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Aim: To investigate the detectability of noninvasive prenatal screening (NIPS) with conventional sequencing depth to detect fetal copy number variants. Methods: We performed a retrospective study in a total of 19 144 pregnant women. Their cell‐free plasma DNA were assessed for trisomy 21, trisomy 18, trisomy 13, sex chromosome aneuploidies, and genome‐wide copy number variants by NIPS at conventional sequencing depth. Results: Three hundred seventy‐four cases (2.0%, 374/19 144) with abnormal results were detected, which including 84 cases (0.4%, 84/19 144) with high risk of trisomy 21, 18, and 13, 90 cases (0.5%, 90/19 144) with high risk of sex chromosome abnormalities (SCA), and 44 cases (0.2%, 44/19 144) with high risk of other chromosome aneuploidies. One hundred fifty‐six cases (0.8%, 156/19 144) with high risk of copy number variations (CNVs) were also detected. In following prenatal diagnosis, composite positive predictive value (PPV) of trisomy 21, 18, and 13 was 69.6% (48/69). The PPV of SCAs was 37.3% (19/51). And the PPVs for CNVs was detected as 51.0% (<5 Mb), 71.4% (5 Mb ≤ CNV ≤10 Mb), 56.5% (>10 Mb). Finally, a follow‐up about the pregnancy outcomes were conducted for all available cases. Conclusions: NIPS yielded high PPVs for trisomy 21, 18, and 13 aneuploidies and moderate PPVs for SCAs and CNVs. The screening effectiveness was closely related to the size of CNV fragments. Larger CNVs, especially larger than 5 Mb, could be detected more accurately by NIPS in our analytic technique. Meanwhile, diagnostic confirmation by microarray analysis was highly recommended. [ABSTRACT FROM AUTHOR]

Objective: The purpose was to evaluate the effectiveness of a non-invasive prenatal test (NIPT) using mass parallel sequencing (MPS) to detect trisomy 13, 18, 21 and fetal sex chromosome abnormalities in maternal blood samples by isolating freely circulating foetal extracellular DNA (eDNA), and to develop an algorithm for prenatal screening. Material and Methods: The research methods used included blood sampling from patients, isolation of eDNA, determination of DNA concentration and quality, library preparation for sequencing, MPS using an Illumina HiSeq2000, positive and negative control samples, monitoring, and analysis of results using the distributed algorithms platform based on calculations of z-value and the average absolute deviation. Pregnant women were divided into two groups based on gestational age at sampling, group 1; 9-14 weeks and group 2; 15-27 weeks. Results: A total of 377 pregnant women were included with a mean (range) age of 33 (23-44) years. The mean gestational age at the time of blood sampling in group 1 was 11 (9-14) weeks, and in group 2 was 21 (15-27) weeks. In the first group, three cases of trisomy 18 chromosomes were detected in patients aged 43 years old, and female children were subsequently born with Edwards syndrome. In the second group, one case of trisomy 21 was detected in a patient aged 36 years and the pregnancy was terminated at 25 weeks. Conclusion: The analysis of freely circulating foetal eDNA was a sensitive method for detecting chromosomal abnormalities. The study has a practical significance, since the NIPT for frequent aneuploidy considerably exceeds the effectiveness of traditional screening methods and allows identifying chromosomal disorders starting from the 9th week of the gestation period. [ABSTRACT FROM AUTHOR]

Twin pregnancy presents unique considerations for aneuploidy screening. Pre-test counseling regarding benefits, alternatives, and options for aneuploidy screening should be provided to all patients carrying twin pregnancy. This article aims to review the options for aneuploidy screening in twin pregnancy including the potential benefits and limitations. [ABSTRACT FROM AUTHOR]

Prenatal screening has come a long way from the discovery of fetal ultrasound markers for Down syndrome followed by improved ultrasound skills where genetic syndromes and major congenital malformations can be diagnosed right in the first trimester itself. The outcome is a key factor for the couple to make informed decision on the future of the high risk pregnancy. Prenatal screening, diagnosis, management and subsequent prevention is now an established practice in fetal medicine. The first trimester screening (at 11-13+6 weeks) includes evaluating markers for common aneuploidies (trisomies) such as Down syndrome along with a detailed fetal anatomy review. This is followed by a genetic sonogram or anomaly scan at around 20 weeks. Any signs of "high risk" for trisomies or malformations prompt invasive testing for precision diagnosis, either a chorion villous sampling (CVS) or an amniocentesis (AC). The fetal sample is used for various genetic tests, such as chromosome microarray analysis (CMA), targeted clinical exome sequencing (CES), or whole exome sequencing (WES) depending upon the abnormality noted or the suspected genetic condition. Non Invasive prenatal screening (NIPS) is now available as a screening tool for Down syndrome (99%accuracy for Down syndrome) if the couple choose to defer invasive testing. Apart from aneuploidies, prenatal screening for non-structural disorders, such as Beta thalassemia (both parents carriers) or investigating any other genetic disorder can also be offered. In addition, Carrier Screening can be considered especially by consanguineous couples who are known to be at increased risk for having an affected baby. The option for NIPS is now preferred by most parents undergoing pre-conception genetic counselling and confirmed to be carriers for an autosomal recessive genetic disease. The prenatal screening is the best choice for secondary prevention of genetic condition. The option for preimplantation genetic diagnosis (PGD) offers primary prevention by specific wild embryo selection and implantation in an in vitro fertilization cycle, following exclusion of affected embryo for aneuploidy (PGD-A), structural chromosome aberration (PGD-A), and a monogenic Mendelian genetic disease (PGD-M). The prenatal screening or diagnosis by the Fetal Medicine Team remains the mainstay for identification and management of pregnancies at high risk of genetic disorders. [ABSTRACT FROM AUTHOR]

Communicating the diagnosis of Down Syndrome to a couple of parents is never easy, whether before or after birth. As doctors, we must certainly rely on our own relational skills, but it is also necessary to be confident in some general indications, which are often overlooked in the strict hospital routine. This article is intended as a summary of the main articles published on this subject in the international literature, collecting and summarising the most important indications that have emerged in years of medical practice all over the world as well as in our personal experience. The diffusion of these guidelines is essential to help the doctor in this difficult task, on which there is often little training, and above all to guarantee to the parents the least traumatic communication possible. [ABSTRACT FROM AUTHOR]

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This article is an ethical evaluation of two familiar views in the debate on foetal diagnosis; one being the mainstream view in medical texts emphasizing early detection of foetuses with Down´s syndrome so they may be aborted, and the other coming from Down´s syndrome activists claiming that such screening is never acceptable. The core question asked is: What ethical weaknesses in modern medical practice does this discussion reveal? I argue that the marketization of noninvasive prenatal testing (NIPT) and the mainstream discussion in the health sector on its application shows two trends undermining the traditional ethos of medicine. Firstly, that doctors are, in their work, concentrating on diseases as isolated entities, whereas the patient and her life remains in the shadow. Secondly, the emphasis has been on the scientific foundation of medicine where the clinical evaluation of these scientific facts has not received due attention. This article is about how we can evaluate ethically two different views on tests done on foetuses. It describes how some medical texts talk about tests done on foetuses to see if they have Down's syndrome; and secondly, how some people with Down´s syndrome and their families talk about such tests. The medical view is criticized for failing to understand the importance of the lives of people with Down´s syndrome and for not taking their views of the value of their lives seriously. The medical texts focus on diseases instead of patients. Thus they tend to ignore the life and value of the person having the disease. The medical view is mainly about science and facts. It ignores the question of whether and how these facts matter for the patient. People with Down´s syndrome and their families have criticized this medical approach. Their criticism is very important. [ABSTRACT FROM AUTHOR]

This clinical report offers guidance for the pediatrician in caring for the child, adolescent and family in whom a diagnosis of Down syndrome has been confirmed by chromosome analysis or suspected by prenatal screening. Topics discussed include cooccurring medical conditions and cognitive impairment in children with Down syndrome, common physical findings such as hypotonia, epicanthal folds, and flat nasal bridge, and common medical conditions such as hearing loss, and obstructive sleep apnea.

The article focuses on prenatal diagnosis of trisomy 21. It mentions the caregiver must give clear and objective information to pregnant women and couples, that can serve as a support for dialogue between the carer and the pregnant woman, between the carer and the couple and allow future parents to discuss and decide whether to commit or not in the screening process.

The article focuses on study of financial analysis is carried out to assess costs and benefits of providing cell-free DNA screening in Finland, using different strategies. Topics discussed include considering the place of cell-free DNA screening it is important to make explicit the additional and marginal costs of different screening strategies and the associated benefits; and most assumptions the balance is favorable for Contingent screening.

Aim: This study aimed to assess the utility of ultrasound screening for pregnancies with positive noninvasive prenatal testing results for trisomy 21, trisomy 18, and trisomy 13. Methods: We performed a retrospective analysis of positive noninvasive prenatal testing results and first‐trimester ultrasound screening at our department between 2013 and 2019. Invasive genetic testing was performed if the patient had positive noninvasive prenatal testing results. Fetal ultrasound and cytogenetic data were collected. Noninvasive prenatal testing was performed in the women for advanced maternal age, nuchal translucency thickness, or history of abnormality in the previous child or relative. Results: Forty‐one pregnant women had positive noninvasive prenatal testing results for trisomy 21, trisomy 18, and trisomy 13. Twenty‐three women had positive results for trisomy 21, 13 had positive results for trisomy 18, and 5 had positive results for trisomy 13 at 11 to 14 weeks of gestation. The positive predictive value of noninvasive prenatal testing was 100% for trisomy 21, 84.6% for trisomy 18, and 100% for trisomy 13. The positive predictive value of positive noninvasive prenatal testing results and fetal morphological abnormalities was 100% for trisomy 21, trisomy 18, and trisomy 13. Conclusion: Combining an ultrasound examination with noninvasive prenatal testing resulted in a higher positive predictive value for trisomy 18. Normal ultrasound examination results can help alleviate stress caused by false‐positive noninvasive prenatal testing results. In contrast, the positive predictive value and negative predictive value for trisomy 21 were not altered by adding an ultrasound examination to noninvasive prenatal testing. [ABSTRACT FROM AUTHOR]

Background: We developed a decision aid (DA) to help pregnant women and their partners make informed decisions about prenatal screening for trisomy. We aimed to determine its usefulness for preparing for decision-making and its acceptability among end-users.Methods: In this mixed-methods pilot study, we recruited participants in three prenatal care settings in Quebec City. Eligible women were over 18 and more than 16 weeks pregnant or had given birth recently. We asked them about the usefulness of the DA using an interview grid based on the Technology Acceptance Model. We performed descriptive statistics and deductive analysis.Results: Thirty-nine dyads or individuals participated in the study. Mean usefulness score was 86.2 ± 13. Most participants found the amount of information in the DA just right (79.5%), balanced (89.7%), and very useful (61.5%). They were less satisfied with the presentation and the values worksheet and suggested different values clarification methods.Conclusion: Rigorous pilot tests of DAs with patients are an important stage in their development before the more formal assessments that precede scaling up the DA in clinical practice.Practice Implications: The next version of the DA will integrate the suggestions of end-users for better decision-making processes about prenatal screening for trisomy. [ABSTRACT FROM AUTHOR]

Objective: To review the uptake rate of non-invasive prenatal testing (NIPT) in the first 12 months of implementation in the obstetric unit of United Christian Hospital. Methods: Between December 2019 and November 2020, women with a fetal Down syndrome (DS) risk ratio of ≥1:250 after first-trimester DS screening (using maternal serum markers and nuchal translucency thickness on ultrasonography) or second-trimester DS screening (using maternal serum markers) were offered free-of-charge second-tier NIPT or invasive testing. Results of NIPT and invasive testing and pregnancy outcome of these women were reviewed. Characteristics of those opting for NIPT versus invasive testing were compared. Univariate and logistic regression analyses were used to determine significant factors associated with opting for NIPT. Results: During the study period, 2182 women underwent first-trimester DS screening (n=2086) or second-trimester DS screening (n=96). 117 women were screen positive, with a DS risk ratio of <1:250. The screen-positive rate was 5.36% overall and 5.23% for first trimester and 8.33% for second trimester. Of the 117 women, 26 had NIPT in private settings before or after being screened positive, 89 opted for NIPT (n=65) or invasive testing (n=24) in our hospital, and two did not have further testing owing to spontaneous miscarriage (n=1) or termination of pregnancy (n=1). Of 91 women with NIPT, 84 (92.3%) were at low risk for common aneuploidies, four were at high risk for T21 (n=2) or T18 (n=2), and three had abnormalities other than common aneuploidies. Six of the high-risk women underwent invasive testing and abnormalities were confirmed. Of the 24 women who opted for invasive testing, 14 had normal results and 10 had abnormal results. In logistic regression analysis, predictors for opting for invasive testing (rather than NIPT) were presence of abnormalities on ultrasonography (odds ratio (OR)=13.9, p=0.01), a nuchal translucency thickness of ≥3 mm (OR=7.62, p=0.01), and education level below tertiary level (OR=7.14, p=0.02). Conclusion: In the first 12 months of implementation in United Christian Hospital, the uptake rate of NIPT as a second-tier test after positive DS screening was 77.8%, which is higher than that reported in previous studies when NIPT was a self-financed test. [ABSTRACT FROM AUTHOR]

Objective: To compile current usage of serum-based prenatal screening for Down syndrome in the United States and compare it with results from a similar 2011/2012 survey. Setting: The College of American Pathologists maternal screening proficiency testing survey includes a supplemental question on the first of three yearly distributions. Methods: Information regarding tests offered and the monthly number of pregnancies tested for US-based laboratories were reviewed. Results were stratified by size of laboratory, tests offered, and pregnancies tested. Findings were compared to an earlier survey. Results: Fifty-six laboratories reported they will have screened 1,131,336 pregnancies in 2020. Of these, 36% are screened by stand-alone first trimester testing, 48% by stand-alone second trimester testing, and 16% using tests that integrate results from both trimesters. Eighty percent of all serum screens were provided by the five laboratories that performed the most screens (at least 50,000). These five performed similar proportions of first or second trimester screens (42.2% and 41.8%, respectively). Compared to eight years earlier, there are now 54% fewer laboratories. Pregnancies screened using the first trimester, second trimester, and integrated protocols were lower by 27%, 69%, and 72%, respectively. The serum screening activity in the US showed a 62% decrease from 2012 levels. During 2012–2020, the number of cell-free DNA tests increased from negligible to 1,492,332. Conclusions: Maternal serum screening for common aneuploidies has changed significantly in eight years with fewer laboratories, a shift toward larger laboratories and a 2.5-fold reduction in pregnancies tested, likely due to the introduction of cell-free DNA screening. [ABSTRACT FROM AUTHOR]

Objective: To investigate the factors associated with cell-free DNA test failure, and the optimal subsequent management of these pregnancies. Methods: This was a retrospective study of 27,363 singleton pregnancies undergoing cell-free DNA testing. Women with cell-free DNA test failure were divided into a high-risk group and a low-risk group according to their indications. The subsequent management and pregnancy outcomes of these women were followed up. Results: The rate of cell-free DNA test failure at the first sampling was 1.49%, and 78.4% of failures were due to a low fetal fraction. Of the 66 women who refused any subsequent management, an adverse pregnancy outcome was seen in 5 cases, all belonging to the high-risk group. Of the 13 low-risk women who chose second-trimester maternal serum screening, all obtained a low-risk maternal serum screening result and an unaffected pregnancy outcome. A redraw was chosen by 171 women, which yielded a result in 75.4% and their pregnancy outcomes were unaffected; 42 women had an uninformative result again and received an amniocentesis. As 158 women had an amniocentesis after the first sampling, this procedure was offered in 200 cases altogether. Abnormal genetic testing results were shown in six (3%, 6/200) cases, all in the high-risk group. Conclusions: High-risk pregnant women with cell-free DNA test failure are at increased risk of adverse pregnancy outcomes. A second sampling for cell-free DNA test or maternal serum screening might be suggested to low-risk women. Invasive prenatal diagnosis should be offered to the high-risk patients, especially those with a second cell-free DNA test failure. [ABSTRACT FROM AUTHOR]

By implementation of non-invasive prenatal testing (NIPT) for the diagnosis of Down syndrome (DS) in maternity care, an ethical debate is newly inflamed how to deal with this information. Fears of the consequences of an increased use of NIPT are justified with the same arguments when amniocentesis and preimplantation genetic diagnosis (PGD) were introduced decades ago. It can be expected that the prevalence of people with DS would significantly increase in Western societies as a result of the increasing age of pregnant women and the improved medical care for people with DS. The net effect as to whether an increasing uptake of NIPT will result in more abortions of fetuses with trisomy 21 cannot be reliably estimated. This holds true since more and more couples will use results of NIPT for information only, but will not opt for termination of pregnancy. Although parents love their children with DS, in a society where reproductive autonomy is seen as an achievement, access to NIPT cannot be limited. On this background, comprehensive and qualified pretest counseling is vital, also to avoid possible stigmatization of people with DS and as the resulting consequence to avoid feared deterioration in their living conditions, for which, however, there is no evidence to date. The personal view of a mother of a child with DS illustrates the complexity in dealing with NIPT, which does not allow simple answers and must be understood as a challenge for society as a whole. [ABSTRACT FROM AUTHOR]

The most well-known goal of non-invasive prenatal testing (NIPT) is still to determine whether or not a fetus has trisomy 21. Since women often terminate the pregnancy upon a positive result, there is concern that the use of NIPT contributes to discrimination against persons with disabilities. If this concern is justified, it could have an impact on the wider social acceptability of existing testing practices and their potential further expansion. This paper demonstrates four different versions of the discrimination worry, indicates how international policy papers have reacted to them, and identifies the ethically most relevant feature of the concern. [ABSTRACT FROM AUTHOR]

Aim: We aimed to evaluate the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of noninvasive prenatal testing (NIPT) in high‐risk pregnant women. Methods: Pregnant women who underwent GeneTech NIPT, the most commonly used NIPT in Japan, between January 2015 and March 2019, at Japan NIPT Consortium medical sites were recruited for this study. The exclusion criteria were as follows: pregnant women with missing survey items, multiple pregnancy/vanishing twins, chromosomal abnormalities in the fetus other than the NIPT target disease, and nonreportable NIPT results. Sensitivity and specificity were calculated from the obtained data, and maternal age‐specific PPV and NPV were estimated. Results: Of the 45 504 cases, 44 263 cases fulfilling the study criteria were included. The mean maternal age and gestational weeks at the time of procedure were 38.5 years and 13.1 weeks, respectively. Sensitivities were 99.78% (95% confidence interval [95% CI]: 98.78–99.96), 99.12% (95% CI: 96.83–99.76), and 100% (95% CI: 88.30–100) for trisomies 21, 18, and 13, respectively. Specificities were more than 99.9% for trisomies 21, 18, and 13, respectively. Maternal age‐specific PPVs were more than 93%, 77%, and 43% at the age of 35 years for trisomies 21, 18, and 13, respectively. Conclusion: The GeneTech NIPT data showed high sensitivity and specificity in the detection of fetal trisomies 21, 18, and 13 in high‐risk pregnant women, and maternal age‐specific PPVs were obtained. These results could provide more accurate and improved information regarding NIPT for genetic counseling in Japan. [ABSTRACT FROM AUTHOR]

Soft markers were originally introduced to prenatal ultrasonography to improve the detection of trisomy 21 over that achievable with age-based and serum screening strategies. As prenatal genetic screening strategies have greatly evolved in the last 2 decades, the relative importance of soft markers has shifted. The purpose of this document is to discuss the recommended evaluation and management of isolated soft markers in the context of current maternal serum screening and cell-free DNA screening options. In this document, "isolated" is used to describe a soft marker that has been identified in the absence of any fetal structural anomaly, growth restriction, or additional soft marker following a detailed obstetrical ultrasound examination. In this document, "serum screening methods" refers to all maternal screening strategies, including first-trimester screen, integrated screen, sequential screen, contingent screen, or quad screen. The Society for Maternal-Fetal Medicine recommends the following approach to the evaluation and management of isolated soft markers: (1) we do not recommend diagnostic testing for aneuploidy solely for the evaluation of an isolated soft marker following a negative serum or cell-free DNA screening result (GRADE 1B); (2) for pregnant people with no previous aneuploidy screening and isolated echogenic intracardiac focus, echogenic bowel, urinary tract dilation, or shortened humerus, femur, or both, we recommend counseling to estimate the probability of trisomy 21 and a discussion of options for noninvasive aneuploidy screening with cell-free DNA or quad screen if cell-free DNA is unavailable or cost-prohibitive (GRADE 1B); (3) for pregnant people with no previous aneuploidy screening and isolated thickened nuchal fold or isolated absent or hypoplastic nasal bone, we recommend counseling to estimate the probability of trisomy 21 and a discussion of options for noninvasive aneuploidy screening through cell-free DNA or quad screen if cell-free DNA is unavailable or cost-prohibitive or diagnostic testing via amniocentesis, depending on clinical circumstances and patient preference (GRADE 1B); (4) for pregnant people with no previous aneuploidy screening and isolated choroid plexus cysts, we recommend counseling to estimate the probability of trisomy 18 and a discussion of options for noninvasive aneuploidy screening with cell-free DNA or quad screen if cell-free DNA is unavailable or cost-prohibitive (GRADE 1C); (5) for pregnant people with negative serum or cell-free DNA screening results and an isolated echogenic intracardiac focus, we recommend no further evaluation as this finding is a normal variant of no clinical importance with no indication for fetal echocardiography, follow-up ultrasound imaging, or postnatal evaluation (GRADE 1B); (6) for pregnant people with negative serum or cell-free DNA screening results and isolated fetal echogenic bowel, urinary tract dilation, or shortened humerus, femur, or both, we recommend no further aneuploidy evaluation (GRADE 1B); (7) for pregnant people with negative serum screening results and isolated thickened nuchal fold or absent or hypoplastic nasal bone, we recommend counseling to estimate the probability of trisomy 21 and discussion of options for no further aneuploidy evaluation, noninvasive aneuploidy screening through cell-free DNA, or diagnostic testing via amniocentesis, depending on clinical circumstances and patient preference (GRADE 1B); (8) for pregnant people with negative cell-free DNA screening results and isolated thickened nuchal fold or absent or hypoplastic nasal bone, we recommend no further aneuploidy evaluation (GRADE 1B); (9) for pregnant people with negative serum or cell-free DNA screening results and isolated choroid plexus cysts, we recommend no further aneuploidy evaluation, as this finding is a normal variant of no clinical importance with no indication for follow-up ultrasound imaging or postnatal evaluation (GRADE 1C); (10) for fetuses with isolated echogenic bowel, we recommend an evaluation for cystic fibrosis and fetal cytomegalovirus infection and a third-trimester ultrasound examination for reassessment and evaluation of growth (GRADE 1C); (11) for fetuses with an isolated single umbilical artery, we recommend no additional evaluation for aneuploidy, regardless of whether results of previous aneuploidy screening were low risk or testing was declined. We recommend a third-trimester ultrasound examination to evaluate growth and consideration of weekly antenatal fetal surveillance beginning at 36 0/7 weeks of gestation (GRADE 1C); (12) for fetuses with isolated urinary tract dilation A1, we recommend an ultrasound examination at ≥32 weeks of gestation to determine if postnatal pediatric urology or nephrology follow-up is needed. For fetuses with urinary tract dilation A2-3, we recommend an individualized follow-up ultrasound assessment with planned postnatal follow-up (GRADE 1C); (13) for fetuses with isolated shortened humerus, femur, or both, we recommend a third-trimester ultrasound examination for reassessment and evaluation of growth (GRADE 1C). [ABSTRACT FROM AUTHOR]

Objective: To determine whether the improved precision of nuchal translucency (NT) measurement used in antenatal screening for Down's syndrome observed over time as evidenced by a decrease in the multiple of the median (MoM) standard deviation requires a modification to the NT MoM truncation limits to maintain accurate risk estimation. Methods: Probability plots were derived from the measurements of NT MoM values used in a 2018 audit of 22,362 unaffected pregnancies. The plots were used to determine whether the NT MoM upper truncation limit should be lowered. Validation plots were used to assess the screening accuracy of Down's syndrome risk estimates calculated from observed NT MoM values in the 22,362 unaffected pregnancies and 69 Down's syndrome pregnancies for original and revised NT MoM truncation limits. Results: Probability plots indicated that with improved precision of NT measurements, there was deviation from a Gaussian distribution at less high MoM values than with less precise measurements. Validation plots showed that using the current NT MoM upper truncation limit of 2.5 MoM with improved precision NT measurements overestimates the Down's syndrome risk (median risk in highest risk category expressed as an odds was 53.3:1 and observed prevalence was 1:1.1). The large discrepancy was corrected by changing the NTupper truncation limit to 2.0 MoM (median risk in highest risk category expressed as an odds was 1:1.78 and observed prevalence 1:2.7). Conclusion: The NT MoM upper truncation limit should be reduced from 2.5 to 2.0 MoM. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the accuracy and diagnostic value of genome-wide noninvasive prenatal testing (NIPT) for the detection of fetal aneuploidies in multiple gestations, with a focus on dichorionic-diamniotic twin pregnancies.Methods: We performed a retrospective cohort study including data from pregnant women with a twin or higher-order gestation who underwent genome-wide NIPT at one of the eight Belgian genetic centers between November 1, 2013, and March 1, 2020. Chorionicity and amnionicity were determined by ultrasonography. Follow-up invasive testing was carried out in the event of positive NIPT results. Sensitivity and specificity were calculated for the detection of trisomy 21, 18, and 13 in the dichorionic-diamniotic twin cohort.Results: Unique NIPT analyses were performed for 4,150 pregnant women with a multiple gestation and an additional 767 with vanishing gestations. The failure rate in multiple gestations excluding vanishing gestations ranged from 0% to 11.7% among the different genetic centers. Overall, the failure rate was 4.8%, which could be reduced to 1.2% after single resampling. There were no common fetal trisomies detected among the 86 monochorionic-monoamniotic and 25 triplet cases. Two monochorionic-diamniotic twins had an NIPT result indicative of a trisomy 21, which was confirmed in both fetuses. Among 2,716 dichorionic-diamniotic twin gestations, a sensitivity of 100% (95% CI 74.12-100%) and a specificity of 100% (95% CI 99.86-100%) was reached for trisomy 21 (n=12). For trisomy 18 (n=3), the respective values were 75% (95% CI 30.06-95.44%) sensitivity and 100% (95% CI 99.86-100%) specificity, and for trisomy 13 (n=2), 100% (95% CI 20.65-100%) sensitivity and 99.96% (95% CI 99.79-99.99%) specificity. In the vanishing gestation group, 28 NIPT results were positive for trisomy 21, 18, or 13, with only five confirmed trisomies.Conclusion: Genome-wide NIPT performed accurately for detection of aneuploidy in dichorionic-diamniotic twin gestations. [ABSTRACT FROM AUTHOR]

Introduction: Austere clinical settings, including remote military installations, face unique challenges in screening pregnant women for aneuploidy. The objective of this study was to compare the direct and indirect prenatal costs of traditional 2-part serum-based screening to cell-free DNA (cfDNA) for detection of trisomies 18 and 21 for a military treatment facility with limited in-house perinatal resources.Materials and Methods: We identified Naval Hospital Guantanamo Bay as a surrogate for an austere clinical environment. A prenatal cost of care analysis incorporating direct and indirect expenses was performed to compare the 2 aneuploidy screening strategies for a theoretical cohort of 100 patients for detection of trisomies 18 and 21. The baseline aneuploidy uptake rate was determined using a historical cohort. Test performance characteristics were obtained from the contracting laboratory. Aneuploidy rates and costs were calculated using previously published data.Results: Assuming a baseline screen uptake rate of 87%, initial screening using the traditional approach would directly cost $8,285.01 versus $44,140.32 with cfDNA. Considering indirect costs such as travel, consultative services, evaluation and follow-up testing of an abnormal screen result, and lost productivity, the cost difference narrows to $14,458.25 over a 5- to 6-year period. Cost equivalence is achieved when cfDNA is priced at $341.17 per test.Conclusion: Cell-free DNA as an initial screening strategy offers enhanced detection rates for trisomies 18 and 21 but remains more costly than traditional screening when incorporating direct and indirect expenses. In a low volume setting with limited resources, the added cost may be justified given the implications of unrecognized aneuploidy. [ABSTRACT FROM AUTHOR]

The landmark decision of Montgomery has established that the patient's right to self-determination and autonomy underpins the doctrine of informed consent. The case of Mordel threw into question the process of obtaining informed consent and whether it was being sufficiently secured in the context of Down's syndrome screening. This case conveyed a paradigm shift to the role of the midwife and sonographers when obtaining consent for screening and the requisite legal standard of care they owe to expectant parents. However, many key issues remain unanswered from the decision in Mordel, in particular, what steps must healthcare professionals take to discharge their duty of care in the process of securing informed consent from expectant parents for screening. [ABSTRACT FROM AUTHOR]

This study aims to present the termination of pregnancy (TOP) rates and elucidate the decision-making process following a prenatal diagnosis of Trisomy 21 in Turkey. This retrospective single-center study was conducted with 146 pregnant women between January 2016 and December 2019 in a tertiary hospital. Data on maternal characteristics, sonographic findings, indications for chromosome analysis, and educational, religious, and economic factors that can influence the parental decision process were collected. The TOP rate of Down syndrome (DS) in our center was 78.8%. We concluded that maternal age, earlier diagnosis, indication for chromosome analysis, and previous pregnancies had no effect on the TOP decision. On the other hand, not having a minor or a major sonographic sign, employed mothers, middle- and high-income families, and families having a secondary or higher education tended to terminate the pregnancy affected by DS at statistically higher rates. There are many studies worldwide investigating the TOP preferences for DS. However, there is limited data about TOP rates and influential factors affecting the decision-making process in Muslim countries. This study contributes by clarifying the factors in the decision-making process and elucidating perspectives about TOP in a Muslim country with a unique status: Turkey. [ABSTRACT FROM AUTHOR]

Aim: Analyze if the evaluation of aberrant right subclavian artery in the prenatal echography has improved the detection of chromosomal, genetic and/or morphological abnormalities in our population. Methods: Descriptive, observational, cross‐sectional study of the cases of aberrant right subclavian artery diagnosed in our Prenatal Diagnosis Unit between January of 2011 and December of 2018. Results: Two hundred and fifty‐seven cases of aberrant right subclavian artery were diagnosed and among them, 179 were considered isolated cases and thus were confirmed after birth. The detection of aberrant right subclavian artery did not improve itself neither the diagnosis of trisomy 21 in the second trimester of pregnancy nor other chromosomal or genetic abnormalities, including the not isolated cases. There were two cases of trisomy 21 diagnosed in the second trimester that presented major sonographic disorders and an inadequate examination during the first trimester. When aberrant right subclavian artery was associated with soft markers of aneuploidy in the second trimester, any case was a trisomy 21. Aberrant right subclavian artery seems to be associated with some minor and major heart defects, especially ventriculoseptal defect and aneurismatic ductus, and in some cases, also with clubfeet. Conclusion: When an adequate screening of aneuploidies and a thorough ultrasound have been performed during the first trimester, aberrant right subclavian artery hardly helps to perform other diagnosis in the second trimester. [ABSTRACT FROM AUTHOR]

Objective: Maternal characteristics and neonatal outcomes associated with cell-free DNA (cfDNA) results were analysed retrospectively to assess the details of false-positive and false-negative results after initial blood sampling in non-invasive prenatal testing (NIPT).Study Design: A multicentre retrospective study was performed for women undergoing NIPT who received discordant cfDNA results between April 2013 and March 2018. The NIPT data obtained using massive parallel sequencing were studied in terms of maternal background, fetal fraction, z-scores, invasive procedure results and neonatal outcomes after birth.Results: Of the 56,545 women who participated in this study, 54 false-positive (0.095 %) and three false-negative (0.006 %) cases were found. Seven of the 54 false-positive cases (13.0 %) had vanishing twin on ultrasonography. Among the 18 false-positive cases of trisomy 18, confined placental mosaicism (CPM) was confirmed in three cases (16.7 %), while CPM was present in one of the three false-negative cases of trisomy 21.Conclusion: These data suggest that the incidence of women with false-positive or false-negative results is relatively low, that such false results can often be explained, and that vanishing twin and CPM are potential causes of NIPT failure. Genetic counselling with regard to false results is important for clients prior to undergoing NIPT. [ABSTRACT FROM AUTHOR]

Down syndrome screening has been available within clinical practice for over 50 years within which time significant innovation and exciting new advances have improved the accuracy, safety, and choice for women who are considering antenatal screening for Down syndrome. The UK National Screening Committee is responsible for setting the national standards regarding screening and it has steadily and consistently directed and facilitated an increase in the detection rate whilst minimising the screen positive rate. This has reduced the number of false positive results and consequently the number of invasive diagnostic procedures and their related miscarriages. Non-invasive pre-natal testing (NIPT) using cell free DNA is a rapidly evolving field and it will soon be incorporated into the existing NHS antenatal screening programme for aneuploidy. It will be offered to women who receive a 'high risk' result following current screening methods (combined test or quadruple test), and will further reduce the number of invasive tests performed, whilst maintaining current detection rates. [ABSTRACT FROM AUTHOR]

To discuss combinations of traditional screening and noninvasive prenatal screening (NIPS) and to compare which traditional screening is the most suitable first-line screening approach to NIPS, pregnant women were recruited in this retrospective observational study. Pregnant women underwent one of four traditional screening tests. The 9 contingent models were combined by high risk cut-offs of 1:50, 1:100, 1:270 and intermediate risk cut-offs of 1:1000, 1:1500, 1:2000. We analyzed cost and performance of various screening models with contingent screening of different risk cut-offs. Compared with other screening tests, combined first-trimester screening (CFTS) had the lowest proportion of high risk (≥1:270) with the highest detection rate (DR) (78.79%) and the lowest proportion of intermediate risk (1:271~1:1000). When intermediate risk was 1:51 ~1:1500, CFTS as first-line screening had the lowest cost with DR of 93.94%. Other screening tests as the first-line screening with intermediate risk of 1:51~1:1000 had the lowest cost, there DR were 90.91%, 84.62%, 91.67%, respectively. Our study demonstrated if only one traditional screening was allowed to screen pregnant women, CFTS was recommended as the first choice. According to local health and economic conditions, adopting appropriate traditional screening with suitable cut-offs as first-line screening will contributed to a cost-effective screening model. [ABSTRACT FROM AUTHOR]

Introduction: The objective of this study was to report on the clinical performance of non-invasive prenatal testing (NIPT) for trisomies 21, 18 and 13 in twin pregnancies and to define the performance of NIPT by combining our cohort study results with published studies in a systematic meta-analysis.Material and Methods: A cohort study was carried out in the First Affiliated Hospital of Sun Yat-sen University and Kanghua Hospital. Meanwhile, searches of PubMed, EMBASE, The Cochrane Library and Web of Science for all relevant peer-reviewed articles were performed with a restriction to English language publication before 15 June 2019. Quality assessments were conducted with the Quality Assessment Tool for Diagnostic Accuracy Studies-2 checklist. Data analysis, heterogeneity, subgroup analysis and publication bias were carried out using META-DISC 1.4 and STATA 12.0.Results: In all, 141 twin pregnancies included in our cohort study; confirmation revealed one true-positive case for trisomy 21 and 140 true-negative cases. The sensitivity and specificity for trisomy 21 by NIPT were both 100%. Twenty-two eligible studies were enrolled in this meta-analysis together with our study. There were 199 cases of trisomy 21, 58 cases of trisomy 18, 14 cases of trisomy 13 and 6347 cases of euploids in total. For trisomy 21, NIPT showed the pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio and diagnostic odds ratio were 0.99, 1.00, 145.81, 0.06 and 1714.09, respectively. For trisomy 18, the pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio and diagnostic odds ratio were 0.88, 1.00, 200.98, 0.19 and 483.68, respectively.Conclusions: The performance of NIPT for trisomy 21 in twin pregnancy was excellent and it was similar to that reported in singleton pregnancy. However, due to publication bias (trisomy 18) and small number of cases (trisomy 13), accurate assessment of the predictive performance of NIPT for trisomies 18 and 13 could not be achieved. [ABSTRACT FROM AUTHOR]

This is the fourth in a series of papers. The previous papers inform midwifery practice by providing insight into whether, to what extent and how cognitive status influences understanding of Down syndrome screening information, the importance of tailoring information, and highlighting areas of communication that are effective in facilitating understanding. These findings led to the development of recommendations to inform a 'best practice' model for midwifery communication of screening information within a conceptual framework that recognises the importance of accurate facts, empathic communication and support for decision-making in a woman-centred approach. These recommendations may have wider relevance beyond midwife communication of Down syndrome screening and may impact upon the communication of other screening information provided within antenatal and neonatal screening. It is important that screening information is communicated effectively in light of changes to screening programmes, such as the introduction of non-invasive prenatal testing. [ABSTRACT FROM AUTHOR]

Objective. To assess the clinical value of prenatal diagnosis using quantitative fluorescent polymerase chain reaction (QF-PCR) and chromosomal microarray analysis (CMA) for the examination of genomic imbalances in prenatal amniotic fluid samples from fetuses with a nuchal translucency (NT) greater than or equal to 2.5 mm. Materials and Methods. A total of 494 amniotic fluid samples and 5 chorionic villus samples were included in this study, with a fetal NT ≥ 2.5 mm at 11–13+6 weeks of gestation from November 2015 to December 2018. All cases were examined with QF-PCR, and those with normal QF-PCR results were then analyzed by CMA. Results. Of the 499 cases, common aneuploidies were detected by QF-PCR in 61 (12.2%) cases. One case of triploidy, one case of trisomy 21 mosaicism, and two cases of X/XX mosaicism were further confirmed by fluorescence in situ hybridization (FISH). Among the 434 cases with normal QF-PCR results, microarray detected additional pathogenic copy number variants (CNVs) in 4.8% (21/434) of cases. Six cases would have been expected to be detectable by conventional karyotyping because of large deletions/duplications (>10 Mb), leaving fifteen (3.5%, 15/428) cases with pathogenic CNVs only detectable by CMA. Pathogenic CNVs, especially those <10 Mb, were centralized in cases with an NT < 4.5 mm, including 5 pathogenic CNVs in cases with an NT of 2.5–3.5 mm and 7 pathogenic CNVs in cases with an NT of 3.5–4.5 mm. Conclusions. It is rational to use a diagnostic strategy in which CMA is preceded by a less-expensive, rapid method, namely, QF-PCR, to detect common aneuploidies. CMA allows for the detection of a number of pathogenic chromosomal aberrations in fetuses with an NT ≥ 2.5 mm. [ABSTRACT FROM AUTHOR]

Background: The purpose of the study was to evaluate the use of contingent prenatal screening for the detection of Down's syndrome and neural tube defects (NTDs) in west of Iran. Methods: A prospective study was conducted on 653 pregnant women referred to a medical diagnostic laboratory (Imam Reza Clinic, Kermanshah, Iran) for contingent prenatal screening tests between October 2016 to September 2017. Results: Among 651 women screened in the first trimester, 8 (1.22%) pregnancies were screen-positive for Down's syndrome. In the second trimester, among 605 women, 25 (4.13%) had a positive result and all of these women voluntarily underwent amniocentesis. Overall, five pregnancies were complicated with chromosomal abnormalities, including five cases of Down's syndrome. Conclusion: In a nutshell, the contingent prenatal screening tests were found to be useful for estimation of Down's syndrome as well as NTDs in both young and older mothers in west of Iran. These tests should be performed for pregnant women before an invasive test for Down's syndrome. [ABSTRACT FROM AUTHOR]

Background: Quantitative fluorescent polymerase chain reaction (QF-PCR) technique is a rapid prenatal aneuploidy detection method. This method can diagnose abnormality in chromosome 13, 18, 21, X and Y. Karyotyping is a technique in which, by the process of pairing and painting, all the chromosomes of an organism are displayed under a microscope. In the present study, a statistical comparison was made between karyotyping and QF-PCR for prenatal diagnosis. Methods: A total of 270 samples were tested for QF-PCR and the results were compared with karyotyping. We also investigated heterozygosity of short tandem repeat (STR) markers by QF-PCR. Deoxyribonucleic acid (DNA) samples (n = 270) were extracted from amniotic fluid (AF) cells. After PCR amplifications, analysis was performed using GeneMarker. A Devyser QF-PCR kit containing 26 primers was used to estimate the observed heterozygosity of STR markers located on chromosome 13, 18, 21, X and Y. Results: The results of karyotyping and QF-PCR were as follows: trisomy 13 (one case), trisomy 18 (five cases), trisomy 21 (five cases) and triploidy (one case). Chromosomal rearrangements and mosaicisms were not detected by QF-PCR but were detected by karyotyping. Maternal cell contamination (MCC) made the karyotyping fail but not the QF-PCR. Conclusion: The QF-PCR method is especially important because it is fast, accurate, low cost and has a short turnaround time. This method will avoid ambiguity of karyotype results and parental anxiety. It will also shorten clinical management for high-risk families. [ABSTRACT FROM AUTHOR]

Objective: To determine the association between second-trimester serum Down syndrome screening (alpha-fetoprotein [AFP] free beta-human chorionic gonadotropin [b-hCG] unconjugated estriol [uE3]) and preterm birth and to create predictive models for preterm birth.Methods: Secondary analysis on a prospective database of pregnancies undergoing second-trimester screen with complete follow-up. The multiples of medians (MoM) of the biomarkers were compared between the group of term, preterm (< 37 weeks), early preterm (< 34 weeks), and very early preterm (< 32 weeks) delivery. Predictive models were developed based on adjusted MoMs and logistic regression and diagnostic performances in predicting preterm birth were determined.Results: Of 20,780 pregnancies, 1,554 (7.5), 363 (1.7), and 158 (0.8%) had preterm, early preterm, and very early preterm birth respectively. High levels of AFP and b-hCG but low levels of uE3 were significantly associated with higher rates of preterm, early preterm and very early preterm delivery. The predictive models had diagnostic performance in predicting preterm birth with the areas under the ROC curve of 0.688, 0.534, 0.599, and 0.718 for AFP, b-hCG, uE3, and combined biomarkers respectively.Conclusion: The second trimester Down syndrome screening could also be used as a tool of risk identification of preterm birth in the same test, without extra-effort and extra-cost. [ABSTRACT FROM AUTHOR]

Background: Quantitative fluorescence-polymerase chain reaction (QF-PCR) is an inexpensive and accurate method for the prenatal diagnosis of aneuploidies that applies short tandem repeats (STRs) as a chromosome-specific marker. Despite its apparent advantages, QF-PCR is not applicable in all cases due to the presence of uninformative STRs. This study was carried out to investigate the efficiency of a method based on applying segmental duplications (SDs) in conjunction with STRs as an alternative to stand-alone STR-based QF-PCR for the diagnosis of Down syndrome. Methods: Fifty amniotic fluid samples from pregnant women carrying Down syndrome fetuses, 9 amniotic fluid samples with 1 or without any informative STR marker (inconclusive), and 100 normal samples were selected from Shiraz, Iran, between October 2015 and December 2016. Analysis was done using an in-house STR-SD-based multiplex QF-PCR and the results were compared. Statistical analysis was performed using MedCalc, version 14. Results: All the normal, Down syndrome, and inconclusive samples were accurately identified by the STR-SD-based multiplex QF-PCR, yielding 100% sensitivity and 100% specificity. Karyotype analysis confirmed all the cases with normal or trisomic results. Conclusion: The STR-SD-based multiplex QF-PCR correctly identified all the normal and trisomy 21 samples regardless of the absence of informative STR markers. The STR-SD-based multiplex QF-PCR is a feasible and particularly useful assay in populations with a high prevalence of homozygote STR markers. [ABSTRACT FROM AUTHOR]

Objective: To assess trends in ultrasound-indicated prenatal diagnostic testing performed over the past two decades in the Australian state of Victoria, in the context of rapidly changing practices in aneuploidy screening and chromosome analysis.Methods: This was a retrospective analysis of all ultrasound-indicated prenatal diagnostic testing (amniocentesis and chorionic villus sampling) performed in the state of Victoria between 1994 and 2016. Ultrasound indications for testing included: fetal structural abnormality, fetal death, fetal growth restriction, abnormal amniotic fluid volume, genetic 'soft marker' and unspecified ultrasound abnormality. Maternal age, indication for testing, type of diagnostic procedure, gestational age, type of chromosome analysis (G-banded karyotyping or chromosomal microarray (CMA)) and test results were obtained. Diagnostic yield (i.e. percentage of tests yielding a major abnormality) was analyzed by year, maternal age and gestational age. Statistical analysis was performed using the χ2 tests for trend or difference in proportions, as appropriate.Results: During the 23-year study period, 1 533 317 births were recorded and 16 152 diagnostic procedures were performed for the primary indication of ultrasound abnormality. In recent years, ultrasound abnormality became the most common indication for prenatal invasive testing (29.4% of diagnostic tests between 2013 and 2016) due to a steep decline in testing for other indications such as positive result on combined first-trimester screening or advanced maternal age alone. In 2016, over 95% of ultrasound-indicated procedures were performed with CMA; among these, pathogenic copy number variant (CNV) was the most common (3.5%) abnormality detected, followed by trisomy 21 (2.8%). The diagnostic yield of ultrasound-indicated tests performed < 16 weeks was significantly higher than that of tests performed after 20 weeks (31.5% vs 9.0%).Conclusions: Ultrasound-indicated invasive testing is contributing to prenatal diagnosis in new ways in the genomic era. A pathogenic CNV is now the most likely diagnosis after ultrasound-indicated testing, rather than trisomy 21 or other whole-chromosome aneuploidy. Despite steady improvements in first-trimester screening for aneuploidy, the diagnostic yield of ultrasound-indicated tests > 20 weeks has remained stable due to increased utilization of CMA. Procedures performed for structural abnormalities < 16 weeks continue to have the highest diagnostic yield, supporting the benefits of early fetal structural assessment at 11-13 weeks. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

Objective: To report on the routine clinical implementation of cell-free DNA (cfDNA) analysis of maternal blood for trisomies 21, 18 and 13, contingent on the results of the first-trimester combined test in twin pregnancy.Methods: Screening for trisomies 21, 18 and 13 was carried out in 959 twin pregnancies by assessment of a combination of maternal age, fetal nuchal translucency thickness, and serum free β-human chorionic gonadotropin and pregnancy-associated plasma protein-A at 11-13 weeks' gestation in two UK NHS hospitals. Women in the high-risk group (risk ≥ 1 in 100) were offered the option of invasive testing, cfDNA testing or no further testing, and those in the intermediate-risk group (risk 1 in 101 to 1 in 2500 in the first phase of the study and 1 in 101 to 1 in 500 in the second phase) were offered cfDNA or no further testing. The trisomic status of the pregnancies was determined by prenatal or postnatal karyotyping or examination of the neonates.Results: In 42 (4.4%) of the 959 pregnancies, there was termination, miscarriage or stillbirth with no known karyotype or there was loss to follow-up. The 917 pregnancies with known trisomic status of both twins included six that were discordant for trisomy 21, four that were discordant for trisomy 18 and 907 with no trisomy 21, 18 or 13. Following combined screening, 47 (5.1%), 203 (22.1%) and 667 (72.7%) of the pregnancies were classified as high risk, intermediate risk and low risk, respectively. The high-risk group included five (83.3%) cases of trisomy 21 and three (75.0%) of trisomy 18. The cfDNA test was carried out in 224 pregnancies and results were provided in 214 (95.5%); this group included six pregnancies with trisomy 21, three with trisomy 18 and 206 with no trisomy 21, 18 or 13. The cfDNA test classified correctly as screen positive all six cases of trisomy 21 and two of the three with trisomy 18, and as screen negative for each of the trisomies all 206 unaffected pregnancies. Contingent screening led to prenatal detection of all cases of trisomy 21 and three of four with trisomy 18.Conclusion: This study has demonstrated the feasibility of introducing cfDNA testing, contingent on the results of the first-trimester combined test for major trisomies, in a routine population of twin pregnancies. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

Objective: Noninvasive prenatal diagnosing for fetal trisomy 21 could help to avoid unnecessary amniocentesis. It is feasible to target the cell-free placental-specific mRNA in maternal plasma, thus eliminating the interference from the maternal genetic background.Study Design: In this study, placental-specific genes on chromosome 21 were identified by searching the TiGER database and reviewing the published literature. These cell-free placental-specific mRNA fragments in maternal plasma were amplified and sequenced. Then, the allelic ratio of heterozygous single-nucleotide polymorphisms(SNPs) was analyzed.Results: Four placental-specific genes (DNMT3L, KRTAP26-1, PLAC4, DSCR4) were identified. This study included 42 cases of normal pregnancies and 19 cases of trisomy 21 pregnancies. The probability density function showed that the allelic ratio of heterozygous SNPs in normal pregnancy reached a peak at 1.0, and that in the trisomy 21 pregnancy was a double-peaked curve in both 0.5 and 2.0. However, the allelic ratio of heterozygous SNPs demonstrated no statistical difference between the normal and trisomy 21 pregnancies.Conclusion: Fetal trisomy 21 could not be diagnosed by examining the heterozygous SNPs of cell-free placental-specific mRNA on chromosome 21. This might be because the low quantity and quality of cell-free placental-specific mRNA fragments in maternal plasma, and the limited available heterozygous SNPs on the placental-specific genes. [ABSTRACT FROM AUTHOR]

Objective: To identify pregnancies at increased risk for trisomy 13, trisomy 18 or triploidy attributable to low fetal fraction (FF).Methods: A FF-based risk (FFBR) model was built using data from more than 165 000 singleton pregnancies referred for single-nucleotide polymorphism (SNP)-based non-invasive prenatal testing (NIPT). Based on maternal weight and gestational age (GA), FF distributions for normal, trisomy 13, trisomy 18 and triploid pregnancies were constructed and used to adjust prior risks for these abnormalities. A risk cut-off of ≥ 1% was chosen to define pregnancies at high risk for trisomy 13, trisomy 18 or triploidy (high FFBR score). The model was evaluated on an independent blinded set of pregnancies for which SNP-based NIPT did not return a result, and for which pregnancy outcome information was gathered retrospectively.Results: The evaluation cohort comprised 1148 cases, of which approximately half received a high FFBR score. Compared with rates expected based on maternal age (MA) and GA, cases with a high FFBR score had a significantly increased rate of trisomy 13, trisomy 18 or triploidy combined (5.7% vs 0.7%; P < 0.001) and also of unexplained pregnancy loss (14.7% vs 10.4%; P < 0.001). For cases that did not receive a high FFBR score, the incidence of a chromosomal abnormality or pregnancy loss was not significantly different from that expected based on MA and GA. In this study cohort, the sensitivity of the FFBR model for detection of trisomy 13, trisomy 18 or triploidy was 91.4% (95% CI, 76.9-98.2%) with a positive predictive value of 5.7% (32/564; 95% CI, 3.9-7.9%).Conclusions: For pregnancies with a FF too low to receive a result on standard NIPT, the FFBR algorithm identified a subset of cases at increased risk for trisomy 13, trisomy 18 or triploidy. For the remainder of cases, the risk of a fetal chromosomal abnormality was unchanged from that expected based on MA and GA. © 2018 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Objectives: The objective of this study is to identify the optimal cut-off points of contingent serum screening excluding nuchal translucency (NT) measurement, to categorize the risk level in the first trimester.Methods: A prospective database of women undergoing contingent serum screening, without NT measurement, was reviewed. In conventional categorization, the results of first-trimester screening were categorized into high risk (>1:30) (invasive diagnosis was offered); intermediate risk (1:30-1:1500) (second-trimester screening was needed); and low risk (<1:1500) (no further test). We recategorized the risk levels using various upper and lower cut-offs and compared detection rates, false-positive rates, and rates of intermediate risk.Results: Among 24,874 women, the prevalence of Down syndrome was 1:691. The previously agreed cut-offs had a detection rate of 88.9% and a false-positive rate of 8.5% with high rate of intermediate risk (38.2%). Re-categorization provided the optimal lower and upper cut-offs 1/900 and 1/50, respectively, giving a detection rate of 86.1%, a false-positive rate of 8.1%, and a rate of intermediate risk of 24.8%.Conclusions: This is the first study on contingent serum screening without NT measurement which shows a high detection rate with an acceptable false-positive rate. The optimal cut-offs to categorize the risk levels of the upper and the lower cut-off was 1:30-1:50 and 1:900, respectively. [ABSTRACT FROM AUTHOR]

Thalassaemia is a common haematologic health condition in Southeast Asian countries (SEA) including Thailand. Reducing the birth of new thalassaemia cases is an effective method to control disease. The background level of knowledge and attitude of pregnant women on the disease influences their decision to perform antenatal screening. Unfortunately, the information about pregnant women's knowledge and attitude on antenatal thalassaemia screening in a developing country such as Thailand is lacking. We therefore conducted this cross-sectional study to examine patients' knowledge and to evaluate the factors which influence the patient's knowledge and attitude on antenatal thalassaemia screening. 1006 pregnant women who attended antenatal care at the Maha Chakri Sirindhorn Medical Center, Faculty of Medicine, Srinakharinwirot University, Ongkharak, Nakhon Nayok, Thailand were enrolled. We found that women's knowledge on antenatal thalassaemia screening is low. A maternal age of ≥35 years was associated with a higher level of knowledge. A higher level of education and multigravidity, a family history of thalassaemia and a positive level of attitude were found more likely to have higher scores for knowledge. A higher level of education and level of knowledge score were also more likely to have a positive attitude score, but multigravidity negatively affected the attitude score. Effective counselling should be monitored among women with a lower levels of education, those with no family history of thalassaemia, and in primigravidas. Lastly, a concurrent Down syndrome screening or foetal sex determination may be useful incentives to encourage the decision to undergo screening. Impact statement What is already known about this subject? Screening for the paternal and maternal thalassaemia carrier status is important for reducing the incidence of severely thalassaemia-affected children. Poorer education and receiving genetic counselling for the first time were the predictive factors for the low post-counselling knowledge in genetic counselling before second trimester genetic amniocentesis. What do the results of this study add? Pregnant women's knowledge of antenatal thalassaemia screening was low. We found that pregnant women aged ≥35 years had a higher level of knowledge. Women with a higher level of education, multigravidity, the presence of a family history of thalassaemia and a positive attitude were more likely to have higher scores for knowledge. A higher level of education and level of knowledge score were also more likely to have a positive attitude score but multigravidity negatively affected the attitude score. The encouraging factors, such as an adjunctive Down syndrome screening or foetal structural screening or foetal sex determination may be useful as the incentive tools. What are the implications of these finding for clinical practice and/or further research? The awareness of a possible incorrect understanding is important for the antenatal counselling in the developing countries. Intensive monitoring of effective counselling using a post-counselling test should be scheduled. The methods of effective counselling for antenatal thalassaemia in developing countries should be evaluated. [ABSTRACT FROM AUTHOR]

Dual detection of α-fetoprotein (AFP) and free β-human chorionic gonadotropin (β-HCG) is a common screening method for Down syndrome in the second trimester and its efficacy is assessed by false-positive rate (FPR). The present study aimed to investigate the effects of the bias in median multiple of the median (mMoM) values of AFP and free β-HCG on FPR. The bias in mMoM values of AFP and free β-HCG and the bias in mMoM values under different gestational ages and weight groups were analyzed. Median equations were adjusted, and medians in LifeCycle software were replaced by local medians. Following two adjustments of the median equations, all indices including FPR, mMoM values of markers and mMoM values under different gestational ages and weight groups generally reached an ideal state. In conclusion, abnormal bias in mMoM values may prompt aberrant application of median equations, and regular monitoring of these indicators may be important for quality control in prenatal screening. [ABSTRACT FROM AUTHOR]

Objective: Maternal plasma cell-free DNA (cfDNA) analysis is a powerful screening tool for Down syndrome. In a pilot series, we examined biologic causes of discordance between the cfDNA test results and the fetal karyotype. We also explored the feasibility of obtaining trio biospecimens by using parental engagement.Methods: A convenience sample of women with discordant cfDNA results were recruited by their care providers. We provided shipping materials and instructions for biospecimen collection. Maternal, newborn, and placental samples were examined with droplet digital PCR.Results: Thirteen of 15 women successfully had biospecimens obtained remotely. High-quality DNA was extracted in 12 of 13 women. Presumed biologic etiologies for discordance were identified in 7 of 12 women: 3 cases from additional clinical review (male renal transplant, vanishing twin, and colon cancer) and 4 cases from additional laboratory investigation using droplet digital PCR (3 with confined placental mosaicism and 1 with true fetal mosaicism).Conclusions: Understanding the biology behind cfDNA-fetal karyotype discordancy is useful for follow-up clinical care. Our study suggests that most cases could be resolved by using a trio biospecimen protocol and parental involvement. To improve accuracy, additional sequencing of biospecimens will be required. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the performance of high-resolution chromosomal microarray (CMA) as the standard diagnostic approach for genomic imbalances in pregnancies with increased risk based on combined first-trimester screening (cFTS).Methods: This was a retrospective study of genomic findings in a cohort of 575 consecutive pregnancies undergoing invasive testing because of a cFTS risk ≥ 1:300 on a publicly funded population-based screening program in the Central and Northern Regions of Denmark, between September 2015 and September 2016. Women with fetal nuchal translucency thickness ≥ 3.5 mm or opting for non-invasive prenatal testing (NIPT) were excluded. Comparative genomic hybridization was performed using a 180-K oligonucleotide array on DNA extracted directly from chorionic villus/amniocentesis samples. Genomic outcomes were reported in relation to cFTS findings.Results: Of the 575 pregnancies that underwent invasive testing, CMA detected 22 (3.8% (95% CI, 2.5-5.7%)) cases of trisomies 21, 18 and 13, 14 (2.4% (95% CI, 1.4-4.0%)) cases of other types of aneuploidy and 15 (2.6% (95% CI, 1.5-4.3%)) cases with a pathogenic or probably pathogenic copy number variant (CNV). Of the 15 CNVs, three were > 10 Mb and would probably have been detected by chromosomal analysis, but the other 12 would most probably not have been detected using conventional cytogenetic techniques; therefore, the overall detection rate of CMA (8.9% (95% CI, 6.8-11.5%)) was significantly higher than that estimated for conventional cytogenetic analysis (6.8% (95% CI, 5.0-9.1%)) (P = 0.0049). Reducing the cFTS risk threshold for invasive diagnostic testing to 1 in 100 or 1 in 50 would have led, respectively, to 60% or 100% of the pathogenic CNVs being missed.Conclusions: CMA is a valuable diagnostic technique that can identify an increased number of genomic aberrations in pregnancies at increased risk on cFTS. Limiting diagnostic testing to pregnancies with a risk above 1 in 100 or 1 in 50, as proposed in contingent NIPT/invasive testing models, would lead to a significant proportion of pathogenic CNVs being missed at first-trimester screening. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

Objective: To estimate the risk of fetal trisomy 21 (T21) and other chromosomal abnormalities (OCA) at 11-13 weeks' gestation using computational intelligence classification methods.Methods: As a first step, a training dataset consisting of 72 054 euploid pregnancies, 295 cases of T21 and 305 cases of OCA was used to train an artificial neural network. Then, a two-stage approach was used for stratification of risk and diagnosis of cases of aneuploidy in the blind set. In Stage 1, using four markers, pregnancies in the blind set were classified into no risk and risk. No-risk pregnancies were not examined further, whereas the risk pregnancies were forwarded to Stage 2 for further examination. In Stage 2, using seven markers, pregnancies were classified into three types of risk, namely no risk, moderate risk and high risk.Results: Of 36 328 unknown to the system pregnancies (blind set), 17 512 euploid, two T21 and 18 OCA were classified as no risk in Stage 1. The remaining 18 796 cases were forwarded to Stage 2, of which 7895 euploid, two T21 and two OCA cases were classified as no risk, 10 464 euploid, 83 T21 and 61 OCA as moderate risk and 187 euploid, 50 T21 and 52 OCA as high risk. The sensitivity and the specificity for T21 in Stage 2 were 97.1% and 99.5%, respectively, and the false-positive rate from Stage 1 to Stage 2 was reduced from 51.4% to ∼1%, assuming that the cell-free DNA test could identify all euploid and aneuploid cases.Conclusion: We propose a method for early diagnosis of chromosomal abnormalities that ensures that most T21 cases are classified as high risk at any stage. At the same time, the number of euploid cases subjected to invasive or cell-free DNA examinations was minimized through a routine procedure offered in two stages. Our method is minimally invasive and of relatively low cost, highly effective at T21 identification and it performs better than do other existing statistical methods. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

Abstract: Aim: Methylated DNA immunoprecipitation real‐time quantitative polymerase chain reaction (MeDIP‐real‐time qPCR) has been introduced as noninvasive prenatal test that has shown absolute detection rate in the screening of Down syndrome. Herein, we aimed to propose a novel modification of MeDIP‐qPCR and assess its potential to alleviate the overall cost of the test, being used in very early weeks of pregnancy, and develop it to a noninvasive prenatal diagnosis biosensor in future researches. Methods: Cell‐free fetal DNA (cffDNA) isolated from 60 pregnant women, including 29 normal and 31 trisomy 21 pregnancies, were analyzed using proposed MeDIP protocol. Enriched methylated DNA sequences were amplified through real‐time qPCR using eight fetal‐specific primer pairs. The status of samples was determined through the calculation of D‐value with the cutoff point of zero. Results: The sensitivity and specificity of the MeDIP protocols using nanoparticles were 100% and 100%, respectively. Conclusion: Remarkable decrease in the price of MeDIP test per each patient would be a reasonable factor to confirm it on larger sample size. Moreover, the high detection rate of screening and the availability of the required instruments around the world make satisfactory reasons to be tested in earlier weeks of pregnancy, thanks to the high sensitivity of gold shell nanoparticles. [ABSTRACT FROM AUTHOR]

Prenatal aneuploidy screening changed significantly in 2012 when cell-free fetal deoxyribonucleic acid (DNA) was introduced as a noninvasive prenatal test. A noninvasive prenatal test detects cell free fragments of fetal DNA from the placenta circulating in maternal blood that coexist with cell-free DNA (cfDNA) of maternal origin. Using next-generation sequencing, the noninvasive prenatal test compares maternal and fetal cfDNA ratios for chromosomes of interest (i.e., 21, 18, 13, X, and Y) to assess chromosomal aneuploidy. Compared to traditional screening using ultrasound and serum markers, the noninvasive prenatal test has superior test characteristics, including a higher detection rate and positive predictive value, and a lower false-positive rate. The noninvasive prenatal test is already used for primary screening in high-risk women and is rapidly expanding to all women. Given its increasing use, understanding the noninvasive prenatal test's limitations is critical. Discordant results (i.e. noninvasive prenatal test is positive for aneuploidy with a normal fetal karyotype) can occur because of biological processes such as aneuploidy confined to the placenta, a vanished twin, maternal aneuploidy or maternal cancer. Use of the noninvasive prenatal test for screening beyond the most common aneuploidies is not recommended. The noninvasive prenatal test is a major advance in prenatal aneuploidy screening but it is not diagnostic and does not replace invasive testing (i.e. chorionic villous sampling or amniocentesis) for confirmation of fetal chromosomal disorders. [ABSTRACT FROM AUTHOR]

Study Question: Are fetal fraction, test failure rate and positive predictive value (PPV) of cell-free fetal DNA (cffDNA) testing different in singleton IVF conceptions compared to spontaneous conceptions?Summary Answer: Fetal fraction is significantly lower; test failure rate is higher and PPV of cffDNA testing is lower in singleton pregnancies conceived by IVF than those conceived spontaneously.What Is Already Known: cffDNA testing, which analyses circulating cffDNA in maternal blood, has very high accuracy for detection of trisomy 21 in the general obstetric population. Focused and conclusive evidence regarding the test characteristics of cffDNA testing in IVF conceived pregnancies is lacking.Study Design, Size, Duration: This was a retrospective cohort study including spontaneously and IVF conceived singleton pregnancies collected consecutively between April 2013 and November 2016. A total of 4633 spontaneously conceived and 992 IVF pregnancies were included.Participants/materials, Setting, Methods: The study was performed at an obstetric and gynecological ultrasound clinic in Melbourne, Australia. Participants had screening for trisomies 21, 18 and 13, as well as sex chromosome aneuploidies (SCA) performed with cffDNA testing after 10 weeks' gestation. Multivariate regression analysis was used to determine significant predictors of logarithmically transformed fetal fraction and test failure. Comparison of test characteristics between study groups was performed adopting a significance level of 5%.Main Results and the Role Of Chance: Median fetal fraction was lower (10.3% [interquartile range (IQR), 7.7-13.5] versus 11.9% [IQR, 9.1-15.0]; P = 0.005), test failure rate was higher (5.2 versus 2.2%; P < 0.001) and positive predictive value (PPV) for trisomies 18, 13 and SCA was poorer in IVF pregnancies compared to those spontaneously conceived. Multivariate linear regression analysis demonstrated that IVF conception, increased BMI, earlier gestational age and South and East Asian ethnicities were independent predictors of lower fetal fraction. Multiple logistic regression analysis found IVF conception and increased BMI to be independently associated with test failure. PPV was high for trisomy 21 in IVF conception (100.0%), but was lower for other trisomies when compared with the non-IVF population.Limitations Reasons For Caution: IVF details were unascertainable for 210 cases, as the information was not available through our data collection points. Inability to karyotype some cases at high-risk for SCA, due to patients' choice, and the occurrence of miscarriages and terminations, resulted in the exclusion of high-risk cases when calculating PPV. Pregnancy outcomes were not available in low-risk pregnancies and negative predictive values could not be calculated.Wider Implications Of the Findings: The limitations revealed by this work should be taken into account during pre-test counseling in pregnant women who conceive by IVF.Study Funding/competing Interest(s): No external source of financial support was provided for this research. The authors report no conflicts of interest. [ABSTRACT FROM AUTHOR]

Objective: To examine preferences for follow-up testing in women screened with high or intermediate risk for Down syndrome in the first or second trimester.Design: Prospective cohort study.Setting: Three public hospitals in Hong Kong, China.Sample: Women with pregnancies termed as high risk (≥1:250; HR) or intermediate risk (1:251-1200; IR) for Down syndrome.Methods: Women with pregnancies screened as HR were offered the choices of: (1) an invasive test plus chromosomal microarray (CMA) to obtain more detailed fetal genetic information; (2) non-invasive cell-free prenatal DNA screening (NIPT) to detect trisomies 13, 18 and 21, and to avoid procedure-related miscarriage; and (3) to decline any further testing. Women received standardised counselling informing them that the reporting times were identical, the procedure miscarriage risk was 0.1-0.2% and that there was no charge for screening. Women with IR pregnancies (1:251-1200) were offered NIPT as a secondary screening test.Main Outcome Measures: Uptake rate for NIPT.Results: Three hundred and forty-seven women had pregnancies deemed as HR; 344 (99.1%) women opted for follow-up testing, 216 (62.2%) of whom chose NIPT. Five hundred and seven of 614 women (82.6%) with IR risk chose NIPT. Seven (21%) of 34 women with nuchal translucency ≥3.5 mm opted for NIPT.Conclusion: In a setting where reporting times are similar and there is no cost difference between options, approximately 60% of women with pregnancies classed as HR would opt for NIPT, offering simple but limited aneuploidy assessment, over a diagnostic procedure with comprehensive and more detailed assessment.Tweetable Abstract: 60% of pregnant Chinese women prefer NIPT over CMA when screened as high risk for Down syndrome. [ABSTRACT FROM AUTHOR]

Objective We aimed to conduct an analysis of the associations between the information provision procedure of prenatal screening for Down’s syndrome and congenital anomalies and the intention to participate in prenatal screening (PS) of ethnicity groups and Dutch language proficiency groups. Design Using a prospective web-based registration form, we asked counselors (midwives, general practitioners, nurses and gynecologists) to report whether and how they offered information about PS to pregnant women. Duration The study was conducted from 2008 to 2010. Participants We collected data on the characteristics of the women who received an information offer about PS from counselors. Measurements Measures included socio-demographic and language proficiency level (LPL) characteristics, key elements of the provision procedure of PS, and intentional participation in PS. Findings The dataset represents 37% of the total population in the study area. Women with a non-native Dutch background and/or insufficient Dutch LPL received fewer information offers about PS, faced a reduced chance of receiving counseling, and showed lower intentional participation rates for PS. Key Conclusions Women with a non-native Dutch background and/or with an insufficient LPL are underserved in the Dutch PS program. These findings present evidence indicating that the fundamental principle of the Dutch Population Screening Act, namely, equal access to PS for all pregnant women, is not being realized. Implications for Practice Therefore, the study findings are important for national and international healthcare, policy makers and governmental professionals to allow ethnic and LPL-related differences in the provision and intentional uptake of PS. [ABSTRACT FROM AUTHOR]