Deep-learning computer vision can identify increased nuchal translucency in the first trimester of pregnancy.

OBJECTIVE: Many fetal anomalies can already be diagnosed by ultrasound in the first trimester of pregnancy. Unfortunately, in clinical practice, detection rates for anomalies in early pregnancy remain low. Our aim was to use an automated image segmentation algorithm to detect one of the most common fetal anomalies: a thickened nuchal translucency (NT), which is a marker for genetic and structural anomalies. METHODS: Standardized mid-sagittal ultrasound images of the fetal head and chest were collected for 560 fetuses between 11 and 13 weeks and 6 days of gestation, 88 (15.7%) of whom had an NT thicker than 3.5 mm. Image quality was graded as high or low by two fetal medicine experts. Images were divided into a training-set (n = 451, 55 thick NT) and a test-set (n = 109, 33 thick NT). We then trained a U-Net convolutional neural network to segment the fetus and the NT region and computed the NT:fetus ratio of these regions. The ability of this ratio to separate thick (anomalous) NT regions from healthy, typical NT regions was first evaluated in ground-truth segmentation to validate the metric and then with predicted segmentation to validate our algorithm, both using the area under the receiver operator curve (AUROC). RESULTS: The ground-truth NT:fetus ratio detected thick NTs with 0.97 AUROC in both the training and test sets. The fetus and NT regions were detected with a Dice score of 0.94 in the test set. The NT:fetus ratio based on model segmentation detected thick NTs with an AUROC of 0.96 relative to clinician labels. At a 91% specificity, 94% of thick NT cases were detected (sensitivity) in the test set. The detection rate was statistically higher (p = 0.003) in high versus low-quality images (AUROC 0.98 vs. 0.90, respectively). CONCLUSION: Our model provides an explainable deep-learning method for detecting increased NT. This technique can be used to screen for other fetal anomalies in the first trimester of pregnancy.

Diagnostic yield of copy number variation sequencing in fetuses with increased nuchal translucency: a retrospective study.

OBJECTIVE: To assess the efficacy of copy number variation sequencing (CNV-seq) and karyotyping for prenatal detection of chromosomal abnormalities in fetuses with increased nuchal translucency. METHODS: Amniotic fluid samples were extracted from 205 fetuses with increased nuchal translucency (NT ≥ 2.5 mm), diagnosed by ultrasound between gestational ages of 11 and 13 + 6 weeks. Karyotyping and CNV-seq were performed for detecting chromosomal abnormalities. RESULTS: There are 40 fetuses (19.51%) showing increased NT detected with chromosomal abnormalities in karyotyping, and trisomy 21 was found to be the most common abnormalities. There are 50 fetuses (24.39%) identified with chromosomal abnormalities by CNV-seq. The detection of the applied techniques indicated that CNV-seq revealed higher chromosomal aberrations. The risk of chromosomal abnormalities was significantly increased with NT thickening, from 13.64% in the NT group of 2.5-3.4 mm, 38.64% in the NT group of 3.5-4.4 mm, and to 51.72% in the NT group of over 4.5 mm (P < 0.05). The investigated cases with increased NT with presence of soft markers in ultrasound or high risk in non-invasive prenatal testing presented chromosomal abnormalities in higher rates, comparing with those with isolated NT or low risk (P < 0.05). CONCLUSION: The results indicated that the risk of chromosomal abnormalities was associated with the NT thickness, detected by karyotype or CNV-seq. The combination application of two analysis was efficient to reveal the possible genetic defects in prenatal diagnosis. The finding suggested that the detection should be considered with ultrasonographic soft markers, and the NT thickness of 2.5-3.4 mm could be a critical value for detecting chromosomal abnormalities to prevent the occurrence of missed diagnosis.

Identification of Fetuses at Increased Risk of Trisomies in the First Trimester Using Axial Planes.

INTRODUCTION: The measurement of nuchal translucency (NT) is crucial for assessing risk of aneuploidies in the first trimester. We investigate the ability of NT assessed by a transverse view of the fetal head to detect fetuses at increased risk of common aneuploidies at 11-13 weeks of gestation. METHODS: We enrolled a nonconsecutive series of women who attended our outpatient clinic from January 2020 to April 2021 for aneuploidy screening by means of a first trimester combined test. All women were examined by operators certified by the Fetal Medicine Foundation. In each patient, NT measurements were obtained both from the median sagittal view and transverse view. We calculated the risk of aneuploidy using NT measurements obtained both with sagittal and axial scans, and then we compared the results. RESULTS: A total of 1,023 women were enrolled. An excellent correlation was found between sagittal and transverse NT measurements. The sensitivity and specificity of the axial scan to identify fetuses that were deemed at risk of trisomy 21 using standard sagittal scans were 40/40 = 100.0% (95% confidence interval [CI]: 91.2-100.0) and 977/983 = 99.4% (95% CI: 98.7-99.7), respectively. The sensitivity and specificity of the axial scan to identify fetuses at risk of trisomy 13 or 18 were 16/16 = 100.0% (95% CI: 80.6-100.0) and 1,005/1,007 = 99.8% (95% CI: 99.3-99.9). CONCLUSIONS: When the sonogram, a part of combined test screening, is performed by an expert sonologist, axial views can reliably identify fetuses at increased risk of trisomies without an increase in false negative results.

Risk factors for delayed termination of pregnancy following increased nuchal translucency.

OBJECTIVES: Termination of pregnancy after increased nuchal translucency (NT) is a common occurrence. This study aimed to identify characteristics of a cohort with a NT ≥3.0 mm who underwent a pregnancy termination ≥15 weeks compared with those who terminated <15 weeks. METHODS: All NT ≥3.0 mm identified within our department over an 11-year period (2010-2021) (n = 689) were retrospectively examined and characteristics of the cohort of increased NTs ending in termination were further categorized. RESULTS: There were 221 (32.1%) individuals with an increased NT (≥3 mm) who underwent a termination of pregnancy within our study period (2010-2021). Pregnancy termination occurred at a gestational age <15 weeks in 162 (73.3%) and ≥15 weeks in 59 individuals. Pregnant individuals without positive NIPT for aneuploidy were at a higher risk for a ≥15-week termination (p = 0.004). In 29% (17/59) of late terminations, there were additional imaging findings after the NT scan (ultrasound, echocardiogram, magnetic resonance imaging) that ultimately triggered the decision to pursue termination. CONCLUSIONS: As the options for workup of an increased NT expand, potential delays in decision-making surrounding termination increase. This study identifies multiple reasons for delayed termination and proposes several approaches to care aimed at maximizing diagnostic information by imaging and diagnostic testing in an expedited manner.

The value of detailed first-trimester ultrasound in the era of noninvasive prenatal testing.

BACKGROUND: In 2020, the American College of Obstetricians and Gynecologists recommended noninvasive prenatal testing be offered to all patients. However, current societal guidelines in the United States do not universally recommend a detailed first-trimester ultrasound. OBJECTIVE: This study aimed to determine the additional findings identified through first-trimester ultrasound that would have otherwise been missed if noninvasive prenatal testing was used alone as a first-trimester screening method. STUDY DESIGN: This was a retrospective cohort study involving 2158 pregnant patients and 2216 fetuses that were seen at a single medical center between January 1, 2020, and December 31, 2022. All those included underwent both noninvasive prenatal testing and detailed first-trimester ultrasound between 11.0 and 13.6 weeks of gestation. Noninvasive prenatal testing results were categorized as low risk or high risk, and first-trimester ultrasound results were categorized as normal or abnormal. Abnormal first-trimester ultrasounds were further classified as first-trimester screening markers (increased nuchal translucency, absent nasal bone, tricuspid regurgitation, and ductus venosus reverse a-wave) or structural defects (the cranium, neck, heart, thorax, abdominal wall, stomach, kidneys, bladder, spine, and extremities). Descriptive statistics were used to report our findings. RESULTS: Of 2216 fetuses, 65 (3.0%) had a high-risk noninvasive prenatal testing result, whereas 2151 (97.0%) had a low-risk noninvasive prenatal testing result. Of those with a low-risk noninvasive prenatal testing result, 2035 (94.6%) had a normal first-trimester ultrasound, whereas 116 (5.4%) had at least 1 abnormal finding on first-trimester ultrasound. The most common screening marker detected within the low-risk noninvasive prenatal testing group was absent nasal bone (52/2151 [2.4%]), followed by reversed a-wave of the ductus venosus (30/2151 [1.4%]). The most common structural defect in this group was cardiac abnormality (15/2151 [0.7%]). Overall, 181 fetuses were identified as having "abnormal screening" through either a high-risk noninvasive prenatal testing result (n=65) or through a low-risk noninvasive prenatal testing result but abnormal first-trimester ultrasound (n=116). In summary, the incorporation of first-trimester ultrasound screening identified 116 additional fetuses (5.4%) that required further follow-up and surveillance than noninvasive prenatal testing alone would have identified. CONCLUSION: Detailed first-trimester ultrasound identified more fetuses with a potential abnormality than noninvasive prenatal testing alone. Therefore, first-trimester ultrasound remains a valuable screening method that should be used in combination with noninvasive prenatal testing.

Whole exome sequencing in fetuses with isolated increased nuchal translucency: a systematic review and meta-analysis.

OBJECTIVE: To estimate the incremental yield of detecting pathogenic or likely pathogenic diagnostic genetic variants (DGV) by whole exome sequencing (WES) over standard karyotype and chromosomal microarray (CMA) analyses in fetuses with isolated increased nuchal translucency (NT) and normal fetal anatomy at the time of 11-14 weeks scan. MATERIALS AND METHODS: Medline and Embase databases were searched. Inclusion criteria were fetuses with NT >95th percentile, normal karyotype and CMA and no associated structural anomalies at the time of the 11-14 weeks scan. The primary outcome was to estimate the incremental yield of detecting pathogenic or likely pathogenic genetic variants by WES over standard karyotype and CMA analyses in fetuses with isolated increased nuchal translucency. The secondary outcomes were the detection of a genetic variant of unknown significance. Sub-analysis according to different NT cutoffs (between 3.0 and 5.5 mm and > 5.5 mm) and considering fetuses with isolated NT in which fetal anatomy was confirmed to be normal at the anomaly scan were also performed. Random effects model meta-analyses of proportion were used to analyze the data. RESULTS: Eight articles (324 fetuses) were included in the systematic review. Of the fetuses with negative standard karyotype and CMA analysis, the 8.07% (95% CI 5.4-11.3) had pathogenic or likely pathogenic genetic variants detected exclusively by WES. When stratifying the analysis according to NT cutoffs, genetic anomalies detected exclusively at WES analysis were found in 44.70% (95% CI 26.8-63.4) of fetuses with NT between 3.0 mm and 5.5 mm and 55.3% (95% CI 36.6-73.2) in those fetuses with NT >5.5 mm and positive WES results. The 7.84% (95% CI 1.6-18.2) had variants of unknown significance identified by WES. When considering fetuses with isolated increased NT and normal fetal anatomy at the anomaly scan, the rate of pathogenic or likely pathogenic genetic variants detected by WES was 3.87% (95% CI 1.6-7.1), while variants of unknown significance were detected in 4.27% (95% CI 2.2-7.0) of cases. CONCLUSIONS: Pathogenic and likely pathogenic genetic variants detected by WES are present in a significant proportion of fetuses with increased NT but normal standard karyotype and CMA analysis, also when no anomalies are detected at the anomaly scan. Further large studies sharing objective protocols of imaging assessment are needed to confirm these findings and to elucidate which gene panels should be assessed in fetuses with isolated increased NT to rule out associated genetic anomalies, which may potentially impact post-natal outcomes.

[Comparison of results of prenatal diagnosis by different techniques for fetuses with increased nuchal translucency].

OBJECTIVE: To assess the value of chromosomal microarray analysis (CMA) and trio-whole exome sequencing (trio-WES) for fetuses with increased nuchal translucency (NT) thickness. METHODS: Sixty two pregnant women who had visited Urumqi Maternal and Child Care Health Hospital between June 2018 and June 2020 for NT ≥ 3.0 mm at 11 ~ 13+6 gestational weeks were selected as study subjects. Relevant clinical data were collected. The patients were divided into 3.0 ~ ＜3.5 mm (n = 33) and ≥3.5 mm groups (n = 29). Chromosome karyotyping analysis and chromosomal microarray analysis were carried out. And trio-WES analysis was performed on 15 samples with NT thickening but negative CMA results. The distribution and incidence of chromosomal abnormalities in the two groups were compared by using chi-square test. RESULTS: The median age of the pregnant women was 29 years old (22 ~ 41 years old), the median thickness of NT was 3.4 mm (3.0 ~ 9.1 mm), and the median gestational age at the detection was 13+4 weeks (11+5 ~ 13+6 weeks). Chromosome karyotyping analysis has detected 12 cases of aneuploidies and 1 case of derivative chromosome. The detection rate was 20.97% (13/62). CMA has detected 12 cases of aneuploidies, 1 case of pathogenic CNV and 5 cases of variant of uncertain significance (VUS), with a detection rate of 29.03% (18/62). The aneuploidy rate for the NT ≥ 3.5 mm group was higher than that for the 3.0 ≤ NT < 3.5 mm group [3.03% (1/33) vs. 41.38% (12/29), χ² = 13.698, P < 0.001]. There was no statistically significant difference between the two groups in the detection rate of fetal pathogenic CNV and VUS (χ² = 0.028, P > 0.05). Trio-WES analysis of 15 samples with negative CMA result and no structural abnormality has identified 6 heterozygous variants, including SOS1: c.3542C>T (p.A1181V) and c.3817C>G (p.L1273V), COL2A1: c.436C>T (p.P146S) and c.3700G>A (p.D1234N), LZTR1: c.1496T>C (p.V499A), and BRAF: c.64G>A (p.D22N), respectively. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), all of the variants were rated as VUS. CONCLUSION: NT thickening can indicate chromosome abnormality, and CMA and trio-WES may be used for the prenatal diagnosis.

Basic sonographic examination of the fetal brain at 11-13 weeks' gestation: Rationale for a simple and reliable four-step technique.

The widespread incorporation of first-trimester scanning between 11 and 13 weeks' gestation has shifted from the screening of chromosomal abnormalities, mainly by measuring nuchal translucency thickness and visualization of the nasal bone, to a more detailed study of the fetal anatomy leading to early detection of several structural congenital anomalies. This goal can be improved by the routine and focused sonographic assessment of specific anatomic planes and the identification of distinctive landmarks that can help disclosing a particular, non-evident condition. In this article we present the basis for a basic, early examination of the fetal brain during screening using a four-step technique, which can be readily incorporated during the first-trimester scan. The technique includes the focused visualization of the cranial contour, choroid plexuses of the lateral ventricles and midline, aqueduct of Sylvius, brainstem, fourth ventricle, and the choroid plexus of the fourth ventricle. The rationale for this approach is presented and discussed.

A Machine Learning Method for Automated Description and Workflow Analysis of First Trimester Ultrasound Scans.

Obstetric ultrasound assessment of fetal anatomy in the first trimester of pregnancy is one of the less explored fields in obstetric sonography because of the paucity of guidelines on anatomical screening and availability of data. This paper, for the first time, examines imaging proficiency and practices of first trimester ultrasound scanning through analysis of full-length ultrasound video scans. Findings from this study provide insights to inform the development of more effective user-machine interfaces, of targeted assistive technologies, as well as improvements in workflow protocols for first trimester scanning. Specifically, this paper presents an automated framework to model operator clinical workflow from full-length routine first-trimester fetal ultrasound scan videos. The 2D+t convolutional neural network-based architecture proposed for video annotation incorporates transfer learning and spatio-temporal (2D+t) modelling to automatically partition an ultrasound video into semantically meaningful temporal segments based on the fetal anatomy detected in the video. The model results in a cross-validation A1 accuracy of 96.10% , F1=0.95 , precision =0.94 and recall =0.95 . Automated semantic partitioning of unlabelled video scans (n=250) achieves a high correlation with expert annotations ( ρ = 0.95, p=0.06 ). Clinical workflow patterns, operator skill and its variability can be derived from the resulting representation using the detected anatomy labels, order, and distribution. It is shown that nuchal translucency (NT) is the toughest standard plane to acquire and most operators struggle to localize high-quality frames. Furthermore, it is found that newly qualified operators spend 25.56% more time on key biometry tasks than experienced operators.

Array study in fetuses with nuchal translucency above the 95th percentile: a 4-year observational single-centre study.

PURPOSE: To evaluate the performance of chromosomal microarray analysis (CMA) in fetuses with nuchal translucency (NT) > 95th percentile. Secondary objectives were to analyze these results according to NT thickness, below or above 3.5 mm, and those without associated anomalies. METHODS: This observational single-cohort study was conducted between 2015 and 2018 in fetuses with NT > 95th percentile. Following an invasive test, quantitative fluorescence-polymerase chain reaction (QF-PCR) was performed, and if normal, CMA was performed. Pathogenic copy number variants (CNVs), non-reported pathogenic CNV, pathogenic autosomal recessive variants and variants of unknown significance (VUS) were analysed. RESULTS: One-hundred and sixty-two fetuses with NT > 95th percentile, normal QF-PCR and CMA were included. Amongst 128 fetuses with NT between the 95th percentile and 3.5 mm, one (0.8%) had a pathogenic CNV, four (3.1%) had non-reported pathogenic CNV, one (0.8%) had pathogenic autosomal recessive variant and 13 (10.2%) had VUS. Amongst 34 fetuses with NT ≥ 3.5 mm, four (11.8%) had pathogenic CNV, one (2.9%) had non-reported pathogenic CNV, one (2.9%) had pathogenic autosomal recessive variant and four (11.8%) had VUS. Four in 162 (2.5%) fetuses had CNVs at the chromosome 16p13.11 region. Amongst 154 fetuses without structural abnormalities and normal QF-PCR, three (1.9%) had a pathogenic CNV, 5 (3.2%) had non-reported pathogenic CNV, one (0.6%) autosomal recessive pathogenic CNV and 16 (10.4%) had VUS. CONCLUSION: Pathogenic CNVs were found in 1% of fetuses with an NT thickness between the 95th percentile and 3.5 mm and in 12% of fetuses with NT ≥ 3.5 mm. CNVs were found at the 16p13.11 region in 2.5% of cases.

Comparison of results of prenatal diagnosis by different techniques for fetuses with increased nuchal translucency / 中华医学遗传学杂志

OBJECTIVE@#To assess the value of chromosomal microarray analysis (CMA) and trio-whole exome sequencing (trio-WES) for fetuses with increased nuchal translucency (NT) thickness.@*METHODS@#Sixty two pregnant women who had visited Urumqi Maternal and Child Care Health Hospital between June 2018 and June 2020 for NT ≥ 3.0 mm at 11 ~ 13+6 gestational weeks were selected as study subjects. Relevant clinical data were collected. The patients were divided into 3.0 ~ ＜3.5 mm (n = 33) and ≥3.5 mm groups (n = 29). Chromosome karyotyping analysis and chromosomal microarray analysis were carried out. And trio-WES analysis was performed on 15 samples with NT thickening but negative CMA results. The distribution and incidence of chromosomal abnormalities in the two groups were compared by using chi-square test.@*RESULTS@#The median age of the pregnant women was 29 years old (22 ~ 41 years old), the median thickness of NT was 3.4 mm (3.0 ~ 9.1 mm), and the median gestational age at the detection was 13+4 weeks (11+5 ~ 13+6 weeks). Chromosome karyotyping analysis has detected 12 cases of aneuploidies and 1 case of derivative chromosome. The detection rate was 20.97% (13/62). CMA has detected 12 cases of aneuploidies, 1 case of pathogenic CNV and 5 cases of variant of uncertain significance (VUS), with a detection rate of 29.03% (18/62). The aneuploidy rate for the NT ≥ 3.5 mm group was higher than that for the 3.0 ≤ NT < 3.5 mm group [3.03% (1/33) vs. 41.38% (12/29), χ² = 13.698, P < 0.001]. There was no statistically significant difference between the two groups in the detection rate of fetal pathogenic CNV and VUS (χ² = 0.028, P > 0.05). Trio-WES analysis of 15 samples with negative CMA result and no structural abnormality has identified 6 heterozygous variants, including SOS1: c.3542C>T (p.A1181V) and c.3817C>G (p.L1273V), COL2A1: c.436C>T (p.P146S) and c.3700G>A (p.D1234N), LZTR1: c.1496T>C (p.V499A), and BRAF: c.64G>A (p.D22N), respectively. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), all of the variants were rated as VUS.@*CONCLUSION@#NT thickening can indicate chromosome abnormality, and CMA and trio-WES may be used for the prenatal diagnosis.

Follow-up of increased nuchal translucency: Results of a study of 398 cases.

INTRODUCTION: Increased fetal nuchal translucency is associated with chromosomal as well as morphological abnormalities. The psychomotor development of children from these pregnancies is still unclear. The main objective of our study was to evaluate pregnancy outcomes and the post-natal progress of fetuses with increased nuchal translucency. We also compared the features of patients and fetuses according to their nuchal translucency measurement (above 3.5 mm or not). METHODS: Retrospective single-center study in 398 patients in a level 3 maternity unit in France. Mothers whose fetus had a nuchal translucency higher than the 95 th percentile between 2009 and 2018 were included. All patients who had a child with a normal karyotype were prospectively given a questionnaire to evaluate their child's psychomotor development. RESULTS: 37.4% (130/348) of fetuses had a chromosomal abnormality and 2.3% (5/218) had a normal karyotype but a pathogenic copy number variant diagnosed by array- CGH. 28.7% (77/268) of fetus without diagnosed chromosomal abnormalities, presented a morphological abnormality with predominant cardiac malformations. Fetuses with a nuchal translucency ≥ 3.5 mm, had more chromosomal abnormalities (p<0.0001) and were at higher risk of hypotrophy (p=0.005) and birth by cesarean (p=0.04). Among the liveborn children, 70% (166/238) were healthy without morphological or chromosomal abnormalities. Lastly, 17% (17/102) of these children had psychomotor disorder. CONCLUSION: According to our results, parents should be warned of the increased risk of hypotrophy and delivery by cesarean section for fetuses with a nuchal translucency ≥ 3.5 mm. We recommend prolonged specialized pediatric follow-up for children who have been carriers of increased nuchal translucency.

Prenatal diagnosis of Coffin-Siris syndrome: What are the fetal features?

OBJECTIVE: To present both our center's and previously reported experience of prenatal diagnosis of Coffin-Siris syndrome (CSS) with regard to the laboratory testing and fetal features of this syndrome. METHODS: This was a retrospective study of eight pregnancies with fetal CSS identified by prenatal or postnatal genetic testing. Clinical and laboratory data were collected and reviewed for these cases, including maternal demographics, prenatal sonographic findings, chromosomal microarray and exome sequencing (ES) results, and pregnancy outcomes. RESULTS: A total of eight cases of fetal CSS based on molecular testing were detected. Two cases presented with an increased nuchal translucency (NT) in the first trimester. The remaining six were identified at the second trimester scan. Agenesis of the corpus callosum (ACC) was the most common sonographic finding, accounting for 5/7 (71.4%) cases in which a second trimester sonogram was performed: four had ACC as an isolated finding, and one had additional features of cerebellar hypoplasia and left congenital diaphragmatic hernia. CONCLUSION: CSS should be included in the differential diagnosis when ACC is found by prenatal ultrasound. Both chromosomal microarray and ES should be options when counseling patients with a structurally anomalous fetus.

Contingent cfDNA Screening Implementation: Increasing Diagnostic Accuracy and Reducing Invasive Testing - 6 Years' Results in a Single Center.

OBJECTIVES: Universal screening for trisomy using cell-free DNA (cfDNA) has proven to be more effective than combined test, but it is not cost efficient currently. Contingent cfDNA screening on the results of the first-trimester combined test can improve the detection rate of the combined test and reduce the number of invasive tests at a lower cost than universal screening. In 2018, a contingent screening program was implemented in the community of Castilla y Leon (Spain). This study aims to compare the results achieved in Salamanca University Hospital during the first 3 years of contingent screening (2018-2020) with those of the previous 3 years (2015-2017) to assess the changes in the trisomy detection rate and the number of invasive tests. METHODS: A total of 9,903 singleton pregnancies without malformations nor nuchal translucency >p99 were included. 5,165 patients underwent combined screening and 4,738 had contingent screening based on the combined test risk. In the combined test group, women were offered an invasive test if the risk was ≥1:270, while risks under 1:270 were considered low risks, and no further testing was offered. In the contingent screening group, invasive testing was offered if the risk was ≥1:100 (≥1:50 from 2020 onwards), while cfDNA was offered if the combined test risk was between 1:100 and 1:1,000 (1:50-1:1,000 from 2020 onwards). When risk was <1:1,000, no further testing was offered. Aneuploidies detected by cfDNA were confirmed by invasive diagnostic testing. RESULTS: There were 33 cases of trisomy 21 (T21) throughout the 6 years of study. Four cases had low/intermediate risks and were spotted by cfDNA. Risk >1:1,000 threshold for contingent test detected 100% T21. There was a false-positive result for trisomy 13. There were no false-negative results. "No-call" cfDNA results were minimized by repeating blood collection 2 weeks later, as fetal fraction (FF) was doubled. Invasive testing had a drop rate of 84% after contingent screening implementation. DISCUSSION: The implementation of population-based contingent screening significantly reduces the number of invasive tests without lowering diagnostic accuracy. To achieve the maximum efficiency of the program, it is important to know the best cut-offs according to the population where the program is to be implemented. The number of uninformative results due to low FF can be reduced by repeating the test 2 weeks after the initial extraction: this increases the FF to twice the initial one, achieving informative results and avoiding unnecessary invasive tests.

Prenatal and perinatal outcomes of twin pregnancy discordant for one fetus with nuchal translucency above the 95th percentile.

OBJECTIVE: To compare prenatal and perinatal outcomes of twin pregnancies in which one twin the nuchal translucency (NT) was above the 95th percentile in dichorionic twins (DCT) and monochorionic twins (MCT). METHOD: In this retrospective study, 93 twin pregnancies (186 fetuses) in which one twin the NT was above the 95th percentile and the co-twin had normal NT were analyzed. Results of of G-banding and Chromosomal microarray (CMA), ultrasound findings and pregnancy outcomes were reviewed. RESULTS: Totally, 57 pregnancies (114 fetuses) were DCT and 36 pregnancies (72 fetuses) were MCT. Karyotyping and CMA results shown that clinically significant chromosomal abnormalities were found in 16 fetuses, including 13 aneuploidies, 2 chromosomal mosaic and 1 pathological Copy number variations (CNVs) (14 were DCT and 2 were MCT). Overall, the incidence of fetal chromosomal abnormalities was 12.3% (14/114) in DCT and 2.8%(2/72) in MCT (χ2 = 3.932, p = 0.047). Among the cases with normal prenatal diagnosis result, structural abnormalities were found in four fetuses (4.0%, 4/100) in DCT and two fetuses (2.9%, 2/70) in MCT (p > 0.999). There were one intrauterine fetal demises (IUFD) and two miscarry in DCT. One IUFD, three subsequently developed Twin-to-Twin Transfusion Syndrome (TTTS) and four developed selective intrauterine growth restriction (sIUGR) in MCT. Totally, the overall fetal survival rate was 85.1% (97/114) in DCT and 80.6% (58/72) in MCT (χ2 = 0.653, p = 0.419). CONCLUSION: Compared to MCT, the incidence of chromosomal abnormalities in DCT discordant for one fetus with NT above the 95th percentile was higher. The risk of structural abnormalities and the rate of fetal survival for both MCT and DCT was similar.

Machine Learning Algorithms for Classification of First-Trimester Fetal Brain Ultrasound Images.

OBJECTIVE: To evaluate the feasibility of machine learning (ML) tools for segmenting and classifying first-trimester fetal brain ultrasound images. METHODS: Two image segmentation methods processed high-resolution fetal brain images obtained during the nuchal translucency scan: "Statistical Region Merging" (SRM) and "Trainable Weka Segmentation" (TWS), with training and testing sets in the latter. Measurement of the fetal cerebral cortex in original and processed images served to evaluate the performance of the algorithms. Mean absolute percentage error (MAPE) was used as an accuracy index of the segmentation processing. RESULTS: The SRM plugin revealed a total MAPE of 1.71% ± 1.62 SD (standard deviation) and a MAPE of 1.4% ± 1.32 SD and 2.72% ± 2.21 SD for the normal and increased NT groups, respectively. The TWS plugin displayed a MAPE of 1.71% ± 0.59 SD (testing set). There were no significant differences between the training and testing sets after 5-fold cross-validation. The images obtained from normal NT fetuses and increased NT fetuses revealed a MAPE of 1.52% ± 1.02 SD and 2.63% ± 1.98 SD. CONCLUSIONS: Our study demonstrates the feasibility of using ML algorithms to classify first-trimester fetal brain ultrasound images and lay the foundation for earlier diagnosis of fetal brain abnormalities.

High rate of abnormal findings in Prenatal Exome Trio in low risk pregnancies and apparently normal fetuses.

OBJECTIVE: Data on the value of exome sequencing in fetuses with no structural anomalies are limited, especially in the early stages of pregnancy and in low risk pregnancies. We investigated the yield of targeted clinical prenatal trio exome sequencing (pES) in pregnancies with and without fetal structural anomalies. METHODS: We performed pES in 353 pregnancies: Group 1 included 143 pregnancies with high clinical suspicion for a genetic disease: pregnancies with increased nuchal translucency, ultrasound structural defects, intrauterine growth restriction, polyhydramnios, or effusion/nuchal edema. Group 2 included 210 pregnancies with no notable abnormal fetal ultrasound findings. 2a. Low risk pregnancies with minor ultrasound findings, referred to the geneticist due to mildly increased risk for genetic disease (50); and 2b. Normal pregnancy surveillance (160). RESULTS: Overall, 26 (7.36%) fetal analyses had pathogenic (P)/likely pathogenic (LP) variants. In group 1, 20/143 (13.99%) cases had P/LP variants. In group 2, 6/210 (2.86%) cases were found to have P/LP variants [5/50 in (2a) and 1/160 in (2b)]. CONCLUSION: These results show a high rate of abnormal findings on pES even in apparently normal pregnancies.

A prospective cohort study on association of first-trimester serum biomarkers and risk of isolated foetal congenital heart defects.

BACKGROUND: This study aims to assess the association between first-trimester biomarkers in foetuses with a non-chromosomal congenital heart defect (CHD) and compares it to the matched healthy foetuses. METHOD: Nuchal Translucency (NT), Pregnancy-Associated Plasma Protein-A (PAPP-A) and free beta-human Chorionic Gonadotropin (ß-hCG) were evaluated in 56 isolated foetal heart defects and 224 controls. The CHDs were further divided into Critical CHD (C-CHD) and Non-critical CHD (N-CHD) groups. RESULTS: The multiple of the median (MoM) values for PAPP-A were significantly lower (0.87 MoM vs. 0.92 MoM; p = 0.008) in the total CHD group than in controls. The median of foetal NT values was significantly higher in the total CHDs than in controls (1.16 MoM vs. 1.03 MoM; p < 0.001), especially for C-CHDs (1.28 MoM; P < 0.001). There were no significant differences in terms of PAPP-A (p = 0.779) and foetal NT values (p = 0.760) between the N-CHDs and control groups. There were no significant differences within the groups based on free ß-hCG, except for a lower ß-hCG in C-CHD group than in the control group (0.95 MoM vs. 1.11 MoM; p = 0.022). CONCLUSION: Lower PAPP-A levels and increased NT thickness were associated with an increased risk of CHDs, especially the critical type of CHDs.Clinical significanceMaternal serum PAPP-A, measured in the first trimester, is significantly lower in CHD.Foetal NT is significantly thicker in foetuses with CHD, especially those with critical CHD.Maternal serum ß-hCG was only decreased among critical CHD group.

Ultrasonographic study of fetal facial profile markers during the first trimester.

BACKGROUND: To establish reference ranges of fetal facial profile markers and study their correlations with crown-rump length (CRL) during the first trimester (11 ~ 13+ 6 weeks' gestation) in a Chinese population. METHODS: Ultrasonographic images of measuring fetal nuchal translucency (NT) were retrospectively selected randomly in normal fetuses whose parents were both Chinese. The facial markers included inferior facial angle (IFA), maxilla-nasion-mandible (MNM) angle, facial maxillary angle (FMA) and profile line (PL) distance. These markers were measured through ViewPoint 6 software by two experienced sonographers. RESULTS: Three hundred and eighty fetuses were selected. The ICCs (95 % CI) of intra-operator 1 reproducibility of IFA, MNM angle, FMA, PL distance were 0.944 (0.886 ~ 0.973), 0.804 (0.629 ~ 0.902), 0.834 (0.68 ~ 0.918) and 0.935 (0.868 ~ 0.969), respectively. The ICCs (95 % CI) of intra-operator 2 reproducibility of IFA, MNM angle, FMA, PL distance were 0.931 (0.857 ~ 0.967), 0.809 (0.637 ~ 0.904), 0.786 (0.600 ~ 0.892) and 0.906 (0.813 ~ 0.954), respectively. The ICCs (95 % CI) of inter-operator reproducibility of IFA, MNM angle, FMA, PL distance were 0.885 (0.663 ~ 0.953), 0.829 (0.672 ~ 0.915), 0.77 (0.511 ~ 0.891) and 0.844 (0.68 ~ 0.925), respectively. The average ± SD of IFA, MNM angle, FMA and PL distance were 80.2°±7.25°, 4.17°±1.19°, 75.36°±5.31°, 2.78 ± 0.54 mm, respectively. IFA and PL distance significantly decreased with CRL, while MNM angle and FMA significantly increased with CRL. CONCLUSIONS: It was feasible to measure fetal facial markers during the first trimester. In Chinese population, the reference ranges of IFA, MNM angle, FMA and PL distance were 80.2°±7.25°, 4.17°±1.19°, 75.36°±5.31°, 2.78 ± 0.54 mm, respectively, and the measurements were found to correlate with CRL.

The effect of nuchal umbilical cord on fetal cardiac and cerebral circulation-cross-sectional study.

OBJECTIVES: The subject of our analysis is the influence of umbilical cord collision around the fetal neck on the fetal heart function and cerebral circulation. METHODS: Our study was carried out on a group of 115 fetuses from single pregnancies with physiological course, during the 15th to 40th week of pregnancy. In our analysis, we examined the following parameters: Tei index for right ventricle, Tei index for left ventricle with Tei index components: isovolumetric contraction time, isovolumetric relaxation time, ejection time and cardiothoracic area ratio, middle cerebral artery peak systolic velocity (PS MCA), middle cerebral artery pulsatility index (PI MCA). Gestational age in our study was: 28+2±34. The study group of patients with fetal umbilical cord around neck group (fUCAN) included 38 fetuses (20 males, 18 females). The control group of patients with no fetal umbilical cord around neck group (NfUCAN) included 77 fetuses (43 males, 34 females). RESULTS: In our study, we found no significant differences in the values obtained: Tei LV in fUCAN: 0.5±0.1 vs. in NfUCAN: 0.5±0.1; p=0.42), Tei RV in fUCAN: 0.5±0.2 vs. in NfUCAN: 0.4±0.1; (p=0.2). Tricuspid valve regurgitation-TR was observed with the following frequency: fUCAN: 7/38, 18% vs. NfUCAN: 13/77, 17%; p=0.8. MCA PS in study fUCAN group was significantly higher than in NfUCAN (40.2±11.5 vs. 32.5±9.5; p=0.003), although other hemodynamic and clinical variables did not differ between the study and control groups. CONCLUSIONS: The fetal nuchal umbilical cord collision did not affect the fetal heart function expressed as Tei index, at the time of fetal heart examination (at mean gestational age 29+4 weeks). The fUCAN group presented elevated PS MCA, which was not related to other hemodynamic and clinical variables between the study and control groups.