by-product midregional-proADM (MR-proADM) is an established indicator of systemic infection and cardiovascular compromise in adult patients. METHODS: A prospective cross-sectional study was performed to investigate the perinatal factors affecting MR-proADM plasma concentrations in 328 newborn infants with a gestational age (GA) between 24 and 41 wk. RESULTS: Blood samples were obtained in 270 infants from umbilical veins (with additional 108 paired samples from umbilical arteries), and at 2-3 d of life in 183 infants. Paired venous and arterial umbilical cord MR-proADM concentrations were closely related (Spearman's rank order correlation coefficient (R(s)) = 0.825, P < 0.001). MR-proADM concentrations at birth and at 2-3 d were inversely related to GA (R(s) = -0.403 and R(s) = -0.541, respectively) and birth weight (BW; R(s) = -0.421 and R(s) = -0.530, respectively; all P < 0.001). On stepwise regression analysis, clinical chorioamnionitis and umbilical arterial blood base excess retained a significant impact on MR-proADM cord venous blood concentrations. At 2-3 d of life, histologic chorioamnionitis and GA at delivery were significantly associated with MR-proADM levels. DISCUSSION: As compared with adults, MR-proADM concentrations are elevated in neonates, especially those born very preterm. Immaturity and infection, which both feature low systemic vascular resistance, are related to increased MR-proADM concentrations.

Assessing clinical utility of preconception expanded carrier screening regarding residual risk for neurodevelopmental disorders.

The magnitude of clinical utility of preconception expanded carrier screening (ECS) concerning its potential to reduce the risk of affected offspring is unknown. Since neurodevelopmental disorders (NDDs) in their offspring is a major concern of parents-to-be, we addressed the question of residual risk by assessing the risk-reduction potential for NDDs in a retrospective study investigating ECS with different criteria for gene selection and definition of pathogenicity. We used exome sequencing data from 700 parents of children with NDDs and blindly screened for carrier-alleles in up to 3046 recessive/X-linked genes. Depending on variant pathogenicity thresholds and gene content, NDD-risk-reduction potential was up to 43.5% in consanguineous, and 5.1% in nonconsanguineous couples. The risk-reduction-potential was compromised by underestimation of pathogenicity of missense variants (false-negative-rate 4.6%), inherited copy-number variants and compound heterozygosity of one inherited and one de novo variant (0.9% each). Adherence to the ACMG recommendations of restricting ECS to high-frequency genes in nonconsanguineous couples would more than halve the detectable inherited NDD-risk. Thus, for optimized clinical utility of ECS, screening in recessive/X-linked genes regardless of their frequency (ACMG Tier-4) and sensible pathogenicity thresholds should be considered for all couples seeking ECS.

Improving Neonatal and Maternal Outcome by Inducing Mild Labor before Elective Cesarean Section: The Lacarus Randomized Controlled Trial.

BACKGROUND: Newborns delivered by elective cesarean section (CS) are at higher respiratory risk than those delivered vaginally or by CS proceeded by labor (secondary CS). The oxytocin challenge test (OCT) induces uterine contractions that trigger the release of fetal hormones regulating lung fluid clearance during transition from the uterine to an air-breathing environment. OBJECTIVES: The aim is to summarize current evidence and outline the Lacarus trial protocol. METHODS: Literature review informed the design of a randomized placebo-controlled multicenter trial of OCT preceding elective CS in 1,450 women with a singleton pregnancy due for CS at >35 weeks gestation, without preceding contractions, rupture of the membranes, or antenatal steroids. OCT comprises the infusion of oxytocin 5 IU/500 mL Ringer lactate at a rate of 12 mL/h, doubling every 10 min until inducing 5 uterine contractions per 15-min interval. The primary endpoint is the occurrence of neonatal respiratory morbidity within 24 h after birth. Secondary endpoints include biochemical and physiological parameters of fetal and maternal well-being, such as breastfeeding rate and fetal plasma copeptin concentrations. CONCLUSION: This is the first trial to test the hypothesis that oxytocin-induced contractions before elective CS is a promising application of physiologic principles gleaned from natural birth to improve neonatal and maternal outcomes.