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1.  Trophoblast Retrieval and Isolation from the Cervix (TRIC) Is Unaffected by Early Gestational Age or Maternal Obesity 
Prenatal diagnosis  2015;35(12):1218-1222.
Objective
The objective of this study is to evaluate whether trophoblast yield obtained by trophoblast retrieval and isolation from the cervix (TRIC) is affected by pregnancy outcome, gestational age (GA) at retrieval, maternal body mass index (BMI), parity, or maternal age.
Methods
TRIC was performed on 224 ongoing pregnancies between 5–20 weeks GA. Trophoblast cells were isolated from cervical cells using anti-human leukocyte antigen (HLA)-G antibody coupled to magnetic nanoparticles. Purity was assessed by the percentage of isolated cells that express β-hCG. Patient records were monitored until delivery, and pregnancy outcomes were determined. Trophoblast yield was compared to GA at time of collection, maternal BMI, parity, maternal age, and outcome of pregnancy, using linear regression.
Results
There was no effect of GA, maternal BMI, parity, and maternal age on trophoblast yield. Trophoblast yield decreased significantly with early pregnancy loss (EPL) compared to uncomplicated pregnancies that delivered at term. Trophoblast yield with preeclampsia or intrauterine growth restriction were decreased compared to healthy term outcomes, however, they did not reach statistical significance.
Conclusions
If TRIC becomes available as a method for non-invasive prenatal testing, our data demonstrate that it is unaffected by BMI and is useful as early as 5 weeks GA.
doi:10.1002/pd.4681
PMCID: PMC4715468  PMID: 26288006
2.  Evidence for feasibility of fetal trophoblastic cell‐based noninvasive prenatal testing†  
Prenatal Diagnosis  2016;36(11):1009-1019.
Abstract
Objective
The goal was to develop methods for detection of chromosomal and subchromosomal abnormalities in fetal cells in the mother's circulation at 10–16 weeks' gestation using analysis by array comparative genomic hybridization (CGH) and/or next‐generation sequencing (NGS).
Method
Nucleated cells from 30 mL of blood collected at 10–16 weeks' gestation were separated from red cells by density fractionation and then immunostained to identify cytokeratin positive and CD45 negative trophoblasts. Individual cells were picked and subjected to whole genome amplification, genotyping, and analysis by array CGH and NGS.
Results
Fetal cells were recovered from most samples as documented by Y chromosome PCR, short tandem repeat analysis, array CGH, and NGS including over 30 normal male cells, one 47,XXY cell from an affected fetus, one trisomy 18 cell from an affected fetus, nine cells from a trisomy 21 case, three normal cells and one trisomy 13 cell from a case with confined placental mosaicism, and two chromosome 15 deletion cells from a case known by CVS to have a 2.7 Mb de novo deletion.
Conclusion
We believe that this is the first report of using array CGH and NGS whole genome sequencing to detect chromosomal abnormalities in fetal trophoblastic cells from maternal blood. © 2016 The Authors. Prenatal Diagnosis published by John Wiley & Sons, Ltd.
What's already known about this topic? Analysis of cell‐free DNA for noninvasive prenatal testing (NIPT) is widely practiced, and the frequency of amniocentesis and CVS has decreased.However, cell‐free NIPT is not adequate for detecting smaller deletions and duplications with high specificity, sensitivity, and positive predictive value.Although fetal nucleated red blood cells and trophoblastic cells are known to be present in the maternal circulation, it has not been possible to develop a reliable cytogenetic cell‐based form of NIPT.
What does this study add? Fetal cytotrophoblasts were successfully recovered from maternal blood.Although a clinical test has not been validated, for the first time, the feasibility of using array comparative genomic hybridization and next generation sequencing to detect chromosomal and subchromosomal abnormalities is demonstrated.The results suggest the possibility of developing a cell‐based form of NIPT with ability to detect abnormalities with a similar accuracy as can currently be obtained with amniocentesis and CVS.
doi:10.1002/pd.4924
PMCID: PMC5129580  PMID: 27616633
3.  Calculating the fetal fraction for noninvasive prenatal testing based on genome‐wide nucleosome profiles 
Prenatal Diagnosis  2016;36(7):614-621.
Abstract
Objective
While large fetal copy number aberrations can generally be detected through sequencing of DNA in maternal blood, the reliability of tests depends on the fraction of DNA that originates from the fetus. Existing methods to determine this fetal fraction require additional work or are limited to male fetuses. We aimed to create a sex‐independent approach without additional work.
Methods
DNA fragments used for noninvasive prenatal testing are cut only by natural processes; thus, influences on cutting by the packaging of DNA in nucleosomes will be preserved in sequencing. As cuts are expected to be made preferentially in linker regions, the shorter fetal fragments should be enriched for reads starting in nucleosome covered positions.
Results
We generated genome‐wide nucleosome profiles based on single end sequencing of cell‐free DNA. We found a difference between DNA digestion of fetal cell‐free DNA and maternal cell‐free DNA and used this to calculate the fraction of fetal DNA in maternal plasma for both male and female fetuses.
Conclusion
Our method facilitates cost‐effective noninvasive prenatal testing, as the fetal DNA fraction can be estimated without the need for expensive paired‐end sequencing or additional tests.
The methodology is implemented as a tool, which we called SANEFALCON (Single reAds Nucleosome‐basEd FetAL fraCtiON). It is available for academic and non‐profit purposes under Creative Commons Attribution‐NonCommercial‐ShareAlike 4.0 International Public License. github.com/rstraver/sanefalcon. © 2016 The Authors. Prenatal Diagnosis published by John Wiley & Sons, Ltd.
What's Already Known About This Topic? Fetal DNA is found in small and varying amounts in maternal blood, enough to detect fetal aberrations such as Down syndrome through next generation sequencing methods.Fetal DNA is generally shorter, and this is believed to be influenced by nucleosomes.
What Does This Study Add? We obtained nucleosome positions from cell‐free DNA over a combination of low‐coverage samples.Our method shows how fetal fragments are influenced by nucleosomes compared with maternal fragments.We deduced the fetal fraction using the distribution of reads starting around nucleosome positions, independent of the fetal sex.
doi:10.1002/pd.4816
PMCID: PMC5111749  PMID: 26996738
4.  Implementation of non‐invasive prenatal testing by semiconductor sequencing in a genetic laboratory 
Prenatal Diagnosis  2016;36(8):699-707.
Abstract
Objectives
To implement non‐invasive prenatal testing (NIPT) for fetal aneuploidies with semiconductor sequencing in an academic cytogenomic laboratory and to evaluate the first 15‐month experience on clinical samples.
Methods
We validated a NIPT protocol for cell‐free fetal DNA sequencing from maternal plasma for the detection of trisomy 13, 18 and 21 on a semiconductor sequencing instrument. Fetal DNA fraction calculation for all samples and several quality parameters were implemented in the workflow. One thousand eighty‐one clinical NIPT samples were analysed, following the described protocol.
Results
Non‐invasive prenatal testing was successfully implemented and validated on 201 normal and 74 aneuploid samples. From 1081 clinical samples, 17 samples showed an abnormal result: 14 trisomy 21 samples, one trisomy 18 and one trisomy 16 were detected. Also a maternal copy number variation on chromosome 13 was observed, which could potentially lead to a false positive trisomy 13 result. One sex discordant result was reported, possibly attributable to a vanishing twin. Moreover, our combined fetal fraction calculation enabled a more reliable risk estimate for trisomy 13, 18 and 21.
Conclusions
Non‐invasive prenatal testing for trisomy 21, 18 and 13 has a very high specificity and sensitivity. Because of several biological phenomena, diagnostic invasive confirmation of abnormal results remains required. © 2016 The Authors. Prenatal Diagnosis published by John Wiley & Sons, Ltd.
What's Already Known about this Topic? Non‐invasive prenatal testing (NIPT) for fetal aneuploidies has been applied worldwide and is mainly offered by commercial service providers.
What does this Study Add? This study demonstrates the performance of non‐invasive prenatal testing in a genetic laboratory by semiconductor sequencing.Advantages of fetal fraction calculation and comprehensive chromosome profiling are discussed in this article and illustrated by several clinical examples.
doi:10.1002/pd.4841
PMCID: PMC5108441  PMID: 27176606
5.  Connexin 43 is overexpressed in human fetal membrane defects after fetoscopic surgery†  
Prenatal Diagnosis  2016;36(10):942-952.
Abstract
Objective
We examined whether surgically induced membrane defects elevate connexin 43 (Cx43) expression in the wound edge of the amniotic membrane (AM) and drives structural changes in collagen that affects healing after fetoscopic surgery.
Method
Cell morphology and collagen microstructure was investigated by scanning electron microscopy and second harmonic generation in fetal membranes taken from women who underwent fetal surgery. Immunofluoresence and real‐time quantitative polymerase chain reaction was used to examine Cx43 expression in control and wound edge AM.
Results
Scanning electron microscopy showed dense, helical patterns of collagen fibrils in the wound edge of the fetal membrane. This arrangement changed in the fibroblast layer with evidence of collagen fibrils that were highly polarised along the wound edge but not in control membranes. Cx43 was increased by 112.9% in wound edge AM compared with controls (p < 0.001), with preferential distribution in the fibroblast layer compared with the epithelial layer (p < 0.01). In wound edge AM, mesenchymal cells had a flattened morphology, and there was evidence of poor epithelial migration across the defect. Cx43 and COX‐2 expression was significantly increased in wound edge AM compared with controls (p < 0.001).
Conclusion
Overexpression of Cx43 in the AM after fetal surgery induces morphological and structural changes in the collagenous matrix that may interfere with normal healing mechanisms. © 2016 The Authors. Prenatal Diagnosis published by John Wiley & Sons, Ltd.
What's Already Known About This Topic? After fetoscopic surgery, the fetal membrane fails to heal spontaneously and the membrane defect is prone to iatrogenic PPROM.
What Does ThisStudy Add? We observed abnormal connexin 43 expression in the wound edge with preferential distribution in the mesenchymal cells compared with the epithelial cells.The overexpression of Cx43 may interfere with normal healing of the amniotic membrane after fetoscopic surgery.
doi:10.1002/pd.4917
PMCID: PMC5082503  PMID: 27568096
6.  An exploration of the potential utility of fetal cardiovascular MRI as an adjunct to fetal echocardiography 
Prenatal Diagnosis  2016;36(10):916-925.
Abstract
Objectives
Fetal cardiovascular magnetic resonance imaging (MRI) offers a potential alternative to echocardiography, although in practice, its use has been limited. We sought to explore the need for additional imaging in a tertiary fetal cardiology unit and the usefulness of standard MRI sequences.
Methods
Cases where the diagnosis was not fully resolved using echocardiography were referred for MRI. Following a three‐plane localiser, fetal movement was assessed with a balanced steady‐state free precession (bSSFP) cine. Single‐shot fast spin echo and bSSFP sequences were used for diagnostic imaging.
Results
Twenty‐two fetal cardiac MRIs were performed over 12 months, at mean gestation of 32 weeks (26–38 weeks). The majority of referrals were for suspected vascular abnormalities (17/22), particularly involving the aortic arch (n = 10) and pulmonary vessels (n = 4). Single‐shot fast spin echo sequences produced ‘black‐blood’ images, useful for examining the extracardiac vasculature in these cases. BSSFP sequences were more useful for intracardiac structures. Real‐time SSFP allowed for dynamic assessment of structures such as cardiac masses, with enhancement patterns also allowing for tissue characterisation in these cases.
Conclusions
Fetal vascular abnormalities such as coarctation can be difficult to diagnose by using ultrasound. Fetal MRI may have an adjunctive role in the evaluation of the extracardiac vascular anatomy and tissue characterisation. © 2016 The Authors. Prenatal Diagnosis published by John Wiley & Sons, Ltd.
What's Already Known About This Topic? Fetal cardiac MRI offers the potential to be a safe adjunct to echocardiography; however, there is no consensus on routine fetal indications or technical protocols for cardiovascular MRI in clinical practice. Previous studies have focused mainly on its utility for intracardiac imaging.
What Does This Study Add? Abnormalities involving the extracardiac vasculature were the most common group of referrals for additional imaging in clinical practice. Fast spin echo MRI sequences offer the potential for better visualisation of these structures than ultrasound alone. Additional MRI benefits such as tissue characterisation can add further value in selected cases.
doi:10.1002/pd.4912
PMCID: PMC5082528  PMID: 27521762
7.  Experiences of informational needs and received information following a prenatal diagnosis of congenital heart defect 
Prenatal Diagnosis  2016;36(6):515-522.
Abstract
Objective
To explore the need for information and what information was actually received following prenatal diagnosis of a congenital heart defect, in a country where termination of pregnancy beyond 22 weeks of gestation is not easily possible because of legal constraints.
Methods
Twenty‐six Swedish‐speaking pregnant women (n = 14) and partners (n = 12) were consecutively recruited for semi‐structured telephone interviews following the prenatal diagnosis of a congenital heart defect. Data were analyzed using content analysis.
Results
Although high satisfaction with the specialist information was described, the information was considered overwhelming and complex. Objective, honest, and detailed information about multiple subjects were needed, delivered repeatedly, and supplemented by written information/illustrations. Eighteen respondents had used the Internet to search for information and identified issues involving searching difficulties, low quality, and that it was too complex, insufficient, or unspecific. Those who terminated their pregnancy criticized that there was a lack of information about termination of pregnancy, both from health professionals and online sources, resulting in unanswered questions and unpreparedness.
Conclusion
Individuals faced with a prenatal diagnosis of a congenital heart defect need individualized and repeated information. These needs are not all adequately met, as individuals are satisfied with the specialist consultation but left with unanswered questions regarding pregnancy termination. © 2016 The Authors. Prenatal Diagnosis published by John Wiley & Sons, Ltd.
What's Already Known About This Topic? The introduction of ultrasound screening during the second trimester of pregnancy has increased the detection rate of major congenital heart defects.Information matched to individual needs is crucial for women to cope with the situation following a prenatal diagnosis.
What Does This Study Add? There is a need for information on multiple subjects following the prenatal diagnosis of congenital heart defect, including termination of pregnancy.Although information is available on the Internet on congenital heart defects, it is not easily searchable and its quality may be less than desired.Apparently, there is insufficient information about termination of pregnancy following the prenatal diagnosis of congenital heart defect.
doi:10.1002/pd.4815
PMCID: PMC5074242  PMID: 26991536
8.  Clinical characteristics of prenatally diagnosed persistent left superior vena cava in low‐risk pregnancies 
Prenatal Diagnosis  2016;36(5):444-448.
Abstract
Objective
To determine the incidence and clinical characteristics of persistent left superior vena cava (PLSVC) among low‐risk pregnancies. We have also compared electrocardiography (ECG) parameters of infants with PLSVC with those of normal controls.
Method
At our institute, fetal echocardiogram is routinely performed in the midtrimester. We retrospectively reviewed the records of prenatally diagnosed PLSVC cases from 2010 to 2014. The ECG findings in infants with isolated PLSVC were compared with those of age‐matched controls.
Results
Sixty‐five cases of fetal PLSVC were detected during the study period. It represents 0.36% (65/18 188) of all fetal echocardiographic examinations during the study period. Twenty cases (30.8%) had other cardiac anomalies, seven cases (10.8%) were associated with extracardiac anomalies, and four cases (6.2%) had both cardiac and extracardiac anomalies, whereas in 34 cases (52.3%), the anomaly was isolated. There were no significant differences in ECG parameters between neonates with PLSVC and normal controls.
Conclusion
Detection of PLSVC should prompt careful search for associated anomalies. Isolated PLSVC is a benign vascular anomaly and the outcomes are excellent. © 2016 The Authors. Prenatal Diagnosis published by John Wiley & Sons, Ltd.
What's Already Known About This Topic? Persistent left superior vena cava (PLSVC) can be accurately diagnosed prenatally and can be associated with cardiac and extracardiac anomalies.The significance of PLSVC when isolated is unclear.
What Does This Study Add? We establish the incidence and clinical characteristics of PLSVC in low‐risk pregnancies.Electrocardiographic parameters in neonates with PLSVC are similar to those of unaffected controls.
doi:10.1002/pd.4801
PMCID: PMC5071676  PMID: 26934675
9.  What results to disclose, when, and who decides? Healthcare professionals' views on prenatal chromosomal microarray analysis†  
Prenatal Diagnosis  2016;36(3):252-259.
Abstract
Objectives
This study explored the views of healthcare professionals (HCPs) in the UK about what information should be disclosed, when; and whether women/parents should be given a choice as to what they wish to know.
Methods
Q‐methodology was used to assess the views of 40 HCPs (genetic HCPs, fetal medicine experts, lab‐scientists).
Results
Most participants agreed that variants of unknown clinical significance should not be disclosed. Participants were divided between those who considered variants of uncertain clinical significance helpful for parents and clinicians, and those who considered them harmful. Although recognising the potential disadvantages of disclosing risks for adult‐onset conditions, participants thought it would be difficult to withhold such information once identified. Participants largely supported some parental involvement in determining which results should be returned. Most participants believed that information obtained via CMA testing in pregnancy should either be disclosed during pregnancy, or not at all.
Conclusion
HCPs taking part in the study largely believed that variants that will inform the management of the pregnancy, or are relevant to other family members, should be reported. Recent UK guidelines, published after this research was completed, reflect these opinions. © 2016 The Authors. Prenatal Diagnosis published by John Wiley & Sons, Ltd.
What's already known about this topic? Empirical data on healthcare professionals' (HCPs) and parents' experience with prenatal CMA are scarce.Published data mainly focused on issues around uncertain results obtained via CMA, and on genetic health professionals.The two main difficulties expressed by genetic counsellors associated with testing were interpreting uncertain results, and termination of pregnancies based on uncertain results
What does this study add? It is the first study examining attitudes of a wide range of professionals involved in CMA testing: laboratory professionals, fetal medicine experts, and genetic health professionals.We describe what types of results professionals think should or should not be disclosed and with whom they consider the onus for such decision making should lie.These views are reflected in the recent UK guidelines about CMA testing.
doi:10.1002/pd.4772
PMCID: PMC5067646  PMID: 26743561
10.  Follow‐up of multiple aneuploidies and single monosomies detected by noninvasive prenatal testing: implications for management and counseling 
Prenatal Diagnosis  2016;36(3):203-209.
Abstract
Objectives
To determine the underlying biological basis for noninvasive prenatal testing (NIPT) results of multiple aneuploidies or autosomal monosomies.
Methods
Retrospective analysis of 113,415 tests to determine the study cohort, consisting of 138 (0.12%) cases reported as a single autosomal monosomy (n = 65), single trisomy with a sex chromosome aneuploidy (n = 36), or with multiple aneuploidies (n = 37). Clinical outcome information was reviewed and stratified into eight categories according to whether the karyotype or sonographic information agreed or disagreed with sequencing results.
Results
Of 67 cases with fetal or neonatal karyotypes available, 16 (24%) were partially or fully concordant with the NIPT result, 4 (6%) had aneuploidy on a reference chromosome, and 47 (70%) had normal fetal chromosomes, in which 5/47 had maternal malignancies reported. One case of maternal mosaic trisomy 8 was also detected. Of cases with no fetal karyotype information, ten had an abnormal clinical outcome, one was a normal live birth, and one reported maternal malignancy.
Conclusions
Noninvasive prenatal test results of autosomal monosomy or multiple aneuploidies are rare but have a diversity of underlying biologic causes. Some reflect the fetal karyotype; some reflect the presence of other maternal or fetal chromosome abnormalities, and a small number are linked to maternal disease. © 2016 Illumina. Prenatal Diagnosis published by John Wiley & Sons, Ltd.
What's already known about this topic? Noninvasive prenatal testing (NIPT) has been validated for common autosomal trisomies (trisomy 21, 18, and 13), sex chromosome aneuploidies, and a selection of microdeletion syndromes.NIPT findings that are discordant with the fetal karyotype can be because of biological reasons, such as confined placental mosaicism, maternal chromosome abnormalities, and other maternal conditions such as occult malignancy.
What does this study add? Clinical and karyotype outcome information for cases that received an NIPT result indicating an autosomal monosomy or multiple aneuploidies. Some autosomal monosomy and multiple aneuploidy results reflect the true fetal karyotype, and some are explained by other factors, such as other fetal or maternal chromosomal abnormalities or maternal disease.This information will help providers with post‐test counseling for these rare and unusual results.
doi:10.1002/pd.4778
PMCID: PMC5067681  PMID: 26785403
11.  Global perspectives on clinical adoption of NIPT 
Prenatal diagnosis  2015;35(10):959-967.
Objective
The goals of this study were to assess global trends in clinical implementation of Noninvasive Prenatal Testing (NIPT) as commercial tests are marketed increasingly worldwide, and to identify potential challenges for current or future use.
Methods
We surveyed clinicians from 46 countries about the availability of NIPT; their experiences with using NIPT; and their views on clinical, ethical, and legal issues affecting implementation in their countries.
Results
Forty-nine respondents from 28 countries completed the survey. The majority reported that NIPT is available in their country (n=43) and that they offer NIPT in their current practice (n=38). Eighteen respondents from 14 countries reported that there are plans to introduce NIPT into routine antenatal care in their country. Test prices varied widely, ranging from $350–$2900, and several respondents observed that high test prices limited or restricted widespread use of NIPT. Responses varied both across and within countries regarding who is offered NIPT, and what the overall screening protocol should be.
Conclusion
This study provides a snapshot of current use and experiences with NIPT globally. It also highlights differences in service provision that exists both across and within countries, emphasizing the need for developing national and international implementation guidelines for NIPT.
doi:10.1002/pd.4637
PMCID: PMC5065727  PMID: 26085345
12.  Clinical performance of non‐invasive prenatal testing (NIPT) using targeted cell‐free DNA analysis in maternal plasma with microarrays or next generation sequencing (NGS) is consistent across multiple controlled clinical studies 
Prenatal Diagnosis  2015;35(12):1243-1246.
Abstract
Objective
To evaluate the clinical performance of non‐invasive prenatal testing for trisomy 21, 18, and 13 using targeted cell‐free DNA (cfDNA) analysis.
Methods
Targeted cfDNA analysis using DANSR™ and FORTE™ with microarray quantitation was used to evaluate the risk of trisomy 21, 18, and 13 in blinded samples from 799 singleton, twin, natural, and IVF pregnancies. Subjects either had fetal chromosome evaluation by karyotype, FISH, QF‐PCR, or karyotype for newborns with suspected aneuploidy at birth. The results of targeted cfDNA analysis were compared to clinical genetic testing outcomes to assess clinical performance.
Results
Targeted cfDNA analysis with microarray quantification identified 107/108 trisomy 21 cases (99.1%), 29/30 trisomy 18 cases (96.7%), and 12/12 trisomy 13 cases (100%). The specificity was 100% for all three trisomies. Combining this data with all published clinical performance studies using DANSR/FORTE methodology for greater than 23 000 pregnancies, the sensitivity of targeted cfDNA analysis was calculated to be greater than 99% for trisomy 21, 97% for trisomy 18, and 94% for trisomy 13. Specificity for each trisomy was greater than 99.9%.
Conclusion
Targeted cfDNA analysis demonstrates consistently high sensitivity and extremely low false positive rates for common autosomal trisomies in pregnancy across quantitation platforms. © 2015 Ariosa Diagnostics Inc. Prenatal Diagnosis published by John Wiley & Sons, Ltd.
What's already known about this topic? NIPT using targeted cfDNA analysis with NGS has high sensitivity and specificity for fetal trisomy 21 and other autosomal trisomies.
What does this study add? This study establishes the high sensitivity and specificity of NIPT using targeted cfDNA analysis with a microarray quantitation platform, and demonstrates that clinical performance is based on the targeted cfDNA analysis method rather than the quantitation method, as the performance using microarray is comparable with performance from previous NGS studies.
doi:10.1002/pd.4686
PMCID: PMC5057317  PMID: 26332378
13.  A qualitative study looking at informed choice in the context of non‐invasive prenatal testing for aneuploidy 
Prenatal Diagnosis  2016;36(9):875-881.
Abstract
Objective
To explore women's attitudes towards non‐invasive prenatal testing (NIPT) and determine factors influencing their decisions around uptake of NIPT.
Method
We conducted qualitative interviews to assess knowledge, attitude and deliberation amongst women offered NIPT in a public health service. In total, 45 women took part in telephone interviews (79% participation rate).
Results
Most women could recount the key aspects of NIPT discussed during pre‐test counselling but had variable knowledge about Down syndrome. Analysis of women's attitudes towards undergoing NIPT revealed three dominant factors they considered when reflecting on the test: (1) how NIPT compared with alternative testing options, (2) reflections on coping and (3) moral or religious values. Exploring the deliberative process revealed the different paths women take when making decisions. For some, it was an extension of the decision to have Down syndrome screening; some considered it early on following the booking‐in appointment; others made step‐wise decisions about NIPT when it became relevant to them.
Conclusion
Our findings support the importance of personalised counselling, whereby women and their partners have the opportunity to reflect on the implications of the test results in the context of their own lives and values. Our data highlight the influence of personal circumstances on decision‐making. © 2016 The Authors. Prenatal Diagnosis published by John Wiley & Sons, Ltd.
What's Already Known About This Topic? Non‐invasive prenatal testing (NIPT) for aneuploidies has entered clinical practice, although concerns exist around the potential for routinisation and erosion of informed choice.Research into informed decision‐making for NIPT is now beginning to emerge, although these are predominantly quantitative studies.
What Does This Study Add? Participants frequently used a combination of clinical information, personal experiences and moral values to guide action.For many participants, decision‐making was a multistep deliberative process which occurred as and when new information became available.
doi:10.1002/pd.4879
PMCID: PMC5053255  PMID: 27477537
14.  Clinical outcome of subchromosomal events detected by whole‐genome noninvasive prenatal testing 
Prenatal Diagnosis  2015;35(10):999-1004.
Abstract
Objective
A novel algorithm to identify fetal microdeletion events in maternal plasma has been developed and used in clinical laboratory‐based noninvasive prenatal testing. We used this approach to identify the subchromosomal events 5pdel, 22q11del, 15qdel, 1p36del, 4pdel, 11qdel, and 8qdel in routine testing. We describe the clinical outcomes of those samples identified with these subchromosomal events.
Methods
Blood samples from high‐risk pregnant women submitted for noninvasive prenatal testing were analyzed using low coverage whole genome massively parallel sequencing. Sequencing data were analyzed using a novel algorithm to detect trisomies and microdeletions.
Results
In testing 175 393 samples, 55 subchromosomal deletions were reported. The overall positive predictive value for each subchromosomal aberration ranged from 60% to 100% for cases with diagnostic and clinical follow‐up information. The total false positive rate was 0.0017% for confirmed false positives results; false negative rate and sensitivity were not conclusively determined.
Conclusion
Noninvasive testing can be expanded into the detection of subchromosomal copy number variations, while maintaining overall high test specificity. In the current setting, our results demonstrate high positive predictive values for testing of rare subchromosomal deletions. © 2015 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.
What's already known about this topic? Circulating cell free DNA is a powerful clinical tool that can detect whole chromosomal aneuploidies in a fetus as early as 10 weeks with high specificity and high sensitivity. Subchromosomal events in the fetus have been shown to be detected via ccfDNA via whole genome sequencing.
What does this study add? This study shows that ccfDNA whole genome analysis for fetal subchromosomal aneuploidies including clinically significant microdeletions can be tested clinically with high specificity and high positive predictive value (PPV).
doi:10.1002/pd.4640
PMCID: PMC5034801  PMID: 26088833
15.  Disparities in the Prenatal Detection of Critical Congenital Heart Disease 
Prenatal diagnosis  2015;35(9):859-863.
Objectives
Prenatal diagnosis of critical congenital heart disease, that requiring surgical or catheter intervention in the first 30 days of life, allows for delivery at a specialized center which can reduce preoperative morbidity and mortality. We sought to identify risk factors for a missed prenatal diagnosis of critical congenital heart disease.
Methods
Patients presenting to the Children’s Hospital of Wisconsin with critical congenital heart disease from 2007-2013 were included. Those with a prenatal diagnosis were compared to those with a postnatal diagnosis.
Results
The cohort included 535 patients with prenatal diagnosis made in 326 (61%). The prenatal diagnostic rate improved from 44% in 2007 to 69% in 2013. Independent factors associated with a postnatal diagnosis were a lesion that required a view other than a 4 chamber view to make the diagnosis (p<0.0001), absence of another organ system anomaly (p<0.0001), and living in a higher poverty (p=0.02) or lower population density communities (p=0.002).
Conclusions
While the prenatal diagnostic rate for critical congenital heart disease is improving, those living in impoverished or rural communities are at highest risk of not having a diagnosis made prenatally. Interventions to improve prenatal detection of congenital heart disease should target these vulnerable areas.
doi:10.1002/pd.4622
PMCID: PMC4558244  PMID: 25989740
16.  Comparing genetic counselor’s and patient’s perceptions of needs in prenatal chromosomal microarray testing 
Prenatal diagnosis  2015;35(9):870-878.
OBJECTIVE
Chromosome microarray analysis (CMA) is poised to take a significant place in the prenatal setting given its increased yield over standard karyotyping, but concerns regarding ethical and counseling challenges remain, especially associated with the risk of uncertain and incidental findings. Guidelines recommend patients receiving prenatal screening undergo genetic counseling prior to testing, but little is known about women’s specific pre- and post-testing informational needs, as well as their preference for return of various types of results.
METHODS
The present study surveys 199 prenatal genetic counselors who have counseled patients undergoing CMA testing and 152 women who have undergone testing on the importance of understanding pre-test information, return of various types of results, and resources made available following an abnormal finding.
RESULTS
Counselors and patients agree on many aspects, although findings indicate patients consider all available information very important, while genetic counselors give more varying ratings.
CONCLUSION
Counseling sessions would benefit from information personalized to a patient’s particular needs and a shared decision-making model, so as to reduce informational overload and avoid unnecessary anxiety. Additionally, policies regarding the return of various types of results are needed.
doi:10.1002/pd.4624
PMCID: PMC4558373  PMID: 25995037
17.  Pregnancy continuation and organizational religious activity following prenatal diagnosis of a lethal fetal defect are associated with improved psychological outcome† 
Prenatal diagnosis  2015;35(8):761-768.
Objective
The aim of the article is to examine the psychological impact, specifically symptoms of grief, post-traumatic stress and depression, in women and men who either terminated or continued a pregnancy following prenatal diagnosis of a lethal fetal defect.
Method
This project investigated a diagnostically homogeneous group composed of 158 women and 109 men who lost a pregnancy to anencephaly, a lethal neural tube defect. Participants completed the Perinatal Grief Scale, Impact of Event Scale – Revised and Beck Depression Inventory-II, which measure symptoms of grief, post-traumatic stress and depression, respectively. Demographics, religiosity and pregnancy choices were also collected. Gender-specific analysis of variance was performed for instrument total scores and subscales.
Results
Women who terminated reported significantly more despair (p = 0.02), avoidance (p = 0.008) and depression (p = 0.04) than women who continued the pregnancy. Organizational religious activity was associated with a reduction in grief (Perinatal Grief Scale subscales) in both women (p = 0.02, p = 0.04 and p = 0.03) and men (p = 0.047).
Conclusion
There appears to be a psychological benefit to women to continue the pregnancy following a lethal fetal diagnosis. Following a lethal fetal diagnosis, the risks and benefits, including psychological effects, of termination and continuation of pregnancy should be discussed in detail with an effort to be as nondirective as possible.
doi:10.1002/pd.4603
PMCID: PMC4968036  PMID: 25872901
18.  Prevalence of defined ultrasound findings of unknown significance at the second trimester fetal anomaly scan and their association with adverse pregnancy outcomes: the Welsh study of mothers and babies population‐based cohort 
Prenatal Diagnosis  2015;36(1):40-48.
Abstract
Objective
The aim of this article was to estimate the population prevalence of seven defined ultrasound findings of uncertain significance (‘markers’) in the second trimester and the associated risk of adverse pregnancy outcomes.
Method
A prospective record‐linked cohort study of 30 078 pregnant women who had second trimester anomaly scans between July 2008 and March 2011 in Wales was conducted.
Results
The prevalence of markers ranged from 43.7 per 1000 singleton pregnancies for cardiac echogenic foci [95% confidence interval (CI): 38.8, 51.1] to 0.6 for mild‐to‐moderate ventriculomegaly (95% CI: 0.3, 1.0). Isolated echogenic bowel was associated with an increased risk of congenital anomalies [risk ratio (RR) 4.54, 95% CI: 2.12, 9.73] and preterm birth (RR 2.30, 95% CI: 1.08, 4.90). Isolated pelvicalyceal dilatation was associated with an increased risk of congenital anomalies (RR 3.82, 95% CI: 2.16, 6.77). Multiple markers were associated with an increased risk of congenital anomalies (RR 5.00, 95% CI: 1.35, 18.40) and preterm birth (RR 3.38, 95% CI 1.20, 9.53).
Conclusions
These data are useful for counselling families and developing clinical guidance and care pathways following the detection of markers in clinical practice, particularly the need for follow‐up scans to monitor placental function and growth in pregnancies with isolated echogenic bowel, and further investigation for multiple markers. © 2015 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.
What's already known about this topic? The prevalence and clinical sequelae of defined ultrasound findings of unknown significance (‘markers’) in pregnant women at low risk of adverse pregnancy outcomes are uncertain.Guidance on the reporting and clinical management of markers varies between and within countries.
What does this study adds? This study provides population‐based estimates for the prevalence of markers in the general obstetric population, using data collected prior to referral to specialist fetal‐medicine centres.There is inter‐sonographer variation in the reporting of markers, suggesting that continuous quality assurance programmes are essential within antenatal ultrasound screening services.Isolated echogenic bowel and multiple markers are associated with an increased risk of congenital anomalies and preterm births, and isolated pelvicalyceal dilatation is associated with an increased risk of congenital anomalies.These data will be useful in counselling families and in the development of clinical guidelines and care pathways for the management of markers detected in the second trimester of pregnancy.
doi:10.1002/pd.4708
PMCID: PMC4949529  PMID: 26475362
19.  Non‐invasive prenatal diagnosis of Duchenne and Becker muscular dystrophies by relative haplotype dosage†  
Prenatal Diagnosis  2016;36(4):312-320.
Abstract
Objective
Development of an accurate and affordable test for the non‐invasive prenatal diagnosis of Duchenne and Becker muscular dystrophies (DMD/BMD) to implement in clinical practice.
Method
Cell‐free DNA was extracted from maternal blood and prepared for massively parallel sequencing on an Illumina MiSeq by targeted capture enrichment of single nucleotide polymorphisms (SNPs) across the dystrophin gene on chromosome X. Sequencing data were analysed by relative haplotype dosage.
Results
Seven healthy pregnant donors and two pregnant DMD carriers all bearing a male fetus were recruited through the non‐invasive prenatal diagnosis for single gene disorders study. Non‐invasive prenatal diagnosis testing was conducted by relative haplotype dosage analysis for X‐linked disorders where the genomic DNA from the chorionic villus sampling (for healthy pregnant donors) or from the proband (for pregnant DMD carriers) was used to identify the reference haplotype. Results for all patients showed a test accuracy of 100%, when the calculated fetal fraction was >4% and correlated with known outcomes. A recombination event was also detected in a DMD patient.
Conclusion
Our new test for NIPD of DMD/BMD has been shown to be accurate and reliable during initial stages of validation. It is also feasible for implementation into clinical service. © 2016 The Authors. Prenatal Diagnosis published by John Wiley & Sons, Ltd.
What's Already Known About This Topic? Recent research has shown that non‐invasive prenatal diagnosis for some single gene disorders is possible, and there is some implementation into clinical practice for the detection or exclusion of the paternal allele. However, this is not yet available for definitive diagnosis of X‐linked conditions.
What Does This Study Add? We have developed an accurate and feasible test for the non‐invasive prenatal diagnosis of Duchenne and Becker muscular dystrophies. Early validation data have proven that the method could potentially be implemented into clinical practice.
doi:10.1002/pd.4781
PMCID: PMC4864947  PMID: 26824862
20.  Noninvasive prenatal testing in the general obstetric population: clinical performance and counseling considerations in over 85 000 cases†  
Prenatal Diagnosis  2016;36(3):237-243.
Abstract
Objective
The primary goal of this study was to provide clinically relevant information for appropriate patient counseling.
Method
Demographics and test metrics were reviewed for 86 658 clinical cases. Outcome information was requested for samples reported as aneuploidy detected or suspected for chromosomes 21, 18, or 13; voluntary outcome reporting was encouraged for all discordant outcomes.
Results
Of 86 658 cases, 85 298 (98.4%) met inclusion criteria for result reporting. Of the 1360 (1.6%) cancellations, only 101 (0.1%) were for technical reasons. Average time to result was 3.3 business days. Aneuploidy was detected or suspected in 2142 (2.5%) samples. For aneuploidy detected cases with known clinical outcomes, the overall positive predictive value (PPV) was 83.5% (608/728); observed PPVs for trisomies 21, 18, and 13 ranged from 50.0 to 92.8%. As individual PPVs are determined by a patient's prior risk, we developed a chart for counseling patients on positive predictive value based on maternal age.
Conclusion
This large‐scale report reinforces that noninvasive prenatal testing is a highly accurate screen for fetal aneuploidy in the general obstetric population. Test improvements have facilitated a reduction in failure rates, time to result, and borderline results/unclassifiable results. We have developed a positive predictive value counseling tool to ensure appropriate patient education, counseling, and clinical utilization. © 2015 Illumina. Prenatal Diagnosis published by John Wiley & Sons, Ltd.
What's already known about this topic? Noninvasive prenatal testing (NIPT) has been shown to screen for common fetal aneuploidies with high sensitivity and low false positive rates.NIPT is a reliable alternative to current fetal aneuploidy serum screening methods in the first and second trimesters.Previous publications detailing NIPT clinical experience have shown that NIPT is performing as well as it performed in clinical validation studies.
What does this study add? Analysis of over 85 000 samples submitted to the clinical laboratory suggests that whole genome sequencing‐based NIPT continues to meet or exceed performance characteristics established by clinical validation studies for screening of fetal aneuploidy.A tool to guide appropriate pre‐test and post-test counseling of patients on estimated positive predictive values based on their personal maternal-age based risk, with recommendations for effective implementation into clinical practice.
doi:10.1002/pd.4766
PMCID: PMC4819889  PMID: 26715197
21.  Normative biometrics for fetal ocular growth using volumetric MRI reconstruction 
Prenatal diagnosis  2015;35(4):400-408.
Objective
To determine normative ranges for fetal ocular biometrics between 19 and 38 weeks gestational age (GA) using volumetric MRI reconstruction.
Method
3D images of 114 healthy fetuses between 19 and 38 weeks GA were created using super-resolution volume reconstructions from MRI slice acquisitions. These 3D images were semi-automatically segmented to measure fetal orbit volume, binocular distance (BOD), interocular distance (IOD), and ocular diameter (OD).
Results
All biometry correlated with GA (Volume, CC = 0.9680; BOD, CC = 0.9552; OD, CC = 0.9445; and IOD, CC = 0.8429), and growth curves were plotted against linear and quadratic growth models. Regression analysis showed quadratic models to best fit BOD, IOD and OD, and a linear model to best fit volume.
Conclusion
Orbital volume had the greatest correlation with GA, though BOD and OD also showed strong correlation. The normative data found in this study may be helpful for the detection of congenital fetal anomalies with more consistent measurements than are currently available.
doi:10.1002/pd.4558
PMCID: PMC4390455  PMID: 25601041
MRI; fetal development; orbit; ocular; eyes; biometrics; volume; gestational age
23.  Changing trends in carrier screening for genetic disease in the United States 
Prenatal Diagnosis  2015;35(10):931-935.
Abstract
Genetic disease is the leading cause of infant death in the United States, accounting for approximately 20% of annual infant mortality. Advances in genomic medicine and technological platforms have made possible low cost, pan‐ethnic expanded genetic screening that enables obstetric care providers to offer screening for over 100 recessive genetic diseases. However, the rapid integration of genomic medicine into routine obstetric practice has raised some concerns about the practical implementation of such testing. These changing trends in carrier screening, along with concerns and potential solutions, will be addressed. © 2015 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.
What's already known about this topic? Expanded carrier screening is being widely used to screen for a large number of genetic disorders.
What does this study add? This study reviews the changing technology being utilized for expanded carrier screening and presents an argument for pre‐conceptual screening.
doi:10.1002/pd.4647
PMCID: PMC4758394  PMID: 26138560
24.  Computer‐assisted surgical planning and intraoperative guidance in fetal surgery: a systematic review†  
Prenatal Diagnosis  2015;35(12):1159-1166.
Abstract
Fetal surgery has become a clinical reality, with interventions for twin‐to‐twin transfusion syndrome (TTTS) and spina bifida demonstrated to improve outcome. Fetal imaging is evolving, with the use of 3D ultrasound and fetal MRI becoming more common in clinical practise. Medical imaging analysis is also changing, with technology being developed to assist surgeons by creating 3D virtual models that improve understanding of complex anatomy, and prove powerful tools in surgical planning and intraoperative guidance.
We introduce the concept of computer‐assisted surgical planning, and present the results of a systematic review of image reconstruction for fetal surgical planning that identified six articles using such technology.
Indications from other specialities suggest a benefit of surgical planning and guidance to improve outcomes. There is therefore an urgent need to develop fetal‐specific technology in order to improve fetal surgical outcome. © 2015 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.
What's already known about this topic? Fetal surgery has now become a clinical reality, with interventions such as laser treatment for twin‐to‐twin transfusion syndrome (TTTS) and open fetal surgery for spina bifida demonstrated in randomised control trials to improve neonatal outcomeOther specialities are increasingly utilising computer‐assisted surgical planning software, with evidence that this can improve outcome
What does this study add? We feel that there is an urgent need to develop fetal‐specific technology for surgical planning as it is likely to play an important role in improving outcomes from fetal surgery
doi:10.1002/pd.4660
PMCID: PMC4737238  PMID: 26235960
25.  Electrophysiologic features of fetal ventricular aneurysms and diverticula 
Prenatal diagnosis  2014;35(2):129-136.
Objective
Congenital ventricular wall defects are very rare and include congenital ventricular aneurysms (CVAs) and diverticula (CVDs).
Method
We report a series of five fetuses: three with CVAs and two with CVDs referred due to fetal arrhythmia. In addition to routine fetal echocardiography, fetal magnetocardiography (fMCG) was used. The literature in CVA and CVD is reviewed.
Results
Incessant premature ventricular contractions (PVC), mainly bigeminy and trigeminy were found in three fetuses with CVAs and in one with CVD, who also had ventricular couplets. The other fetus with CVD, referred because of PVCs, had only sinus tachycardia. ST elevation was noted in two. Fetal movement had a variable impact on PVC’s. Postnatal evaluation demonstrated two persistent left ventricular aneurysms and one persistent right CVD; one CVD resolved at 35 weeks gestation. Two neonates had incessant PVCs. Both arrhythmias resolved spontaneously while being treated with propranolol.
Conclusion
FMCG is complementary to echocardiographic imaging. In fetuses with left ventricular wall defects, additional electrophysiological diagnosis can be made by fMCG, including the complexity of ventricular ectopy, arrhythmic response to fetal movement, presence of ST-T wave abnormalities, and atrial amplitude increases. Prenatal risk factor assessment using fMCG can additionally support post-natal treatment and follow-up.
doi:10.1002/pd.4501
PMCID: PMC4319987  PMID: 25284224
electrophysiology; fetal magnetocardiography (fMCG); ventricular aneurysm; fetus; premature ventricular contractions; ventricular diverticulum

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