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To evaluate the performance of noninvasive prenatal screening (NIPS) in the detection of common aneuploidies in a population-based study, a total of 86,262 single pregnancies referred for NIPS were prospectively recruited. Among 86,193 pregnancies with reportable results, follow-up was successfully conducted in 1160 fetuses reported with a high-risk result by NIPS and 82,511 cases (95.7%) with a low-risk result. The screen-positive rate (SPR) of common aneuploidies and sex chromosome abnormalities (SCAs) provided by NIPS were 0.7% (586/83,671) and 0.6% (505/83,671), respectively. The positive predictive values (PPVs) for Trisomy 21, Trisomy 18, Trisomy 13 and SCAs were calculated as 89.7%, 84.0%, 52.6% and 38.0%, respectively. In addition, less rare chromosomal abnormalities, including copy number variants (CNVs), were detected, compared with those reported by NIPS with higher read-depth. Among these rare abnormalities, only 23.2% (13/56) were confirmed by prenatal diagnosis. In total, four common trisomy cases were found to be false negative, resulting in a rate of 0.48/10,000 (4/83,671). In summary, this study conducted in an underdeveloped region with limited support for the new technology development and lack of cost-effective prenatal testing demonstrates the importance of implementing routine aneuploidy screening in the public sector for providing early detection and precise prognostic information.

Objective: Cell-free DNA (cfDNA) fragments in maternal plasma contain DNA damage and may negatively impact the sensitivity of noninvasive prenatal testing (NIPT). However, some of these DNA damages are potentially reparable. We aimed to recover these damaged cfDNA molecules using PreCR DNA repair mix., Methods: cfDNA was extracted from 20 maternal plasma samples and was repaired and sequenced by the Illumina platform. Size profiles and fetal DNA fraction changes of repaired samples were characterized. Targeted sequencing of chromosome Y sequences was used to enrich fetal cfDNA molecules following repair. Single-molecule real-time (SMRT) sequencing platform was employed to characterize long (>250 bp) cfDNA molecules. NIPT of five trisomy 21 samples was performed., Results: Size profiles of repaired libraries were altered, with significantly increased long (>250 bp) cfDNA molecules. Single nucleotide polymorphism (SNP)-based analyses showed that both fetal- and maternal-derived cfDNA molecules were enriched by the repair. Fetal DNA fractions in maternal plasma showed a small but consistent (4.8%) increase, which were contributed by a higher increment of long fetal cfDNA molecules. z-score values were improved in NIPT of all trisomy 21 samples., Conclusion: Plasma DNA repair recovers and enriches long cfDNA molecules of both fetal and maternal origins in maternal plasma., (© 2018 John Wiley & Sons, Ltd.)

Objective: To investigate the intraobserver and interobserver reproducibility of a novel sonographic parameter named facial maxillary angle (FMA) and to establish nomograms of FMA, inferior facial angle (IFA), frontal nasal-mental angle (FNMA), maxilla-nasion-mandible angle (MNMA), and fetal profile line (FPL) in Chinese fetuses., Methods: In this prospective cross-sectional study, FMA, IFA, FNMA, MNMA, and FPL were measured in 592 normal fetuses between 16 and 36 gestational weeks. FMA was measured twice by the same and another operator with a blinded method on the first 50 cases. The reference interval was defined as ±2SD. The efficacy of five sonographic markers was tested in 10 fetuses with micrognathia retrieved from the database of our unit., Results: The intraclass correlation coefficient (95% CI) of intraobserver and interobserver reproducibility of FMA was 0.937 (0.890-0.964) and 0.891 (0.809-0.938), respectively. FMA, FNMA, and IFA increased slightly from 16 weeks till 28-31 weeks and decreased minimally thereafter. FMA and FNMA made correct diagnosis in all affected fetuses; MNMA and IFA identified nine and eight cases respectively, and FPL only detected five cases., Conclusion: A fixed cutoff of 66° for FMA and 136° for FNMA may be adopted as simple screening criteria of micrognathia., (© 2018 John Wiley & Sons, Ltd.)

Background: Prenatal sonographic diagnosis of Optiz G/BBB syndrome is difficult because the common clinical features, such as hypertelorism, hypospadias and abnormalities of midline structures, including laryngotracheoesophageal defects, are subtle., Method: Chromosomal microarray (CMA) analysis using a target enriched Fetal DNA Chip design was performed on the DNA of a fetus with congenital cardiac abnormalities., Results: Fetal DNA chip revealed a 48Kb single copy number loss within chromosome region Xp22.2 (arr[hg18]Xp22.2(10,627,354-10,675,946)x0 mat). This deletion included the 3' UTR region of the MID1 gene predicted to cause the X-linked Opitz G/BBB syndrome., Conclusions: This case supports the use of CMA in prenatal diagnosis of fetuses with congenital heart disease. CMA allows prenatal diagnosis of genomic aberrations at a much higher resolution compared with conventional karyotyping, and such findings enable proper genetic counseling and decision making in the pregnancy., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Objectives: To study the angle of the deviation of a presumed midsagittal plane of the fetal spine from the true midsagittal planes by three-dimensional (3D) ultrasound and to investigate whether the experience of operators has an effect on the degree of this deviation., Methods: Eight sonographers, four were trained to perform routine anomaly scan (Trained Group) and four were trained to perform fetal biometric measurement only (Non-trained Group), were asked to use a 3D transducer to obtain a 2D image which they thought to represent the true midsagittal plane of the fetal spine. A 3D volume was then acquired. Stored volumes were analyzed using the multiplanar mode. In the transverse plane, the angle of the deviation of presumed midsagittal planes from the true midsagittal planes was measured., Results: The mean angle of deviation of the trained group was significantly lower than that of the non-trained group (7.9 vs. 21.1, p < 0.001). There were no significant variations among the four operators within each group. However, even among the Trained Group, the angle of deviation could be as large as 27.2°., Conclusions: Training improved the ability to obtain a midsagittal plane of the fetal spine. 3D ultrasound might provide potential useful information to guide the acquisition of standard image planes.

Objective: To assess the effect of the prostaglandin E2 (PGE2) on fetal vascular blood flow during cervical priming., Study Design: In a prospective, observational study, 32 pregnant women > or =37 weeks of gestation requiring PGE2 for induction of labor were recruited. The resistance indices (RIs) of umbilical artery, middle cerebral artery, renal artery and ductus venosum were measured before, 2 and 4 hours after insertion of a PGE2 vaginal pessary., Results: There were no significant changes in RIs of various fetal vessels during cervical priming with PGE2., Conclusion: There was no significant change in fetal hemodynamics after vaginal prostaglandin administration. This finding provides further evidence to support the safety of prostaglandin for normal fetuses.

Background: The aim of the study was to assess fetal vascular blood flow after amniotomy., Methods: This was a prospective observational study. Thirty-five women with singleton pregnancy beyond 36 weeks of gestation, who underwent amniotomy, were recruited. The pulsatility indices of the fetal middle cerebral artery (MCA), the renal artery, and the ductus venosum were measured before and 30 min following amniotomy. The changes in pulsatility index were compared by means of Wilcoxon signed rank test., Results: There was a significant reduction in pulsatility indices of the MCA (median reduction: 0.23; interquantile range (IQR): -0.04, 0.4) and the renal artery (median reduction: 0.12; IQR: -0.12, 0.54) after amniotomy. However, there was no obvious change in the ductus venosum (median reduction: 0.00; IQR: -0.06, 0.1)., Conclusions: Amniotomy is associated with significant reduction in the impedance of the fetal MCA and the renal artery. The former may be a result of fetal stress response and the latter could be related to the release of vasoactive substances after amniotomy.

Background: Low-pass genome sequencing (GS) detects clinically significant copy number variants (CNVs) in prenatal diagnosis. However, detection at improved resolutions leads to an increase in the number of CNVs identified, increasing the difficulty of clinical interpretation and management. Methods: Trio-based low-pass GS was performed in 315 pregnancies undergoing invasive testing. Rare CNVs detected in the fetuses were investigated. The characteristics of rare CNVs were described and compared to curated CNVs in other studies. Results: A total of 603 rare CNVs, namely, 597 constitutional and 6 mosaic CNVs, were detected in 272 fetuses (272/315, 86.3%), providing 1.9 rare CNVs per fetus (603/315). Most CNVs were smaller than 1 Mb (562/603, 93.2%), while 1% (6/603) were mosaic. Forty-six de novo (7.6%, 46/603) CNVs were detected in 11.4% (36/315) of the cases. Eighty-four CNVs (74 fetuses, 23.5%) involved disease-causing genes of which the mode of inheritance was crucial for interpretation and assessment of recurrence risk. Overall, 31 pathogenic/likely pathogenic CNVs were detected, among which 25.8% (8/31) were small (<100 kb; n = 3) or mosaic CNVs (n = 5). Conclusion: We examined the landscape of rare CNVs with parental inheritance assignment and demonstrated that they occur frequently in prenatal diagnosis. This information has clinical implications regarding genetic counseling and consideration for trio-based CNV analysis. [ABSTRACT FROM AUTHOR]

Introduction: Chromosomal microarray analysis is recommended as the first‐tier test for the evaluation of fetuses with structural anomalies. This study aims to investigate the incremental diagnostic yield of chromosomal microarray over conventional karyotyping analysis in fetuses with anomalies restricted to one anatomic system and those with nonspecific anomalies detected by sonography. Material and methods: This is a retrospective cohort analysis of 749 fetuses undergoing prenatal diagnosis for abnormal ultrasound findings isolated to one anatomic system and normal karyotype, utilizing chromosomal microarray. Overall, 495 (66%) fetuses had anomalies confined to one anatomic system and 254 (34%) had other nonspecific anomalies including increased nuchal translucency (≥3.5 mm), cystic hygroma, intrauterine growth restriction and hydrops fetalis. Results: Fetuses with ultrasound anomalies restricted to one anatomic system had a 3.0% risk of carrying a pathogenic copy number variant; the risk varied dependent on the anatomic system affected. Fetuses with confined anomalies of the cardiac system had the highest diagnostic yield at 4.6%, but there were none in the urogenital system. Fetuses with nonspecific ultrasound anomalies had the highest diagnostic yield in fetuses with an intrauterine growth restriction at 5.9%. Overall, fetuses with a nonspecific ultrasound anomaly were affected with pathogenic copy number variants in 1.6% in the cases. Conclusions: The diagnostic yield of chromosomal microarray in fetuses with normal karyotype and ultrasound abnormality confined to a single anatomic system was highest if it involved cardiac defects or intrauterine growth restriction. This diagnostic yield ranges from 0% to 4.6% depending on the anatomic system involved. Chromosomal microarray has considerable diagnostic value in these pregnancies. [ABSTRACT FROM AUTHOR]

Background: Increased nuchal translucency (NT) is an important biomarker associated with increased risk of fetal structural anomalies. It is known to be contributed by a wide range of genetic etiologies from single-nucleotide variants to those affecting millions of base pairs. Currently, prenatal diagnosis is routinely performed by karyotyping and chromosomal microarray analysis (CMA); however, both of them have limited resolution. The diversity of the genetic etiologies warrants an integrated assay such as genome sequencing (GS) for comprehensive detection of genomic variants. Herein, we aim to evaluate the feasibility of applying GS in prenatal diagnosis for the fetuses with increased NT. Methods: We retrospectively applied GS (> 30-fold) for fetuses with increased NT (≥3.5 mm) who underwent routine prenatal diagnosis. Detection of single-nucleotide variants, copy number variants, and structural rearrangements was performed simultaneously, and the results were integrated for interpretation in accordance with the guidelines of the American College of Medical Genetics and Genomics. Pathogenic or likely pathogenic (P/LP) variants were selected for validation and parental confirmation, when available. Results: Overall, 50 fetuses were enrolled, including 34 cases with isolated increased NT and 16 cases with other fetal structural malformations. Routine CMA and karyotyping reported eight P/LP CNVs, yielding a diagnostic rate of 16.0% (8/50). In comparison, GS provided a twofold increase in diagnostic yield (32.0%, 16/50), including one mosaic turner syndrome, eight cases with microdeletions/microduplications, and seven cases with P/LP point mutations. Moreover, GS identified two cryptic insertions and two inversions. Follow-up study further demonstrated the potential pathogenicity of an apparently balanced insertion that disrupted an OMIM autosomal dominant disease-causing gene at the insertion site. Conclusions: Our study demonstrates that applying GS in fetuses with increased NT can comprehensively detect and delineate the various genomic variants that are causative to the diseases. Importantly, prenatal diagnosis by GS doubled the diagnostic yield compared with routine protocols. Given a comparable turnaround time and less DNA required, our study provides strong evidence to facilitate GS in prenatal diagnosis, particularly in fetuses with increased NT. [ABSTRACT FROM AUTHOR]

Problem To determine if maternal immune maladaptation associated with pre-eclampsia is reflected in the rubella immunity status. Method of study Incidence of pre-eclampsia was compared between rubella non-immune and immune gravidae carrying a singleton pregnancy beyond 24 weeks, taking into account maternal characteristics and reported risk factors for pre-eclampsia. Results The 9870 (10.4%) rubella non-immune gravidae among the 95 024 in the cohort exhibited no difference in incidence of underlying medical disorders, but they were slightly but significantly older, shorter, heavier, and had more pre-eclampsia ( OR 1.24, 95% CI 1.05-1.47) despite having fewer nulliparas. Regression analysis confirmed an overall association between rubella non-immunity with pre-eclampsia ( aOR 1.27, 95% CI 1.06-1.54), which was related to multiparas ( aOR 1.42, 95% CI 1.05-1.91) and carrying a male fetus ( aOR 1.37, 95% CI 1.06-1.78). Conclusion The association between rubella non-immunity and pre-eclampsia reflects immune maladaptation in multiparas and toward a male fetus. [ABSTRACT FROM AUTHOR]

The association between hypoechoic hepatomegaly in the third trimester and transient abnormal myelopoiesis (TAM) was reported previously in six fetuses with trisomy 21 (T21). We report a series of three cases of T21 in which hypoechoic liver (HL) was found in the second trimester but without evidence of TAM on both hematological and histological examination. We postulate that the hypo-echogenicity may be due to liver congestion secondary to hemodynamic disturbances seen in T21 fetuses. All three cases had negative first trimester Down syndrome screening and one case was detected solely because of the isolated finding of HL. HL per se may be associated with T21 and more positive cases are required to support this association. [ABSTRACT FROM AUTHOR]

Objective. To elucidate the significance of isolated absent or hypoplastic nasal bone in the second trimester ultrasound scan. Methods. All cases of absent or hypoplastic nasal bone (length < 5th percentile) encountered during 2007--2009 were retrieved from database and all the ultrasound findings including structural abnormalities and soft markers for Down syndrome and fetal karyotype were reviewed. The cases were categorized into a study group with isolated absent or hypoplastic nasal bone and a comparison group with additional ultrasound findings. The incidence of Down syndrome confirmed by karyotyping was compared between the two groups. Results. Among 14 fetuses with absent or hypoplastic nasal bone identified, six (42.9%%) had Down syndrome and eight (57.1%%) were normal. All (100%%) of the six fetuses with isolated absent or hypoplastic nasal bone (Study Group) had normal karyotype, while six (75%%) of the other eight fetuses with additional ultrasound findings (Comparison Group) had Down syndrome ( p == 0.010). Conclusions. The use of isolated absent or hypoplastic nasal bone in the second trimester ultrasound scan for Down syndrome screening may not be effective. Amniocentesis, however, is indicated for fetuses with structural abnormality or additional soft marker which should be carefully searched by an experienced ultrasonographer. [ABSTRACT FROM AUTHOR]

Objective. We investigated the application of microarray-based comparative genomic hybridization (array CGH) on a fetus showing hemivertebrae and intra-abdominal mass at 15 weeks. Methods. Conventional karyotyping and high-resolution array CGH techniques using 244K CGH microarray were performed to investigate the possibility of genomic imbalance on the opted chorionic villus sample. Results. G-banded fetal chromosome analysis showed 46,XY,der(6)t(6;7)(q26;q31.2)pat. Whole genome scan by array CGH fine mapped the origin of the aberrant chromosomes to be a partial single copy gain of 42.5 Mb from chromosome region 7:116266547 → qter and concurrent partial single copy loss of 8.1 Mb from chromosome region 6:162756975 → qter. Pathological examination of the abortus showed gastrointestinal malformations, hemivertebrae with scoliosis, clinodactyly and club feet. Conclusions. Prenatal and perinatal findings of concurrent trisomy 7q and monosomy 6q were unique. This study demonstrated array CGH can interrogate the entire genome at a resolution and rapidity unattainable by conventional cytogenetic techniques and may have wide application in prenatal diagnosis. [ABSTRACT FROM AUTHOR]

Objective. To examine the effectiveness of first trimester fetal Trisomy 21 (T21) screening using a combination of maternal age, nuchal translucency, maternal serum levels of free β-hCG and PAPP-A in a predominantly Chinese population in Hong Kong. Methods. Consecutive women who underwent the combined screening for T21 between 11 and 13 + 6 weeks of gestation between 2003 and 2007 were recruited. Risk of T21 was calculated using Fetal Medicine Foundation algorithm and karyotyping was advised when the risk was 1:300 or above. All women were followed up for pregnancy and fetal outcome. Results. 10,363 fetuses underwent screening. 99% of the women were Chinese and 27.4% were at or above 35 years old. 618 fetuses were screened positive (5.9%), which included 31 cases of T21, 14 cases of T18, 7 cases of T13, 10 cases of 45XO and 7 cases of other chromosomal abnormalities. Among the 9745 screened negative fetuses all but 50 (0.5%) had a known outcome, which included three T21 and four other chromosomal abnormalities. All were subsequently identified at the morphology scan except for one case of T21. The detection rate and false positive rates for T21 were 91.2% and 5.4%, respectively and the positive predictive value for all chromosomal abnormalities was 1 in 9. Conclusions. Combined screening for T21 is highly effective among Chinese women. Training, quality control, regular auditing and follow up are essential to maintain screening standards. [ABSTRACT FROM AUTHOR]