Adverse pregnancy outcome in fetuses with early increased nuchal translucency: prospective cohort study.

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.

Resultado adverso del embarazo en fetos con aumento precoz de la translucencia nucal: estudio prospectivo de cohortes OBJETIVOS: El aumento del grosor de la translucencia nucal (TN) de ≥3,5 mm es un marcador bien establecido de anomalías congénitas y resultados adversos del embarazo entre las semanas 11 y 14 de gestación, pero se sabe poco sobre su rendimiento como herramienta de cribado antes de las 11 semanas. El objetivo fue investigar, en un contexto prospectivo, si los fetos con aumento de la TN antes de las 11 semanas corren riesgo de presentar resultados adversos del embarazo. MÉTODOS: Se trató de un estudio prospectivo de cohortes que incluyó a embarazadas con un feto viable con una TN ≥2,5 mm y una longitud céfalo­caudal (LCC) <45 mm. Todas las mujeres incluidas fueron remitidas a una unidad de medicina fetal (UMF) y con cita para una prueba de seguimiento en la que se volvió a medir la TN al cabo de 1 semana cuando la LCC era >45 mm. Se evaluaron dos grupos: casos con una TN normalizada (<3.5 mm) y casos con una TN persistentemente aumentada (≥3,5 mm). A los casos se les dio seguimiento hasta 4 semanas después del parto. El resultado principal fue un resultado adverso compuesto de aneuploidía, otros trastornos genéticos, anomalías estructurales y pérdida del embarazo. Se realizaron análisis de subgrupos del grosor de la TN en el momento de la inclusión y de la TN normalizada o persistentemente aumentada en el seguimiento. RESULTADOS: El estudio incluyó 109 casos, de los cuales 39 (35,8%) tuvieron un resultado adverso del embarazo. De ellos, el 64,1% (25/39) eran aneuploides, lo que supone el 22,9% (25/109) de la población total del estudio. En los subgrupos de grosor de la TN en el momento de la inclusión de 2,5­3,4 mm, 3,5­4,4 mm y ≥4,5 mm, se notificó un resultado adverso en el 22,0% (9/41), el 40,0% (18/45) y el 52,2% (12/23), respectivamente. En los fetos con una TN normalizada y sin anomalías ecográficas en la ecografía de seguimiento, la incidencia de resultados adversos fue del 8,5% (5/59), de los cuales el 5,1% (3/59) de los casos eran aneuploides. CONCLUSIONES: Los fetos con un aumento precoz del grosor de la TN corren un riesgo considerable de sufrir un resultado adverso del embarazo, incluso si la TN se normaliza después de 11 semanas. No todas las anomalías congénitas pueden diagnosticarse con un cribado rutinario en el primer trimestre, como las pruebas prenatales no invasivas y/o una ecografía de anomalías en el primer trimestre. Por lo tanto, los futuros padres siempre deben ser remitidos a una UMF para una ecografía detallada. Se debería ofrecer una prueba prenatal invasiva si se observa un aumento de la TN de ≥2,5 mm antes de las 11 semanas de gestación.

Detection of Fetal Anomalies by Remotely Directed and Interpreted Ultrasound (Teleultrasound): A Randomized Noninferiority Trial.

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..

The Eyes Absent proteins in development and in developmental disorders.

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.

Whole exome sequencing of fetal structural anomalies detected by ultrasonography.

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.

Etiology and perinatal outcome of periviable fetal growth restriction associated with structural or genetic anomaly.

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 ≤ 3rd 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.

Associations between embryo grading and congenital malformations in IVF/ICSI pregnancies.

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.

Neurocristopathies: Enigmatic Appearances of Neural Crest Cell-derived Abnormalities.

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.

Role of late amniocentesis in the era of modern genomic technologies.

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.

Patterns of Placental Injury in Congenital Anomalies in Second Half of Pregnancy.

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.

Surgical termination of pregnancy for fetal anomaly: what role can an independent abortion service provider play?

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.

Two Web Resources Linking Major Human Embryology Collections Worldwide.

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.

Xenopus: An Undervalued Model Organism to Study and Model Human Genetic Disease.

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.

Outcome of fetuses with prenatal diagnosis of isolated severe bilateral ventriculomegaly: systematic review and meta-analysis.

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.

Utility of chromosomal microarray in anomalous fetuses.

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.

FGF8, c-Abl and p300 participate in a pathway that controls stability and function of the ΔNp63α protein.

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.

Complex malformations involving the fetal body wall - definition and classification issues.

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.

Teleultrasound: How Accurate Are We?

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.

"Lying-Down" Adrenal Sign: There Are Exceptions to the Rule Among Fetuses and Neonates.

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.

Umbilical Cord Occlusion via Laser Coagulation in Monochorionic Multifetal Gestations before and after 20 Weeks of Gestation.

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.

LRP2, an auxiliary receptor that controls sonic hedgehog signaling in development and disease.

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.