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Objective: To determine the diagnostic accuracy of virtual autopsy using whole-body postmortem ultra-high field magnetic resonance imaging (MRI) at 7 Tesla (T), using a short T2-weighted imaging (T2-WI) protocol, compared with classical autopsy, for detecting structural abnormalities in small second-trimester fetuses., Methods: Thirty consecutive fetuses at 13-19 weeks' gestation (weight, 17-364 g) were included following spontaneous pregnancy loss or termination of pregnancy. After fixation in 10% formaldehyde solution (48 h to 1 week), all fetuses were scanned using a two-dimensional turbo high-resolution T2-WI protocol with multislice relaxation time, followed by an invasive autopsy. The diagnostic accuracy of virtual autopsy vs classical autopsy was calculated for 990 anatomical structures (30 fetuses × 33 items). Sensitivity, specificity, positive and negative predictive values and Cohen's κ coefficient of agreement, with their 95% CIs, as well as the McNemar test, were used to evaluate the accuracy and agreement of the two diagnostic methods. Analysis was stratified by anatomical segment (nervous, pulmonary, cardiovascular, digestive, renal, facial and skeletal) and across three gestational-age intervals (13-14, 15-16 and 17-19 weeks)., Results: Considering classical autopsy as the gold standard, virtual autopsy had a sensitivity of 92.04% (95% CI, 85.42-96.29%) and a specificity of 97.87% (95% CI, 94.64-99.42%), with a positive predictive value of 96.30% (95% CI, 90.78-98.56%) and a negative predictive value of 95.34% (95% CI, 91.61-97.45%), achieving a diagnostic accuracy of 95.68% (95% CI, 92.73-97.68%) for detecting structural abnormalities in second-trimester fetuses. Cohen's κ for virtual vs classical autopsy was 0.907. The diagnostic ability of virtual autopsy at 7 T for malformed fetuses was superior to that of classical autopsy for analyzing the nervous system in small fetuses with pronounced autolysis, equivalent to that of classical autopsy when analyzing pulmonary, cardiovascular and renal systems and inferior when evaluating the fetal intestines. The sensitivity of virtual autopsy at 7 T for describing structural abnormalities increased with gestational age., Conclusion: Virtual fetal autopsy using 7-T MRI and a turbo high-resolution T2-WI protocol with multislice relaxation time is a feasible postmortem diagnostic tool for the identification of fetal structural anomalies. © 2024 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology., (© 2024 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.)

Objectives: An increased nuchal translucency (NT) thickness of ≥ 3.5 mm is a well-established marker for congenital anomalies and adverse pregnancy outcome between 11 and 14 weeks' gestation, but little is known about its performance as a screening tool before 11 weeks. We aimed to investigate, in a prospective setting, whether fetuses with increased NT before 11 weeks are at risk for adverse pregnancy outcome., Methods: This was a prospective cohort study including pregnant women with a viable fetus with NT ≥ 2.5 mm and a crown-rump length (CRL) < 45 mm. All included women were referred to our fetal medicine unit (FMU) and scheduled for a follow-up scan where the NT was remeasured after 1 week when the CRL was > 45 mm. Two groups were evaluated: cases with a normalized NT (< 3.5 mm) and cases with persistently increased NT (≥ 3.5 mm). The cases were monitored until 4 weeks after delivery. The main outcome was a composite adverse outcome of aneuploidy, other genetic disorders, structural anomalies and pregnancy loss. We performed subgroup analyses of NT thickness at inclusion and normalized or persistently increased NT at follow-up., Results: The study included 109 cases, of which 39 (35.8%) had an adverse pregnancy outcome. Of these, 64.1% (25/39) were aneuploid, corresponding to 22.9% (25/109) of the total study population. In the subgroups of NT thickness at inclusion of 2.5-3.4 mm, 3.5-4.4 mm and ≥ 4.5 mm, an adverse outcome was reported in 22.0% (9/41), 40.0% (18/45) and 52.2% (12/23), respectively. In fetuses with a normalized NT and without ultrasound abnormalities at the follow-up scan, the incidence of adverse outcome was 8.5% (5/59), of which 5.1% (3/59) cases were aneuploid., Conclusions: Fetuses with an early increased NT thickness are at considerable risk of an adverse pregnancy outcome, even if the NT normalizes after 11 weeks. Not all congenital anomalies can be diagnosed with routine first-trimester screening, such as non-invasive prenatal testing and/or a first-trimester anomaly scan. Therefore, expectant parents should always be referred to a FMU for detailed ultrasonography. Invasive prenatal testing should be offered if an increased NT of ≥ 2.5 mm is observed before 11 weeks' gestation. © 2024 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology., (© 2024 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.)

Background: Conceptions following in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) have an increased risk of congenital anomalies. Few studies have explored the prognosis of fetuses with congenital anomalies. This study aimed to investigate the prevalence and prognosis of congenital anomalies in IVF/ICSI pregnancies, and to analyze the influencing factors contributing to poor prognosis., Methods: In this multicenter retrospective cohort study, we followed 405,473 embryo transfer cycles at 15 reproductive centers between January 2010 and December 2019 and enrolled 2,006 intrauterine pregnancies with congenital anomalies. The relatively positive prognosis group with one or more live births and neonatal survival for more than 7 days was compared with the poor prognosis group with poorer outcomes., Results: Among the 168,270 ongoing intrauterine pregnancy cycles, the prevalence of congenital anomalies was 1.19%, wherein the malformation rates of cycles with late abortion and delivery were 2.37% (716/30,202) and 0.93% (1,290/138,068), respectively. Among all IVF/ICSI cycles with congenital anomalies, the relatively positive prognosis rate was 61.39%. Moreover, the fertilization failure rate (2 pro-nuclei rate < 25%) in the poor prognosis group was significantly higher than that in the relatively positive prognosis group (10.89% vs. 5.09%, p < 0.001). Multivariate logistic regression analysis revealed no significant differences in the relatively positive prognosis rate among the various IVF/ICSI protocols. The relatively positive prognosis rate of fertilization failure cycles was 0.180 times that of normal fertilization cycles., Conclusion: Poor fertilization rates during IVF/ICSI treatments are more likely to have poor prognosis in fetuses or neonates with congenital anomalies, and obstetric management should be strengthened in pregnant women, with which pregnant women should be recommended to strengthen obstetric management., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bao, Chen, Hao, Wu, He, Lu, Ji, Qiao, Wang and Chi.)

Objective: To determine the accuracy and reliability of remotely directed and interpreted ultrasound (teleultrasound) as compared with standard in-person ultrasound for the detection of fetal anomalies, and to determine participants' satisfaction with teleultrasound., Study Design: This was a single-center, randomized (1:1) noninferiority study. Individuals referred to the maternal-fetal medicine (MFM) ultrasound clinic were randomized to standard in-person ultrasound and counseling or teleultrasound and telemedicine counseling. The primary outcome was major fetal anomaly detection rate (sensitivity). All ultrasounds were performed by registered diagnostic medical sonographers and interpretations were done by a group of five MFM physicians. After teleultrasound was completed, the teleultrasound patients filled out a satisfaction survey using a Likert scale. Newborn data were obtained from the newborn record and statewide birth defect databases., Results: Of 300 individuals randomized in each group, 294 were analyzed in the remotely interpreted teleultrasound group and 291 were analyzed in the in-person ultrasound group. The sensitivity of sonographic detection of 28 anomalies was 82.14% in the control group and of 20 anomalies in the telemedicine group, it was 85.0%. The observed difference in sensitivity was 0.0286, much smaller than the proposed noninferiority limit of 0.05. Specificity, negative predictive value, positive predictive value, and accuracy were more than 94% for both groups. Patient satisfaction was more than 95% on all measures, and there were no significant differences in patient satisfaction based on maternal characteristics., Conclusion: Teleultrasound is not inferior to standard in-person ultrasound for the detection of fetal anomalies. Teleultrasound was uniformly well received by patients, regardless of demographics. These key findings support the continued expansion of telemedicine services., Key Points: · For detection of major anomalies, teleultrasound is comparable to standard ultrasound.. · Teleultrasound was well accepted by patients.. · Teleultrasound use should be expanded.., Competing Interests: None declared., (Thieme. All rights reserved.)

Objective: To analyze the results of contingent screening for common aneuploidies at our center from June 2017 to June 2019., Materials and Methods: Traditional screening tests were performed using a combination of biochemical markers and ultrasound measurements in the first and second trimesters to assess the risk of trisomies 21 (T21), 18 (T18) and 13 (T13). Cell-free DNA (cf-DNA) testing was offered (Harmony test) to pregnant women at high risk (>1/280 for T21 and > 1/150 for T13 and T18) and a normal early morphology scan. In positive cases, prenatal sampling was strongly recommended to confirm the results by gold standard methods (QF-PCR and karyotyping). Newborns' phenotypes were corroborated after birth in all cases., Results: In this prospective study, 8153 pregnant women were enrolled, resulting in 390 at high risk according to traditional screening tests. cfDNA testing was offered to 383 women. Traditional screening tests showed a false negative rate of 9.68% for T21. Traditional test sensitivity for T21 was 90.3%, for a false positive rate of 4.17% and a positive predictive value of 7.6%. The positive and negative predictive value for cfDNA testing was 100%. The approach used avoided invasive procedures in 91.3% of women at high risk. The prevalence of chromosomal abnormalities in the population analyzed was 1 in 164, and 1 in 210 for T21., Conclusions: Our results show that offering cf-DNA testing to women at high risk in traditional tests (including those with risks >1 in 50) significantly reduces false positives and, therefore, the number of invasive tests. Extending the use of cf-DNA testing to intermediate risk categories may be cost effective., Competing Interests: Declaration of competing interest None., (Copyright © 2021. Published by Elsevier B.V.)

Background: Arrhinia is defined as the partial or complete absence of the nasal structures. It is a defect of embryonal origin and can be seen in association with other craniofacial anomalies, central nervous system anomalies, absence of paranasal sinuses, and other palatal and ocular abnormalities. Very few patients with arrhinia have been reported so far in the history of modern medicine., Case Report: This study reports an adult patient with congenital partial arrhinia and reviews the literature along with the embryological basis of such a rare disease., Conclusion: Arrhinia is a medical condition with scarce documentation in the literature. This article presents the clinical as well as radiological features of this rare entity.

The Eyes Absent (EYA) transactivator-phosphatase proteins are important contributors to cell-fate determination processes and to the development of multiple organs. The transcriptional regulatory activity as well as the protein tyrosine phosphatase activities of the EYA proteins can independently contribute to proliferation, differentiation, morphogenesis and tissue homeostasis in different contexts. Aberrant EYA levels or activity are associated with numerous syndromic and non-syndromic developmental disorders, as well as cancers. Commensurate with the multiplicity of biochemical activities carried out by the EYA proteins, they impact upon a range of cellular signaling pathways. Here, we provide a broad overview of the roles played by EYA proteins in development, and highlight the molecular signaling pathways known to be linked with EYA-associated organ development and developmental disorders., (© 2021 The Author(s).)

The objective of this study was to evaluate the efficacy of whole exome sequencing (WES) for the genetic diagnosis of cases presenting with fetal structural anomalies detected by ultrasonography. WES was performed on 19 cases with prenatal structural anomalies. Genomic DNA was extracted from umbilical cords or umbilical blood obtained shortly after birth. WES data were analyzed on prenatal phenotypes alone, and the data were re-analyzed after information regarding the postnatal phenotype was obtained. Based solely on the fetal phenotype, pathogenic, or likely pathogenic, single nucleotide variants were identified in 5 of 19 (26.3%) cases. Moreover, we detected trisomy 21 in two cases by WES-based copy number variation analysis. The overall diagnostic rate was 36.8% (7/19). They were all compatible with respective fetal structural anomalies. By referring to postnatal phenotype information, another candidate variant was identified by a postnatal clinical feature that was not detected in prenatal screening. As detailed phenotyping is desirable for better diagnostic rates in WES analysis, we should be aware that fetal phenotype is a useful, but sometimes limited source of information for comprehensive genetic analysis. It is important to amass more data of genotype-phenotype correlations, especially to appropriately assess the validity of WES in prenatal settings.

Third trimester ultrasound has long been in obstetrics a topic of debate. This issue is framed in a historical debate on the effectiveness of routine obstetrical ultrasound and two opposing trends originated in America and Europe, respectively. Primary function of this ultrasound has been to detect fetal growth restriction, but no study has shown evidence of improving perinatal outcomes. Other secondary functions are detection of fetal abnormalities or evaluation of fetal presentation, and they have also shown no evidence. Despite the continuous appearance of works in this regard, health policies of both american and european trends have not been modified. Future seems to show a prolongation of the stalemate. Those health systems with a universal third trimester policy should propose an optimization of the test, in order to improve the benefits and obtain data for future studies that could resolve this longstanding debate., Competing Interests: Declaration of competing interest The authors report no conflict of interest., (Copyright © 2021. Published by Elsevier B.V.)

Objective: To present the experience on prenatal features of 17q12 microdeletion and microduplication syndromes., Materials and Methods: Prenatal chromosomal microarray analysis (CMA) were conducted between January 2015 and December 2018 at a single Chinese tertiary medical centre. Information of cases identified with 17q12 microdeletion or microduplication syndromes were retrospectively collected. Foetal ultrasonographic findings were reviewed, and other information about the gestation week at diagnosis, inheritance and pregnancy outcomes were also included., Results: Ten pregnancies with 17q12 microdeletion and 4 with 17q12 microduplication were identified. The copy number variation (CNV) sizes were 1.39-1.94 Mb in the deleted cases and 1.42-1.48 Mb in the duplicated cases, respectively. All the duplicated and deleted regions included HNF1B and LHX1 genes. Most individuals with 17q12 deletion presented kidney anomalies (9/10), with renal hyperechogenicity being the most common finding (7/10). Fetuses with 17q12 duplication presented a wide phenotypic spectrum, including "double bubble" sign, structural anomalies of the heart and growth anomalies., Conclusions: Our experience further demonstrated the high correlation between 17q12 microdeletion and renal anomalies especially hyperechogenic kidneys. Structural anomalies of the heart were newly identified phenotypes of 17q12 duplication during prenatal period. Besides, growth anomalies and duodenal atresia might be associated with the duplication., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2021. Published by Elsevier B.V.)

Objective: To investigate the etiology and perinatal outcome of periviable fetal growth restriction (FGR) associated with a structural defect or genetic anomaly., Methods: This was a retrospective study of singleton pregnancies seen at a referral fetal medicine unit between 2005 and 2018, in which FGR (defined as fetal abdominal circumference ≤ 3 rd percentile for gestational age) was diagnosed between 22 + 0 and 25 + 6 weeks of gestation. The study group included pregnancies with periviable FGR associated with a genetic or structural anomaly (anomalous FGR), while the control group consisted of structurally and genetically normal pregnancies with periviable FGR (non-anomalous FGR). Results of genetic testing, TORCH screen and postmortem examination, as well as perinatal outcome, were investigated., Results: Of 255 pregnancies complicated by periviable FGR, 188 were eligible; of which 52 (28%) had anomalous FGR and 136 (72%) had non-anomalous FGR. A confirmed genetic abnormality accounted for 17/52 cases (33%) of anomalous FGR, with trisomy 18 constituting over 50% (9/17; 53%). The most common structural defects associated with FGR were central nervous system abnormalities (13/35; 37%). Overall, 12 (23%) cases of anomalous FGR survived the neonatal period. No differences were found in terms of perinatal survival between pregnancies with anomalous and those with non-anomalous FGR., Conclusions: Most pregnancies complicated by anomalous FGR were associated with a structural defect. The presence of an associated genetic defect was invariably lethal, while those with a structural defect, in the absence of a confirmed genetic abnormality, survived into infancy in over 90% of cases, with an overall one in three chance of perinatal survival. These data can be used for counseling prospective parents. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.)

Research Question: Does the quality of transferred embryos have an impact on the rate of congenital malformations in IVF/intracytoplasmic sperm injection (ICSI)-conceived babies?, Design: Retrospective cohort study involving 6637 pregnancies of ≥20 weeks' gestation from women undergoing embryo transfer with a single Day 5 embryo at a private multisite IVF clinic between 2005 and 2015. Embryos were classified as good quality (n = 5537) or poor quality (n = 1100) based on an internal grading system of morphological parameters; malformation rates were compared., Results: In pregnancies proceeding to delivery (≥20 weeks' gestation), poor quality embryos were associated with increased odds of at least one anomaly (adjusted odds ratio [OR] 1.33, 95% confidence interval [CI] 1.03-1.71), major anomalies (adjusted OR 1.42, 95% CI 1.05-1.91), musculoskeletal anomalies (adjusted OR 2.09, 95% CI 1.35-3.22), particularly talipes (adjusted OR 2.88, 95% CI 1.33-6.25), and the International Classification of Diseases (ICD) classification 'Other congenital malformations' (adjusted OR 2.34, 95% CI 1.13-4.34). Furthermore, for pregnancies ≥9 weeks' gestation, poor embryos had more than double the odds of chromosomal anomalies than good embryos (adjusted OR 2.33, 95% CI 1.30-4.18, P = 0.005)., Conclusions: This is the first study to compare the rates of individual congenital malformations for good and poor quality embryos. It provides insight into potential risks of transferring poor quality embryos. In pregnancies ≥20 weeks' gestation, poor quality Day 5 embryos are associated with major malformations, at least one anomaly, musculoskeletal anomalies, talipes and the ICD classification 'Other congenital malformations'. In pregnancies ≥9 weeks' gestation, poor quality Day 5 embryos are associated with chromosomal anomalies., (Copyright © 2019 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

The neural crest is an important transient structure that develops during embryogenesis in vertebrates. Neural crest cells are multipotent progenitor cells that migrate and develop into a diverse range of cells and tissues throughout the body. Although neural crest cells originate from the ectoderm, they can differentiate into mesodermal-type or endodermal-type cells and tissues. Some of these tissues include the peripheral, autonomic, and enteric nervous systems; chromaffin cells of the adrenal medulla; smooth muscles of the intracranial blood vessels; melanocytes of the skin; cartilage and bones of the face; and parafollicular cells of the thyroid gland. Neurocristopathies are a group of diseases caused by the abnormal generation, migration, or differentiation of neural crest cells. They often involve multiple organ systems in a single person, are often familial, and can be associated with the development of neoplasms. As understanding of the neural crest has advanced, many seemingly disparate diseases, such Treacher Collins syndrome, 22q11.2 deletion syndrome, Hirschsprung disease, neuroblastoma, neurocutaneous melanocytosis, and neurofibromatosis, have come to be recognized as neurocristopathies. Neurocristopathies can be divided into three main categories: dysgenetic malformations, neoplasms, and combined dysgenetic and neoplastic syndromes. In this article, neural crest development, as well as several associated dysgenetic, neoplastic, and combined neurocristopathies, are reviewed. Neurocristopathies often have clinical manifestations in multiple organ systems, and radiologists are positioned to have significant roles in the initial diagnosis of these disorders, evaluation of subclinical associated lesions, creation of treatment plans, and patient follow-up. Online supplemental material is available for this article. ©RSNA, 2019.

Background: Placental pathology in fetal congenital anomalies in second half of pregnancy is largely unknown., Methods: Twenty-six clinical and 45 independent placental phenotypes from pregnancies ≥20 weeks of gestation with congenital anomalies divided into 4 groups were retrospectively compared with analysis of variance or χ 2 with 3 degrees of freedom and with Bonferroni correction for multiple comparisons: group 1 : 112 cases with heart malformations (with or without chromosomal anomalies), group 2 : 41 cases with abnormal karyotypes and anomalies other than heart malformations, group 3 : 87 cases with intrathoracic or intraabdominal mass-forming anomalies (mostly congenital diaphragmatic hernias and adenomatoid airway malformation), and group 4 : 291 miscellaneous cases with mostly skeletal, renal, and central nervous system anomalies not fulfilling the criteria of inclusion into groups 1 to 3., Results: Eight of 26 clinical (30.8%) and 16 of 45 (35.5%) placental phenotypes varied statistically significantly among the 4 groups ( P  <  .05), of those, 7 (26.9%) and 4 (8.9%), respectively, remained statistically significant after Bonferroni correction ( P Bonferroni ≤  .002). Those placental phenotypes were placental weight, chorionic disc chorionic microcysts, fetal vascular ectasia, and luminal vascular abnormalities of chorionic villi., Conclusions: Fetal anomalies in second half of pregnancy feature abnormal clinical phenotypes much more frequently than abnormal placental phenotypes. Chromosomal abnormalities with or without heart malformations tend to feature villous edema, and erythroblastosis of fetal blood, likely due to fetal heart failure. Mass-forming fetal anomalies feature placental histological lesions of shallow placental implantation, diffuse chronic hypoxic patterns of placental injury, and lesions of fetal vascular malperfusion, likely stasis-induced.

Most hospitals in Great Britain only offer a medical termination of pregnancy for a fetal anomaly (TOPFA) in the second trimester. We describe the safety and acceptability of a surgical TOPFA service delivered by an independent-sector abortion provider. Non-identifiable data for women undergoing TOPFA at British Pregnancy Advisory Service from 1 January 2015 to 31 March 2016 was extracted from existing databases. Anonymous feedback was obtained using a questionnaire. Women ( n  = 389) were treated along a specialised care pathway within routine abortion lists. The anomalies were chromosomal (64.0%), structural (30.8%), suspected chromosomal and/or structural or unknown (5.1%). The termination method was vacuum aspiration (41.9%) or dilation and evacuation (58.1%). No complications were reported. Feedback (173 women, 122 partners) indicated care was sensitive (99.6%), supportive (100.0%), knowledgeable (99.2%), and helpful (100.0%). Most (92.1%) reported the right amount of partner involvement. All of the respondents were likely/very likely to recommend the service. A cross-sector approach safely and satisfactorily increases the choice of TOPFA methods. Impact Statement What is already known on this subject? A surgical abortion in the first and second trimesters has been demonstrated to be safe and acceptable, if not preferable, to a medical induction for most women, including those seeking a termination of pregnancy for a foetal anomaly (TOPFA). However, most hospitals in Britain only offer a medical TOPFA in the second trimester, often due to a lack of skills to provide a surgical alternative. The lack of choice of method has a negative impact on women's experiences of TOPFA care. Independent sector abortion clinics provide the majority of surgical abortions in the second trimester in Britain, and are therefore a potential site of surgical TOPFA care. What do the results of this study add? Women and NHS service providers can be reassured that when a dedicated care pathway for TOPFA is employed in the context of routine abortion provision in the independent sector, the choice of termination method can be safely and satisfactorily increased. What are the implications of these findings for clinical practice and/or further research? The main implication is the raising of awareness among NHS providers of the availability and acceptability of this model of TOFPA service delivery, so it can become an option for more women who do not want to have a medical induction. We hope that the demonstration of some women's preferences for surgical TOPFA and the safety of this option will lead to development of this service within routine abortion lists within hospital settings. Further research could include determining the reasons why women and their partners may ultimately not choose to pursue a surgical TOPFA within the independent sector abortion service and an in-depth exploration of women's experiences of being treated within this setting.

Objective: The objective of this study is to examine the frequency of abnormal Chromosomal Microarray (CMA) analyses among fetuses with isolated non-visualization of fetal gallbladder., Methods: Data from CMA analyses performed due to isolated non-visualization of fetal gallbladder between January 2013 and September 2016 were retrospectively acquired from a computerized database of the Israeli Ministry of Health. The results were compared with the rate for clinically significant CMA findings in general population, based on a large cohort of 5541 pregnancies undergoing CMA due to maternal request, and a systematic review of 9272 cases with normal ultrasound., Results: Of 45 pregnancies with isolated non-visualization of fetal gallbladder, CMA testing yielded one (2.22%) gain-of-copy-number variant at 16p11.2, categorized as "pathogenic". In addition, one finding of unknown significance was demonstrated. The risk for clinically meaningful CMA findings among pregnancies with isolated absent gallbladder was not significantly increased compared to control population., Conclusions: To the best of our knowledge, this study is the first report describing the rate of pathogenic CMA results in fetuses with isolated non-visualization of fetal gallbladder. The results, in conjunction with previous studies, show that the risk for abnormal CMA results in pregnancies diagnosed with non-visualized gallbladder is not significantly different from pregnancies with normal ultrasound.

Objective: Traditionally, amniocentesis is performed between 17 and 23 weeks of gestation. This enables decisions regarding the course of pregnancy to be made before viability. Less frequently, amniocentesis is performed in the third trimester. Advanced genomic technologies such as chromosomal microarray analysis (CMA) provide more detailed information about the fetus compared with traditional G-banded chromosomal analysis. The aim of this study was to assess the indications for and safety of late amniocentesis, genetic-test results (especially in the context of CMA technology) and outcome of pregnancies that underwent the procedure after 24 weeks., Methods: Medical records were analyzed retrospectively of all women in whom amniocentesis was performed at a gestational age of 24 + 0 to 38 + 6 weeks, at Hadassah Medical Center, between June 2013 and March 2017. Parameters investigated included indications for late amniocentesis, complications, CMA results and pregnancy outcome., Results: During the study period, 291 women (303 fetuses, 277 singleton and 14 twin pregnancies; in two twin pairs, one fetus was terminated before amniocentesis) underwent late amniocentesis. CMA was performed in all instances of amniocentesis. The most frequent indication was abnormal sonographic finding(s) (204/303 fetuses, 67%). Preterm delivery occurred in 1.7% and 5.1% of pregnancies within the first week and within 1 month following the procedure, respectively. Aneuploidy was detected in nine (3%) fetuses and nine (3%) others had a pathogenic/likely pathogenic copy number variant, suggesting that CMA doubled the diagnostic yield of traditional karyotyping. Maximal diagnostic yield (17.5%) was achieved for the subgroup of fetuses referred with abnormal sonographic findings in two or more fetal anatomical systems. Variants of uncertain significance or susceptibility loci were found in another nine (3%) fetuses., Conclusions: In pregnancies undergoing late amniocentesis, CMA increased detection rates of fetal abnormalities and had a shorter turnaround time compared with traditional chromosomal analysis; therefore, late amniocentesis may serve as a helpful tool for detecting fetal abnormalities or reassuring parents following late-appearing abnormal sonographic findings. However, CMA may expose findings of uncertain significance, about which the couple should be precounseled. The procedure appears to be safe. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.)

The emerging field of transcriptional regulation of cell shape changes aims to address the critical question of how gene expression programs produce a change in cell shape. Together with cell growth, division, and death, changes in cell shape are essential for organ morphogenesis. Whereas most studies of cell shape focus on posttranslational events involved in protein organization and distribution, cell shape changes can be genetically programmed. This review highlights the essential role of transcriptional regulation of cell shape during morphogenesis of the heart, lungs, gastrointestinal tract, and kidneys. We emphasize the evolutionary conservation of these processes across different model organisms and discuss perspectives on open questions and research avenues that may provide mechanistic insights toward understanding birth defects., (© 2018 Sivakumar and Kurpios.)

Objective: To quantify from the published literature survival and neurodevelopmental outcome of fetuses with prenatally detected isolated severe bilateral ventriculomegaly., Methods: MEDLINE, EMBASE and the Cochrane Library were searched electronically. Only cases with a prenatal diagnosis of apparently isolated severe ventriculomegaly and postnatal neurodevelopmental assessment were selected and included. Severe ventriculomegaly was defined as enlargement of the ventricular atria, with a diameter of greater than 15 mm in the transventricular plane. All cases in which the investigators were unable to detect associated structural abnormality, chromosomal abnormality or fetal infection, and in which the ventriculomegaly was therefore regarded as apparently isolated, were included. Those for which the etiology was identified prenatally were excluded, whereas those with postnatal identification of the underlying cause were not excluded, since this information was not available prenatally. The quality of the included studies was assessed using the Newcastle-Ottawa Scale (NOS) for cohort studies. Pregnancy outcomes such as termination, stillbirth, neonatal survival and developmental outcome of the baby, were recorded. The degree of disability was classified as no, mild or severe disability. Statistical assessment was performed by meta-analysis of proportions to combine data, weighting the studies using the inverse variance method and a random-effects model. Proportions and CIs were reported., Results: Eleven studies including 137 fetuses were found. Twenty-seven pregnancies underwent termination and were excluded. The remaining 110 fetuses with apparently isolated severe ventriculomegaly for which continuation of pregnancy was intended, form the study population. Overall quality assessed using NOS for cohort studies was good. Survival was reported in 95/110 (pooled proportion 87.9% (95% CI, 75.6-96.2%)) cases. In 15/110 (pooled proportion 12.1% (95% CI, 3.8-24.4%)), either stillbirth or neonatal demise was reported. No disability was reported in 41/95 survivors (pooled proportion 42.2% (95% CI, 27.5-57.6%)). However, 17/95 showed mild/moderate disability (pooled proportion 18.6% (95% CI, 7.2-33.8%)) and 37/95 were reported to have severe disability (pooled proportion 39.6% (95% CI, 30.0-50.0%))., Conclusions: Four-fifths of fetuses with severe ventriculomegaly survive and, of these, just over two-fifths show normal neurodevelopment. The overall survivors without disability account for more than one third of the total. Given that many cases undergo termination of pregnancy and require longer follow-up in order to detect subtle abnormalities, mortality and prevalence of developmental delay may be even higher than that reported in this paper. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.)

Fetal structural anomalies are found in up to 3% of all pregnancies and ultrasound-based screening has been an integral part of routine prenatal care for decades. The prenatal detection of fetal anomalies allows for optimal perinatal management, providing expectant parents with opportunities for additional imaging, genetic testing, and the provision of information regarding prognosis and management options. Approximately one-half of all major structural anomalies can now be detected in the first trimester, including acrania/anencephaly, abdominal wall defects, holoprosencephaly and cystic hygromata. Due to the ongoing development of some organ systems however, some anomalies will not be evident until later in the pregnancy. To this extent, the second trimester anatomy is recommended by professional societies as the standard investigation for the detection of fetal structural anomalies. The reported detection rates of structural anomalies vary according to the organ system being examined, and are also dependent upon factors such as the equipment settings and sonographer experience. Technological advances over the past two decades continue to support the role of ultrasound as the primary imaging modality in pregnancy, and the safety of ultrasound for the developing fetus is well established. With increasing capabilities and experience, detailed examination of the central nervous system and cardiovascular system is possible, with dedicated examinations such as the fetal neurosonogram and the fetal echocardiogram now widely performed in tertiary centers. Magnetic resonance imaging (MRI) is well recognized for its role in the assessment of fetal brain anomalies; other potential indications for fetal MRI include lung volume measurement (in cases of congenital diaphragmatic hernia), and pre-surgical planning prior to fetal spina bifida repair. When a major structural abnormality is detected prenatally, genetic testing with chromosomal microarray is recommended over routine karyotype due to its higher genomic resolution., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Review Question/objective: The objective of this review is to identify, appraise and synthesize the best available evidence on the impact of maternal obesity on mid second trimester ultrasound detection of fetal anomalies in pregnancy.

Human embryology is a core subject for medicine and current research. While animal models of development now have significant online resources available, the vast majority of human embryonic material is locked up in historic collections. When accessed today, these collections are still contributing to our understanding of human development. This paper describes two online resources for studying human development that are unlocking these invaluable collections and providing related human developmental resources. The first of these is the online Embryology website (http://tiny.cc/Embryo) that links the human developmental timeline to historic and current research findings. Secondly is the Digital Embryology Consortium (https://human-embryology.org), an international research partnership to digitise, preserve, and make the major embryology histological collections available for researchers. By making this histological material more widely available to researchers with new methods of analysis, a better understanding of human development can be reached. This also opens the opportunity for new 3D reconstruction and virtual reality representation of these embryos., (© 2019 S. Karger AG, Basel.)

Introduction: Gestational diabetes is one of the most common medical disorders and may cause numerous of maternal and foetal complications, such as: preterm births, congenital defects, hypertrophic cardiomyopathy, metabolic changes, and macrosomia in neonates. One of the types of diabetes that may clinically manifest in pregnancy is GCK-MODY, caused by mutations in the glucokinase (GCK) gene., Aim of the Study: The aim of the study was to assess the impact of diabetes during pregnancy in women with GCK-MODY on their children's health outcome and to determine the clinical and biochemical characteristics of children delivered by patients with GCK-MODY., Material and Methods: Study was multicentre, involving 50 children from paediatric diabetology departments in Gdansk, Katowice, Bialystok, and Lodz. The risk of GCK-MODY was evaluated on the basis of the medical history of the patient, the clinical course of the disease, and laboratory tests performed during diagnostic procedures. Data concerning family history, mothers' health status, course of pregnancy, and perinatal period was collected., Results: The study showed that among children with glucokinase mutation, born by mothers affected with GCK-MODY, 62% received 10 points in Apgar score in the first minute of life, whereas 92% (n = 46) obtained 10 points in Apgar score in the fifth minute of life. The average age of diagnosis of GCK-MODY in children was 8.25 ±4.76 years, and the average HbA1c during diagnosis was 6.43 ±0.71%. Statis-tically significant difference between the absence of macrosomia (birth weight > 91st percentile) in children with GCK-MODY diabetes in comparison to the general paediatric population (p = 0.0229) was observed., Conclusion: According to the presented study, possible consequences of GCK-MODY during pregnancy on foetal development are generally less severe and may differ from those characteristic for other types of diabetes. Children born by mothers with diabetes should be followed up regarding glucose disorders. Further investigation of particular phenotypes of GCK-MODY, depending on the type of inherited mu-tation in mothers and their children, is required.

Objective: The objective of this study was to determine the association of copy number variants (CNV) with perinatal outcomes among fetuses with sonographic abnormalities., Methods: This was a retrospective cohort study of anomalous fetuses evaluated at a single fetal center, who underwent chromosomal microarray (CMA) testing. Pathogenic CNV or variants of uncertain significance were classified as abnormal. The primary outcome of perinatal death was compared among fetuses with normal vs abnormal CMA. Secondary outcomes included preterm birth, small for gestational age birth weight, and death prior to discharge. The odds ratio (OR) of perinatal death was determined, adjusting for potential confounders., Results: Of 280 fetuses, 60 (21.4%) had abnormal CMA results-21 (35.0%) were classified as pathogenic, 39 (65.0%) were variants of uncertain significance. Among 212 (75.7%) continuing pregnancies, abnormal CMA was not associated with increased odds of perinatal death (adjusted OR 0.81, 95% CI 0.34-1.93), after adjustment for the presence of hydrops and specific anomalies. The overall frequency of perinatal death was 21.2%. No differences in secondary outcomes were observed., Conclusions: Abnormal CMA was not associated with increased odds of perinatal death in this cohort. Fetal CNV are common among fetal center patients; such fetuses are at high risk of perinatal death irrespective of CMA results., (© 2018 John Wiley & Sons, Ltd.)

The function of normal and defective candidate genes for human genetic diseases, which are rapidly being identified in large numbers by human geneticists and the biomedical community at large, will be best studied in relevant and predictive model organisms that allow high-speed verification, analysis of underlying developmental, cellular and molecular mechanisms, and establishment of disease models to test therapeutic options. We describe and discuss the pros and cons of the frog Xenopus, which has been extensively used to uncover developmental mechanisms in the past, but which is being underutilized as a biomedical model. We argue that Xenopus complements the more commonly used mouse and zebrafish as a time- and cost-efficient animal model to study human disease alleles and mechanisms., (© 2018 S. Karger AG, Basel.)

A linear-shaped or "lying-down" adrenal gland is a sign often seen with the absence of the kidney in the renal fossa due to renal agenesis, renal ectopia, or horseshoe kidney. It is theorized that the presence of the kidney in the normal location within the renal fossa is important for the formation of the normal triangular inverted V or Y adrenal shape. There are exceptions to this rule whereby a kidney is missing from the renal fossa, yet a normal adrenal shape is present. This series looked at 18 cases of an empty renal fossa in fetal, neonatal, and pediatric patients and recorded the shape of the adrenal gland. Nine cases (50%) appropriately showed the linear or lying-down adrenal gland; 6 (33%) showed an exception to the rule, with a normally shaped adrenal gland; and 3 (17%) showed a pseudo exception in which the adrenal gland was linear but blended with the diaphragmatic crus to simulate a triangular adrenal gland. The sonographic characteristics of the crus are different from those of the adrenal gland; thus, this pseudo exception can be avoided by careful inspection. Because the absence of the kidney is often a difficult diagnosis, the lying-down adrenal gland sign can be a helpful secondary sign for confirming that a kidney is absent or ectopic in position and not within the renal bed., (© 2017 by the American Institute of Ultrasound in Medicine.)

Objectives: Ultrasound serves an important role in the prenatal diagnosis of fetal structural anomalies. Recently, there has been increased use of teleultrasound protocols. We aimed to evaluate the sensitivity and accuracy of teleultrasound., Methods: We conducted an Institutional Review Board-approved retrospective cohort study determining the sensitivity and accuracy of teleultrasound. In addition, we evaluated the number of ultrasound examinations required to complete an anatomic survey. Only ultrasound examinations performed for anatomic surveys were included. Studies were excluded if performed before 16 completed weeks' gestation, if they had multiple gestations, or for reasons other than anatomy (eg, Doppler studies and fluid assessment). Prenatal diagnoses were compared with postnatal diagnoses obtained from a robust mandatory birth defects surveillance program that records all birth defects in the entire state, from deliveries before 20 weeks' gestation through infants up to 2 years of age., Results: A total of 2499 studies were evaluated; 2368 were included. The teleultrasound cohort had a congenital anomaly prevalence of 5.66%. The sensitivity of teleultrasound was 57.46%; the specificity was 98.21%; and the accuracy was 95.9%. Anatomic surveys were completed after 1 visit in 82% of patients, whereas 63% and 61% of the remaining patients required 2 and 3 visits, respectively., Conclusions: Teleultrasound for prenatal diagnosis has similar sensitivity and accuracy as the published literature for on-site ultrasound. Further studies are needed to compare the sensitivity and accuracy within the same population and further validate this potentially cost-saving modality., (© 2017 by the American Institute of Ultrasound in Medicine.)

Objective: The objective of the study is to analyse the sonographic features, cytogenetic results and pregnancy outcomes in complex malformations involving the body wall in a large cohort of fetuses with regard to different definitions proposed in the literature., Method: A retrospective study on 96 fetuses with complex malformations comprising ventral wall, craniofacial structures, limbs and umbilical cord that were evaluated between 1997 and 2015., Results: The most common sonographic finding was an extensive ventral wall defect (95.8%; 92/96) comprising liver (94.6%; 87/92), intestine (82.6%; 76/92), heart (17.4%; 16/92) and bladder (8.7%; 8/92). Acrania and encephalocoele were observed in 24 and 9 fetuses (25.0%, 24/96; 9.4%, 9/96), respectively. Limb anomalies were present in 54 fetuses (56.3%; 54/96). Rudimentary or absent umbilical cord was observed in 62 fetuses (64.6%; 62/96). In 79 fetuses, there were additional multiple structural anomalies detected prenatally. None of the currently used definitions encompasses all possible phenotypes of body wall defects present in our cohort. Chromosomal aberrations were seen in 8 out of 60 cases with conclusive cytogenetic result (13.3%, 8/60)., Conclusion: Chromosomal anomalies are common, and karyotyping should be offered. There is a need for a more rigorous classification of complex malformations in order to better understand the underlying pathophysiology. © 2017 John Wiley & Sons, Ltd., (© 2017 John Wiley & Sons, Ltd.)

Prenatal diagnosis is a rapidly evolving speciality. Screening for aneuploidy begins with non-sonographic features of background risk of maternal age and past and family history. It is possible to diagnose major structural defects in the foetus using second trimester scans. Serum biochemistry markers in the early second trimester were added to increase the detection rate of aneuploidy. However, as some of these abnormalities were amenable to detection earlier in the first trimester, newer modalities were introduced. Nuchal translucency (NT) measurement was one of the main advances with regard to first trimester screening. Additional markers such as the presence of nasal bone, tricuspid regurgitation, ductus venosus and megacystis; together with first trimester serum biochemistry, further enhanced the detection rate of chromosomal abnormalities. Advances in research and technology have resulted in the availability of non-invasive prenatal testing from 10 weeks of gestation. This has facilitated the detection of the three major chromosomal aneuploidies at very early gestation. However, there are a wide range of genetic syndromes that are not confined to the main trisomies. There are specific markers on ultrasound that can be linked to specific syndromes. Hence, a structured and stepwise approach is needed to identify and reach a possible diagnosis. As anomalies are classified into malformations, deformations and disruptions, it is important to note that not all markers detected are due to genetic syndromes and not all genetic syndromes can be detected on ultrasound scan. In this chapter, we outline common structural markers and their association with main genetic syndromes., (Copyright © 2017. Published by Elsevier Ltd.)

Objectives: The systematic use of ultrasound during pregnancy aims at birth defect detection. Our objective was to assess the economic efficiency of prenatal ultrasound screening for fetal malformations., Methods: We carried out a literature review on Medline via PubMed between 1985 and 2015, from the economic perspective of the prenatal ultrasound screening for fetal malformations., Results: The literature on this subject was sparse and we selected only twelve articles presenting relevant economic data, of which only eight were proper medico-economic studies. We found arguments for the economic effectiveness of ultrasound screening for fetal malformation detection, which is largely linked to the terminations of pregnancies and to the cost of the handicaps "avoided". However, none of the reviewed articles could reach medico-economic conclusions. Additionally, we highlighted various elements making economic analyses more complex in this field: the choice of the method, the uncertainty around two essential parameters (the efficiency of ultrasound and the costs of procedures) and the difficulties to compare or to generalize results. We also noticed important methodological heterogeneity among the studies and the absence of French study., Conclusions: Previously published data are insufficient to assess the economic efficiency of prenatal ultrasound screening for fetal malformations., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Introduction: Umbilical cord occlusion (UCO) utilizing laser photocoagulation is often not considered an option for selective termination after 20 weeks of gestation due to reported limitations of the procedure because of umbilical cord size. We compared outcomes after laser umbilical cord occlusion (L-UCO) before and after 20 weeks of gestation., Materials and Methods: We examined all patients with monochorionic- diamniotic twins and higher-order multiples (monoamniotic excluded) that underwent L-UCO at our facility between 2006 and 2014. Statistical analysis was performed using Fisher's exact and Kruskal-Wallis tests as appropriate., Results: Of 43 L-UCO cases, 11 cases (25.6%) had a discordant anomaly, and 32 cases (74.4%) had twin reversed arterial perfusion (TRAP) sequence. We achieved complete vascular occlusion in 100% (43/43) of cases of attempted L-UCO. There were 22 cases (51.2%) with gestational age ≤20 weeks, and 21 cases (48.8%) with gestational age >20 weeks. Perioperative patient characteristics and outcomes did not differ between the two groups. Survival rates were 90.9% (20/22) and 100% (21/21) at ≤20 weeks of gestation and >20 weeks of gestation, respectively., Discussion: The results of this study suggest that L-UCO is a reasonable surgical modality for patients prior to and beyond 20 weeks of gestation., (© 2016 S. Karger AG, Basel.)

Gene expression often requires interaction between promoters and distant enhancers, which occur within the context of highly organized topologically associating domains (TADs). Using a series of engineered chromosomal rearrangements at the Shh locus, we carried out an extensive fine-scale characterization of the factors that govern the long-range regulatory interactions controlling Shh expression. We show that Shh enhancers act pervasively, yet not uniformly, throughout the TAD. Importantly, changing intra-TAD distances had no impact on Shh expression. In contrast, inversions disrupting the TAD altered global folding of the region and prevented regulatory contacts in a distance-dependent manner. Our data indicate that the Shh TAD promotes distance-independent contacts between distant regions that would otherwise interact only sporadically, enabling functional communication between them. In large genomes where genomic distances per se can limit regulatory interactions, this function of TADs could be as essential for gene expression as the formation of insulated neighborhoods., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To assess the extent to which the distribution of crown-rump length (CRL) values may be correlated with different criteria for the quality of the CRL images., Study Design: This is a retrospective analysis of a series of 977 CRL images, by two independent observers, for the presence or the absence of 14 quality hallmarks. Inter-observer agreement for the hallmarks was assessed by the proportion of agreement and Cohen's kappa. The association between the quantiles of the CRL distribution and the presence or absence of the 14 quality hallmarks was modeled using quantile regression., Results: The overall inter-observer agreement across the 14 hallmarks was 91.7%, kappa=0.81, 95% CI [0.80-0.82]. Distribution of CRL measurements varied considerably as a function of image quality: when the fetus was in extension, the mean CRL was +5.7mm (vs. not in extension, p<0.001), when the fetus was in flexion (vs. not), the mean CRL was -4.7mm (p<0.001) and when the image magnification was <65% (vs. >65%), the mean CRL was -4.2mm (p<0.001). There was a global trend to over-estimate the CRL for the higher deciles and to under-estimate the CRL for the lower deciles when the sagittal quality hallmarks were absent. No significant impact on CRL distribution was observed in association with the precise placement of the calipers nor with the horizontal orientation of the fetus., Conclusion: Distribution of CRL measurements was influenced by the quality of CRL images. In particular, inadequate position of the fetus (flexion/extension) and insufficient image magnification were associated with systematic changes in the values of CRL. Our results show that as the quality of CRL images decreases, the associated variations in the distribution of CRL can have an impact on the chromosomal risk assessment and may lead to inappropriate obstetrical decisions., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objective: Fraser syndrome (FS) is a rare malformation recessive disorder. Major criteria are cryptophtalmos, syndactyly, respiratory, genital and urinary tract anomalies. Few prenatal presentations have been reported., Method: We analyzed the prenatal and postnatal fetal phenotype in 38 cases of FS, including 25 pregnancy termination cases, 8 intra-uterine death cases and 4 cases that died after birth., Results: Including both prenatal and postnatal fetal phenotypic evaluation, all cases presented dysmorphic features with nose and ear dysplasia. Renal anomalies and syndactyly were present in 37/38 cases, cryptophtalmos in 36/38, airways anomalies in 30/37 and genital anomalies in 30/35 cases. Anomalies of the abdominal wall such as low set umbilicus and omphalocele were found in 31 cases. Among the 26 cases for which ultrasound data were available, detectable anomalies included oligohydramnios (22), ascites/hydrops (9), renal anomalies (20), evidence for high airways obstruction (11), ophthalmologic anomalies (4), ear dysplasia (2) and syndactyly (2)., Conclusion: This study shows that the postnatal phenotype of FS is very specific, whereas oligohydramnios hampers the prenatal recognition of the cardinal FS diagnosis criteria. Association of oligohydramnios, kidney agenesis and CHAOS should lead to consider this diagnosis. © 2016 John Wiley & Sons, Ltd., (© 2016 John Wiley & Sons, Ltd.)

Background: A prenatal diagnosis of a fetal anomaly involves acute grief and psychological distress. The Internet has the potential to provide virtual support following the diagnosis. The overall aim was to explore communication of support and critique in Swedish virtual community threads about prenatal diagnoses of fetal anomalies., Methods: Systematic searches in Google resulted in 117 eligible threads. Fifteen of these were purposefully selected and subjected to deductive content analysis., Results: The virtual support involved mainly emotional support (meaning units n = 1,992/3,688, 54 %) and was described as comforting and empowering. Posters with experience of a prenatal diagnosis appreciated the virtual support, including the opportunity to gain insight into other cases and to write about one's own experience. Critique of the decision to continue or terminate the pregnancy occurred, primarily against termination of pregnancy. However, it was met with defense., Conclusions: Peer support, mainly emotional, is provided and highly appreciated in threads about prenatal diagnoses of a fetal anomaly. Critique of the decision to terminate the pregnancy occurs in virtual community threads about prenatal diagnoses, but the norm is to not question the decision. Future studies need to investigate if virtual peer support promotes psychosocial function following a prenatal diagnosis and what medium would be most suitable for these types of supportive structures.

To fulfill their multiple roles in organ development and adult tissue homeostasis, hedgehog (HH) morphogens act through their receptor Patched (PTCH) on target cells. However, HH actions also require HH binding proteins, auxiliary cell surface receptors that agonize or antagonize morphogen signaling in a context-dependent manner. Here, we discuss recent findings on the LDL receptor-related protein 2 (LRP2), an exemplary HH binding protein that modulates sonic hedgehog activities in stem and progenitor cell niches in embryonic and adult tissues. LRP2 functions are crucial for developmental processes in a number of tissues, including the brain, the eye, and the heart, and defects in this receptor pathway are the cause of devastating congenital diseases in humans. Developmental Dynamics 245:569-579, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Boyden's nomenclature, which was based on postmortem specimens and published in 1955 prior to the advent of computed tomography (CT), is commonly used to describe the normal segmental bronchial anatomy and various abnormalities. However, several additional anomalies have been recognized since that time, and there is some confusion over the names used to describe these anomalies. Several congenital branching anomalies affecting the trachea, main bronchi, and intermediate bronchus have been reported, all of which can be recognized at chest CT but are often overlooked. These anomalies, which probably occur early in fetal life, can be either supernumerary, with defects occurring at 29-30 days gestation, or displaced, with defects occurring later. Tracheobronchial positional anomalies are often associated with other congenital abnormalities but may be isolated. They often are asymptomatic but can be responsible for pulmonary symptoms such as dyspnea, recurrent pneumonia, and hemoptysis. It is essential that these anomalies are recognized prior to lung resection to avoid complications, especially when video-assisted thoracoscopic surgery is performed. In addition, bronchoscopists should be aware of these anomalies before performing diagnostic or therapeutic bronchoscopic procedures. Awareness of a few key bronchial anatomic principles and use of a lobe-based classification scheme will facilitate recognition of tracheobronchial positional anomalies., ((©)RSNA, 2016.)

Context: Termination of pregnancy (TOP) is regulated by French law for decades. Indications of TOP may vary depending on progress performed in perinatal medicine and in diagnosis of fetal anomalies, and also according to the way malformations are perceived in society., Objectives: To determine whether the frequency and indications of TOP had varied in the Lorraine Centre for Perinatal Diagnosis from 2000 to 2012., Subjects and Methods: Retrospective study performed on a randomized sample of medical files presented in the Lorraine Centre for Perinatal Diagnosis in years 2000, 2006 and 2012. We analyzed the number of files presented by parents-to-be, the indication motivating TOP, general characteristics of both pregnancies and mothers. We also performed a prospective enquiry among the French Centres for Perinatal Diagnosis in order to determine national rates., Results: General characteristics of mothers and pregnancies were similar from 2002 to 2012. No modification in indications of TOP was measured. In Lorraine, most TOPs were performed for chromosomal abnormality. On the national level, centres for perinatal diagnosis received more requests for TOPs in the study period. There were also more TOPs for non-lethal fetal anomalies, and parents refusing TOPs though the centres had agreed with its indication., Conclusion: The national trends were not measured in Lorraine region., (Copyright © 2016. Published by Elsevier Masson SAS.)

Background: A total of 75% of monozygotic twins share 1 monochorionic placenta where placental anastomoses cause several serious complications, for example, acardiac twinning. Acardiac twins lack cardiac function but grow by perfusion of arterial blood from the pump twin. This rare pregnancy has 50% natural pump twin mortality but accurate risk prediction is currently impossible. Recent guidelines suggest prophylactic surgery before 18 weeks, suggesting 50% unnecessary interventions. We hypothesize that (1) adverse pump twin outcome relates to easy-to-measure pump/acardiac umbilical venous diameter (UVD) ratios, representing acardiac perfusion by the pump's excess cardiac output. This hypothesis suggests that (2) UVD-ratios are large, mildly varying in cases without complications but small and decreasing when complications develop, thus predicting that (3) UVD-ratios may allow risk prediction of pump twins. In this exploratory clinical pilot, we tested whether UVD-ratio measurements support these predictions., Methods: We included 7 uncomplicated (expectant management), 3 elective surgical, and 17 complicated cases (pump decompensation, emergency intervention/delivery or demise). Nine UVD-ratios were measured sonographycally and 18 by pathology., Results: Uncomplicated cases have larger, two serial measurements showing mildly varying UVD-ratios; elective surgical cases show larger UVD-ratios; complicated cases have smaller, two serial measurements showing decreasing UVD-ratios. There were no false-positives, no false-negatives and noncrossing linear trendlines of uncomplicated and complicated cohorts., Conclusion: Our data provide first evidence that UVD-ratios allow risk prediction of pump twins. More early uncomplicated and late complicated cases are needed, for example, in a prospective trial, before the separation between uncomplicated and complicated cohorts is accurate enough to support a well-founded decision on (early) intervention., (© 2015 Wiley Periodicals, Inc.)

Maternal diabetes mellitus is a significant risk factor for structural birth defects, including congenital heart defects and neural tube defects. With the rising prevalence of type 2 diabetes mellitus and obesity in women of childbearing age, diabetes mellitus-induced birth defects have become an increasingly significant public health problem. Maternal diabetes mellitus in vivo and high glucose in vitro induce yolk sac injuries by damaging the morphologic condition of cells and altering the dynamics of organelles. The yolk sac vascular system is the first system to develop during embryogenesis; therefore, it is the most sensitive to hyperglycemia. The consequences of yolk sac injuries include impairment of nutrient transportation because of vasculopathy. Although the functional relationship between yolk sac vasculopathy and structural birth defects has not yet been established, a recent study reveals that the quality of yolk sac vasculature is related inversely to embryonic malformation rates. Studies in animal models have uncovered key molecular intermediates of diabetic yolk sac vasculopathy, which include hypoxia-inducible factor-1α, apoptosis signal-regulating kinase 1, and its inhibitor thioredoxin-1, c-Jun-N-terminal kinases, nitric oxide, and nitric oxide synthase. Yolk sac vasculopathy is also associated with abnormalities in arachidonic acid and myo-inositol. Dietary supplementation with fatty acids that restore lipid levels in the yolk sac lead to a reduction in diabetes mellitus-induced malformations. Although the role of the human yolk in embryogenesis is less extensive than in rodents, nevertheless, human embryonic vasculogenesis is affected negatively by maternal diabetes mellitus. Mechanistic studies have identified potential therapeutic targets for future intervention against yolk sac vasculopathy, birth defects, and other complications associated with diabetic pregnancies., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: With advances in therapy, more neonates with severe congenital anomalies are surviving, albeit some with neurologic disorders, possibly related to antenatal low brain blood flow. This autopsy series reports antenatal brain injury in neonates expiring due to severe anomalies, and provides correlation with umbilical cord blood gas and acid-base analysis., Methods: We identified autopsies of third trimester neonates expiring shortly following delivery due to severe anomalies or malformations. Brain injury classified as "older" included periventricular leukomalacia, gliosis and karyorrhectic neurons, and "recent" included red neurons and reactive glial changes., Results: We identified 22 cases (nine term, 13 preterm). 16 (73%) had brain injury, including 11 with older injury. Cord arterial blood was analyzed in 17, and six had pH <7 or base deficit >12 mmol/L. Four out of 5 (80%) neonates with neuronal necrosis compared to two out of 12 (17%) without had a pH <7 or base deficit >12 mmol/L (p = 0.03). Five out of nine (56%) neonates with white matter injury compared to one out of 8 (13%) without had pH <7 or base deficit >12 mmol/L (p = NS)., Conclusions: Antenatal brain injury is frequent in neonates with severe congenital anomalies. Severely abnormal cord blood analysis results correlate significantly with neuronal necrosis and show a trend toward white matter injury; however, the absence of these abnormal results does not preclude the presence of brain injury.

The p63 transcription factor, homolog to the p53 tumor suppressor gene, plays a crucial role in epidermal and limb development, as its mutations are associated to human congenital syndromes characterized by skin, craniofacial and limb defects. While limb and skin-specific p63 transcriptional targets are being discovered, little is known of the post-translation modifications controlling ΔNp63α functions. Here we show that the p300 acetyl-transferase physically interacts in vivo with ΔNp63α and catalyzes its acetylation on lysine 193 (K193) inducing ΔNp63α stabilization and activating specific transcriptional functions. Furthermore we show that Fibroblast Growth Factor-8 (FGF8), a morphogenetic signaling molecule essential for embryonic limb development, increases the binding of ΔNp63α to the tyrosine kinase c-Abl as well as the levels of ΔNp63α acetylation. Notably, the natural mutant ΔNp63α-K193E, associated to the Split-Hand/Foot Malformation-IV syndrome, cannot be acetylated by this pathway. This mutant ΔNp63α protein displays promoter-specific loss of DNA binding activity and consequent altered expression of development-associated ΔNp63α target genes. Our results link FGF8, c-Abl and p300 in a regulatory pathway that controls ΔNp63α protein stability and transcriptional activity. Hence, limb malformation-causing p63 mutations, such as the K193E mutation, are likely to result in aberrant limb development via the combined action of altered protein stability and altered promoter occupancy., (© The Author 2015. Published by Oxford University Press.)