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Objective: The aim of the study was to assess the diagnostic yield of 2 different next-generation sequencing (NGS) approaches: gene panel and “solo” clinical exome sequencing (solo-CES), in fetuses with structural anomalies and normal chromosomal microarray analysis (CMA), in the absence of a known familial mutation. Methodology: Gene panels encompassing from 2 to 140 genes, were applied mainly in persistent nuchal fold/fetal hydrops and in large hyperechogenic kidneys. Solo-CES, which entails sequencing the fetus alone and only interpreting the Online Mendelian Inheritance in Man genes, was performed in multisystem or recurrent structural anomalies. Results: During the study period (2015–2020), 153 NGS studies were performed in 148 structurally abnormal fetuses with a normal CMA. The overall diagnostic yield accounted for 35% (53/153) of samples and 36% (53/148) of the fetuses. Diagnostic yield with the gene panels was 31% (15/49), similar to 37% (38/104) in solo-CES. Conclusions: A monogenic disease was established as the underlying cause in 35% of selected fetal structural anomalies by gene panels and solo-CES.

Kagami-Ogata syndrome (KOS14) is a rare congenital disorder associated with defective genomic imprinting of the chromosome 14q32 domain. Typical features include polyhydramnios, small and bell-shaped thorax, coat-hanger ribs, dysmorphic facial features, abdominal wall defects, placentomegaly, severe postnatal respiratory distress and intellectual disability. To the best of our knowledge, this may be the first case where ultrasound findings such as: severe polyhydramnios, a small bell- shaped thorax, a protuberant abdomen and characteristic dysmorphic face prompted directed family interrogation finally leading to the prenatal diagnosis of KOS14.

Introduction Our objective was to evaluate the perinatal outcome of selective termination of dichorionic twin pregnancies with discordant anomalies, according to gestational age at time of procedure. Material and methods Retrospective review of 147 dichorionic twin pregnancies referred to our Fetal Medicine Unit between 2003 and 2018 for selective termination. Gestational age at delivery, fetal loss, and overall and 28-day post-delivery survival rates, were evaluated according to gestational age at time of procedure. Selective termination procedure was defined as early, intermediate, and late when performed before 18 weeks, between 18 and 23 weeks, and after 23 weeks, respectively. Kruskal-Wallis and chi-squared test were used to compare groups. Results Overall survival at 28 days post-delivery, pregnancy loss, and preterm delivery before 32 weeks of gestation rates were 93.4%, 6.9%, and 15.5%, respectively. When stratified by gestational age at procedure, intermediate selective termination was associated with a lower survival rate than early and late procedures (86% vs. 96.9% and 100%, respectively; p = 0.035), and a nonsignificant trend for higher pregnancy loss (12% vs. 3.1%). Preterm delivery before 32 weeks of gestation occurred in 27% of late procedures, which was significantly higher than in early (9.5%) and intermediate (18.2%) procedures. Conclusions Selective termination in dichorionic twin pregnancies with discordant fetal anomaly is associated with low pregnancy loss and preterm delivery rate, primarily when performed before 18 weeks. When legally possible, late procedures can be a good alternative, particularly in those cases diagnosed beyond the 18th week of gestation.

A new maternal age-dependent method to estimate absolute excess risks of trisomy 21, either after a previous trisomy 21 (homotrisomy) or after another trisomy (heterotrisomy), is proposed to be added to the estimated risk by conventional screening methods. Excess risk at term for a subsequent trisomy 21 was calculated from midtrimester risks reported by Morris et al., decreasing from 0.49% at 20 years to 0.01% at 46 years at the index pregnancy. Excess risk after a previous uncommon trisomy was derived from data reported by Warburton et al., decreasing from 0.37% at 20 years to 0.01% at 50 years.

Aim: The potential of uterine artery (UA) Doppler pulsatility index (PI) and maternal serum placental growth factor (PlGF) level to predict perinatal outcome was explored in pregnancies complicated by intrauterine fetal growth restriction (IUGR) or preeclampsia (PE). Methods: This longitudinal, prospective, and case-controlled study was conducted over a period of 24 months. At-risk pregnancies involving small-for-gestational-age (SGA) fetuses, IUGR, gestational hypertension (GH), or PE were investigated, analyzing UA Doppler PI findings and maternal PlGF levels determined at the time of diagnosis (third trimester). Results: UA Doppler PI and maternal serum PlGF values differed significantly in pregnancies complicated by IUGR and/or PE (vs. SGA or GH, p < 0.01). In the context of IUGR or PE, both parameters also differed significantly by perinatal outcome (adverse vs. normal, p < 0.01), although no predictive advantage over UA Doppler PI alone was conferred by adding a PlGF assay. Conclusion: UA Doppler PI and maternal serum PlGF determinations in the third trimester help identify pregnancies at the highest risk of adverse perinatal outcomes due to IUGR and/or PE. Although joint testing confers no predictive benefit over UA Doppler PI alone, the two diagnostics are interchangeable for this purpose.

Objective This study aimed to evaluate the application of two quality assurance methods to the ductus venosus pulsatility index (DVPI), as a first-trimester aneuploidy marker, including retrospective assessment of distribution parameters and cumulative sum (CUSUM) plots. Methods The DVPI was measured in 14 444 singleton fetuses at 11+0 to 13+6 weeks in two Fetal Medicine centers during a 4-year period. Sonologist-specific quality assurance distribution parameters, previously described for nuchal translucency, were assessed: the median multiples of the median (MoM), the logarithmic standard deviation of DVPI MoMs and the weekly DVPI percent decrease. Quality assurance results were compared between median MoMs and MoM-based CUSUM plots. Results When sonologist-specific DVPI distribution parameters were retrospectively applied for quality assurance, a 1.0 median MoM, a 0.1 median logarithmic standard deviation and a 3.4 median weekly DVPI drop percentage were observed. CUSUM plots showed good agreement with 0.9–1.1 MoMs range for median MoM, in the assessment of sonologist-specific performances. Conclusion Retrospective and prospective DVPI quality assurance methods appear to be applicable to DVPI at 11+0 to 13+6 weeks. Its use should be encouraged if DVPI is to be added to first-trimester Down syndrome or cardiac defects screening. © 2013 John Wiley & Sons, Ltd.

BACKGROUND: Prediction of neonatal respiratory morbidity may be useful to plan delivery in complicated pregnancies. The limited predictive performance of the current diagnostic tests together with the risks of an invasive procedure restricts the use of fetal lung maturity assessment. OBJECTIVE: The objective of the study was to evaluate the performance of quantitative ultrasound texture analysis of the fetal lung (quantusFLM) to predict neonatal respiratory morbidity in preterm and early-term (

Background: Little information is available about the risk of microdeletion and microduplication syndromes in fetal growth restriction (FGR) with a normal karyotype. Objective: To assess the incremental yield of genomic microarray over conventional karyotyping in fetuses with early growth restriction. Study Design: Genomic microarray was prospectively performed in fetuses with early growth restriction defined as a fetal weight below the 3rd percentile estimated before 32 weeks of pregnancy, and a normal quantitative fluorescent polymerase chain reaction result. The incremental yield of genomic microarray was defined by the rate of fetuses presenting with a pathogenic copy number variant below 10 Mb. Results: Among 133 fetuses with early FGR, a 6.8% (95% CI: 2.5-11.0) incremental yield of genomic microarray over karyotyping was observed. This incremental yield was 4.8% (95% CI: 0.2-9.3) in isolated FGR, 10% (95% CI: 0-20.7) in FGR with nonstructural anomalies, and 10.5% (95% CI: 0-24.3) in FGR with structural anomalies. Conclusion: Our multicenter study reveals that 6.8% of fetuses with early growth restriction present with submicroscopic anomalies after common aneuploidies were excluded. Even when FGR is observed as an isolated finding, genomic microarray analysis should be considered after or instead of karyotyping, due to its 4.8% incremental yield.

The aim of this study was to assess the performance of first-trimester combined screening when replacing the chronological maternal age by Anti-Mullerian hormone (AMH) and antral follicle count (AFC)-derived ovarian ages, as the background risk in trisomy risk estimation. A total of 639 pregnant women who completed first-trimester combined screening together with AMH and AFC determination were included. Trisomy risks were estimated based on three distinct ‘maternal ages' as a-priori risk (chronological age, AMH- and AFC-derived ovarian age). The screening performance was assessed using three different approaches: received operator curve; detection rate and false positive rates for a fixed 1/250 threshold; and detection rates for a fixed 3% false positive rate. A non-significant trend was shown for AMH-derived age for both an increased area under the curve (0.986 versus 0.979) and an increased detection rate (from 83% to 100%) for a 1/250 risk threshold. For a 3% false-positive rate, a non-significant trend for increased detection with the use of both AMH- and AFC-derived ovarian ages was observed (from 67% to 83%). These results indicate that, although ovarian derived ages seem to potentially reflect a more precise background risk for fetal trisomies, the improvement in screening performance is only residual.

Resumen Un aspecto esencial e imprescindible de los programas de cribado prenatal es el control de calidad. En este sentido, contrariamente a lo que ocurre en el ambito del laboratorio clinico, donde las pruebas analiticas estan sometidas a estrictos controles de calidad para determinar y confirmar su fiabilidad, en el campo de la medicina fetal y mas concretamente en el ambito de la ecografia prenatal, el concepto de evaluacion de la calidad y la certificacion solo recientemente ha sido objeto de interes. En todo programa de cribado prenatal, aunque la tasa de deteccion del sindrome de Down (SD) sigue siendo una prioridad y un indicador de su efectividad, este parametro no puede ser utilizado como un marcador fiable de la calidad del mismo, fundamentalmente debido a la baja prevalencia de dicha condicion. Los esfuerzos en el control de calidad del cribado prenatal de aneuploidias deben incluir indicadores mas fiables, realistas y de aplicacion individualizada. Este articulo pretende revisar y clarificar los conceptos fundamentales en el ambito del control de calidad en el cribado prenatal de aneuploidias y propone estrategias para mejorar su fiabilidad.

Objective: To update the reference ranges for the ductus venosus pulsatility index (DVPI) at 11+0 to 13+6 gestational weeks. Methods: DVPI was calculated in 14,444 singleton fetuses at 11+0 to 13+6 weeks in two Fetal Medicine Centers, during a 4-year period. Using previously described medians, DVPI evolution was assessed both over the study period on a yearly basis and over gestation, grouping fetuses according to 5-mm crown-rump length (CRL) ranges. Weighted DVPI medians, the 5th and 95th percentiles and distribution parameters for unaffected and trisomy 21 fetuses were newly calculated. Results: A significant DVPI multiple of the median decrease was observed over both the study period (p < 0.01) and over gestation (p < 0.01) using previous medians, in the two centers. Newly calculated weighted medians were lower than those previously described, decreasing with CRL. Distribution parameters calculated using the new medians were different from those previously described. Conclusion: DVPI reference ranges were lower than those previously reported and decreased with CRL. Updated medians and distribution parameters should be considered to include the DVPI as a Gaussian marker in trisomy 21 screening and for quality control purposes.

Objective Quantitative analysis of the quality of nuchal translucency (NT) measurements. Methods This is a retrospective single-center study. NT was measured according to the Fetal Medicine Foundation (FMF) criteria by 20 trained obstetricians (October 2003-November 2009). The performance of NT measurements was analyzed with regard to several quality control standards. Accuracy according to experience, professional profile, crown-rump length (CRL) values and FMF certification was statistically tested. Results A total of 14,978 NT measurements were assessed. (1) The mean operator-specific median NT-MoM values was 0.98. (2) Mean percentage of cases >95th and 60 mm had a statistical impact improving these standards. Conclusion Overall quality standards show optimal NT measurements in our unit. Experience a dedicated profile to fetal medicine ultrasound, CRL over 60 mm and FMF certification has a significant positive impact on the quality standards.

Resumen Objetivos Valoracion de la via y el modo de finalizacion de la segunda gestacion en pacientes con cesarea anterior (CA) por desproporcion pelvi-fetal (DPF). Material y metodos Hemos revisado 102 pacientes con CA y gestacion superior a 40 semanas, en las que se realiza induccion de parto (54 casos) o cesarea electiva (48 casos) y 98 pacientes con CA por DPF que inician trabajo de parto espontaneamente. Resultados Gestacion cronologicamente prolongada (GCP) con CA por DPF: el 51% de los casos finaliza la gestacion con cesarea electiva y el 49% con induccion de parto. De estos, el 65% acaba con cesarea durante el trabajo de parto y el 35% con parto vaginal. Induccion segun motivo de CA: CA por DPF, el 35% acaba en parto vaginal versus el 65%, que acaba en cesarea durante trabajo de parto. En CA por induccion fallida, el 45 versus el 55%. En CA por presentacion de nalgas, el 28 versus el 72%. En CA por riesgo de perdida de bienestar fetal, el 66% versus el 33%, y en CA por otras causas, el 62 versus el 38%. Estas diferencias son estadisticamente significativas. De las CA por DFP que inician trabajo de parto espontaneamente, el 36% acaba en cesarea y el 64% en parto vaginal. En estos resultados hay diferencias significativas con inducciones por GCP en CA con DPF. La edad gestacional media del inicio de parto espontaneo es de 39,63 semanas, concentrandose el 81% del total entre 39–41 semanas. Conclusiones Consideramos indicado conducta expectante en gestantes con CA por DPF hasta la semana 41 y, en este momento, decidir cesarea electiva o induccion de parto.

Synchronous primary cancers of the endometrium and ovary are found in 10% of women with ovarian cancer and 5% of women with endometrial cancer. The classification into synchronous primary cancers or metastasis has different consequences in the prognosis and treatment. But this classification is still difficult. We describe four cases from our service. Endometrioid cancers are the most frequent and have the best prognosis. The median age of the patients is younger than patients with metastasic tumours and the most common sign or symtom is abnormal uterine bleeding. Treatment is still controversial.

Objectives To design a cumulative sum (CUSUM) test for prospective nuchal translucency (NT) measurement quality review that is as stringent as the retrospective quality review methods based on distribution parameters currently in use. Methods The database including all fetal NT measurements obtained during a 2-year period in a single center was reviewed, and measurements obtained by sonologists who measured fewer than 100 cases were excluded. The NT distribution parameters proposed by The Fetal Medicine Foundation (FMF) and the Women & Infants Hospital of Rhode Island (WIHRI) were assessed in the whole NT series and in sonologist-specific distributions. A previously described CUSUM model was adapted to fulfil our objective. Results Two thousand four hundred and seventy-five NT measurements were obtained by seven sonologists during the study period (January 2007–December 2008). In the assessment of sonologist-specific NT distributions, two sonologists fulfilled all the FMF and WIHRI criteria, one showed NT overestimation and four failed due to NT underestimation. Our new CUSUM test model, based on multiples of the median deviations, showed good agreement with the FMF and WIHRI methods in the assessment of sonologist-specific performance. Conclusions Our CUSUM test model showed close agreement with the retrospective quality review methods based on distribution parameters currently in use, but with the advantage that it can be applied prospectively, allowing for earlier correction of deviations from target performance. Copyright © 2011 ISUOG. Published by John Wiley & Sons, Ltd.

To determine the relation between weight deficit at birth and IGF-I, IGFBP-I, Leptin, and AFP levels in amniotic fluid after 14-18 weeks; to assess the diagnostic usefulness of these biochemical markers.Longitudinal, prospective study. Amniocentesis was performed in pregnant women after 14-18 weeks of gestation.86 controls, 18 IUGR10 percentile, and 17 IUGR5 percentile.No significant correlation was found between severity of IUGR and IGF-I, IGFBP-I, or Leptin. AFP was inversely correlated with severity of IUGR; results for the IUGR10 percentile were: S: 65.7%, SP: 56.9%, PPV: 38.3%, NPV: 80.3%, and an overall diagnostic capacity of 65.6%. Results for the IUGR5 percentile were: S: 76.4%, SP: 54.8%, PPV: 21.6%, NPV: 93.4% were obtained, and an overall capacity of 70.6%.Elevated values of AFP in amniotic fluid may help early detection of populations at risk of developing IUGR.

Setting: Prenatal diagnosis unit of the Suleymaniye Maternity Hospital and Dr. Fehmi Yazicioglu’s FMF center Materials and Methods: All women screened with a protocol including nuchal translucency + nasal bone + tricuspid regurgitation + biochemistry during the first trimester and having known outcome data were reevaluted retrospectively by dropping out the TR data and recalculation of the risks using the FMF software. With a risk level of 1/300 as the threshold for invasive testing, the diagnostic efficiency of both models for the diagnosis of aneuploidy was compared in terms of sensitivity, specifity and positive and negative predictive values. Findings: A total of 429 patients with a mean age 28,6 ± 5,1 had complete outcome data after FTS. 8 fetuses had aneuploidy consisting of trisomy 21, 18, 13 and 5pin 4, 2, 1and 1fetuses respectively. 28 in TR and 23 in non TR protocol were screen positive. Both models could identify 7 of 8 aneuploidies. False positive rate was 4.8% with and 3.7% without TR. The sensitivity, specifity, positive and negative predictive values of the FTS with and without TR were 0.87, 0.95, 0.25, 0.99 and 087, 0.96, 0.30, 0.99 respectively. Conclusions: Adding TR to FTS in a low risk population resulted in increased false positivity without affecting the overall sensitivity for aneuploidy

Objective: To determine if the fetal peripheral pulmonary artery Doppler evaluation can predict the presence of lethal pulmonary hypoplasia in cases of congenital diaphragmatic hernia. Methods: Distal pulmonary artery Pulsatility Index (PI) was calculated in 13 pregnancies with congenital diaphragmatic hernia between 32 and 36 gestational weeks. Associated malformations were discarded by a normal second trimester ultrasound and a normal echocardiography in all cases except one presenting a coarctation of the aorta, this one was eliminated for the posterior data analysis. Associated chromosomal defects were also discarded by fetal kariotype in all cases. Other variables as the presence of polyhydramnios, the side of the hernia, the presence of stomach or liver herniation, the gestational weeks at diagnosis, the weight at birth and the newborn evolution were also recorded. All these variables were compared between the cases that died postnatally and the one’s that survive. Results: All deaths were attributable to pulmonary hypoplasia. The distal pulmonary artery PI was higher in the group that died than in the survivors (P < 0.01); with a mean of PI value of 2.64 (95% CI 2.51–2.76) in those dying and a mean of 2.05 (95% CI 1.71–2.39) in the survivors. All the other analysed values did not present differences between the two groups. Conclusions: Distal pulmonary artery Doppler PI may be useful in the prediction of lethal pulmonary hypoplasia in fetuses affected with congenital diaphragmatic hernia. These results agree with other author’s works which suggest lower pulmonary artery PI values in fetuses without risk of developing pulmonary hypoplasia, showing a low resistance vascular pulmonary bed.