A visual tool inclusive of fetal ultrasound and autopsy findings to reach a balanced approach to counseling on trisomy 18 in early second trimester.

Identified by the eponym "Edwards' Syndrome," trisomy 18 (T18) represents the second most common autosomal trisomy after T21. The pathophysiology underlying the extra chromosome 18 is a nondisjunction error, mainly linked with the advanced maternal age. More frequent in female fetuses, the syndrome portends high mortality, reaching a rate of 80% of miscarriages or stillbirths. The three-step evaluation includes first trimester screening for fetal aneuploidy using a combination of maternal age, fetal nuchal translucency thickness, fetal heart rate and maternal serum free ß-hCG and PAPP-A; followed by the research for fragments of fetal DNA in maternal blood; and, finally, invasive techniques leave to the established diagnosis. Starting with the first trimester scan, selected ultrasound findings should be investigated to define not only the impact of the genetic problem on the fetus, but also to address the prenatal counseling. Previous series underline that T18 is not uniformly lethal. An active dialogue on the choices in the management of infants with T18 has emerged, sustained by the transition from the comfort care to the intervention attitude. Survival rates for individuals with supposedly fatal conditions have increased. In this novel scenario, an ad hoc counseling is pivotal. To support it, a comparative analysis by pictorial assays between ultrasound and autopsy findings could be beneficial. We provide an illustrative tool from a clinical case managed in early second trimester, with the purpose to strive a balanced approach in the hard choice faced by couples of fetuses with T18.

Is there still a role for nuchal translucency measurement in the changing paradigm of first trimester screening?

OBJECTIVES: To give an overview of the genetic and structural abnormalities occurring in fetuses with nuchal translucency (NT) measurement exceeding the 95th percentile at first-trimester screening and to investigate which of these abnormalities would be missed if cell-free fetal DNA (cfDNA) were used as a first-tier screening test for chromosomal abnormalities. METHODS: This is a national study including 1901 pregnancies with NT≥95th percentile referred to seven university hospitals in the Netherlands between 1 January 2010 and 1 January 2016. All cases with unknown pregnancy outcome were excluded. Results of detailed ultrasound examinations, karyotyping, genotyping, pregnancy and neonatal outcomes, investigation by a clinical geneticist and post-mortem investigations were collected. RESULTS: In total, 821 (43%) pregnancies had at least one abnormality. The rate of abnormalities was 21% for fetuses with NT between 95th and 99th percentile and 62% for fetuses with NT≥99th percentile. Prevalence of single-gene disorders, submicroscopic, chromosomal and structural abnormalities was 2%, 2%, 30% and 9%, respectively. CONCLUSION: Although cfDNA is superior to the combined test, especially for the detection of trisomy 21, 34% of the congenital abnormalities occurring in fetuses with increased NT may remain undetected in the first trimester of pregnancy, unless cfDNA is used in combination with fetal sonographic assessment, including NT measurement.

Prenatal screening in the era of non-invasive prenatal testing: a Nationwide cross-sectional survey of obstetrician knowledge, attitudes and clinical practice.

BACKGROUND: Non-invasive prenatal testing (NIPT) has revolutionized the prenatal screening landscape with its high accuracy and low false positive rate for detecting Trisomy 21, 18 and 13. Good understanding of its benefits and limitations is crucial for obstetricians to provide effective counselling and make informed decisions about its use. This study aimed to evaluate obstetrician knowledge and attitudes regarding NIPT for screening for the common trisomies, explore how obstetricians integrated NIPT into first-line and contingent screening, and determine whether expanded use of NIPT to screen for sex chromosome aneuploidies (SCAs) and microdeletion/microduplication syndromes (CNVs) was widespread. METHODS: A questionnaire was designed and administered with reference to the CHERRIES criteria for online surveys. Doctors on the Obstetrics & Gynaecology trainee and specialist registers were invited to participate. Medians and 95% confidence intervals (CI) were reported for confidence and knowledge scores. RESULTS: 94/306 (30.7%) doctors responded to the survey. First trimester screening (FTS) remained the main method offered to screen for the common trisomies. 45.7% (43/94) offered NIPT as an alternative first-line screen for singletons and 30.9% (29/94) for monochorionic diamniotic twins. A significant proportion offered concurrent NT and NIPT (25/94, 26.6%), or FTS and NIPT (33/94, 35.1%) in singletons. Varying follow up strategies were offered at intermediate, high and very-high FTS risk cut-offs for Trisomy 21. Respondents were likely to offer screening for SCAs and CNVs to give patients autonomy of choice (53/94, 56.4% SCAs, 47/94, 50% CNVs) at no additional cost (52/94, 55.3% SCAs, 39/94, 41.5% CNVs). Median clinical knowledge scores were high (10/12) and did not differ significantly between specialists (95% CI 10-11) and non-specialists (95% CI 9.89-11). Lower scores were observed for scenarios in which NIPT would be more likely to fail. CONCLUSIONS: Our findings show the diversity of clinical practice with regard to the incorporation of NIPT into prenatal screening algorithms, and suggest that the use of NIPT both as a first-line screening tool in the general obstetric population, and to screen for SCAs and CNVs, is becoming increasingly prevalent. Clear guidance and continuing educational support are essential for providers in this rapidly evolving field.

Measurement of inferior facial angle and prefrontal space ratio in first trimester fetuses with aneuploidies: a retrospective study.

Objective To determine whether the measurement of inferior facial angle (IFA) and prefrontal space ratio (PFSR) in two-dimensional (2D) ultrasound images in the first trimester of pregnancy is reliable and to describe these markers in normal and aneuploid fetuses. Methods IFA and PFSR were measured in stored 2D midsagittal images of 200 normal and 140 aneuploid fetal profiles between 11 + 0 and 13 + 6 weeks of gestation. Limits of agreement (LOAs) and intraclass correlation coefficients (ICCs) for inter- and intraobserver differences were calculated. Results The mean IFA in normal fetuses was 76.5° ± 6.3. Between the two measurement rounds of the same observer, the LOAs were -5.4 to 7.1 (obs. 1) and 7.4 to 8.4 (obs. 2). For IFA measurements by the same observer the ICC was 0.88 (obs. 1) and for measurements by two different observers the ICC was 0.74. The mean PFSR was 0.76 ± 0.40 and the intraobserver LOAs were -0.372 to 0.395 (obs. 1) and -0.555 to 0.667 (obs. 2). For PFSR measurements by the same observer the ICC was 0.89 (obs. 1) and for measurements by two different observers the ICC was 0.65. Among aneuploid fetuses, IFA was below the normal range in one third of the cases with trisomy 18. PFSR was below the 95% prediction limit in 16.2% of fetuses with trisomy 21% and 17.9% of fetuses with trisomy 18. Conclusion IFA can be reliably measured in 2D ultrasound images in the first trimester of pregnancy with a high interobserver agreement and may provide information about retrognathia associated with various syndromes and aneuploidies at early stages of pregnancy.

First trimester uterine artery pulsatility index levels in euploid and aneuploid pregnancies.

OBJECTIVE: To examine whether the uterine artery PI is different in aneuploid and euploid pregnancies. METHODS: Retrospective case-matched study at the department of prenatal medicine at the University of Tuebingen, Germany. The study involved patients with complete data on first trimester screening for trisomies and preeclampsia except PlGF. For each case with trisomy 21 we randomly selected 50 cases with a euploid fetus where complete data on screening for aneuploidy and preeclampsia were also available. The uterine artery pulsatility index and the corresponding MoM values of euploid and the aneuploid population were compared with a Man-Whitney U test. RESULTS: The dataset consisted of 4591 singleton pregnancies. The karyotype was normal in 4500 cases and was abnormal in the remaining 91 pregnancies. There were 50 pregnancies with trisomy 21, 31 with trisomy 18 and 13, and 10 with triploidy. In the group with euploid fetuses, median uterine artery PI was 1.55 (0.99 MoM). In the group with trisomy 21, the median PI (1.42) and MoM (0.89) levels were both significantly lower than in the euploid (p < 0.001). However, the measurements in the trisomy 18 and 13 [1.61 (0.93 MoM)] and in the triploidy [1.99 (1.13 MoM)] groups were not significantly different from those in the euploid group (p = 0.468 and p = 0.632, respectively). CONCLUSION: In conclusion, uterine artery PI levels in the first trimester are slightly lower in pregnancies with trisomy 21. This knowledge may prove to be useful in cases where a low PAPP-A level is seen on the first trimester maternal serum biochemical evaluation to differentiate whether the more likely cause for this finding is placental dysfunction or aneuploidy, specifically trisomy 21.

Long Survival of a Patient with Trisomy 18 and Dandy-Walker Syndrome.

Trisomy 18 is a genetic disease resulting from an extra chromosome 18, characterized by a broad clinical spectrum, poor prognosis and low rates of survival. This is the case of a 12 year-old girl diagnosed with full trisomy 18, and multiple malformations, including Dandy-Walker Syndrome and congenital heart defects on long term survival. At nine months, a new echocardiogram showed a double outlet right ventricle, significant pulmonary stenosis, patent ductus arteriosus and ventricular septal defect. Cardiac surgery was performed at one year and seven months. Early surgical intervention and multidisciplinary follow-up may change the clinical outcome of the disease. Further studies are required to evaluate the benefit of invasive procedures such as cardiac surgery on survival of patients with trisomy 18.

Utility of fetal anteroposterior to transverse cerebellar diameter ratio to exclude cerebellar hypoplasia in trisomy 18.

AIM: This study was aimed to determine reference ranges for fetal cerebellar hemisphere biometry, including the transverse cerebellar diameter (TCD), anteroposterior cerebellar diameter (APCD) and APCD/TCD ratio in normal fetuses. In addition, we investigated which parameter would be useful for cerebellar hypoplasia in trisomy 18. METHODS: This retrospective study included 340 normal singleton pregnancies and 15 cases of trisomy 18, in all of which fetal cerebellar biometry was performed between 14 and 40 weeks of gestational age (GA). The TCD, APCD and APCD/TCD ratio were assessed ultrasonographically. RESULTS: In normal fetuses, the TCD (rs = 0.876, P < 0.001) and APCD (rs = 0.791, P < 0.001) were strongly correlated with GA. However, the APCD/TCD ratio was not correlated with GA (rs = 0.058, P = 0.289), with median values of 0.52. Low TCD, APCD and APCD/TCD ratio values were detected in 53%, 100% and 100% of trisomy 18 cases, respectively. The median APCD/TCD ratio for trisomy 18 was 0.39 (range, 0.30-0.43), which was significantly lower than that of normal fetuses (P < 0.001). A cut-off APCD/TCD ratio of 0.44 served as a good predictor for trisomy 18 (sensitivity 100%, specificity 95.3% and negative predictive value 100%). CONCLUSION: This study shows that TCD and APCD are correlated with GA, while the APCD/TCD ratio is a fixed value throughout gestation. Using the APCD/TCD ratio to assess cerebellar hypoplasia in trisomy 18 is useful because it does not require the individual evaluation of the TCD and APCD.

Sphenofrontal distance in euploid and aneuploid fetuses.

OBJECTIVE: To examine the sphenofrontal distance (SFD) in a large series of aneuploid fetuses in the second and third trimesters and compare findings with those of a euploid population. METHODS: The database at our unit was searched to identify pregnancies with a diagnosis of trisomy 21, 18 or 13, triploidy or Turner syndrome after 15 weeks' gestation. Stored ultrasound images obtained between 19 and 22 weeks were reviewed. For the normal population, two euploid fetuses matched for gestational age were selected randomly for each aneuploid case. The SFD was measured from the anterior edge of the sphenoid bone to the lowest posterior edge of the frontal bone using on-screen calipers. The SFD measurement was parallel to the long axis of the maxilla. If the sphenoid bone did not extend superiorly enough for direct measurement of the SFD, a tangential line was drawn at the anterior wall of the sphenoid bone and extended cranially. In these cases, the distance between the extended line and the frontal bone was measured. One operator measured the SFD twice and was blinded to the results and karyotype. RESULTS: The study population consisted of 591 pregnancies: 394 euploid fetuses, 122 fetuses with trisomy 21, 45 with trisomy 18, 16 with trisomy 13, eight with Turner syndrome and six with triploidy. For both euploid and aneuploid groups, mean gestational age at examination was 22.8 (range: euploid, 15.0-40.7; aneuploid, 15.0-40.3) weeks. For euploid fetuses, mean SFD was 1.27 cm and measurements ranged from 0.53 cm to 2.56 cm. SFD was significantly dependent on gestational age (SFD = 0.138 + 0.005 × gestational age, P < 0.001, r = 0.802). Mean SFD was significantly smaller in each aneuploid group compared with the euploid population (trisomies 21, 18 and 13: all P < 0.001; triploidy: P = 0.026; Turner syndrome: P = 0.047). For 32 (26.2%), nine (20.0%) and six (37.5%) fetuses with trisomy 21, 18 and 13, respectively, SFD was < 5th percentile. Only one (12.5%) fetus with Turner syndrome and none with triploidy had SFD < 5th percentile. CONCLUSION: In aneuploid fetuses, the SFD is smaller than in their euploid counterparts. However, for a false-positive rate of 5%, the detection rate of trisomy 21 is only 26%. Therefore, using the method we have proposed, it is unlikely that this marker will play a major role in second- and third-trimester screening for aneuploidy. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Chromosomal Microarray Analysis Results From Pregnancies With Various Ultrasonographic Anomalies.

OBJECTIVE: To examine chromosomal microarray analysis results in pregnancies with various ultrasonographic anomalies and to characterize the copy number variants in diverse fetal phenotypes. METHODS: We retrospectively examined chromosomal microarray analyses of amniocenteses performed nationwide as a result of fetal ultrasonographic anomalies (structural defects, fetal growth restriction, and polyhydramnios) between January 2013 and September 2017. The rate of abnormal chromosomal microarray findings was compared between the different phenotypes and with a previously described control population of 15,225 pregnancies with normal ultrasonographic findings. RESULTS: Clinically significant chromosomal microarray aberrations were detected in 272 of 5,750 pregnancies (4.7%): 115 (2%) karyotype-detectable and 157 (2.7%) submicroscopic. Most commonly detected copy number variants were 22q11.21 deletions (0.4%) followed by 22q11.21 gain of copy number (0.2%). Specific copy number variants detected among pregnancies with abnormal ultrasonographic findings were up to 20-fold more prevalent compared with low-risk pregnancies. Some variants were associated with specific phenotypes (eg, 22q11.21 microdeletions with cardiovascular and 17q12 microdeletions with genitourinary defects). CONCLUSION: The rate of abnormal amniotic chromosomal microarray analysis results is twice that of karyotypic abnormalities in pregnancies with various abnormal ultrasonographic findings.

Hypoxia due to positive pressure ventilation in Edwards' syndrome: A case report.

Edwards' syndrome also known as trisomy 18 is a congenital disorder associated with cardiovascular issues including ventricular septal defect (VSD), atrial septal defect (ASD) and patent duct arteriosus (PDA). An emergency colostomy was performed on a neonate born with an imperforate anus. Pre-operative transthoracic echocardiography showed presence of VSD, a patent foramen ovale (PFO) or ASD. Even though the baby had a good general condition and optimal peripheral oxygen saturation (SpO2), during positive pressure ventilation, she suffered severe hypoxia (50% SpO2). The cause of the hypoxia was thought to be the right-left shunt and so during a second attempt at anaesthesia a vasopressor (noradrenaline 0.03 µg/kg/min) was infused to increase systemic vascular resistance. Thereafter, SpO2 increased to 80-90% and the surgery was completed. The baby recovered without any neurological complications. Genetic testing post-partum showed she had Edwards' syndrome.

Application of Neural Networks for classification of Patau, Edwards, Down, Turner and Klinefelter Syndrome based on first trimester maternal serum screening data, ultrasonographic findings and patient demographics.

BACKGROUND: The usage of Artificial Neural Networks (ANNs) for genome-enabled classifications and establishing genome-phenotype correlations have been investigated more extensively over the past few years. The reason for this is that ANNs are good approximates of complex functions, so classification can be performed without the need for explicitly defined input-output model. This engineering tool can be applied for optimization of existing methods for disease/syndrome classification. Cytogenetic and molecular analyses are the most frequent tests used in prenatal diagnostic for the early detection of Turner, Klinefelter, Patau, Edwards and Down syndrome. These procedures can be lengthy, repetitive; and often employ invasive techniques so a robust automated method for classifying and reporting prenatal diagnostics would greatly help the clinicians with their routine work. METHODS: The database consisted of data collected from 2500 pregnant woman that came to the Institute of Gynecology, Infertility and Perinatology "Mehmedbasic" for routine antenatal care between January 2000 and December 2016. During first trimester all women were subject to screening test where values of maternal serum pregnancy-associated plasma protein A (PAPP-A) and free beta human chorionic gonadotropin (ß-hCG) were measured. Also, fetal nuchal translucency thickness and the presence or absence of the nasal bone was observed using ultrasound. RESULTS: The architectures of linear feedforward and feedback neural networks were investigated for various training data distributions and number of neurons in hidden layer. Feedback neural network architecture out performed feedforward neural network architecture in predictive ability for all five aneuploidy prenatal syndrome classes. Feedforward neural network with 15 neurons in hidden layer achieved classification sensitivity of 92.00%. Classification sensitivity of feedback (Elman's) neural network was 99.00%. Average accuracy of feedforward neural network was 89.6% and for feedback was 98.8%. CONCLUSION: The results presented in this paper prove that an expert diagnostic system based on neural networks can be efficiently used for classification of five aneuploidy syndromes, covered with this study, based on first trimester maternal serum screening data, ultrasonographic findings and patient demographics. Developed Expert System proved to be simple, robust, and powerful in properly classifying prenatal aneuploidy syndromes.

Dandy-Walker syndrome with duplex kidney abnormalities in trisomy 18 - A rare case report.

OBJECTIVE: Trisomy 18 is one of the major numerical chromosomal disorders. The incidence of trisomy 18 is approximately one in 6000 live births. Dandy-Walker malformation (DWM) is the most common congenital malformation of the cerebellum, with an incidence of about one in 5000 live births. The incidence of trisomy 18 associated with DWM is rare and long-term survival rate is very low. CASE REPORT: A case involving a 39-year-old pregnant female with a case of trisomy 18 associated with DWM. CONCLUSION: The incidence of trisomy 18 associated with DWM is rare, and our report presents an unusual case that supplements our knowledge of this condition. We report a case involving a 39-year-old pregnant female with a case of trisomy 18 associated with Dandy-Walker malformation (DWM). Fetal ultrasonography showed hypoplasia of the cerebellar vermis and dilatation of the fourth ventricle and was characterized by an enlarged posterior fossa. Fetal magnetic resonance imaging showed inferior vermian hypoplasia and a large posterior fossa cyst communicating with the fourth ventricle causing high insertion of the torcular herophili, which was compatible with DWM. Furthermore, the karyotyping report revealed trisomy 18. The incidence of trisomy 18 associated with DWM is rare, and our report presents an unusual case that supplements our knowledge of this condition.

Sindrome de Edwards o Trisomia 18: reporte de un caso / Edwards syndrome or trisomy 18: a case report

RESUMEN Se presenta un caso de síndrome de Edwards, por sospecha ecográfica desde la semana 18 de gestación, con seguimiento ecográfico 2D, 3D y 4D, confirmado por cariotipo post natal. Óbito 48 hs post nacimiento.

ABSTRACT An Edwards’ case is presented, because of an ultrasound suspicion since the 18th gestation week, with an ultrasound follow-up using 2D, 3D and 4D, confirmed by post natal karyotype. Fetus died after 48 hours of its birth.