Copy number variation analysis and outcomes of 1 658 fetuses with increased nuchal translucency / 中华围产医学杂志

Objective:To analyze the genetic etiology and prognosis in fetuses with increased nuchal translucency (NT) in order to assist in the clinical prenatal genetic counseling and diagnosis.Methods:This study retrospectively enrolled 1 658 cases of singleton pregnancy (<35 years old) receiving invasive prenatal diagnosis, including karyotype analysis and/or chromosome microarray analysis or copy number variation (CNV) sequencing, due to NT value ≥2.5 mm in the first trimester in Henan Provincial People's Hospital from August 2014 to December 2021. They were divided into different groups according to the thickness of NT (≥2.5-<3.0, ≥3.0-<3.5, ≥3.5-<4.5, ≥4.5-<5.5, ≥5.5-<6.5 and ≥6.5 mm groups) and abnormal ultrasound findings (isolated increased NT group, increased NT complicated by soft markers/non-severe structural abnormality group and increased NT complicated by severe structural abnormality group). The results of invasive prenatal diagnosis and pregnancy outcomes were compared between different groups using Chi-square test and trend Chi-square test. Results:The detection rates of numerical abnormalities of chromosomes were 15.8% (262/1 658) and 17.6% (252/1 431) when the NT thickness cut-off value were 2.5 mm or 3.0 mm, respectively. Overall, the detection rate of numerical abnormalities of chromosomes increased with thickness of NT ( χ2trend=180.75, P<0.001), ranging from 6.6% (44/671) in the NT≥2.5-<3.5 mm group to 45.6% (113/248) in the NT≥5.5 mm group. The incidence of pathogenic/likely pathogenic CNV(P/LP CNV) did not increased with NT thickness ( χ2trend=3.26, P=0.071), and the highest detection rate was observed in the NT≥4.5-<5.5 mm group (9.0%, 19/211). The detection rate of numerical abnormalities of chromosomes plus P/LP CNV in the isolated NT≥2.5-<3.0 mm group and NT≥3.0-<3.5 mm group were 5.3% (10/188) and 9.6% (36/375), respectively, however, the difference was not statistically significant ( χ2=3.06, P=0.080). The detection rates of numerical abnormalities of chromosomes plus P/LP CNV in the isolated NT≥3.5-<4.5 mm group and NT≥2.5-<3.0 mm complicated by soft markers/ non-severe structural abnormality group were 12.7% (52/410) and 24.1% (7/29), respectively, and the risk were 2.6 times (95% CI: 1.3-5.2) and 5.7 times (95% CI: 2.0-16.4) of the isolated NT≥2.5-<3.0 mm group, respectively. The pregnancy termination rate increased with the NT thickness ( χ2trend=304.42, P<0.001), ranging from 10.8% (23/212) in the NT≥2.5-<3.0 mm group to 90.7% (117/129) in the NT≥6.5 mm group. After exclusion of the pregnancies terminated due to numerical abnormalities of chromosomes and P/LP CNV, 87.6% (862/984) of the fetus with increased NT were born alive. Conclusions:The detection rate of numerical abnormalities of chromosomes increases with the thickness of NT. Invasive prenatal diagnosis is required for non-advance aged singleton pregnant women when fetuses present with isolated NT≥2.5 mm with or without soft markers/structural abnormalities.

Características ecográficas y anomalías congénitas en fetos con síndrome de Down / Ultrasound features and congenital anomalies in fetuses with Down syndrome

Resumen Objetivo: Describir y analizar los hallazgos ecográficos en 97 fetos portadores de síndrome de Down (SD) confirmado. Método: Se incluyeron todas las gestantes con diagnóstico prenatal de SD de nuestro centro, realizado por cariograma o reacción en cadena de la polimerasa cuantitativa fluorescente para aneuploidía. Se analizaron los informes genéticos y ecográficos, y se realizó un seguimiento posnatal. Resultados: De los 97 casos de SD, el 73% de los diagnósticos fueron entre las 11 y 14 semanas. El promedio de edad de las madres fue de 35,7 años. El 83% de los fetos con SD, evaluados a las 11-14 semanas, tuvieron una translucencia nucal ≥ 3,5 mm. Del total de los casos analizados, el 33% fueron portadores de una cardiopatía congénita, correspondiendo el 58% de estas a defectos mayores, principalmente anomalías del tabique auriculoventricular. Un 7,6% de los casos terminaron como mortinato, principalmente durante el tercer trimestre. Conclusiones: El ultrasonido es una herramienta muy sensible para la sospecha prenatal de SD y la detección de sus anomalías asociadas. Consideramos que la información aportada será útil para programar estrategias de pesquisa, organizar el control perinatal y precisar el consejo a los padres de fetos portadores de esta condición.

Abstract Objective: To describe and analyze the ultrasound findings in 97 fetuses with confirmed Down syndrome (DS). Method: All pregnant women with prenatal diagnosis of DS in our center, performed by karyotype or quantitative fluorescent polymerase chain reaction for aneuploidy, were included. Genetic and ultrasound reports were analyzed, as well as postnatal follow-up. Results: Of the 97 cases of DS, 73% of the diagnoses were between 11-14 weeks. The average age of the mothers was 35.7 years. 83% of our fetuses with DS, evaluated between 11-14 weeks, had a nuchal translucency ≥ 3.5 mm. Of the total of the fetuses analyzed, 33% were carriers of congenital heart disease, 58% of these correspond to a major defect, mainly anomalies of the atrioventricular septum. 7.6% of cases ended as stillbirth, mainly during the third trimester. Conclusions: Ultrasound is a very sensitive tool for prenatal suspicion of DS and the detection of its associated abnormalities. We believe that the information provided will be useful to program screening strategies, organize perinatal control and to counselling parents of fetuses carrying this condition.

Higroma quístico retronucal como marcador de anomalías cromosómicas en el primer trimestre de la gestación - Actualización

Objetivo. Evaluar la asociación del higroma quístico retronucal (HQR) y anomalías cromosómicas fetales. Métodos. Estudio observacional retrospectivo de 323 fetos del primer trimestre con riesgo para anomalías cromosómicas diagnosticados por ecografía entre las 11 y 13,6 semanas. Resultados. De 323 fetos con riesgo para anomalías cromosómicas, se encontró 132 casos de anomalías cromosómicas (40,9%). Se identificaron 145 casos de HQR; en 64 (56,6%) se realizó biopsia de vellosidades coriales y en 81 (43,5%) amniocentesis, hallándose cariotipo anómalo en 82 (56,6%). De 88 fetos con HQR aislado, 33 casos (37,5%) tuvieron alguna anomalía cromosómica; en 58 fetos con HQR asociado a otros hallazgos anormales, se encontró que en 43 fetos (74,1%) hubo anomalías cromosómicas, y de ellos 24 (41,4%) tenían onda de flujo (OVF) anormal del ductus venoso, 17 (29,3%) tenían edema generalizado, 8 casos (13,8%) con cardiopatía, 7 (12,1%) ausencia del hueso nasal. Los valores predictivos del HQR fueron: sensibilidad (S) 62,1%, especificidad (E) 67%, valor predictivo positivo (VPP) 56,6%, valor predictivo negativo (VPN) 71,9%, p<0,001, OR: 3,3. El HQR asociado a otros hallazgos anormales, tuvo los siguientes valores predictivos: S 52,4%, E 76,2%, VPP 76,2%, OR: 3,5, LR+: 2,2, p<0,000. El edema generalizado y el ductus venoso anormal tuvieron los valores predictivos más altos: VPP 88,2% y 83,3%, respectivamente. Las anomalías cromosómicas encontradas con mayor frecuencia fueron: T21 (53,7%), monosomía X (18,3%), T18 (15,9%), T13 (6,1%). Conclusiones. El higroma quístico retronucal es un marcador de riesgo con alto valor predictivo para anomalías cromosómicas, siendo mayor cuando está asociado a otros hallazgos ecográficos anormales. La identificación ecográfica del HQR en el tamizaje prenatal del primer trimestre debería ser indicación para recomendar una prueba diagnóstica para anomalías cromosómicas.

Objective: To evaluate the association of retronucal cystic hygroma (RCH) and fetal chromosomal abnormalities. Methods: Retrospective observational study of 323 first trimester fetuses at risk for chromosomal abnormalities diagnosed by ultrasound between 11 and 13.6 weeks. Results: Of 323 fetuses at risk for chromosomal abnormalities, 132 cases of chromosomal abnormalities were found (40.9%). A total of 145 cases of RCH were identified; chorionic villus biopsy was performed in 64 (56.6%) and amniocentesis in 81 (43.5%); an abnormal karyotype was found in 82 (56.6%). Of 88 fetuses with isolated RCH, 33 (37.5%) had some chromosomal abnormality. In 58 fetuses with RCH associated with other abnormal findings, chromosomal abnormalities were found in 43 fetuses (74.1%) and of these 24 (41.4%) had abnormal ductus venosus flow wave (DVF), 17 (29.3%) had generalized edema, 8 cases (13.8%) with cardiopathy, 7 (12,1%) with absent nasal bone. The predictive values of RCH were sensitivity (S) 62.1%, specificity (Sp) 67%, positive predictive value (PPV) 56.6%, negative predictive value (NPV) 71.9%, p<0.001, OR: 3.3. RCH associated with other abnormal findings were S 52.4%, Sp 76.2%, PPV 76.2%, OR: 3.5, LR+: 2.2, p<0.000. Generalized edema and abnormal ductus venosus had the highest predictive values: PPV 88.2% and 83.3%, respectively. The most frequently found chromosomal abnormalities were T21 (53.7%), monosomy X (18.3%), T18 (15.9%), T13 (6.1%). Conclusions: Retronucal cystic hygroma is a risk marker with high predictive value for chromosomal abnormalities, being higher when associated with other abnormal ultrasound findings. Ultrasonographic identification of RCH in first trimester prenatal screening should be an indication to recommend diagnostic testing for chromosomal abnormalities.

Copy number variant sequencing for chromosome analysis in 487 fetuses with increased nuchal translucency / 中华围产医学杂志

Objective:To analyze the genetic etiology of 487 fetuses with increased nuchal translucency (NT) using copy number variant sequencing (CNV-seq) and explore the relationship between increased NT and chromosomal abnormality.Methods:A retrospective study was performed on 487 fetuses with increased NT who received CNV-seq in the First Affiliated Hospital of Zhengzhou University from January 2018 to December 2020. These fetuses either had NT of ≥3.0-<3.5 mm (Group A, n=129) or ≥3.5 mm (Group B, n=358), the distribution and incidence of chromosomal abnormalities in the two sets of fetuses were analyzed using Chi square test or Fisher's exact test. Results:Fetuses with abnormal chromosomes accounted for 25.9%(126/487) of cases, including 107 with chromosome aneuploidy (22.0%) and 19 with pathogenic or likely pathogenic copy number variation (CNV, 3.9%). The detection rate of fetal aneuploidy in Group B was higher than that in Group A [14.0% (18/129) vs 24.9% (89/358), χ2=6.58, P=0.010]. However, no significant difference was observed regarding the detection rate of pathogenic or likely pathogenic CNV between the two groups ( χ2=0.30, P=0.584). Conclusions:The risk of fetal chromosome aneuploidy increased with NT thickness, but not with pathogenic or likely pathogenic CNV, which needed further verification due to the small sample size. CNV-seq is an option to detect the conventional detection methods for the genetic etiology of NT thickening fetuses.

Prenatal diagnosis and pregnancy outcome of increased nuchal translucency with or without nuchal cystic hygroma in fetuses during first trimester / 中华围产医学杂志

Objective:To compare the prenatal diagnosis and pregnancy outcome of increased nuchal translucency (NT) with or without nuchal cystic hygroma (CH) in fetuses with first-trimester NT ≥5 mm.Methods:Data from 131 fetuses with NT ≥5 mm who received invasive prenatal diagnosis at Guangzhou Women and Children's Medical Center from July 2017 to December 2020 were retrospectively collected and analyzed. Those with a septum in the cyst were grouped as NT with CH group ( n=57), and those without as increased NT without CH group ( n=74). Genetic test results, incidence of structural malformations, survival rate after birth were compared using Chi-square test or Fisher's exact test and non-parametric test. Results:There was no significant difference in the incidence of fetal genetic abnormalities[67.6%(50/74) vs 61.4%(35/57), χ 2=0.54, P=0.464], ultrasonic structural malformations [21.6%(16/74) vs 33.3%(19/57), χ 2=2.26, P=0.133], or in the survival rate (12/14 vs 3/8, P=0.053) between increased NT without CH group and NT with CH group. Conclusions:For increased NT with or without CH, although the two groups had different spectrum of disease, they had a high incidence of chromosomal abnormalities and structural malformations, and both groups had a certain healthy survival rate after birth.

Value of fetal ultrasonography index in twin fetal heart malformation screening at 11-13 + 6 weeks of gestation / 中华超声影像学杂志

Objective:To investigate the clinical value of fetal ultrasonography in the screening of congenital heart malformations in twins at 11-13 + 6 weeks of gestation. Methods:A retrospective cohort study method was used.Cases were collected from Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital (January 2012 to December 2016) and the Fourth Hospital of Shijiazhuang City (January 2014 to December 2018). The twins with singleton or twins with cardiac malformation were screened out as the cardiac malformation group, and the twins with normal delivery during the same period were selected as the control group. Ultrasound data such as the nuchal translucency (NT), crown-rump-length (CRL), chorionicity, conception method, NT discordance, CRL discordance, NT discordance ≥20% incidence rate between twins, and the CRL discordance ≥10% incidence rate between twins in the two groups at 11-13 + 6 weeks were compared and analyzed. Results:①There were 30 cases in the cardiac malformation group (including 27 twins with singleton cardiac malformation and 3 twins with twin cardiac malformation) and 1 906 cases in the control group. ②The incidence rates of NT value ≥95th percentile and NT value ≥99th percentile in one or two pregnancies were significantly higher in the cardiac malformation group than in the control group (20.00% vs 2.20%, P<0.001; 10.00% vs 0.63%, P=0.002), the area under the ROC curve (AUC) for cardiac malformation screening was 0.589 and 0.549, respectively; CRL discordance in cardiac malformation group was higher than that in control group ( P=0.018), the incidence of CRL discordance ≥10% in the cardiac malformation group was higher than that in the control group (26.67% vs 12.70%, P=0.024), the AUC of cardiac malformation screening was 0.570; there were no significant differences in the incidence of NT discordance, the incidence of NT discordance ≥20%, pregnancy pattern and chorionicity between the two groups (all P>0.05). ③Multivariate Logistic regression analysis was performed using the incidence rates of NT value ≥95% and NT value ≥99%, CRL discordance ≥10%, and NT discordance ≥20%. The incidences of fetal NT value ≥95% and NT value ≥99% were risk factors for cardiac malformation in twins ( OR=11.095, 105.778; 95% CI=4.311-28.558, 16.984-658.796). Conclusions:Ultrasound at 11-13 + 6 weeks of gestation showing thickened value of one or two fetuses, and the CRL discordance≥10%, indicates an increased risk of cardiac malformation in the twins; NT value ≥95% and NT value ≥99% is a risk factor for heart defects in twins.

Higroma quístico y la importancia de su diagnóstico prenatal: a propósito de un caso / Cystic hygroma and the importance of the prenatal diagnosis: about a case

RESUMEN El higroma quístico es la malformación del sistema linfático que más frecuentemente se observa en el período prenatal y que se ubica principalmente en el cuello y/o la nuca. Su tasa de detección ha aumentado desde la implementación de la translucencia nucal fetal (TN) en el primer trimestre de embarazo, y su presencia se ha relacionado con anomalías congénitas, aneuploidías, pérdida del embarazo y trastornos en el desarrollo. El objetivo de la presentación de este caso es resaltar la importancia del diagnóstico antenatal del higroma quístico, con el fin de realizar una intervención precoz y evitar la muerte fetal. Se recibe para estudio anatomopatológico, feto de sexo indeterminado producto del primer embarazo de una madre de 19 años de edad sin previos controles prenatales, con presencia de una gran masa quística que se extiende desde el rostro hasta la nuca. Mediante el estudio histológico se confirma el diagnóstico de higroma quístico. Al carecer de análisis de cariotipo no fue posible establecer la preexistencia de alguna anomalía genética. El también conocido como linfangioma quístico, es un tumor vascular benigno cuyo diagnóstico antenatal mediante la ultrasonografía resulta fundamental en la evolución y pronóstico de la enfermedad. Desafortunadamente en nuestro caso, la falta de controles prenatales y la ausencia de estudios ultrasonográficos que permitieran conocer las características de este linfangioma, pudo impactar significativamente en el desenlace fatal.

ABSTRACT The cystic hygroma is the malformation of the lymphatic system that is most frequently observed in the prenatal period and is located mainly in the neck and/or the nape of the neck. Its detection rate has increased since the implementation of fetal nuchal translucency (NT) in the first trimester of pregnancy and its presence has been associated with congenital abnormalities, aneuploidies, pregnancy loss, and developmental disorders. The aim of this case is to highlight the importance of antenatal diagnosis of cystic hygroma in order to perform early intervention and avoid fetal death. It is received, for anatomopathological study, a fetus of undetermined sex product of the first pregnancy of a 19 year-old mother without previous prenatal controls, with the presence of a large cystic mass that extends from the face to the neck. The histological study confirms the diagnosis of cystic hygroma. As there was no karyotype analysis, it was not possible to establish the preexistence of any genetic abnormality. Also known as cystic lymphangioma, is a benign vascular tumor whose antenatal diagnosis by ultrasonography is essential in the evolution and prognosis of the disease. Unfortunately in our case, the lack of prenatal controls and the absence of ultrasonographic studies that would allow knowing the characteristics of this lymphangioma, could significantly impact in the fatal outcome.

Prospective cohort study of fetal nuchal translucency in first-trimester and pregnancy outcome / 中华妇产科杂志

Objective@#To explore the relationship between fetal nuchal translucency (NT) in the first trimester and pregnancy outcome.@*Methods@#A prospective cohort study was conducted in Nanjjing Drum Tower Hospital from December 2015 to December 2018, 4 958 singleton pregnant women were enrolled to screen fetal ultrasound structure and serology in the first trimester, ultrasound in the second trimester and neonatus physical examination 28 days after birth. According to the results of NT, 167 cases of fetus with increased NT (≥3.0 mm) and 4 791 cases of normal NT were divided, moreover, 86 cases with isolate increased NT and 81 cases of increased NT combined with structural abnormality. The prognosis of fetuses with different NT thickness was analyzed, and the pregnancy outcome of fetuses with isolate increased NT or combined with structural abnormality were analyzed. In the first trimester, if the fetal structure was abnormal or the serological screening result was high risk, the chromosomal microarray analysis (CMA) would be performed by chorionic villus sampling to determine the prenatal diagnosis.@*Results@#(1) The pregnancy outcome for fetus of normal NT: there were 4 791 cases with normal NT. Totally, 4 726 cases with normal NT and no structural abnormalities were screened out in the firsttrimester. In this group, 5 cases of aneuploidies were diagnosed based on high risk of maternal serum biomarkers and 83 cases of structural abnormalities were screened out in the subsequent ultrasound scan and the neonatal examination. Another 65 cases with normal NT present complicated with structural anomalies were screened out in the first trimester and 4 cases were diagnosed as aneuploidies. (2) The pregnancy outcome for fetus of isolate increased NT: 66 (76.7%, 66/86) cases of isolated increased NT were performed CMA, 3 cases were diagnosed as trisomy 21 and terminated pregnancy. Another 4 cases were terminated pregnancy privately without cytogenetic diagnosis. No further anomalies were found in 79 cases till 6 to 21 months postnatally. (3) The pregnancy outcome for fetus of increased NT with structural anomalies: increased NT present with structural anomalies were screened out by detailed anomaly scan in the first trimester and 32 of them were confirmed as aneuploidies. In this group, 70 cases terminated pregnancy, 2 cases had spontaneous miscarriages and 9 cases had liveborns (1 newborn was found ventricular septal defect). (4) The pregnancy outcome for fetus of increased NT with or without structural anomalies: the percentage of aneuploidies in fetuses with isolated increased NT (3.5%, 3/86) was significantly lower than those with structural abnormalities (39.5%,32/81). The healthy survival rate in fetuses with isolated increased NT (91.9%,79/86) was significantly higher than those with structural abnormalities (9.9%, 8/81).@*Conclusions@#A detailed first-trimester anomaly scan could improve prenatal screening efficiency of birth defects. Compared to the fetuses with increased NT combined with structural abnormalities, the healthy survival rate of fetuses with isolated increased NT based on detailed first-trimester anomaly scan is higher and the percentage of fetal aneuploidies is lower.

Genetic analysis and clinical phenotype of a family with lymphedema-distichiasis syndrome / 浙江大学学报·医学版

OBJECTIVE@#To identify the genetic causes of a family with lymphedema-distichiasis syndrome (LDS).@*METHODS@#The whole exome sequencing was performed in a aborted fetus as the proband, and a candidate gene was identified. Peripheral blood of 8 family members were collected. Genotypic-phenotypic analysis were carried out through PCR amplification and Sanger sequencing.@*RESULTS@#The proband, and the mother, grandmother, uncle, granduncle of the proband all had distichiasis or varix of lower limb carried a @*CONCLUSIONS@#The

Síndrome de Down y su pesquisa durante el primer trimestre de la gestación / Down Syndrome and Screening During Pregnancy First Trimester

RESUMEN Introducción: La pesquisa prenatal de anomalías cromosómicas, mediante el uso de marcadores epidemiológicos y ecográficos del primer trimestre permite identificar gestantes con riesgo incrementado de síndrome de Down. Objetivos: Analizar la edad materna, la translucencia nucal, el ductus venoso y el hueso nasal, durante el cribaje del primer trimestre, en las gestantes que se realizaron diagnóstico prenatal citogenético, con el fin de evaluar la efectividad del mismo en la detección temprana del síndrome Down y su utilidad para la reducción del número de pruebas invasivas. Métodos: Se realizó un estudio descriptivo retrospectivo de corte transversal y se analiza una muestra de 3439 gestantes a las que se realizó el estudio citogenético indicado en el Centro Provincial de Genética Médica de La Habana, en el período comprendido entre el 3 de enero de 2006 y el 30 de diciembre de 2008. Resultados: La edad materna avanzada mostró una sensibilidad de un 87 por ciento del test y una tasa de falsos positivos de 99 por ciento. La translucencia nucal se comportó con una sensibilidad de 10 por ciento. El hueso nasal no mostró asociación con los cariotipos positivos para síndrome de Down. Al no realizarse sistemáticamente la presencia del ductus venoso, no se pudo establecer una asociación estadística. La estimación de riesgo de síndrome de Down basada únicamente en la edad materna avanzada determina una alta tasa de falsos positivos. Por lo que este marcador, unido a la evaluación de los marcadores ecográficos del primer trimestre para recalcular el riesgo individual, puede aumentar la efectividad en el diagnóstico y disminuir el número de pruebas invasivas. Conclusiones: La estimación de riesgo de síndrome de Down basada únicamente en la edad materna avanzada determina una alta tasa de falsos positivos. Por lo que este marcador, unido a la evaluación de los marcadores ecográficos del primer trimestre para recalcular el riesgo individual, puede aumentar la efectividad en el diagnóstico y disminuir el número de pruebas invasivas(AU)

ABSTRACT Introduction: The prenatal investigation of chromosomal abnormalities through the use of epidemiological and echographic markers on the first trimester, allows to identify pregnant women with an increased risk of Down syndrome. Objectives: To analyze maternal age, nuchal translucency, venous ductus and nasal bone, during the first trimester screening, in pregnant women who underwent prenatal cytogenetic diagnosis, in order to evaluate effectiveness in early detection of Down syndrome and the value for reducing the number of invasive tests. Methods: A descriptive retrospective cross-sectional study was carried out and a sample of 3439 pregnant women was studied. The cytogenetic study ordered at Havana Provincial Center for Medical Genetics was carried out from January 3, 2006 to December 30, 2008. Results: Advanced maternal age showed 87 percent sensitivity and 99 percent of false positive rate. Nuchal translucency accounted 10 percent of sensitivity. The nasal bone showed no association with positive karyotypes for Down syndrome. A statistical association of the venous ductus presence could not be established since the search was not systematically. Conclusions: The estimation of Down syndrome risk based solely on advanced maternal age determines high false positive rate. Therefore, this marker, together with the evaluation of the first trimester ultrasound markers for recalculating the individual risk, can increase the diagnostic effectiveness and decrease the number of invasive tests(AU)

Pronóstico de la translucencia nucal fetal ≥ 5,5 mm en Lima, Perú

Introduction: First trimester screening has been performed for over 19 years in Peru, but there is no information on the outcomes. Objective: To determine the prognosis of an increased fetal nuchal thickness (NT). Patients: Ultrasound assessment of fetal nuchal thickness in 10 340 consecutive fetuses, 11 to 13 weeks gestation. Interventions. Fetal screening was performed by nine sonographers accredited by the Fetal Medicine Foundation (FMF); the FMF recommendations were followed. Data were recorded using Astraia software. Results: Thirty-seven (0.36%) fetuses presented NT ≥ 5.5mm. Eight patients were lost to follow up. The remaining 29 cases were included in this report. Prenatal karyotyping was performed in 18 cases; 17 of them were abnormal and presented trisomy 21 (7), trisomy 18 (4), monosomy X (5), and trisomy 22 (1). Four of the seven cases of trisomy 21 were born at term without major anomalies. Eleven did not have prenatal testing; one of them was a healthy newborn at term, the remaining 10 died in utero. Seventeen of the 19 known karyotypes were abnormal, which significantly differs from Kagan's results (89% vs 64%, p<0.05) Conclusion: Fetuses with nuchal translucency ≥ 5.5mm in our institution presented a worse prognosis in significantly more cases, compared to other reports.

Introducción. El tamizaje ecográfico del primer trimestre se realiza en el Perú desde hace 19 años, pero se carece de información del seguimiento de las pacientes evaluadas. Objetivos. Determinar el pronóstico de una translucencia nucal (TN) muy aumentada en el feto. Diseño. Estudio retrospectivo observacional. Pacientes. Se evaluó 10 340 fetos consecutivos entre las 11 y 13 semanas, en madres que llegaron al servicio de ecografía. Intervenciones. Evaluación por nueve ecografistas acreditados por la Fetal Medicine Foundation (FMF) siguiendo las recomendaciones de la FMF. Los resultados fueron registrados en el software Astraia. Resultados. Treintaisiete (0,36%) pacientes tuvieron TN ≥ 5,5 mm; ocho no regresaron a la institución y se desconoce el desenlace de su embarazo, por lo que no fueron considerados en el análisis posterior. De los 29 reportados, en 18 se realizó cariotipo prenatal, 17 de ellos fueron anormales (7 trisomías 21; 4 trisomías 18; 5 monosomías X; una trisomía 22). Cuatro de los 7 fetos con trisomía 21 nacieron a término sin malformaciones importantes; uno falleció durante el embarazo, otro embarazo fue interrumpido en el extranjero y se desconoce el desenlace de un caso. De los 11 que no se realizaron cariotipo prenatal, uno (3,2%) nació vivo y sano y los otros 10 fallecieron durante el embarazo. Diecisiete cariotipos de 19 conocidos fueron anormales, lo que difiere significativamente de los resultados de Kagan (89% vs 64%, p<0,05). Conclusiones. El pronóstico de los fetos con TN ≥5,5 mm en nuestra institución fue significativamente peor que el publicado en la literatura.

False negative non-invasive prenatal screening result for trisomy 18: a case report / 中华围产医学杂志

We hereby reported a case of false negative non-invasive prenatal screening (NIPS) for trisomy 18. The fetus with increased nuchal translucency (3.2 mm) detected by ultrasound scan at 13+4 gestational weeks received NIPS and the result was negative in chromosomes 21, 18 and 13. A routine ultrasound examination at 22 weeks of gestation revealed multiple anomalies and a second NIPS was offered, which showed a negative result again. The pregnancy was terminated at 22+3 weeks. Multiple fetal and placental biopsies were collected for chromosome analysis using copy number variation sequencing based on high-throughput sequencing and fluorescence in situ hybridization. The fetal karyotype was shown to be 47,XY,+18 in fetal tissues (skin and liver) and umbilical cord, while no chromosomal abnormalities was detected at or near the center of the fetal and maternal surface of the placenta. Results of the chromosomal analysis along the edges of the fetal and maternal surfaces of the placenta were Chr18:47,XY,+18[60]/46,XY[40] and Chr18:47,XY,+18[35]/46,XY[65], respectively. We inferred that placental mosaicism was the cause of the false negative NIPS result. Therefore, genetic counseling before and after NIPS is necessary. Follow-up ultrasound is important for NIPS-negative patients. Invasive prenatal diagnosis is recommended when abnormal ultrasound markers with possible genetic etiology were recognized.

Predictive value of first-trimester ultrasound markers for complicated monochorionic diamniotic twins / 中华围产医学杂志

Objective@#To investigate the value of first-trimester ultrasound parameters in predicting complicated monochorionic diamniotic (MCDA) twins.@*Methods@#In this retrospective study, pregnant women diagnosed as MCDA twins by ultrasound in the First Affiliated Hospital of Sun Yat-sen University from January 2013 to January 2018 were recruited and divided into the following four groups: non-complicated MCDA twins group, twin-twin transfusion syndrome (TTTS) group, selective intrauterine growth restriction (sIUGR) group and twin anemia-polycythemia sequence (TAPS) group. Thickness of nuchal translucency (NT), crown-rump length (CRL), umbilical cord insertion (UCI) and ductus venosus (DV) flow at 11-14 weeks of gestation were recorded. The predictive value for complicated MCDA twins was analyzed using t-test, Chi-square (or Fisher's exact) test, multivariate logistic regression analysis and receiver operating characteristic (ROC) curve.@*Results@#(1) A total of 430 MCDA twin pregnancies were included in this study with 152 in the TTTS group, 142 in the sIUGR group, seven in the TAPS group and 129 in the normal MCDA twins group. No further analysis was performed on the TAPS group due to the small sample size. (2) NT discordance in twins of the TTTS group was significantly greater than that in the normal MCDA twins group[(21.5±16.0)% vs (14.6±13.5)%, t=-3.533, P<0.001]. The area under ROC curve (AUC) of TTTS predicted by NT discordance was 0.649. Stratified analysis showed that TTTS was best predicted when NT discordance was 20% with the sensitivity of 57.9% and specificity of 70.6%. (3) The sIUGR group had greater discordance in CRL and NT and higher UCI discordance than the normal MCDA twins group [NT: (27.8±21.3)% vs (14.6±13.5)%, t=-5.556, P<0.001; CRL: (8.6±6.9)% vs (5.4±4.4)%, t=-3.144, P=0.002; UCI: 47.9% (68/142) vs 13.9% (18/129), χ2=35.929, P<0.001]. The AUC of sIUGR was 0.675 predicted by NT discordance and 0.649 by CRL discordance. Stratified analysis showed that NT discordance of 20% and CRL discordance of 10% were the best prediction for sIUGR with the sensitivity of 53.1% and 34.7% and specificity of 72.1% and 83.8%, respectively. Multivariate logistic regression analysis suggested that UCI discordance was the risk factor for sIUGR (OR=7.165, 95%CI: 2.637-19.472).@*Conclusions@#MCDA twins with NT discordance greater than 20% during early pregnancy are at increased risk for TTTS. CRL discordance greater than 10%, NT discordance greater than 20% and abnormal UCI are risk factors for sIUGR.

Application of chromosomal microarray analysis in prenatal diagnosis of fetuses with increased nuchal translucency / 中华医学遗传学杂志

Objective@#To determine the frequency of chromosomal abnormalities and outcome of pregnancy for fetuses with increased nuchal translucency (NT).@*Methods@#Between July 2014 and February 2018, 247 fetuses with increased NT (>95th centile)were analyzed by chromosome microarray analysis (CMA). The fetuses were divided into ones with isolated increased NT(168 cases), increased NT with cystic hygroma(20 cases), increased NT with edema(12 cases) or increased NT with other abnormalities(47 cases). All couples were followed up by telephone calls.@*Results@#The rate of chromosomal abnormalities was 31.6% (78/247), which included 66 cases with chromosomal aneuploidies and 12 with copy number variants(CNVs). CNVs accounted for 31.4% (11/35) of total abnormalities among fetuses with isolated increased NT, whilst only 2.3% (1/43)of the total abnormalities among fetuses with non-isolated increased NT. Three fetuses with a normal CMA result had mental and physical retardation. Two of them were diagnosed with single gene disorders by whole exome sequencing.@*Conclusion@#CMA can detect more chromosomal microdeletion/microduplications among fetuses with isolated increased NT. Furthermore, fetuses with increased NT and anegative CMA result during pregnancy cannot exclude all adverse outcomes.

Predictive value of first-trimester ultrasound markers for complicated monochorionic diamniotic twins / 中华围产医学杂志

Objective To investigate the value of first-trimester ultrasound parameters in predicting complicated monochorionic diamniotic (MCDA) twins. Methods In this retrospective study, pregnant women diagnosed as MCDA twins by ultrasound in the First Affiliated Hospital of Sun Yat-sen University from January 2013 to January 2018 were recruited and divided into the following four groups: non-complicated MCDA twins group, twin-twin transfusion syndrome (TTTS) group, selective intrauterine growth restriction (sIUGR) group and twin anemia-polycythemia sequence (TAPS) group. Thickness of nuchal translucency (NT), crown-rump length (CRL), umbilical cord insertion (UCI) and ductus venosus (DV) flow at 11-14 weeks of gestation were recorded. The predictive value for complicated MCDA twins was analyzed using t-test, Chi-square (or Fisher's exact) test, multivariate logistic regression analysis and receiver operating characteristic (ROC) curve. Results (1) A total of 430 MCDA twin pregnancies were included in this study with 152 in the TTTS group, 142 in the sIUGR group, seven in the TAPS group and 129 in the normal MCDA twins group. No further analysis was performed on the TAPS group due to the small sample size. (2) NT discordance in twins of the TTTS group was significantly greater than that in the normal MCDA twins group[(21.5±16.0)% vs (14.6±13.5)%, t=－3.533, P<0.001]. The area under ROC curve (AUC) of TTTS predicted by NT discordance was 0.649. Stratified analysis showed that TTTS was best predicted when NT discordance was 20% with the sensitivity of 57.9% and specificity of 70.6%. (3) The sIUGR group had greater discordance in CRL and NT and higher UCI discordance than the normal MCDA twins group [NT: (27.8±21.3)% vs (14.6±13.5)%, t=－5.556, P<0.001; CRL: (8.6±6.9)% vs (5.4±4.4)%, t=－3.144, P=0.002; UCI: 47.9% (68/142) vs 13.9% (18/129), χ2=35.929, P<0.001]. The AUC of sIUGR was 0.675 predicted by NT discordance and 0.649 by CRL discordance. Stratified analysis showed that NT discordance of 20% and CRL discordance of 10% were the best prediction for sIUGR with the sensitivity of 53.1% and 34.7% and specificity of 72.1% and 83.8%, respectively. Multivariate logistic regression analysis suggested that UCI discordance was the risk factor for sIUGR ( OR=7.165, 95% CI : 2.637-19.472). Conclusions MCDA twins with NT discordance greater than 20% during early pregnancy are at increased risk for TTTS. CRL discordance greater than 10%, NT discordance greater than 20% and abnormal UCI are risk factors for sIUGR.

Chromosomal microarray analysis of 339 fetuses with increased nuchal translucency and normal karyotype / 中华围产医学杂志

Objective To explore the value of chromosome microarray analysis (CMA) in determining the genetic etiology of fetuses with increased nuchal translucency (NT) but normal karyotype. Methods Amniocentesis, karyotype analysis and CMA were performed to singleton pregnant women with increased fetal NT ( ≥ 3.0 mm) in early pregnancy (11+1-13+6 gestational weeks) at Shenzhen Maternity and Child Healthcare Hospital from March 2015 to December 2017. A total of 339 fetuses with normal G banding karyotype analysis were recruited retrospectively. Peripheral blood samples were collected for CMA in parents whose fetuses were detected with pathogenic copy number variations (CNVs) or variants of uncertain significance (VUS). Descriptive analysis was used for CMA results. Moreover, Pregnancy outcomes and postnatal conditions of fetuses with abnormal CNVs were followed up. Results Pathogenic CNVs, ranging from 68 kb to 12.636 Mb, were detected in 15 out of the 339 fetuses (4.4%) including four microduplications and 11 microdeletions. Among them, there were eight known microdeletion or microduplication syndromes (nine cases) including Williams-Beuren syndrome, 18p deletion syndrome,Wolf-Hirschhorn syndrome, 22q11 duplication syndrome, 16p11.2 deletion syndrome, 17p13.3 duplication syndrome, 16p11.2 duplication syndrome (one case respectively) and DiGeorge syndrome/velocardiofacial syndrome (two cases). Of the 11 fetuses with VUS, five cases originated from parents with normal phenotype and the identified VUS were benign and the rest six were de novo mutations[1.8%(6/339)]. Of the 15 fetuses with pathogenic CNVs, one was lost to follow-up, four were live born and two of which was found to be growth retardation at the age of two. Among the 11 fetuses with VUS, nine were live born and no abnormality was reported in any cases at one year old. Conclusions For fetus with increased NT and normal karyotype, CMA is able to identify chromosomal microdeletion/microduplication that are not recognized by conventional karyotyping analysis, and may play an important role in prenatal diagnosis and genetic counseling.

Prenatal diagnosis of fetal nuchal fold thickening: a retrospective study of 17 cases / 中华围产医学杂志

Objective To investigate the prenatal diagnosis and genetic counseling of fetal nuchal fold (NF) thickening.Methods This study retrospectively analyzed 17 fetuses with increased NF detected by prenatal ultrasound examination in Peking Union Medical College Hospital,Peking Union Medical College & Chinese Academy of Medical Sciences from December 1,2016 to December 1,2017.All cases were divided into isolated (isolated group) or non-isolated increased NF group (non-isolated group) according to whether the fetus had concomitant ultrasonographic abnormalities or not.Karyotype and chromosomal microarray analysis (CMA) were performed on all cases.Clinical data,prenatal genetic testing results and pregnancy outcomes were analyzed.Results Of those twelve cases in the isolated group,two were terminated due to the identification of chromosomal abnormalities and pathogenic copy number variations (CNVs) and the fetal autopsy results were consistent with the prenatal diagnosis.The rest 10 pregnancies were all continued including one fetus carrying a variant of unknown significance,which was proved to be a paternal heredity by CMA,and nine without genetic abnormalities and all-these infants were healthy during follow-up.Among the five non-isolated cases,one was diagnosed as trisomy 21 by karyotyping and CMA,and the other four were found to have structural abnormalities under ultrasound scan,but without genetic abnormalities in karyotyping and CMA.And all the five pregnancies were terminated after genetic counseling and three of them chose whole exome sequencing (WES) for further test.One homozygous mutation in CHRNA 1 gene and one de novo mutation in SETD2 gene were found in two cases,respectively,while no abnormality was identified in the other one case.Conclusions Once increased NF were indicated by ultrasound examination,prenatal genetic testing should be offered to the patients,including CMA,regardless of other ultrasonographic abnormalities,and WES should also be offered when necessary.Considering a thickened NF is associated with increased risks of structural defects,a close follow-up with fetal echocardiography and ultrasound is required even the prenatal tests are normal.

Prenatal diagnosis and genetic analysis of increased fetal nuchal translucency due to 2p15-16.1 microdeletion: a case report / 中华围产医学杂志

We reported the prenatal molecular diagnosis and pregnant outcome of a fetus with increased nuchal translucency.The ultrasound findings of the gravida at 12+5 gestational weeks indicated that the fetal nuchal translucency thickness was 4.5 mm,and non-invasive prenatal testing suggested as low risk.Amniocentesis was performed at 18 gestational weeks.Fetal chromosomal karyotype was normal but chromosome microarray comparative genomic hybridization analysis identified a 1.878 Mb deletion on chromosome 2p15-16.1.No copy number variation was found in the parents.The microdeletion was also verified by multiplex ligation-dependent probe amplification.Literature reported that chromosome 2p 15-16.1 microdeletion syndrome was characterized by mental retardation,language developmental disorder,microcephaly and so on.This case we reported here was a de novo 2p 15-16.1 microdeletion which contained the critical region and genes of 2p 15-16.1 microdeletion syndrome and was inferred to be a pathogenetic mutation.The gravida chose to terminate the pregnancy after genetic consultation.

Diagnostic value of ultrasound scan at 16 to 18 gestational weeks in euploid fetuses with increased nuchal translucency / 中华围产医学杂志

Objective To investigate the diagnostic value of ultrasound scan at 16 to 18 gestational weeks in euploid fetuses with increased nuchal translucency (NT).Methods From January 2015 to June 2017,214 fetuses diagnosed with increased NT thickness (NT ≥ 3.0 mm) during early pregnancy in Guangzhou Panyu Central Hospital were enrolled.Fetal chromosome karyotype analysis was carried out prenatally.Those cases with normal karyotype underwent ultrasound scan at 16-18 and 20-24 gestational weeks and their outcomes were followed up via telephone.Descriptive statistics was used for statistical analysis.Results There were 198 out of the 214 cases undergoing chromosome karyotype analysis and among them,78 (39％) pregnancies were terminated due to chromosomal abnormalities.Out of the 107 cases with normal karyotype and successful followups,35％(37/107) had structural malformations.There were 19,11 and 6 cases of fetal structural malformations diagnosed at 11-13+6,16-18 and 20-24 weeks of gestational age,respectively,and the rest one was at 28 weeks.Structural deformities detected at 16-18 weeks included cleft lip and palate (n=2),cardiac malformations (n=2),spinal deformities (n=2),body deformities (n=2),diaphragmatic hernia (n=1),encephalocele (n=1) and left multicystic dysplastic kidney (n=1).About 91％ (70/77) of the fetuses with normal karyotype but without abnormal ultrasound findings at 16-18 weeks were free of structural malformations and achieved good pregnant outcomes.Conclusions Ultrasound screening at 16 to 18 weeks of pregnancy can be used to detect multiple structural malformations in fetuses with increased NT and normal karyotype,which may contribute to early detection of fetal structural malformations and help gravidas and their families make timely decisions.

Reference centile charts of first-trimester aneuploidy screening & Doppler parameters for Indian population

Background & objectives: The risk estimation for foetal aneuploidies in the first trimester of pregnancy uses reference curves based on western data. The objective of this study was to construct the reference curves of first-trimester foetal aneuploidy screening parameters for the Indian women. Methods: Cross-sectional data were obtained from 1204 singleton pregnancies between the crown-rump length (CRL) of 40-84 mm. Linear regression models were constructed; the mean, median and standard deviation were derived as a function of CRL. Results: The mean value of CRL was 61.3 mm. The regression analysis showed a significant correlation between all variables and CRL (P< 0.001). There was a positive correlation of CRL with nuchal translucency (NT) (y=0.010x+0.629, R2=0.116) and pregnancy-associated plasma protein-A (PAPP-A) (y=0.107x?1.079, R2=0.173), whereas inverse correlation was seen with free ?-human chorionic gonadotropin (?-hCG) (y=?0.409x+75.025, R2=0.018) and Doppler parameters pulsatility index (PI) (y=?0.008x+1.924 R2=0.053). The centile charts of NT, PAPP-A, free ?-hCG and uterine artery (Ut A) Doppler PI were constructed. Interpretation & conclusions: The reference centile charts of first trimester aneuploidy screening along with Doppler parameters were derived in Indian pregnant women. These centile charts may be used as a reference for clinical use in Indian population.