Pregnancy outcomes of fetuses with congenital heart disease after a prenatal diagnosis with chromosome microarray.

OBJECTIVE: To evaluate the pregnancy outcomes of fetuses with congenital heart disease (CHD) after chromosome microarray (CMA)-based prenatal diagnosis. METHOD: Amniocentesis was performed in 1035 pregnant women carrying fetuses with CHD between September 2014 and December 2019. Chromosomal aberrations in fetuses with CHD were evaluated using CMA. The pregnancy outcomes were followed up from 6 months to 5 years. RESULTS: The overall CHD detection rate by CMA was 10.1% (105/1035; 50 fetuses: aneuploidy, 55 fetuses: pathogenic or likely pathogenic copy number variations). Among 1003 fetuses who were followed up, 4, 236, 763, and 18 cases were of miscarriages, pregnancy termination, live births, and postnatal deaths, respectively. Self-healed CHD was observed in 401 (52.6%) fetuses. The pregnancy termination rate of fetuses with chromosomal anomalies was significantly higher than that of fetuses without chromosomal anomalies (93.1% vs. 15.5%, p < 0.001). However, other pregnancy outcomes, including mortality, preterm labor, and low-weight birth rate, were similar between the two groups. CONCLUSION: The outcome of CMA is an important factor influencing parents' choice of whether to continue the pregnancy. Self-healing rate of prenatal diagnosed CHD is high. The mortality and morbidity of fetuses with CHD following prenatal CMA testing are relatively low.

Should vanishing twin pregnancies be systematically excluded from cell-free fetal DNA testing?

OBJECTIVE: To demonstrate the feasibility of cell-free DNA (cfDNA) testing in vanishing twin (VT) pregnancies in routine clinical practice. METHODS: Our study included 24 874 singleton and 206 VT consecutive pregnancies. Cell-free DNA was analyzed by massively parallel sequencing. Both aneuploidy analysis (chromosomes 13,18, 21, X, and Y) and fetal fraction estimation were performed according to an Illumina algorithm. Contaminant DNA contribution from the demised co-twin was studied in detail. RESULTS: VT pregnancies exhibited a higher prevalence of screen-positive cases (5.8% vs 2.5%), sex discrepancies (10.2% vs 0.05%), and false positive rates (FPR) (2.6% vs 0.3%) than singleton pregnancies. However, their incidence was significantly lower in tests performed after the 14th week (screen-positive cases: 3.1%; sex discrepancies: 7.8%; and FPR: 0.8%). Among the 12 cases in which cfDNA was performed at two time points, fading of contaminating cfDNA was observed in four cases with a sex discrepancy and in one false positive for trisomy 18, resulting in a final correct result. CONCLUSIONS: Our data suggest VT pregnancies could be included in cfDNA testing as long as it is applied after the 14th week of pregnancy. However, future studies to validate our findings are needed before including VT cases in routine clinical practice. Once established, unnecessary invasive procedures could be avoided, mitigating negative emotional impact on future mothers.

Confirmation rate of cell free DNA screening for sex chromosomal abnormalities according to the method of confirmatory testing.

OBJECTIVE: To examine the positive predictive value (PPV) of cfDNA screening for sex chromosome aneuploidies (SCA) in a large series of over 90 000 patients. METHODS: Retrospective study based on samples that were sent to Cenata, a private laboratory which uses the Harmony Prenatal Test. The SCA high-risk results were stratified according to the method of diagnostic testing and according to karyotype result. RESULTS: The study population consisted of 144 cases. The CfDNA test indicated monosomy X, XXX, XXY, and XYY in 62, 37, 40, and 5 cases, respectively. The overall PPV was 38.9% (30.9-47.4), 29.0% (18.2-42.9) for monosomy X, 29.7% (15.9-47.9) for 47,XXX, 57.5% (40.9-73.0) for 47,XXY, and 80.0% (28.4-99.5) for 47,XYY). A total of 112 (77.8%) women with a high-risk result for SCAs opted for prenatal karyotyping. In this group, there were significant differences in the PPV if the karyotype was assessed by amniocentesis or by CVS: 29.5% vs 50.0%. This significant difference was driven by the monosomy X result which shows a significantly higher PPV in CVS (54.6% (23.4-83.3) vs 17.1% (6.6-33.6)). For the other SCAs, the differences were not significant. CONCLUSION: PPV of an abnormal cfDNA test for SCAs is low, particularly for monosomy X. The confirmation rate depends on the type of confirmatory test.

Improving antenatal engagement for Aboriginal women in Australia: A scoping review.

BACKGROUND: Aboriginal women have an increased risk of poor antenatal engagement in pregnancy in comparison with Caucasian women, due to inequalities in health care provision. The Pregnancy Outcome in South Australia reports Aboriginal women having 10 times the risk of non-attendance of antenatal care throughout their pregnancy, 3 times the risk of attending the initial booking appointment later than recommended in their pregnancy, and Aboriginal women have an increased risk of attending significantly less antenatal appointments than Caucasian women. OBJECTIVE: The primary purpose of the scoping review is to map the body of literature known about Aboriginal women engaging with antenatal care in Australia, and the factors that facilitate or cause barriers to this engagement. Secondary to this, the review will describe how culturally safe care influences antenatal engagement. METHODS: Scoping reviews utilise a broad range of literature, encompassing all types of studies. An online search of 6 databases was conducted to identify and critically analyse sources discussing antenatal engagement for Aboriginal women in Australia. Using the JBI framework for Scoping Reviews, the researcher was able to strengthen the rigour of the methodology. FINDINGS: The search produced 9 articles, relating to 6 studies addressing antenatal engagement for Aboriginal women in Australia. Several themes were prevalent in the research that impact antenatal engagement including: Smoking, Relocation, Continuity of Care, Aboriginal maternity infant care workers, home visits, birthing on country, age, family and culturally safe care. CONCLUSION: Aboriginal women have identified continuity of care, Aboriginal workforce, home visits, family involvement, birthing on country and cultural safety as factors that improve antenatal engagement. Aboriginal women have reported smoking, rural and remote location, cultural incompetence and young age as factors that deter them from engaging with antenatal care. In order to improve antenatal engagement for Aboriginal women in South Australia, culturally safe care is essential. In order to determine the factors that facilitate and/or deter Aboriginal women from antenatal engagement, further research is required.

Low-Cost Fetal Magnetocardiography: A Comparison of Superconducting Quantum Interference Device and Optically Pumped Magnetometers.

Background Fetal magnetocardiography (fMCG) is a highly effective technique for evaluation of fetuses with life-threatening arrhythmia, but its dissemination has been constrained by the high cost and complexity of Superconducting Quantum Interference Device (SQUID) instrumentation. Optically pumped magnetometers (OPMs) are a promising new technology that can replace SQUIDs for many applications. This study compares the performance of an fMCG system, utilizing OPMs operating in a person-sized magnetic shield, to that of a conventional fMCG system, utilizing SQUID magnetometers operating in a magnetically shielded room. Methods and Results fMCG recordings were made in 24 subjects using the SQUID system with the mother lying supine in a magnetically shielded room and the OPM system with the mother lying prone in a person-sized, cylindrical shield. Signal-to-noise ratios of the OPM and SQUID recordings were not statistically different and were adequate for diagnostic purposes with both technologies. Although the environmental noise was higher using the small open-ended shield, this was offset by the higher signal amplitude achieved with prone positioning, which reduced the distance between the fetus and sensors and improved patient comfort. In several subjects, fMCG provided a differential diagnosis that was more precise and/or definitive than was possible with echocardiography alone. Conclusions The OPM-based system was portable, improved patient comfort, and performed as well as the SQUID-based system at a small fraction of the cost. Electrophysiological assessment of fetal rhythm is now practical and will have a major impact on management of fetuses with long QT syndrome and other life-threatening arrhythmias.

Fetal XCMR: a numerical phantom for fetal cardiovascular magnetic resonance imaging.

BACKGROUND: Validating new techniques for fetal cardiovascular magnetic resonance (CMR) is challenging due to random fetal movement that precludes repeat measurements. Consequently, fetal CMR development has been largely performed using physical phantoms or postnatal volunteers. In this work, we present an open-source simulation designed to aid in the development and validation of new approaches for fetal CMR. Our approach, fetal extended Cardiac-Torso cardiovascular magnetic resonance imaging (Fetal XCMR), builds on established methods for simulating CMR acquisitions but is tailored toward the dynamic physiology of the fetal heart and body. We present comparisons between the Fetal XCMR phantom and data acquired in utero, resulting in image quality, anatomy, tissue signals and contrast. METHODS: Existing extended Cardiac-Torso models are modified to create maternal and fetal anatomy, combined according to simulated motion, mapped to CMR contrast, and converted to CMR data. To provide a comparison between the proposed simulation and experimental fetal CMR images acquired in utero, images from a typical scan of a pregnant woman are included and simulated acquisitions were generated using matching CMR parameters, motion and noise levels. Three reconstruction (static, real-time, and CINE), and two motion estimation methods (translational motion, fetal heart rate) from data acquired in transverse, sagittal, coronal, and short-axis planes of the fetal heart were performed to compare to in utero acquisitions and demonstrate feasibility of the proposed simulation framework. RESULTS: Overall, CMR contrast, morphologies, and relative proportions of the maternal and fetal anatomy are well represented by the Fetal XCMR images when comparing the simulation to static images acquired in utero. Additionally, visualization of maternal respiratory and fetal cardiac motion is comparable between Fetal XCMR and in utero real-time images. Finally, high quality CINE image reconstructions provide excellent delineation of fetal cardiac anatomy and temporal dynamics for both data types. CONCLUSION: The fetal CMR phantom provides a new method for evaluating fetal CMR acquisition and reconstruction methods by simulating the underlying anatomy and physiology. As the field of fetal CMR continues to grow, new methods will become available and require careful validation. The fetal CMR phantom is therefore a powerful and convenient tool in the continued development of fetal cardiac imaging.

Magnetic resonance imaging of the fetal brain at 3 Tesla: Preliminary experience from a single series.

To report our preliminary experience with cerebral fetal magnetic resonance imaging (MRI) with a 3 Tesla (3T) scanner. We assessed feasibility, time of acquisition, and possibility to establish a diagnosis.Fifty-nine pregnant women had fetal MRI performed during the third trimester of pregnancy due to clinical or sonography concern of a central nervous system anomaly. No fetal or maternal sedation was used. The MRI protocol consisted of T2 turbo-spin-echo images in 3 planes of space. No T1-weighted images were performed. All images were analyzed by 2 pediatric neuroradiologists, who evaluated spatial resolution, artifacts, time of acquisition, and possibility to establish a diagnosis suspected by sonography.Examinations were performed safely for all patients. The images required longer time of acquisition (approximately 75 seconds for each plane in the space). The specific absorption rate was not exceeded in any fetus. Cerebral fetal MRI was normal in 22 cases. The spectrum of diagnostics included isolated ventriculomegaly, posterior fossa malformation, corpus callosum malformation, gyration anomalies, craniosynostosis, tuberous sclerosis, microcephaly, external hydrocephaly, midline arachnoid cyst, cerebral lesions, and persistent hyperplastic primitive vitreous.In our series, 3 T MRI of fetal brain was feasible and able to establish a diagnosis but required longer time of acquisition.

Adducted thumb as an isolated morphologic finding: an early sonographic sign of impaired neurodevelopment: A STROBE compliant study.

Fetal adducted thumbs have been described in association with hydrocephalus and other abnormalities, but in cases without other structural malformations the determination of prognosis and recurrence risk is challenging. The aim of our study is to analyze the characteristics, natural history, and postnatal outcome of such cases.A retrospective study was conducted over a period of 4 years in a tertiary referral center. All fetuses diagnosed as adducted thumbs without other structural malformations comprised the study group. Prenatal sonographic features and neonatal outcome are documented.There were 4 cases of fetal adducted thumbs diagnosed during the study period. No cases demonstrated other structural malformations throughout the gestation. A smaller head was noted in 2 cases during the follow-up, and all cases presented with polyhydramnios on the first or ensuing scans. Three cases died after birth due to swallowing or breathing difficulty, and the surviving 1 showed convulsion and mental retardation.Fetal adducted thumb might be an early and specific sonographic marker of impaired neurodevelopment. Close follow-up and genetic investigation should be performed in these cases. Ultrasound examination plays an important role in the prenatal diagnosis and counseling of cases without detailed prenatal genetic analysis.

Frequency-enhanced transferrin receptor antibody-labelled microfluidic chip (FETAL-Chip) enables efficient enrichment of circulating nucleated red blood cells for non-invasive prenatal diagnosis.

Fetal aneuploidy and other chromosomal aberrations affect 9 in 1000 live births. Unlike the invasive diagnosis with high risk of miscarriage, non-invasive prenatal diagnosis (NIPD) sampling from maternal blood becomes a promising way for fetal genetic screening. However, fetal cell-based NIPD has a major challenge due to the small number of fetal cells present in maternal blood. We designed a frequency-enhanced transferrin receptor antibody-labelled microfluidic chip (FETAL-Chip) for efficient enrichment and identification of circulating fetal cells, i.e., circulating nucleated red blood cells (cNRBCs) from maternal blood. The FETAL-Chip can dramatically enhance the interaction of fetal cells with antibody-coated microposts to increase the capture efficiency while minimizing nonspecific adsorption. With the help of immunostaining, we can identify cNRBCs from as little as 2 milliliter maternal blood. Various numbers of cNRBCs were detected from volunteers as early as 7 weeks after conception and throughout the entire pregnancy. Gene analysis was also carried out to confirm the fetal origin of captured cells. With easy, non-invasive and highly efficient enrichment of cNRBCs, the method presented here offers great potential for non-invasive prenatal diagnosis.

[Application for prenatal diagnosis using both chromosomal karyotype analysis and BACs-on-Beads assay].

OBJECTIVE: To assess the application value in prenatal diagnosis using karyotype analysis combined with BACs-on-Beads (BoBs) assay. METHODS: Nine hundred sixty five pregnant women were subjected to amniocentesis, chromosomal karyotype analysis and detection of BoBs were employed simultaneously for abnormal number of chromosomes and 9 chromosome microdeletion syndrome in prenatal diagnosis. RESULTS: Fifty cases common chromosome aneupoidies were successfully detected by both karyotype analysis and BoBs which included 31 cases of trisomy 21,10 cases of trisomy 18 and 9 cases with sex chromosome abnormality. BoBs in addition detected 1 case of DiGeorge-1 microdeletion syndrome and 1 case of 7q11.23 microduplication syndrome. All 9 fetuses with chromosome abnormalities detected by karyotyping were missed by BoBs, including 2 cases of marker chromosomes,4 cases of chromosomal translocation,1 case of chromosomal inversion, 2 cases of Sex chromosome mosaicism; 2 cases of fetal inherited from the parents,7 cases for novel mutations. CONCLUSION: Karyotype analysis combined with BoBs dedtection is a rapid, effective and highly accurate prenatal diagnosis model that may should be widely used in clinical diagnosis.

An efficient sequence for fetal brain imaging at 3T with enhanced T1 contrast and motion robustness.

PURPOSE: Ultrafast single-shot T2 -weighted images are common practice in fetal MR exams. However, there is limited experience with fetal T1 -weighted acquisitions. This study aims at establishing a robust framework that allows fetal T1 -weighted scans to be routinely acquired in utero at 3T. METHODS: A 2D gradient echo sequence with an adiabatic inversion was optimized to be robust to fetal motion and maternal breathing optimizing grey/white matter contrast at the same time. This was combined with slice to volume registration and super resolution methods to produce volumetric reconstructions. The sequence was tested on 22 fetuses. RESULTS: Optimized grey/white matter contrast and robustness to fetal motion and maternal breathing were achieved. Signal from cerebrospinal fluid (CSF) and amniotic fluid was nulled and 0.75 mm isotropic anatomical reconstructions of the fetal brain were obtained using slice-to-volume registration and super resolution techniques. Total acquisition time for a single stack was 56 s, all acquired during free breathing. Enhanced sensitivity to normal anatomy and pathology with respect to established methods is demonstrated. A direct comparison with a 3D spoiled gradient echo sequence and a controlled motion experiment run on an adult volunteer are also shown. CONCLUSION: This paper describes a robust framework to perform T1 -weighted acquisitions and reconstructions of the fetal brain in utero. Magn Reson Med 80:137-146, 2018. © 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Síndrome de obstrucción congénita de vía aérea superior: diagnóstico prenatal / Congenital high airway obstruction syndrome: prenatal diagnosis

Introducción: el síndrome de obstrucción congénita de la vía aérea superior (CHAOS) es una condición infrecuente que consiste en el estrechamiento severo u obstrucción completa de la vía aérea superior, de pronóstico nefasto en ausencia de intervención, y con hallazgos ecográficos característicos que conducirán al diagnóstico. Caso clínico: gestante en semana 20.3 que acude a la ecografía morfológica donde se evidencia pulmones aumentados de tamaño, hiperecongénicos, dilatación del árbol traqueobronquial, aplanamiento diafragmático y compresión cardiaca. Asocia ascitis e hidramnios. Con todo ello, se establece el diagnóstico del síndrome de obstrucción congénita. Discusión: el correcto diagnóstico prenatal del síndrome de obstrucción congénita, con hallazgos ecográficos constantes, es esencial para optimizar el manejo gestacional y planificar el tratamiento. La cesárea EXIT y la cirugía endoscópica se proponen entre las alternativas terapéuticas disponibles en la actualidad. Es imprescindible identificar la causa de la obstrucción, así en algunos casos muy seleccionados, la fetoscopia puede ser curativa. No obstante, la morbilidad y mortalidad en la mayor parte de casos es alta (AU)

Background: Congenital high airway obstruction syndrome is a rare life-threatening condition. It is characterized by severe narrowing or complete obstruction of the upper airway, grim prognosis in absence of intervention, and with characteristic sonographic findings that lead to diagnosis. Clinical case: Pregnant in week 20.3 that goes to the routine ultrasound that demonstrated enlarged echogenic lungs, dilated tracheobronchial tree, flattened diaphragms and cardiac compression. It associates fetal ascites and polyhydramnios. In all, the diagnosis established is congenital high airway. Discussion: The accurate prenatal diagnosis of congenital high airway, with constant sonographic findings, is essential to optimize gestational management and treatment planning. EXIT procedure and endoscopic surgery are proposed among the therapeutic alternatives available today. It is essential to identify the cause of the obstruction, as fetoscopy can be curative in some highly-selected cases. However, morbidity and mortality are high in most cases (AU)

Use of radiotelemetry to assess perinatal cardiac function in the ovine fetus and newborn.

The late gestation fetal ECG (fECG) has traditionally been difficult to characterize due to the low fECG signal relative to high maternal noise. Although new technologies have improved the feasibility of its acquisition and separation, little is known about its development in late gestation, a period in which the fetal heart undergoes extensive maturational changes. Here, we describe a method for the chronic implantation of radiotelemetry devices into late gestation ovine fetuses to characterize parameters of the fECG following surgery, throughout late gestation, and in the perinatal period. We found no significant changes in mean aortic pressure (MAP), heart rate (HR), or ECG in the 5 days following implantation; however, HR decreased in the first 24 h following the end of surgery, with associated increases in RR, PR, and QRS intervals. Over the last 14 days of fetal life, fetal MAP significantly increased, and HR significantly decreased, as expected. MAP and HR increased as labor progressed. Although there were no significant changes over time in the ECG during late gestation, the duration of the PR interval initially decreased and then increased as birth approached. These results indicate that although critical maturational changes occur in the late gestation fetal myocardium, the mechanisms that control the cardiac conduction are relatively mature in late gestation. The study demonstrates that radiotelemetry can be successfully used to assess fetal cardiac function, in particular conduction, through the process of labor and delivery, and may therefore be a useful tool for study of peripartum cardiac events.

[The value of a novel prenatal diagnosis model with combination of karyotyping and BACs-on-BeadsTM technique].

OBJECTIVE: To explore the value of a novel prenatal diagnosis model using combined chromosomal karyotyping and BACs-on-BeadsTM(BoBs), a newly-developed technique. METHODS: 1048 single pregnancy pregnant women with various diagnostic indications were performed amniocentesis for prenatal diagnosis with karyotyping and BoBs simultaneously. RESULTS: Among 1047 successfully cultured specimens, 50 chromosomal abnormalities were identified with BoBs, including 43 common chromosomal trisomies, 3 chimeric chromosomes and 4 structural abnormalities, of which 3 microdeletions/microduplications were not detected with karyotyping. Except for extra yield of 1 Robertsonian translocation, the other numerical chromosomal abnormalities were detected with both karyotyping and BoBs. Ten fetal chromosome abnormalities were confirmed with karyotyping, including 8 structural abnormalities and 2 chimeric chromosomes. CONCLUSION: Combination of karyotyping and BoBs turned out to be a rapid, complementary and effective diagnostic model for fetal chromosomal abnormalities and microdeletion syndromes, which could yield a higher detection rate of fetal chromosomal abnormalities and chromosomal microdeletions/microduplications.

Determining the accuracy of pregnancy-length dating among women presenting for induced abortions in Ghana.

OBJECTIVE: To determine the proportion of women presenting for an induced abortion in Ghana who could use a gestational wheel to determine if they had reached at least 13 weeks or fewer than 13 weeks of pregnancy accurately. METHODS: The present cross-sectional study was conducted at four facilities in Ghana between February 1, and July 31, 2014. Women aged at least 18 years seeking induced abortions who had not previously been informed of the length of their pregnancy by a clinician were enrolled. Women self-assessed pregnancy duration using a gestational wheel before a clinician assessed the length via clinical assessment and bimanual exam for use as a respective reference point. The proportion of participants who used the wheel successfully was calculated. RESULTS: The study enrolled 780 participants, 770 of whom used the gestational wheel. Of these, 221 (28.7%) could use the wheel without verbal instructions, and 465 (60.4%) described it as easy to use. Agreement in pregnancy-length assessments was recorded for 728 (94.5%) patients. There were 10 (1.3%) and 28 (3.6%) participants who made evaluations with "low-risk disagreement" and "high-risk disagreement" with the clinician assessment, respectively. CONCLUSION: Almost all participants could use the gestational wheel to date their pregnancies correctly. This tool could help women perform medical abortions safely in the community, reducing morbidity and mortality from unsafe abortions.

Noninvasive detection of F8 int22h-related inversions and sequence variants in maternal plasma of hemophilia carriers.

Direct detection of F8 and F9 sequence variants in maternal plasma of hemophilia carriers has been demonstrated by microfluidics digital PCR. Noninvasive prenatal assessment of the most clinically relevant group of sequence variants among patients with hemophilia, namely, those involving int22h-related inversions disrupting the F8 gene, poses additional challenges because of its molecular complexity. We investigated the use of droplet digital PCR (ddPCR) and targeted massively parallel sequencing (MPS) for maternal plasma DNA analysis to noninvasively determine fetal mutational status in pregnancies at risk for hemophilia. We designed family-specific ddPCR assays to detect causative sequence variants scattered across the F8 and F9 genes. A haplotype-based approach coupled with targeted MPS was applied to deduce fetal genotype by capturing a 7.6-Mb region spanning the F8 gene in carriers with int22h-related inversions. The ddPCR analysis correctly determined fetal hemophilia status in 15 at-risk pregnancies in samples obtained from 8 to 42 weeks of gestation. There were 3 unclassified samples, but no misclassification. Detailed fetal haplotype maps of the F8 gene region involving int22h-related inversions obtained through targeted MPS enabled correct diagnoses of fetal mutational status in 3 hemophilia families. Our data suggest it is feasible to apply targeted MPS to interrogate maternally inherited F8 int22h-related inversions, whereas ddPCR represents an affordable approach for the identification of F8 and F9 sequence variants in maternal plasma. These advancements may bring benefits for the pregnancy management for carriers of hemophilia sequence variants; in particular, the common F8 int22h-related inversions, associated with the most severe clinical phenotype.