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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.

STUDY QUESTION Can maternal plasma cell-free DNA (cfDNA) detect chromosomal anomalies in early pregnancy loss (EPL) and recurrent pregnancy loss (RPL)? SUMMARY ANSWER Genome-wide cfDNA testing can serve as an alternative to cytogenetic analysis in products of conception (POCs) in RPLs and can guide further management. WHAT IS KNOWN ALREADY Random chromosomal anomalies are the single most common cause for EPL and RPL. Cytogenetic analysis in POCs may be used to direct management in RPL because the detection of random chromosomal anomalies can eliminate further unwarranted testing. STUDY DESIGN, SIZE, DURATION This was a prospective diagnostic test study from March 2018 to January 2019 of 109 patients experiencing pregnancy loss before 14 weeks gestation at a tertiary-care academic medical center. PARTICIPANTS/MATERIALS, SETTING, METHODS Blood samples were drawn for genome-wide cfDNA testing prior to chorionic villous sampling for cytogenetic analysis of POCs with both short-term cultures (STCs) and long-term cultures (LTCs). Final analysis included 86 patients with non-mosaic cytogenetic results in POCs and available cfDNA results. Aneuploidy detection rates by cfDNA testing and POC cytogenetic analysis were compared. The first 50 samples served as the Training Set to establish pregnancy loss-specific log-likelihood ratio (LLR) thresholds using receiver-operator characteristic (ROC)-like analyses. These were then used for the entire cohort. MAIN RESULTS AND THE ROLE OF CHANCE Seventy-eight samples (71.5%) had results available from both STC and LTC; 12 samples (11%) had a result from STC only, and 7 samples (6.4%) had a result from LTC only. A chromosomal anomaly was detected in 55/86 (64%). The rates of chromosomal anomalies were 61, 72, 73 and 44% in patients undergoing their first, second, third and ≥4th pregnancy losses, respectively. The median cfDNA fetal fraction was 5%. With standard LLR thresholds used for noninvasive prenatal screening, the sensitivity of cfDNA in detecting aneuploidy was 55% (30/55) and with a specificity of 100% (31/31). Using pregnancy loss-specific LLR thresholds, the sensitivity of cfDNA in detecting aneuploidy was 82% (45/55), with a specificity of 90% (28/31). The positive and negative likelihood ratios were 8.46 and 0.20, respectively. Fetal sex was correctly assigned in all cases. LIMITATIONS, REASONS FOR CAUTION Cases with a false-positive result by cfDNA analysis would not receive the indicated RPL workup. Specificity could be improved by using a fetal fraction (FF) cutoff of 4%, but this would result in exclusion of more than a quarter of cases. WIDER IMPLICATIONS OF THE FINDINGS cfDNA-based testing can serve as an alternative to POC cytogenetic analysis and can guide further RPL management: if cfDNA demonstrates aneuploidy, no further action is taken and if no abnormality is detected, the recommended RPL workup is performed. STUDY FUNDING/COMPETING INTEREST(S) Cell-free DNA testing was funded by Illumina, Inc., San Diego, CA. Y.Y. is a member of Illumina’s Clinical Expert Panel and has received travel grants. A.B. has received travel grants from Illumina. All authors have no competing interest to declare.

OBJECTIVE To assess the frequency of atypical chromosomal and submicroscopic anomalies, as well as fetal structural abnormalities, observed on first-trimester ultrasound scan in fetuses with nuchal translucency (NT) thickness > 99th centile, in order to evaluate the suitability of using standard cell-free DNA (cfDNA) testing as the sole screening test in these pregnancies. METHODS This was a retrospective cohort study of 226 fetuses with NT > 99th centile at 11-14 weeks' gestation, between January 2013 and December 2017, in a clinical setting in which greater than 95% of pregnant women receive first-trimester combined screening. All patients underwent genetic testing by means of quantitative fluorescence polymerase chain reaction and chromosomal microarray analysis, mainly in chorionic villus samples. We assessed the theoretical yield of two cfDNA testing models, targeted cfDNA (chromosomes 21, 18 and 13) and extended cfDNA (chromosomes 21, 18, 13 and sex chromosomes), and compared it with that of cytogenetic testing and ultrasound assessment in the first and second or third trimesters. RESULTS In the 226 fetuses analyzed, cytogenetic testing revealed 84 (37%) anomalies, including 68 typical aneuploidies (involving chromosomes 13, 18 or 21), six sex chromosome aneuploidies (four cases of monosomy X and two of trisomy X), three clinically relevant atypical chromosomal anomalies (one trisomy 22, one trisomy 21 mosaicism and one unbalanced translocation), five submicroscopic pathogenic variants and two cases with Noonan syndrome. Targeted and extended cfDNA testing would miss at least 12% (10/84) and 19% (16/84), respectively, of genetic anomalies, accounting for 4.4% and 7.1% of the fetuses with an increased NT, respectively. Finally, of the 142 fetuses with no identified genetic anomaly, a major fetal malformation was observed in 15 (10.6%) fetuses at the early anomaly scan, and in 19 (13.4%) in the second or third trimester. CONCLUSIONS cfDNA does not appear to be the appropriate genetic test in fetuses with NT > 99th centile, given that it would miss 12-19% of genetic anomalies in this group. Additionally, first-trimester ultrasound will identify a major structural abnormality in 11% of the fetuses with NT > 99th centile and no genetic anomaly. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Objective: To assess whether the cisterna magna (CM) width measured in first-trimester fetuses is a useful marker for aneuploidy detection. Methods: This was a prospective study in 2 different cohorts in a tertiary referral center. The first cohort comprised 913 fetuses from the general pregnancy population during the period 2012–2016 and was used to construct the CM reference ranges applying the λ-μ-σ (LMS) method. The second cohort included 714 high-risk fetuses undergoing chorionic villus sampling during the period 2012–2016. Mean detection rates using the 95th percentile for CM width observed in chromosomal anomaly groups were compared with those obtained in chromosomally normal fetuses. Results: The 50th percentile for CM ranged from 1.66 to 2.75 mm when crown-rump length (CRL) increased from 45 to 84 mm. Among high-risk fetuses, the following chromosomal anomalies were diagnosed in 125 (17%) fetuses: trisomy 21 (n = 63), trisomy 18 or 13 (n = 21), monosomy X (n = 9), submicroscopic anomalies (n = 11), and other anomalies (n = 22). The mean CM width for euploid fetuses was 2.4 mm (1.13 multiples of the median, MoM). While CM width was significantly increased in trisomy 21 (mean 2.7 mm; 1.23 MoM; p > 0.05), no differences were found in the other anomaly groups. Among the 63 fetuses with trisomy 21, a CM width above the 99th percentile was observed in 23 fetuses (37%). Conclusions: The new reference range for CM width at 11–13 weeks of gestation did not differ from previous studies. In first-trimester fetuses with trisomy 21, CM width appears to be increased, although its value as an ultrasound marker is limited, because of its detection rate of 37%.

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.

Objective To assess fetal cardiac function in first-trimester trisomy-21 fetuses as compared with fetuses with other aneuploidies, euploid fetuses with cardiac defects or isolated increased nuchal translucency (NT) and controls. Methods During a 2.5-year period, NT, ductus venosus (DV) blood flow, diastolic filling time, early filling time, tricuspid flow, tricuspid and mitral valve E/A velocity ratios, left ventricle shortening fraction, left myocardial performance index and fetal heart rate were assessed in fetuses with a crown–rump length between 45 and 84 mm undergoing chorionic villus sampling at our center. Cardiac parameters among study groups were compared with the use of 95% CIs. Results The study population comprised 28 fetuses with trisomy 21, 25 with other aneuploidies, 94 euploid fetuses with abnormal findings (27 with cardiac defects, 31 with other structural anomalies and 36 with isolated increased NT) and 271 controls. Trisomy-21 fetuses showed signs of diastolic dysfunction such as increased DV pulsatility index and E/A ratios together with a higher prevalence of tricuspid regurgitation. However, no differences were found in euploid fetuses with cardiac defects or isolated increased NT. Conclusions No signs of cardiac dysfunction were observed in euploid fetuses with increased NT or cardiac defects, while in trisomy-21 fetuses signs of diastolic dysfunction could be potentially attributed to volume overload. Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.

Objective The aim of this study was to assess the role of nuchal translucency (NT) in the prediction of unbalanced translocation in offspring of couples in which one of the parents is a balanced translocation carrier. Material and methods From January 1996 to December 2012, fetal NT was measured before chorionic villus sampling in 86 pregnancies referred because of parental balanced translocation. Results No significant differences in pregnancy characteristics and in NT expressed in millimetres or in multiples of the median (MoMs) were observed between the 41 fetuses with a normal karyotype [1.72 mm, 95% confidence interval (CI): 1.49–1.96; 1.14 MoM; 95% CI: 1.01–1.26], the 38 fetuses with balanced translocations (1.78 mm, 95% CI: 1.44–2.12; 1.22 MoM; 95% CI: 1.01–1.43) and the 7 fetuses with unbalanced translocations (2.21 mm, 95% CI: 1.33–3.09; 1.59 MoM; 95% CI: 0.72–2.45). The proportions of fetuses with NT above 95th centile in the three groups were 9.1% in fetuses with normal karyotype, 18.4% in balanced translocations and 28.6% in unbalanced translocations, not significantly different. Conclusion Although a trend to an increased NT was observed in fetuses with unbalanced translocation, no significant differences were reached. According to our results, a normal NT evaluation should not preclude the performance of CVS in pregnancies of balanced translocation parents. © 2014 John Wiley & Sons, Ltd.

Objective To investigate whether increased nuchal translucency (NT) in fetuses with a crown–rump length (CRL) below 45 mm needs to be re-evaluated at a later stage, or whether the early NT measurement can be used effectively as an aneuploidy marker. Methods This was a prospective cohort study including all singleton fetuses with a CRL between 28 and 44 mm, scanned in our center during 2002–2012. The CRL, NT, fetal karyotype (when available) and pregnancy outcome were recorded. NT reference ranges were constructed using the Lambda-Mu-Sigma (LMS) method in non-referred pregnancies after exclusion of chromosomal anomalies. The 95th percentile was used to calculate detection rates for chromosomally abnormal fetuses. Results NT was successfully measured in 643 of 672 fetuses with a CRL of 28–44 mm. Subsequent cytogenetic analysis revealed 11 cases of trisomy 21, 14 cases of trisomy 13 or 18, three cases of monosomy X, three sex trisomies, three triploidies and 12 balanced anomalies. NT was above the 95th percentile in 64% of the fetuses with trisomy 21, in 71% with trisomy 13 or 18 and in all three cases of monosomy X. Conclusion NT appears to be useful as a marker for the early detection of fetal trisomies at 9–10 weeks' gestation (28–44 mm CRL). Copyright © 2013 ISUOG. Published by John Wiley & Sons Ltd.

Resumen La amniocentesis es un procedimiento de diagnostico prenatal invasivo de segundo trimestre, descrito inicialmente en 1966 por Steele y Berg. Consiste en la introduccion de una aguja espinal a traves de la pared abdominal, la pared uterina y la cavidad amniotica bajo guia ecografica continua, de forma que se pueda aspirar una muestra del liquido amniotico que envuelve el feto y que contiene celulas de origen fetal. La amniocentesis se realiza a partir de las 16 semanas de gestacion y en el liquido amniotico se pueden realizar estudios cromosomicos, bioquimicos, moleculares o microbiologicos. El procedimiento conlleva un riesgo de perdida fetal de aproximadamente el 0,5% cuando se realiza en el segundo trimestre, despues de la fusion de la membrana amniotica con el corion, ademas de un riesgo menor de otras complicaciones, como la perdida de liquido amniotico (0,3%), hemorragia placentaria, infeccion intraamniotica, hematoma de la pared abdominal o traumatismo fetal. A medida que la experiencia internacional se acumula, se van determinando los factores que pueden ayudar a mejorar aun mas la seguridad y la facilidad tecnica del procedimiento. Hemos descrito un nuevo metodo de aspiracion para realizar la amniocentesis que emplea un Vacutainer® (BD Vacutainer Systems, Plymouth, Reino Unido), para obtener un vacio continuo cuando la aguja ya esta insertada dentro de la cavidad amniotica, en contraste con la tecnica estandar de aspiracion mediante jeringa o «pistola» en que las presiones negativas son discontinuas. Sin embargo, la tecnica clasica con aspiracion con jeringa continua siendo valida y la mas utilizada. Basados en la experiencia de 30 anos y en el volumen de procedimientos realizados en nuestro centro (mas de 20.000 procedimientos invasivos realizados), junto con una revision de la bibliografia publicada hasta la fecha, hemos planteado una guia practica actualizada para la realizacion de la amniocentesis.

Objective To assess the best method of combining fetal nuchal translucency (NT) and ductus venosus (DV) blood flow measurements in the detection of major cardiac defects in chromosomally normal fetuses during the first-trimester scan. Methods During an 8-year period NT and DV blood flow were routinely assessed at 11–14 weeks' gestation. Only chromosomally normal singleton pregnancies were included in the study. When a cardiac defect was suspected, or when increased fetal NT and/or absent or reversed (AR) A-wave in the DV was observed, early fetal echocardiography was offered. Data on routine second- and third-trimester scans, neonatal follow-up or postmortem examination were obtained from hospital records. The detection and false-positive rates for all major cardiac defects were calculated for several screening strategies, including: NT or DV pulsatility index for veins (DV-PIV) above a fixed normal centile; AR A-wave; risk based on NT and DV-PIV or A-wave velocity above a fixed normal centile; and combinations of these strategies. Results The study population included 37 chromosomally normal fetuses with a major cardiac defect and 12 799 unaffected pregnancies. Fetal NT above the 95th or the 99th centile and AR A-wave was observed in 40, 27 and 39% of the fetuses with major cardiac defects, respectively. A 47% detection rate with a 2.7% false-positive rate was obtained when AR A-wave or NT above the 99th centile was used as the selection criterion. Conclusions Half of major fetal cardiac defects could be detected in the first trimester if NT and DV Doppler are used to select 2.7% of the general pregnant population for extended fetal echocardiography. Copyright © 2013 ISUOG. Published by John Wiley & Sons Ltd.

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 Objetivo Evaluar la aplicacion clinica de los metodos no invasivos en el manejo de la isoinmunizacion, durante el periodo de 2006-2010. Sujetos y metodos Se estudiaron 70 gestaciones con riesgo de anemia fetal en las que se realizo el estudio Doppler de la velocidad sistolica de la arteria cerebral media (VS-ACM). Se comparo la eficacia de la VS-ACM despues de una, 2 o 3 transfusiones intrauterinas. El genotipado fetal RHD en sangre materna se realizo en las gestaciones seguidas en nuestro centro. Resultados Se practico cordocentesis en 22 de gestaciones y en 20 se practico transfusion intrauterina. Las tasas de deteccion y de falsos positivos de la VS-ACM en la prediccion de anemia fetal moderada o severa fueron del 89 y el 15% en gestaciones sin transfusion previa, del 100 y el 41% en los casos con una transfusion previa y del 40 y el 24% cuando se practicaron mas de una transfusion. Conclusiones La VS-ACM mantiene una sensibilidad alta en una transfusion previa aunque su especificidad disminuye.

Objective To assess a new contingent screening strategy for Down syndrome completed in the first trimester. Methods First-trimester screening combining nuchal translucency thickness measurement and assessment of serum analytes (combined test) was offered to pregnant women who presented for prenatal care during the first trimester to nine health centers and community hospitals in the area served by the Catalan Public Health Service. If an intermediate risk (1/101–1/1000) for Down syndrome was identified, women were referred to the Hospital Clinic Barcelona for risk reassessment that included the use of secondary ultrasound markers (nasal bone, ductus venosus blood flow and tricuspid flow). Intermediate-risk women were divided into two subgroups for further analysis: high-intermediate risk (1/101–1/250) and low-intermediate risk (1/251–1/1000). We compared feasibility and efficacy of both combined and contingent screening strategies. Results The combined test, the first screening stage, was performed in 16 001 pregnant women, of whom 1617 (10.1%) were found to have an intermediate risk. Further division of this group showed that 1.8% (n = 289) of women were at high-intermediate risk and 8.3% (n = 1328) at low-intermediate risk. The contingent screening strategy significantly reduced the false-positive rate, from 3.0% to 1.3–1.8% (P < 0.001), without affecting the detection rate (which was 75–79% and 76%, with and without the contingent screening strategy, respectively). However, only 45% of intermediate-risk patients underwent the second screening step due to a preference among high-intermediate-risk (1/101–1/250) women for invasive testing and to low uptake among low-intermediate-risk (1/251–1/1000) women. Conclusions The proposed first-trimester contingent strategy reduces the screen false-positive rate without impacting on the detection rate of Down syndrome. The low compliance observed in our study may prevent its use in certain populations. Copyright © 2012 ISUOG. Published by John Wiley & Sons, Ltd.

Objectives To determine the sensitivity of first-trimester ultrasound for diagnosing different structural anomalies in chromosomally normal pregnancies, and to establish the role of aneuploidy markers in the detection of abnormalities. Methods This was a retrospective study of chromosomally normal singleton pregnancies with an 11–14-week scan performed in our center during 2002–2009. The ultrasound examination included an early fetal anatomy survey and assessment of nuchal translucency, ductus venosus blood flow and nasal bone. Results Among 13 723 scanned first-trimester pregnancies with no genetic anomalies and complete follow-up, 439 fetuses (3.2%) were found to present with structural anomalies (194 with major anomalies and 245 with only minor anomalies). Forty-nine per cent of major structural anomalies were detected during the first-trimester scan, the highest rates corresponding to acrania (17/17), holoprosencephaly (three of three), hypoplastic left heart syndrome (10/10), omphalocele (six of six), megacystis (seven of eight) and hydrops (eight of nine). Higher than expected detection rates were obtained for skeletal (69%) and cardiac (57%) defects, coincidentally showing the highest presence of an increased nuchal translucency or abnormal ductus venosus blood flow (38% and 52%, respectively). The finding of an absent nasal bone did not appear to be associated with structural defects. Conclusion About half of major structural abnormalities can be diagnosed in the first trimester. Increased nuchal translucency or abnormal ductus venosus blood flow appear to be associated with cardiac and skeletal defects and may facilitate early detection. Copyright © 2012 ISUOG. Published by John Wiley & Sons, Ltd.

Resumen La anticipacion del cribado de las aneuploidias fetales al primer trimestre ha requerido implementar tecnicas diagnosticas en este momento de la gestacion. La biopsia de vellosidades coriales (BVC) es un procedimiento diagnostico invasivo en Medicina Materno-Fetal, que consiste en la obtencion de vellosidades coriales para estudio citogenetico, molecular o bioquimico. Existen dos vias para la realizacion de la BVC, la transcervical y la transabdominal. La preferencia por una de las dos vias se ha basado historicamente en factores como son la localizacion placentaria, paridad, peso materno, preferencias del operador, etc. En nuestra institucion pasamos a utilizar la via transcervical de manera casi exclusiva, con resultados ventajosos para la gestante y el laboratorio. Todo ello, sin diferencias en cuanto a la tasa de perdida gestacional u otras complicaciones. A pesar de 3 decadas de uso de la BVC transcervical, existe poco consenso en cuanto a su tecnica y las guias clinicas especificas para su realizacion son escasas. Aprovechando la experiencia y el volumen acumulado de procedimientos realizados en nuestro centro, hemos planteado una guia clinica eminentemente practica para la realizacion de BVC transcervical.

First trimester screening for fetal aneuploidies has made the implementation of diagnostic techniques essential. Chorionic villus sampling (CVS) is the method of choice for obtaining chorionic villi for molecular and cytogenetic analysis in the first trimester. Two techniques have been developed, a transcervical and a transabdominal. The selection criteria have been based historically on factors, such as placental location, parity, maternal weight and preference of the operator. In our institution, we developed an elevated level of expertise in the field of transcervical approach, resulting in good quality of samples and comparable fetal loss rate to other approaches. Despite three decades of transcervical CVS performance, little consensus in terms of its technique and clinical guidelines exists. Considering the expertise and the volume of procedures performed at our center, we suggest a practical clinical guideline for transcervical CVS.

Objective To describe the false-positive diagnoses of prenatal ultrasound screening of fetal structural anomalies. Methods Pregnancies with fetal structural anomalies either detected prenatally in our center or referred to us, were registered, evaluated, and followed-up prospectively by a multidisciplinary Congenital Defects Committee. After postnatal follow-up was completed, cases were assigned as true positives, false positives or false negatives and categorized by anatomical systems. Pregnancies referred with a nonconfirmed suspicion of anomaly were not included. The false-positive diagnoses were analyzed. Results From 1994 to 2004, 903 new registry entries of fetuses structurally abnormal at ultrasound with a complete follow-up were included in the Committee database. There were 76 false positives, accounting for 9.3% of all the prenatally established diagnoses. The urinary tract anomalies were the most frequent false-positive diagnoses found (n = 25; accounting for 8.7% of the urinary tract defects), but the genital anomalies showed the higher rate of no confirmation (n = 5; 15.2%). The specific anomalies most commonly not confirmed were renal pyelectasis (n = 9), cerebral ventriculomegaly (n = 9), abdominal cysts (n = 7) and short limbs (n = 7). Conclusion Several prenatally diagnosed anomalies would benefit from prudent counseling, because they may be normal variants or transient findings. Copyright © 2007 John Wiley & Sons, Ltd.

Resumen Objetivo Evaluar los resultados de la transfusion fetal intravascular en el tratamiento de la isoinmunizacion, durante el periodo 1990-2003. Sujetos y metodos Se ofrecio una cordocentesis para realizar un hemograma fetal a las gestantes isoinmunizadas con sospecha de anemia fetal significativa. Se practico transfusion intrauterina cuando el valor del hematocrito fetal fue inferior a –2 desviaciones estandar para la edad gestacional. Las transfusiones se repitieron aproximadamente cada 3 semanas hasta la semana 34-35. Resultados Se practico una cordocentesis en 32 gestaciones, en 11 (34%) de las cuales no se objetivo una anemia fetal significativa de acuerdo con los criterios establecidos. En 19 gestaciones se realizaron un total de 50 transfusiones entre las 21 y 35 semanas. No se observo ninguna perdida fetal espontanea. A los 0-13 anos de vida, todos los ninos presentan una evolucion correcta para su edad. Conclusion La transfusion intravascular fetal es una tecnica efectiva en el tratamiento prenatal de la anemia fetal con resultados favorables a largo plazo.

Objective To assess the potential value of ductus venosus Doppler studies in the detection of fetal aneuploidy on measurement of nuchal translucency. Methods The pulsatility index for veins (PIV) and the lowest velocity during atrial contraction (A-wave) were determined in the fetal ductus venosus in 3382 consecutive pregnancies at 10 to 14 weeks and studied from December 1996 to December 2001. Nuchal translucency was also measured. The population studied included 1664 pregnancies at high risk and 1718 at low risk for fetal aneuploidy. Results In relation to the prenatal detection of trisomy 21, the ductus venosus PIV was increased in 75% (36/48), the A-wave was decreased in 58% (28/48), and nuchal translucency was enlarged in 81% (39/48) of the trisomy 21 fetuses [71% (22/31) when nuchal translucency referrals were excluded]. The corresponding figures for trisomies 18 and 13 were 71, 58 and 83%, respectively, being 33, 33 and 33% for other unbalanced anomalies. Conclusion There is a high proportion of fetuses with trisomies 21, 18 and 13 (around 75%) in which the ductus venosus PIV is increased (above the 95th percentile) at 10 to 14 weeks, this proportion being similar to that observed for increased nuchal translucency measurement. Copyright © 2003 John Wiley & Sons, Ltd.

Objective To assess the role of two ovarian reserve markers, antimullerian hormone (AMH) and antral follicle count (AFC), as markers of the background risk for fetal trisomy. Design Prospective study. Setting Tertiary referral hospital. Patient(s) Assessment was carried out either in ongoing pregnancies or miscarriages in our center. Intervention(s) AFC was assessed transvaginally during a routine (11–13 weeks) or referral scan. AMH was determined either during the first-trimester maternal serum markers assessment or in cases referred for chorionic villi sampling after the invasive procedure. Main Outcome Measure(s) AMH reference ranges were constructed according to maternal age, and AMH- and AFC-derived ovarian ages were compared among three different cytogenetic groups (normal karyotype, autosomal trisomies, and other chromosomal anomalies) in both ongoing pregnancies and miscarriages. Result(s) In autosomal trisomies, the median AFC-derived ovarian age was 3–5 years above the median maternal age. No differences were observed between AMH-derived ovarian age and maternal age. Conclusion(s) AFC-derived ovarian biologic age reflects a more precise background risk for fetal aneuploidy that is not observed for AMH-derived age.

Study question Can antral follicle count (AFC) measured during pregnancy be used as a marker of ovarian age to assess the background risk of fetal aneuploidy? Summary answer AFC was lower than expected according to maternal chronological age in trisomic pregnancies; therefore ovarian age could potentially reflect a more precise background risk of fetal aneuploidy screening. What is known already The decline in a woman's reproductive function is determined by a decline in the ovarian follicle pool and the quality of oocytes. The quantitative status of ovarian reserve can be indirectly assessed by AFC, but the role of AFC as an aneuploidy risk marker in pregnant women has not been assessed yet. Study design, size, duration Our study comprised a prospective cohort including 1239 singleton pregnancies scanned before 14 weeks in our center during a 14-month period. Participants/materials, setting, methods Reference ranges for AFC were constructed using 812 spontaneously conceived, chromosomally normal singleton ongoing pregnancies using the Lambda-Mu-Sigma method. The study population (n = 934) included 19 pregnancies with viable autosomal trisomies (trisomies 21, 18 and 13), 17 non-viable autosomal trisomies (other than 21, 18 or 13), 7 monosomies X, 1 sex trisomy and 3 triploidies (total n = 47 with chromosomal abnormalities). AFC in chromosomally abnormal pregnancies was plotted against the reference ranges. AFC multiple of the median was calculated according to the median AFC obtained by each year of age. Main results and the role of chance Sixty-eight percent of women carrying a pregnancy with viable trisomies and 65% with non-viable trisomies presented an AFC below the 50th percentile. The median ovarian age in viable trisomies and non-viable trisomies was estimated to be 3 and 6 years above than median maternal age, respectively. However, the median ovarian age in monosomies X and triploidies was not higher than median maternal age. Limitations, reasons for caution We did not assess the intra- and inter-observer reliability, or use specific three-dimensional analysis which may have advantages over our two-dimensional study. In clinical practice, a drawback for assessing AFC during pregnancy is that transvaginal ultrasound is needed at the 11- to 13-week scan, when the transabdominal approach is used most commonly. Furthermore identifying ovaries by ultrasound during pregnancy could be challenging. Wider implications of the findings Considering that AFC reflects ovarian aging, this 'ovarian biological age' could potentially reflect a more precise background risk of fetal aneuploidy. Study funding/competing interest(s) This study was supported by PI 11/00685. Instituto de Salud Carlos III. Fondo de Investigacion Sanitaria. No competing interests declared.

Amniocentesis is a technique for withdrawing amniotic fluid from the uterine cavity using a needle, via a transabdominal approach and under continuous ultrasound guidance, in order to obtain a sample of fetal exfoliated cells, transudates, urine or secretions. It can be performed from 16 weeks of pregnancy onwards, with various chromosomal, biochemical, molecular and microbial studies being performed on the amniotic fluid sample. The most common reasons for the procedure are to enable prenatal diagnosis of chromosomal abnormalities, single gene disorders, fetal infection and intra-amniotic inflammation, as well as to assess fetal lung maturity and blood or platelet type. The procedure has a risk of fetal loss of approximately 0.5% (range, 0.06–1%)1 when performed in the second trimester, after the amniotic membrane has fused with the chorion; there is also a risk of amniotic fluid leakage (approximately 0.3% of cases) and other rare complications, such as placental hemorrhage, intra-amniotic infection, abdominal wall hematoma and fetal lesion. There is an important lack of good-quality evidence to support most recommendations for the procedure, and a recent review suggested that operators should use those methods and technique modifications with which they are most familiar when performing an amniocentesis2. The aim of this summary article and the full version, included as supplementary material online, is to describe the amniocentesis technique, presenting a practical guideline for its performance. We also describe the use of a Vacutainer® (BD Vacutainer Systems, Plymouth, UK) aspiration system in order to produce a continuous vacuum for amniotic fluid aspiration as an alternative to using manually operated syringes.

Objective: To assess the feasibility of nasal bone (NB), ductus venosus (DV) and tricuspid flow (TF) at the 11-13 weeks' scan, calculate likelihood ratios for each of the markers and evaluate their efficacy in expanded and contingent screening strategies for Down syndrome. Material and Methods: NB, DV and TF were assessed in 11,261 singleton fetuses undergoing first trimester combined screening. For each marker, Down syndrome detection rate (DR), false positive rate (FPR), positive, negative and isolated likelihood ratios (PLR, NLR and iLR) were calculated. Likelihood ratios were multiplied to the combined test risk either to the entire population or to the intermediate risk group (expanded and sequential strategies, respectively). Results: Down syndrome was diagnosed in 101 pregnancies. Feasibility for marker assessment ranged from 71 to 97%, DRs for isolated markers from 20 to 54% and FPRs from 1.3 to 5.3%. PLR ranged from 10 to 15, NLR from 0.5 to 0.8 and iLR from 3.9 to 5.6. When ultrasound markers were added to both strategies, a significant FPR reduction was observed. Conclusion: The application of NB, DV and TF likelihood ratios to the combined test risk, either in an expanded or contingent strategy, result in a FPR reduction.

Study question Is there any effect of maternal age on chromosomal anomaly rate and spectrum in recurrent miscarriage? Summary answer There was no significant difference in the chromosome abnormality rate between sporadic and recurrent miscarriage but the chromosome abnormality rate increased significantly with maternal age. What is known already About 50-70% of non-recurrent miscarriages occur because of a chromosomal anomaly, but no agreement about the effect of either maternal age or the number of previous miscarriages on the chromosomal anomaly rate has been reached. Study design, size, duration A retrospective cohort of 353 miscarriages successfully karyotyped in the same center between 2002 and 2011, grouped according to the number of miscarriages and maternal age. Participants/materials, setting, methods Among the 353 women, 153 were below 35 years (73 with sporadic, 48 with two and 32 with recurrent miscarriage) and 200 were 35 years or more (81 with sporadic, 55 with two and 64 with recurrent miscarriage). The chromosomal anomaly rate and the anomaly spectrum were compared between sporadic and recurrent miscarriage, within the two maternal age groups, using the chi-square test and the Bonferroni correction for all the P-values. Risk of chromosomal anomaly was estimated for maternal age, number of miscarriages and previous live births by multivariate binary logistic regression analysis. Main results and the role of chance Sporadic and recurrent miscarriage did not show significantly different chromosomal anomaly rates (68 versus 60%) and maternal age was the only statistically significant predictor of the chromosomal anomaly risk we identified. Some trends were observed in the chromosomal anomaly spectrum when sporadic was compared with recurrent miscarriage: recurrent miscarriage exhibited a decrease in viable trisomies (37 versus 11%) and an increase in non-viable trisomies (38 versus 57%) in women >35 years, together with an increase in unbalanced structural anomalies (4.9 versus 29%) in younger women. Limitation, reasons for caution The mixed origin of our study population, and the limited number of recurrent miscarriages, particularly in the younger group, limits statistical power to detect differences. Wider implications of the findings The most commonly observed chromosomal anomaly type in recurrent miscarriage depends on maternal age: non-viable autosomal trisomies in older women and unbalanced structural anomalies in younger women. When a chromosomal anomaly is identified as the cause of miscarriage, additional maternal evaluation may be avoided. Study funding/competing interests No competing interests declared.

Objective To assess second-trimester screening for trisomy 21 by combining ultrasound nuchal fold (NF) measurement with maternal serum biochemistry. Methods NF, maternal serum α-fetoprotein (AFP) and free β-human chorionic gonadotropin (β-hCG) were determined concurrently at 14–19 weeks’ gestation in a study population comprising 1813 women with singleton pregnancies, including 1257 unselected women undergoing serum screening for trisomy 21 (1999–2002), and 556 high-risk pregnancies prior to amniocentesis (2003–2005), 402 of whom had positive serum screening tests. The results were expressed in multiples of the gestation-specific normal median (MoMs). Results There were 1799 unaffected singleton pregnancies, and their NF values approximately fitted a log Gaussian distribution over a wide range. There was a weak but statistically significant correlation between log NF and log AFP (r =− 0.069, P < 0.005) and the correlation coefficient between log NF and log free βhCG was even smaller and not statistically significant (r = 0.038, P = 0.11). Among the seven trisomy 21 pregnancies, the median NF level was 1.53 MoM (geometric mean 1.75 MoM), a highly statistically significant increase compared with unaffected pregnancies (P < 0.0001, onetail Wilcoxon Rank Sum Test). In pregnancies referred because of positive serum screening tests (391 unaffected, seven cases of trisomy 21, one of monosomy X and three other chromosomal anomalies) the use of NF to modify the serum screening risk would have reduced the invasive procedures in unaffected pregnancies by 46% without affecting the detection rate of trisomy 21 or other anomalies. Statistical modeling predicted that adding NF to AFP and free β-hCG would increase detection more than would adding unconjugated estriol as well as inhibin-A, an analyte that is difficult to measure with precision. Conclusions The addition of NF measurement to second-trimester biochemical markers improves screening performance, and could overcome drawbacks in the implementation of inhibin-A assay in clinical practice. Copyright  2007 ISUOG. Published by John Wiley & Sons, Ltd.

Objectives: The aim of this study is to asses the feasibility of 3D ultrasound for fetal evaluation at 20–22 weeks. Methods: A cross-sectional study was designed in order to evaluate the correlation between 2D standard ultrasound and 3D multiplanar mode by means of a General Electric Voluson 730 Expert. 35 women were scanned at 20–22 weeks of gestation. A standard anatomical ultrasound was performed in each pacient. Also six volumes of each fetus were obtained (axial head, coronal face, chest, abdominal, upper extremities and lower extremities). Observer A analysed off line the 18 cases obtained by observer B, using 4D view program. Reversaly, observer B analysed the volumes obtained by observer A in 17 pacients. A third observer C also analysed the volumes obteined by A and B in order to evaluate the interobserver reproducibility in a second step. A check list of landmarks (31)was used to study the complete fetal anatomy in both ultrasound methods. For measurements, the intraclass correlation coefficient was calculated between both techniques. Results: While with 2D standard ultrasound 99% of landmarks were identified, it was 94% with 3D off line examination. Grouping by view regions : head and face 97%, 94% respectively; heart : fourchamber 100%, three vassels and trachea wiew 97%, outflow tracts 74%; abdominal structures 100% unless both kidneys 89%; both arms 89%, both hands 57%, both legs 97% and both feet 80%. Spine was completly seen in 85%. One choroid plexus cyst was seen in 2D/3D, one foot with equinovarus position was not satisfactory visualized using 3D and it was two cases of sex error. Intraclass correlation coefficient was almost perfect for biparietal diameter, cephalic circunference and femoral length, and very good for abdominal circunference. Conclusions: 3D ultrasound seems to allow a good anatomical assesment and yield reliable mesurements at 20–22 weeks of gestation. Hands, cardiac outflow tracts and feet are, by now, structures poorly assesed by 3D standard multiplanar mode

Graves’disease is the most common cause of hyperthyroidism in pregnancy and may cause fetal and neonatal thyroid dysfunction. A case of maternal Graves’disease treated with propylthiouracil (PTU) is presented and prenatal detection and management of fetal goiter are discussed. A 30-year-old-woman, gravida 3, para 2, with Graves’disease was treated with 300 mg/day PTU. Maternal serum concentration of free thyroxine (FT4) was 0.9 ηg/dL (normal 0.6–1.54), thyroidstimulating hormone (TSH) 2.28 mU/L (normal 0.5–4.2) and TSH-receptor autoantibody (TRAb) 14% (normal less than 12%). Fetal thyroid enlargement was noted by sonography at 25 weeks’ gestation. Cordocentesis was performed to assess fetal thyroid function. The fetal serum FT4 was 0.9 ηg/dL (normal 2.3–2.7) and TSH was 98.65 mU/L (normal 8.7–10.5) indicating hypothyroidism. PTU was decreased to 150 mg/day and the fetus was treated with injection of L-thyroxine (250 μg) into amniotic fluid at 32 and 35 weeks’ gestation. The patient remained euthyroid and serial ultrasound scans showed a shrinking of the fetal goiter. Spontaneous onset of labor occurred at 39 weeks’ gestation. The male neonate weighed 2630 g with no discernible thyroid enlargement. The thyroid function tests at birth and on 16th day of life showed euthyroid status. Maternal antithyroid antibodies in patients with Graves’disease, known as THS-receptor autoantibodies (TRAb), can result in stimulation or inhibition of fetal thyroid gland. PTU treatment of Graves’disease in pregnancy may be associated with neonatal goitrous hypothyroidism whereas transplacental passage of stimulating immunoglobulin may cause fetal goiter with hyperthyroidism. Therefore, when fetal goiter is detected, cordocentesis should be offered to assess fetal thyroid function. In cases of fetal hypothyroidism, intra-amniotic injection of thyroxine has shown to be effective in raising serum levels of thyroxine, reducing those of TSH and decreasing the size of goiter.

Jarcho-Levin syndrome (or spondylothoracic dysplasia) is a congenital disease characterized by multiple vertebral and rib malformations, causing a short trunk dwarfism commonly leading to respiratory insufficiency and death during the first years of life. Prenatal sonographic diagnosis of Jarcho-Levin syndrome has been reported in both the first and second trimester. But always in families at risk. The most characteristic sonographic features were malaligned vertebrae, disorganization of vertebral bodies, and posteriorly fused ribs. We describe a case diagnosed during the second trimester ultrasound scan for screening of fetal anomalies in a couple without history of affected children. This was the first pregnancy of a 24-year-old woman. The course of the pregnancy was uneventful until a structural defect of the fetal spine was detected at the 20 weeks’ scan. Fetal karyotype by cordocentesis was 46 XY, and major cardiac malformations were excluded by detailed fetal echocardiography. The fetus had a severe disorganization of the spine and ribs, skeletal kyphosis, with several hemivertebrae and a small thorax. The ultrasonographic findings allowed us making a reliable diagnosis of a variety of Jarcho-Levin syndrome, and adequate genetic counselling to the couple, even though no other malformations were associated and there was no family history for the syndrome. All of the findings at postmortem examination confirmed the ultrasound features and were consistent with the Jarcho-Levin syndrome. Our case illustrates the importance of an accurate ultrasound examination at both first and second trimester in order to detect any rare congenital syndromes.