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Li Yang,1 Jing Yang,2 Guosen Bu,3 Rui Han,1 Jiamila Rezhake,1 Xiaolin La1 1Center of Reproductive Medicine, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, People’s Republic of China; 2Department of Gynaecology, The Fifth Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, People’s Republic of China; 3Department of Neurology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, People’s Republic of ChinaCorrespondence: Xiaolin La, Center of Reproductive Medicine, The First Affiliated Hospital of Xinjiang Medical University, No. 137, Liyushannan Road, Urumqi, 830054, People’s Republic of China, Tel +86-991-4362889, Email 909232905@qq.comPurpose: Screening of pathological copy number variations (CNVs) is important for early-diagnosis of hereditary disease. This study was designed to investigate the efficiency of non-invasive prenatal testing (NIPT) in detecting fetal CNVs.Methods: This retrospective analysis included fetuses with CNVs between January 2018 and December 2020. Karyotype analysis and CNV sequencing (CNV-seq) were performed. We then analyzed the positive predictive values of the subchromosomal microdeletions and microduplications.Results: Fifty-eight subjects with aberrant CNVs were screened after NIPT, among which 44 finally underwent amniocentesis. CNV-seq confirmed the presence of CNVs in 24 cases. This indicated that false positivity rate of NIPT was 45.5%. Among 24 cases with CNVs after CNV-seq, only 4 showed consistent findings with karyotype analysis, which showed that karyotyping analysis yielded a missed diagnosis rate of 83.3% for the genome CNV. Positive predictive value (PPV) was 50.0% for CNVs with a length of < 5 Mb after NIPT screening. PPV for CNVs with a length of 5 Mb-10 Mb was 33.3%, while that for CNVs with a length of ≥ 10Mb was 60%. For CNVs duplication after NIPT, the PPV was 65.2%, while that for deletion was 36.4%.Conclusion: For CNVs detected after NIPT, it should be combined with ultrasonographic findings, karyotype analysis, CNV-seq or CMA to determine the pregnancy outcome. Expanding NIPT may increase the risk of unnecessary invasive surgery and unintended selective termination of pregnancy.Keywords: non-invasive prenatal screening, genome copy number variation, next-generation sequencing, prenatal diagnosis

Abstract Exploring efficient and easily implementable prenatal screening strategies aims at birth defect prevention and control. However, there have been limited economic evaluations of non-invasive prenatal screening (NIPS) strategies in China. Furthermore, these studies were predominantly confined to local or geographically proximate provinces and lacked universality and representativeness. This study assesses the health economics of current prenatal screening strategies and NIPS as first-line screening programs, analyzing their efficacy to determine an optimal strategy. From the perspective of health economics, cost-effectiveness, cost-benefit, and single-factor sensitivity were conducted for five different screening strategies using a decision tree model. Among pregnant women aged

Exploring efficient and easily implementable prenatal screening strategies aims at birth defect prevention and control. However, there have been limited economic evaluations of non-invasive prenatal screening (NIPS) strategies in China. Furthermore, these studies were predominantly confined to local or geographically proximate provinces and lacked universality and representativeness. This study assesses the health economics of current prenatal screening strategies and NIPS as first-line screening programs, analyzing their efficacy to determine an optimal strategy. From the perspective of health economics, cost-effectiveness, cost-benefit, and single-factor sensitivity were conducted for five different screening strategies using a decision tree model. Among pregnant women aged < 35 years who underwent only one screening for foetal Down syndrome (DS), the detection rate, false positive rate and positive predictive value of NIPS for foetuses with DS were superior to those of the other four serological screening methods. Although applying NIPS as first-line screening method yields the highest efficacy and benefits, it currently lacks cost-effectiveness when compared to serological screening and sequential NIPS screening strategies. [ABSTRACT FROM AUTHOR]

Multiple non‐invasive prenatal tests (NIPT) are available to screen for risk of fetal trisomy, however, there is no national prenatal screening program in Republic of Ireland. This study aimed to analyze pregnant people's opinions on availability, cost, and knowledge of NIPT for fetal aneuploidy. An anonymous questionnaire on prenatal screening tests and termination of pregnancy was distributed to patients attending antenatal clinics at a tertiary hospital. Descriptive analyses and chi‐squared tests were completed. Among respondents, 62% (200/321) understood the scope of prenatal screening tests, with 77% (251/326) and 76% (245/323) correctly interpreting low‐ and high‐risk test results, respectively. Only 26% (83/319) of participants had heard of NIPT. Chi‐square tests showed a higher proportion of these people were ≥40 years old (p‐value, <0.001), had post‐graduate education (p‐value, <0.001), or attended private clinics (p‐value <0.001). Over 91% (303/331) of participants said every pregnant person should be offered prenatal screening tests for aneuploidy and 88% (263/299) believed these should be free. While pregnant Irish individuals have reasonable understanding of screening test interpretation, most were unaware of screening options. Additionally, participants' views on availability and associated cost of tests show the need for a national prenatal screening program, including education on fetal aneuploidy. These findings have relevance for countries without screening policies and are pertinent for broader maternity services. [ABSTRACT FROM AUTHOR]

Objectives: The performance of non‐invasive prenatal screening using cell‐free DNA testing of maternal blood in twin pregnancy is underevaluated, while serum marker‐based strategies yield poor results. This study aimed to assess the performance of non‐invasive prenatal screening for trisomy 21 in twin pregnancy as a first‐tier test. Secondary objectives were to assess its failure rate and factors associated with failure. Methods: This retrospective cohort study included twin pregnancies in which non‐invasive prenatal screening using cell‐free DNA was performed as the primary screening strategy between May 2017 and October 2019. We used the NIPT VeriSeq® test for in‐vitro diagnosis and set a fetal fraction cut‐off of 4% for monochorionic pregnancies and 8% for dichorionic ones. Clinical data and pregnancy outcome were collected from physicians or midwives via a questionnaire or were retrieved directly on‐site. We calculated the performance of non‐invasive cell‐free DNA screening for trisomy 21, analyzed its failure rate and assessed potentially associated factors. Results: Among 1885 twin pregnancies with follow‐up, there were six (0.32%) confirmed cases of trisomy 21. The sensitivity of non‐invasive prenatal screening for trisomy 21 was 100% (95% CI, 54.1–100%) and the false‐positive rate was 0.23% (95% CI, 0.06–0.59%). The primary failure rate was 4.6%, with 4.0% being due to insufficient fetal fraction. A successful result was obtained for 65.4% of women who underwent a new blood draw, reducing the overall failure rate to 2.8%. Maternal body mass index, gestational age at screening as well as chorionicity were significantly associated with the risk of failure. Conclusion: This study provides further evidence of the high performance, at an extremely low false‐positive rate, of non‐invasive prenatal screening in twins as part of a primary screening strategy for trisomy 21. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Abstract Background Although the traditional contingent screening strategy is effective, there are still undetected low-risk trisomy 21. This study aims to define appropriate cut-off values of serum biochemical markers at low-risk and develop a strategy for sequential prenatal testing associated with first-trimester screening to increase the detection rate of trisomy 21. Methods This was a 9-year retrospective analysis of singleton pregnant women who underwent serum biochemical screening or combined first-trimester screening (CFTS) in the first trimester. For the low-risk group, the cut-off values of the serum biochemical markers were adjusted to determine the appropriate detection efficiency. Gravidas with abnormal serum biochemical markers at low-risk were advised to undergo further non-invasive prenatal screening (NIPS), whereas others continued with routine prenatal care. Results When cut-off values of free beta subunit of human chorionic gonadotropin (free β-hCG) multiples of the median (MoM) or pregnancy-associated plasma protein A (PAPP-A) MoM were defined with ≥ 2.75 or ≤ 0.5, 7.72% (2,194/28,405) in the serum biochemical screening group and 12.36% (4,005/32,403) in CFTS group could be detected as abnormal results for further NIPS. Finally, 55.56% (5/9) and 85.71% (6/7) of trisomy 21 cases with false-negative results were detected, and the overall detection rate for trisomy 21 was improved by 10.64% (5/47) and 12.77% (6/47), respectively. Conclusions The new contingent screening strategy can increase the detection rate of trisomy 21 compared with the traditional contingent screening strategy.

Background: Although the traditional contingent screening strategy is effective, there are still undetected low-risk trisomy 21. This study aims to define appropriate cut-off values of serum biochemical markers at low-risk and develop a strategy for sequential prenatal testing associated with first-trimester screening to increase the detection rate of trisomy 21. Methods: This was a 9-year retrospective analysis of singleton pregnant women who underwent serum biochemical screening or combined first-trimester screening (CFTS) in the first trimester. For the low-risk group, the cut-off values of the serum biochemical markers were adjusted to determine the appropriate detection efficiency. Gravidas with abnormal serum biochemical markers at low-risk were advised to undergo further non-invasive prenatal screening (NIPS), whereas others continued with routine prenatal care. Results: When cut-off values of free beta subunit of human chorionic gonadotropin (free β-hCG) multiples of the median (MoM) or pregnancy-associated plasma protein A (PAPP-A) MoM were defined with ≥ 2.75 or ≤ 0.5, 7.72% (2,194/28,405) in the serum biochemical screening group and 12.36% (4,005/32,403) in CFTS group could be detected as abnormal results for further NIPS. Finally, 55.56% (5/9) and 85.71% (6/7) of trisomy 21 cases with false-negative results were detected, and the overall detection rate for trisomy 21 was improved by 10.64% (5/47) and 12.77% (6/47), respectively. Conclusions: The new contingent screening strategy can increase the detection rate of trisomy 21 compared with the traditional contingent screening strategy. [ABSTRACT FROM AUTHOR]

For decades, prenatal screening and genetic testing strategies were limited, requiring less complex decisions. Recently, however, several new advanced technologies were introduced, including chromosomal microarray analysis (CMA) and non-invasive prenatal screening (NIPS), bringing about the need to choose the most appropriate testing for each pregnancy. A worrisome issue is that opposed to the wide implementation and debates over public funding of NIPS, currently invasive testing is still recommended only in selected pregnancies with increased risk for chromosomal aberrations (according to screening tests or sonographic anomalies). This current decision-making regarding public funding for invasive and screening testing might compromise informed consent and patient's autonomy. In this manuscript, we compare several characteristics of CMA vs. NIPS, namely: the accuracy and the diagnostic scope, the risks for miscarriage and for clinically uncertain findings, the timing for testing, and pretest counselling. We argue that it must be recognized that one size might not fit all, and suggest that both options should be presented to all couples through early genetic counseling, with public funding for the specific selected test. [ABSTRACT FROM AUTHOR]

Non‐invasive prenatal screening (NIPS) using cell‐free DNA is a screening test for fetal aneuploidy offered by a variety of prenatal healthcare providers. Guidelines for genetic screening consistently recommend that providers facilitate informed choices, which have been associated with better psychological and clinical outcomes than uninformed choices. The multidimensional measure of informed choice (MMIC) is a widely used and theory‐based measure that combines knowledge, values, and behavior to classify decisions as either informed or uniformed. We implemented a previously validated version of the MMIC for women offered NIPS to describe the choices made by women receiving prenatal care at the Vanderbilt University Medical Center. The survey included the Ottawa Decisional Conflict scale, an outcome measure used for validation of choice categorization. We found that most women (87%) made an informed choice about NIPS. Of the women categorized as uninformed, 67% had insufficient knowledge, and 33% had an attitude discordant with their decision. The vast majority of respondents (92.5%) underwent NIPS and had a positive attitude toward screening (94.3%). Ethnicity (p = 0.04) and education (p = 0.01) were found to be significantly associated with informed choice. Decisional conflict was extremely low among all participants, with only 5.6% of all participants demonstrating any form of decisional conflict, and all being categorized as having made an informed choice. This study suggests that pre‐test counseling by a genetic counselor results in high rates of informed choice and low‐decisional conflict amongst women offered NIPS by genetic counselors, though more research is required to determine if rates of informed choice remain high when NIPS is offered by other prenatal providers. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the theoretical added value of two types of non‐invasive prenatal screening (NIPS) expansions in pregnancies without major structural anomalies over the commonly used NIPS for chromosomes 13, 18, 21, X and Y (5‐NIPS) and to compare them with the added value of chromosomal microarray analysis (CMA). Methods: This was a retrospective cohort study based on CMA results of all pregnancies with normal ultrasound (including pregnancies with soft markers and with abnormal maternal serum screening) that had undergone amniocentesis between January 2013 to February 2022 and were registered in the database of the Rabin Medical Center genetic laboratory. We calculated the theoretical yield of 5‐NIPS and compared the added value of expanded 5‐NIPS for common microdeletions (1p36.3–1p36.2, 4p16.3–4p16.2, 5p15.3–5p15.1, 15q11.2–15q13.1 and 22q11.2) and genome‐wide NIPS (including variants > 5 Mb) with the added value of CMA in the overall cohort and in subgroups according to indication for invasive testing. Results: Among the 8605 examined pregnancies, 122 (1.4%) clinically significant CMA results were demonstrated. Of these, 44 (36.1%) were theoretically detectable on 5‐NIPS, with the rates of 1.56% in 642 pregnancies with abnormal maternal serum screening, 0.63% in 318 pregnancies with soft markers, 0.62% in 4378 women with advanced maternal age (≥ 35 years) and 0.15% in 3267 women younger than 35 years. In addition to aneuploidies detectable on 5‐NIPS, three (0.03%) cases detectable on 5‐NIPS expanded for common microdeletions and nine (0.10%) cases detectable on genome‐wide NIPS (excluding common microdeletions) were identified in the overall cohort. The added value of expanded NIPS tools over 5‐NIPS was significantly lower compared with that of CMA, for the overall cohort and subgroups. Conclusions: 5‐NIPS and even genome‐wide NIPS would miss 63.9% and 54.1% of clinically significant CMA findings, respectively. The added value of 5‐NIPS expanded to detect common microdeletions over 5‐NIPS is about 0.035%, and the overall added value of genome‐wide NIPS aimed at large CNVs is about 0.14%, both much lower compared with the added value of CMA (0.91%). These findings should assist healthcare practitioners in guiding couples towards informed decision‐making regarding the choice between prenatal invasive testing and NIPS. © 2023 International Society of Ultrasound in Obstetrics and Gynecology. Linked article: There is a comment on this article by Lei et al. Click here to view the Correspondence. [ABSTRACT FROM AUTHOR]

ObjectiveCell-free DNA (cfDNA) is a useful biomarker in various clinical contexts. Herein, we aimed to identify maternal characteristics and pregnancy outcomes associated with a failed NIPS test due to high cfDNA concentrations.MethodsA retrospective study of cases with high plasma cfDNA concentration in pregnant women in which NIPS test was performed (from 174,318 cases). We reported the detection of 126 cases (118 with complete clinical information) in which the high amount of cfDNA did not allow the performance of NIPS and study the possible causes of this result.Results622 (0.35%) of 174,318 pregnant women had failed the NIPS test, including 126 (20.3%) cases with high plasma cfDNA concentrations. The failed NIPS due to high plasma cfDNA concentrations was associated with maternal diseases and treatment with low-molecular-weight heparin (LMWH). Further follow-up of the 118 pregnant women in the case group revealed that the pregnancy outcomes included 31 premature deliveries, 21 abortions. The cfDNA concentrations of pregnant women with preterm deliveries were 1.15 (0.89, 1.84), which differed significantly from those who had full-term deliveries.ConclusionsAmong pregnant women with high cfDNA concentrations, systemic autoimmune diseases, pregnancy complications and LMWH were associated with increased incidence of failed NIPS test. High maternal cfDNA concentrations may not be associated with chromosomal abnormalities in the fetus. However, they should be alerted to the possibility of preterm births and stillbirths. Further clinical studies on pregnant women with high cfDNA concentrations are required.

Abstract Objective This study explores and discusses the possible factors affecting the positive predictive value (PPV) of non-invasive prenatal screening (NIPS) for the detection of fetal copy number variants (CNVs) in pregnant women. Methods NIPS was performed for 50,972 pregnant women and 212 cases were suspected as fetal CNVs. Post additional genetic counseling for these women, 96 underwent invasive prenatal diagnosis (amniocentesis), following which they received chromosomal microarray analysis (CMA). We analyzed the PPV of NIPS for the detection of fetal CNVs and the possible interference factors that could affect the PPV. Results Among the 96 pregnant women that received prenatal diagnosis by CMA, 37 cases were confirmed to be true positive for fetal CNVs with a PPV of 38.5%. There was no significant difference between the women with different NIPS indications. Five cases were reported as the false positive and false negative of fetal CNVs and the differences were mainly reflected in the inconsistency of chromosome fragments. Depending on the sizes of the CNVs, the PPVs were 48.7% for CNVs 10 Mb. Based on the chromosomal locations of CNVs, the PPV(4.8%) of the chromosomes of group C(including chromosomes 6 ~ 12), was lower than that of the other groups (41.2% ~ 66.7%) (p = 0.021). However, there were no significant differences in the CNV characteristics, fetal fractions, unique reads, and the Z-scores between these groups. Conclusion NIPS with a low-coverage sequencing depth has a certain effect on detection of fetal CNVs with the PPV of 38.5%. Chromosomal locations of CNVs may be the main factor that influences its effect. This study can contribute to an increased accuracy in genetic counseling and in predicting NIPS results that are positive for fetal CNVs.

Xiaosong Yuan, Xiaoya Han, Chenbo Jia, Wenbo Zhou, Bin Yu Department of Medical Genetics, Changzhou Maternal and Child Health Care Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou, People’s Republic of ChinaCorrespondence: Bin Yu, Email binyu@njmu.edu.cnObjective: To examine the association between low fetal fraction (FF) of cell free DNA determined at non-invasive prenatal screening (NIPS) and the subsequent risk of preterm birth in uncomplicated singleton pregnancy.Methods: We retrospectively interrogated NIPS System and hospitalization records from April 2018 to August 2019 and obtained results from 1521 consecutive and uncomplicated women with singleton pregnancy in which plasma FF of cell free DNA at NIPS had been investigated together with birth outcomes. We examined the association between FF and preterm birth (PTB) by regression analysis.Results: The incidence of preterm birth, low birthweight, and macrosomia in the study population was 5.06%, 2.89%, and 7.17%, respectively. FF at NIPS in the second to fourth quartiles (8.40– 11.07, 11.08– 13.70, and > 13.70%, respectively) was associated with higher gestational age at delivery relative to the lowest quartile (< 8.40%), with estimated mean increases of 0.27 weeks (95% CI: 0.05– 0.49), 0.29 weeks (95% CI: 0.06– 0.51), and 0.28 weeks (95% CI: 0.05– 0.51), respectively (P for trend = 0.027). Low FF (< the 5th percentile) was associated with an increased risk of PTB (adjusted OR: 2.23, 95% CI: 1.01– 4.98, P = 0.047) compared to normal FF (≥ the 5th and ≤ the 95th percentiles). In addition, when compared to women with normal FF and body mass index (BMI) < 25 at NIPS, the risk of early PTB (< 34 weeks gestation) was remarkably significantly higher among those with low FF and BMI ≥ 25 (adjusted OR: 6.29, 95% CI: 1.71– 23.15, P = 0.006).Conclusion: Our study supports the association of low FF at NIPS with PTB (especially early PTB) for uncomplicated singleton pregnancy.Keywords: preterm birth, cell-free fetal DNA, fetal fraction, non-invasive prenatal screening, birth outcomes

This article summarizes several Canadian court decisions from 2015 onward stemming from wrongful birth and wrongful life litigation. Plaintiff success often turns on whether causation is established, on a balance of probabilities, between a physician’s breach of standard of care and the harm to the parents and/or the child later born. Physicians’ failure to offer or order screening or diagnostic tests has been a source of wrongful birth liability, as too can be failure to ensure patient understanding of results. Physicians should ensure that they recommend diagnostic testing when presented with concerning clinical indications in accordance with professional practice guidance. Given non-invasive prenatal screening’s (NIPS) advantages and the threat of wrongful birth liability for failure to discuss this procedure, it is likely to be propelled into an ever more prominent position as a first-choice offering for aneuploidy screening. Appropriately cautious physician behaviour involves discussing and offering NIPS, and also involves ensuring that results are understood. This can reduce physician liability, improve patient reproductive autonomy, and sometimes benefit patient health by preventing or lessening trauma that informed women may opt to mitigate when granted the opportunity.

Many non‐invasive prenatal testing (NIPT) platforms screen for sex chromosome aneuploidy (SCA) and SCA analysis is generally included in Australia where NIPT is available as a self‐funded test. Little is known about the experience of receiving an NIPT result indicating an increased chance of SCA. This study aimed to explore the experiences of people who received this result and their perspectives on the information, care, and support they received from healthcare practitioners (HCPs). Semi‐structured interviews were conducted with people who received an NIPT result indicating an increased chance of SCA and continued their pregnancy. Most participants only had contact with a genetic counselor after receiving their result. Transcribed data were analyzed using rigorous thematic analysis to identify important patterns and themes. Participants (18 women, 2 male partners) described embarking on NIPT, primarily based on advice from their HCP and without much consideration. Consequently, participants expressed feeling unprepared for the unanticipated complexity of their NIPT result and were faced with making a time‐sensitive decision about a condition they had not previously considered. While more pre‐test information was desired, timely access to genetic counseling post‐test assisted with adjustment to the result. These findings suggest that routinization of NIPT may be compromising informed decision‐making, resulting in unpreparedness for an increased chance result. Given the increasing uptake and expanding scope of NIPT, resources should be dedicated to educating HCPs offering NIPT and ensuring timely access to genetic counseling post‐result. With appropriate funding, genetics services may be able to play a central role in offering information and support to both people who undertake NIPT and their HCPs ordering the testing. Implementing a publicly funded screening program in Australia could assist with standardizing prenatal screening care pathways and consequently better access to appropriate resources. [ABSTRACT FROM AUTHOR]

Non-invasive prenatal screening (NIPS) offers an opportunity to screen or determine features associated with the fetus. Earlier, prenatal testing was done with cytogenetic procedures like karyotyping or fluorescence in-situ hybridization, which necessitated invasive methods such as fetal blood sampling, chorionic villus sampling or amniocentesis. Over the last two decades, there has been a paradigm shift away from invasive prenatal diagnostic methods to non-invasive ones. NIPS tests heavily rely on cell-free fetal DNA (cffDNA). This DNA is released into the maternal circulation by placenta. Like cffDNA, fetal cells such as nucleated red blood cells, placental trophoblasts, leukocytes, and exosomes or fetal RNA circulating in maternal plasma, have enormous potential in non-invasive prenatal testing, but their use is still limited due to a number of limitations. Non-invasive approaches currently use circulating fetal DNA to assess the fetal genetic milieu. Methods with an acceptable detection rate and specificity such as sequencing, methylation, or PCR, have recently gained popularity in NIPS. Now that NIPS has established clinical significance in prenatal screening and diagnosis, it is critical to gain insights into and comprehend the genesis of NIPS de novo. The current review reappraises the development and emergence of non-invasive prenatal screen/test approaches, as well as their clinical application, with a focus, on the scope, benefits, and limitations.

The purpose of this study was to assess the additional contribution of karyotyping compared with genome-wide non-invasive prenatal testing (NIPT) for pregnancies at intermediate risk for trisomy 21 (T21), calculated using the maternal serum screening without major structural anomalies detected through sonography. Karyotype results of all pregnancies undergoing invasive prenatal diagnostic testing between January 2013 and March 2022 were obtained from a large hospital-based laboratory. Pregnancies with no major structural anomalies on ultrasound (including soft markers) and an intermediate risk for T21 on maternal serum screening were included in this study. The additional contribution of karyotyping for abnormal karyotype results was calculated after excluding results that could theoretically be identified with genome-wide NIPT. Among the 511 pregnancies analyzed, 13 (2.54%) were found to have abnormal karyotype results, 9 (1.76%) of which could theoretically have been detected with genome-wide NIPT. Within the cohort, 6/263 (2.28%) of women aged 35 years and older, and 3/248 (1.20%) of women younger than 35 years had results that could have been detected with genome-wide NIPT. After excluding results detectable using genome-wide NIPT, the additional contribution of karyotyping was found as 4/502 (0.79%) for the entire cohort, 2/257 (0.77%) for women aged 35 years and older, 2/245 (0.81%) for women younger than 35 years. Of the 511 examined pregnancies at intermediate risk for T21 by maternal serum screening, genome-wide NIPT would have failed to detect 4 of 13 abnormal karyotype results. The findings hold importance in guiding couples' informed decision-making processes regarding their choice of genetic screening and diagnostic testing in case of intermediate risk for T21., (© 2024 The Author(s). Journal of Genetic Counseling published by Wiley Periodicals LLC on behalf of National Society of Genetic Counselors.)

This study explored the diagnostic efficiency of different prenatal diagnostic approaches for women with positive non-invasive prenatal screening (NIPS) results by analyzing their clinical information and pregnancy outcomes. We collected data on 626 NIPS-positive pregnant women from January 2017 to June 2021 and arranged subsequent prenatal diagnostic operations for them after genetic counseling, along with long-term intensive follow-up. A total of 567 women accepted invasive prenatal diagnosis (IPD) (90.58%), and 262 cases were confirmed as true positives for NIPS. The positive predictive values for trisomies 21 (T21), 18 (T18), and 13 (T13); sex chromosome aneuploidies (SCAs); rare autosomal trisomies (RATs); and microdeletion and microduplication syndromes (MMS) were 81.13%, 37.93%, 18.42%, 48.83%, 18.37%, and 41.67%, respectively. Discordant results between NIPS and IPD were observed in 48 cases, with the discordance rate being 8.47%. Additionally, there were 43 cases with discordant results between karyotyping and chromosomal microarray analysis (CMA)/copy number variation sequencing. Additional reporting of RATs and MMS with routine NIPS that only detects T21/T18/T13 and SCAs can yield more accurate diagnoses. However, NIPS cannot be used as a substitute for IPD owing to its high false positive rate and discordance with other diagnostic methods. Therefore, we recommend CMA combined with karyotyping as the preferred method for accurately diagnosing NIPS-positive women. [ABSTRACT FROM AUTHOR]

Background and aims: X-linked ichthyosis (XLI) is a common recessive genetic disease caused by the deletion of steroid sulfatase (STS) in Xp22.31. Maternal copy-number deletions in Xp22.31 (covering STS) can be considered an incidental benefit of genome-wide cell-free DNA profiling. Here, we explored the accuracy and clinical value of maternal deletions in Xp22.31 during non-invasive prenatal screening (NIPS). Materials and methods: We evaluated 13,156 pregnant women who completed NIPS. The maternal deletions in Xp22.31 revealed by NIPS were confirmed with maternal white blood cells by chromosome microarray analysis (CMA) or copynumber variation sequencing (CNV-seq). Suspected positive women pregnant with male fetuses were informed and provided with prenatal genetic counseling. Results: Nineteen maternal deletions in Xp22.31 covering STS were detected by NIPS, which were all confirmed, ranging in size from 0.61 to 1.77 Mb. Among them, eleven women with deletions in male fetuses accepted prenatal diagnoses, and finally nine cases of XLI were diagnosed. The nine XLI males had differing degrees of skin abnormalities, and of them, some male members of ten families had symptoms associated with XLI. Conclusion: NIPS has the potential to detect clinically significant maternal X chromosomal CNVs causing XLI, which can guide the prenatal diagnosis of X-linked ichthyosis and reflect the family history, so as to enhance pregnancy management as well as children and family members' health management. [ABSTRACT FROM AUTHOR]

Partial tetrasomy of distal 13q has a reported association with a variable phenotype including microphthalmia, ear abnormalities, hypotelorism, facial dysmorphisms, urogenital defects, pigmentation and skin defects, and severe learning difficulties. A wide range of mosaicism has been reported, which may, to some extent, account for the variable spectrum of observed phenotypes. We report here a pregnancy conceived using intrauterine insemination in a 32-year-old female with a history of infertility. Noninvasive prenatal screening (NIPS) was performed in the first trimester which reported an increased risk for trisomy 13. Follow-up cytogenetic workup using chorionic villus sampling (CVS) and amniotic fluid samples showed a mosaic karyotype with a small supernumerary marker chromosome (sSMC). Chromosomal microarray analysis (CMA) identified a mosaic 31.34 Mb terminal gain on chr13q31.1q34 showing the likely origin of the sSMC to distal chromosome 13q. Follow-up metaphase FISH testing suggested an inverted duplication rearrangement involving 13q31q34 in the marker chromosome and the presence of a neocentromere. At 21 months of age, the proband has a history of gross motor delay, hypotonia, left microphthalmia, strabismus, congenital anomaly of the right optic nerve, hemangiomas, and a tethered spinal cord. Postnatal chromosome analyses in buccal, peripheral blood, and spinal cord ligament tissues were consistent with the previous amniocentesis and CVS findings, and the degree of mosaicism varied from 25 to 80%. It is often challenging to pinpoint the chromosomal identity of sSMCs using banding cytogenetics. A combination of low-pass genome sequencing of cell-free DNA, chromosomal microarray, and FISH enabled the identification of the precise chromosomal rearrangement in this patient. This study adds to the growing list of clinically identified neocentric marker chromosomes and is the first described instance of partial tetrasomy 13q31q34 identified in a mosaic state prenatally. Since NIPS is now being routinely performed along with invasive testing for advanced maternal age, an increased prenatal detection rate for mosaic sSMCs in otherwise normal pregnancies is expected. Future studies investigating how neocentromeres mediate gene expression changes could help identify potential epigenetic targets as treatment options to rescue or reverse the phenotypes seen in patients with congenital neocentromeres. [ABSTRACT FROM AUTHOR]

Objective: This study explores and discusses the possible factors affecting the positive predictive value (PPV) of non-invasive prenatal screening (NIPS) for the detection of fetal copy number variants (CNVs) in pregnant women.Methods: NIPS was performed for 50,972 pregnant women and 212 cases were suspected as fetal CNVs. Post additional genetic counseling for these women, 96 underwent invasive prenatal diagnosis (amniocentesis), following which they received chromosomal microarray analysis (CMA). We analyzed the PPV of NIPS for the detection of fetal CNVs and the possible interference factors that could affect the PPV.Results: Among the 96 pregnant women that received prenatal diagnosis by CMA, 37 cases were confirmed to be true positive for fetal CNVs with a PPV of 38.5%. There was no significant difference between the women with different NIPS indications. Five cases were reported as the false positive and false negative of fetal CNVs and the differences were mainly reflected in the inconsistency of chromosome fragments. Depending on the sizes of the CNVs, the PPVs were 48.7% for CNVs < 3 Mb, 41.4% for CNVs falling within 3 ~ 5 Mb, 42.9% for the CNVs falling within 5 ~ 10 Mb, and 14.3% for CNVs > 10 Mb. Based on the chromosomal locations of CNVs, the PPV(4.8%) of the chromosomes of group C(including chromosomes 6 ~ 12), was lower than that of the other groups (41.2% ~ 66.7%) (p = 0.021). However, there were no significant differences in the CNV characteristics, fetal fractions, unique reads, and the Z-scores between these groups.Conclusion: NIPS with a low-coverage sequencing depth has a certain effect on detection of fetal CNVs with the PPV of 38.5%. Chromosomal locations of CNVs may be the main factor that influences its effect. This study can contribute to an increased accuracy in genetic counseling and in predicting NIPS results that are positive for fetal CNVs. [ABSTRACT FROM AUTHOR]

This article summarizes several Canadian court decisions from 2015 onward stemming from wrongful birth and wrongful life litigation. Plaintiff success often turns on whether causation is established, on a balance of probabilities, between a physician's breach of standard of care and the harm to the parents and/or the child later born. Physicians' failure to offer or order screening or diagnostic tests has been a source of wrongful birth liability, as too can be failure to ensure patient understanding of results. Physicians should ensure that they recommend diagnostic testing when presented with concerning clinical indications in accordance with professional practice guidance. Given noninvasive prenatal screening's (NIPS) advantages and the threat of wrongful birth liability for failure to discuss this procedure, it is likely to be propelled into an ever more prominent position as a first-choice offering for aneuploidy screening. Appropriately cautious physician behaviour involves discussing and offering NIPS, and also involves ensuring that results are understood. This can reduce physician liability, improve patient reproductive autonomy, and sometimes benefit patient health by preventing or lessening trauma that informed women may opt to mitigate when granted the opportunity. [ABSTRACT FROM AUTHOR]

Partial tetrasomy of distal 13q has a reported association with a variable phenotype including microphthalmia, ear abnormalities, hypotelorism, facial dysmorphisms, urogenital defects, pigmentation and skin defects, and severe learning difficulties. A wide range of mosaicism has been reported, which may, to some extent, account for the variable spectrum of observed phenotypes. We report here a pregnancy conceived using intrauterine insemination in a 32-year-old female with a history of infertility. Non-invasive prenatal screening (NIPS) was performed in the first trimester which reported an increased risk for trisomy 13. Follow-up cytogenetic workup using chorionic villus sampling (CVS) and amniotic fluid samples showed a mosaic karyotype with a small supernumerary marker chromosome (sSMC). Chromosomal microarray analysis (CMA) identified a mosaic 31.34 Mb terminal gain on chr13q31.1q34 showing the likely origin of the sSMC to distal chromosome 13q. Follow-up metaphase FISH testing suggested an inverted duplication rearrangement involving 13q31q34 in the marker chromosome and the presence of a neocentromere. At 21 months of age, the proband has a history of gross motor delay, hypotonia, left microphthalmia, strabismus, congenital anomaly of the right optic nerve, hemangiomas, and a tethered spinal cord. Postnatal chromosome analyses in buccal, peripheral blood, and spinal cord ligament tissues were consistent with the previous amniocentesis and CVS findings, and the degree of mosaicism varied from 25 to 80%. It is often challenging to pinpoint the chromosomal identity of sSMCs using banding cytogenetics. A combination of low-pass genome sequencing of cell-free DNA, chromosomal microarray, and FISH enabled the identification of the precise chromosomal rearrangement in this patient. This study adds to the growing list of clinically identified neocentric marker chromosomes and is the first described instance of partial tetrasomy 13q31q34 identified in a mosaic state prenatally. Since NIPS is now being routinely performed along with invasive testing for advanced maternal age, an increased prenatal detection rate for mosaic sSMCs in otherwise normal pregnancies is expected. Future studies investigating how neocentromeres mediate gene expression changes could help identify potential epigenetic targets as treatment options to rescue or reverse the phenotypes seen in patients with congenital neocentromeres.

The implementation of a new technology is one step in the translation of a discovery into a clinical application. Numerous models have been proposed to study such translation; Goering, Holland and Kelley’s model puts forward priorities that resonate with bioethics. We propose the application of a tool from the implementation sciences, the Consolidated Framework for Implementation Research (CFIR), to identify the ethical issues of a new technology. This tool is designed to identify the barriers and facilitators to the implementation of a technology and is therefore part of the translational research model. An example is the non-invasive prenatal genomic test (NIPGT). This test is offered in some provinces in Canada as a second-line test for pregnant persons with a high probability of having a fetus with aneuploidy. Potential innovations of NIPGT are to offer it as a first-line test and to expand the number of genetic conditions screened. We thus propose to use CFIR to identify the ethical issues that arise from the barriers and facilitators to these innovations in NIPGT. By identifying barriers and facilitators to the implementation of a technology, this tool allows bioethicists to use a proven tool from another discipline to study ethical issues. Bioethicists can then turn to their traditional tools to identify the ethical issues raised by these elements. Our proposal is just one example of what this approach can accomplish: identifying ethical issues in a new technology in an innovative way. [ABSTRACT FROM AUTHOR]

This study was performed to assess the association between detection of rare autosomal trisomies (RATs) by non‐invasive prenatal screening (NIPS) and adverse pregnancy outcomes. We retrospectively analyzed women with high‐risk RATs results from January 2014 to December 2020. The women's clinical information was collected, and their pregnancy outcomes were compared with those of women with low‐risk results. In total, 151 (0.24%) RATs results were reported among 62,752 NIPS examinations. Sixty‐five women chose to undergo amniocentesis for confirmation, which revealed 3 cases of true fetal mosaicism for RATs and a positive predictive value of 4.6% (3/65). Among the 139 women with available outcomes, 26 (18.7%) had a preterm birth, 10 (7.2%) underwent pregnancy termination because of fetal defects and 5 (3.6%) had miscarriages. Interestingly, compared with the control group, pregnancies in which NIPS revealed trisomy 16 (T16), T22, T9 and T2 were at higher risk of adverse outcomes, including preterm birth, miscarriage and ultrasound abnormalities. However, the risk of adverse outcomes was comparable between the control group and pregnancies with positive results of T7, T3, T8 and T20. In summary, the risk of adverse pregnancy outcomes was higher in women with specific RATs‐positive NIPS results. Pregnancies with T16, T22, T9 and T2 results, even if false‐positive, should be considered high‐risk pregnancies. [ABSTRACT FROM AUTHOR]

ObjectiveTo determine the effects of alanine transaminase (ALT) levels on the screening failure rates or “no calls” due to low fetal fraction (FF) to obtain a result in non-invasive prenatal screening (NIPS).MethodsNIPS by sequencing and liver enzyme measurements were performed in 7,910 pregnancies at 12–26 weeks of gestation. Univariate and multivariable regression models were used to evaluate the significant predictors of screening failure rates among maternal characteristics and relevant laboratory parameters.ResultsOf the 7,910 pregnancies that met the inclusion criteria, 134 (1.69%) had “no calls.” Multiple logistic regression analysis demonstrated that increased body mass index, ALT, prealbumin, albumin levels, and in vitro fertilization (IVF) conception rates were independently associated with screening failures. The test failure rate was higher (4.34 vs. 1.41%; P < 0.001) in IVF pregnancies relative to those with spontaneous conceptions. Meanwhile, the screening failure rates increased with increasing ALT levels from 1.05% at ≤10 U/L to 3.73% at >40 U/L. In particular, IVF pregnancies with an ALT level of >40 U/L had a higher test failure rate (9.52%). Compared with that for an ALT level of ≤10 U/L, the adjusted odds ratio of “no calls” for ALT levels of 10–20, 21–40, and >40 U/L was 1.204 [95% confidence interval (CI), 0.709–2.045], 1.529 (95% CI, 0.865–2.702), and 2.764 (95% CI, 1.500–5.093) (Ptrend < 0.001), respectively.ConclusionsIncreased ALT and IVF conceptions were associated with a higher screening failure rates in NIPS. Therefore, a feasible strategy to adjust these factors to reduce the probability of “no calls” due to low FF would be of great clinical significance.

• To guarantee the NIPS reproducibility in laboratories. • Performance validation, enrichment operations, and reporting content should be standardized. Non-invasive prenatal screening (NIPS) has been introduced as a routine screening technique for aneuploidies in the clinic. To evaluate its reliability and reporting standardization, the National Center for Clinical Laboratories launched an external quality assessment (EQA) program based on highly simulated samples. Maternal and child paired cell lines were digested by enzymes to obtain DNA fragments for the analysis panel, which were composed of 5% T21, 5% T18, 10% T13, 10% euploid, and 20% T18 samples. The samples were validated and distributed to laboratories along with scenarios and questionnaires for analysis. Out of 350 participating laboratories, 98.6% correctly identified all samples. The concurrence rates of laboratories for the 5% T21, 5% T18, 10% T13, 10% euploid, and 20% T18 samples were 98.9%, 99.7%, 99.7%, 100%, and 100%, respectively. Enrichment increased the foetal fraction (FF) values by 2 ∼ 3-fold, but the z scores generated by the enrichment group fluctuated greatly. Other FF estimation techniques, such as the size-based and FF-QuantSC methods, generated slightly different FF values from the chr Y-based method. Furthermore, some laboratories omitted the suggestions of results in reports. The participating laboratories provided highly reliable results for samples with relatively higher FF values. However, the absence of performance validation, laboratory errors, and low FF values were potential reasons for false-negative results. In addition, enrichment operations should be validated and normalized to guarantee NIPS reproducibility, plus further efforts are required to standardize the NIPS reports. [ABSTRACT FROM AUTHOR]

Prenatal screening is an important issue during pregnancy to ensure fetal and maternal health, as well as preventing the birth of a defective fetus and further problems such as extra costs for the family and society. The methods for the screening have progressed to non-invasive approaches over the recent years. Limitations of common standard screening tests, including invasive sampling, high risk of abortion and a big delay in result preparation have led to the introduction of new rapid and non-invasive approaches for screening. Non-invasive prenatal screening includes a wide range of procedures, including fetal cell-free DNA analysis, proteome, RNAs and other fetal biomarkers in maternal serum. These biomarkers require less invasive sampling than usual methods such as chorionic villus sampling, amniocentesis or cordocentesis. Advanced strategies including the development of nanobiosensors and the use of special nanoparticles have provided optimization and development of NIPS tests, which leads to more accurate, specific and sensitive screening tests, rapid and more reliable results and low cost, as well. This review discusses the specifications and limitations of current non-invasive prenatal screening tests and introduces a novel collection of detection methods reported studies on nanoparticles' aided detection. It can open a new prospect for further studies and effective investigations in prenatal screening field. [ABSTRACT FROM AUTHOR]

Introduction: Non-invasive prenatal testing (NIPT) allows for genetic testing of a fetus through the analysis of cell-free DNA from the mother's plasma. NIPT is easy and safe for the fetus, since it only requires a blood draw from the mother and therefore holds no risk of miscarriage. It is considered superior to other prenatal screening tests and can also be performed earlier in the pregnancy. NIPT has the future potential for fetal whole genome sequencing (FWGS) for an expanded range of conditions, such as late onset genetic conditions and carrier status. Objective: To review ethical, legal, social, and policy implications of the potential use of non-invasive prenatal testing for FWGS. Methods: This study is a critical interpretive literature review exploring and reporting ethical, legal, social, and policy implications of potential future implementation of NIPT for FWGS, which will be referred to as non-invasive prenatal whole genome sequencing (NIPW). Database and reference list searching was conducted between 2010 and 2019 for terms related to "non-invasive prenatal testing" AND "fetal whole genome sequencing" and derivatives. Results: Following screening, 32 articles were included. Data were grouped into four thematic categories: 1) ethical implications for the future child concerning autonomy and harms, as well as for prospective parents involving autonomy, informed consent concerns, and harms; 2) legal implications including privacy concerns; 3) social implications including changes in family dynamics, altered societal perceptions and disability concerns, justice and equity in accessing the test, and social pressure to use the test; and 4) policy implications including cost and funding concerns, limiting the scope of testing, as well as counseling, education, and support. Discussion: The discussion of results highlights several ethical, legal, social, and policy implications of NIPT use for FWGS. These findings have implications on NIPT implementation for FWGS including how the autonomy of the future child should be balanced with the autonomy of prospective parents, the scope of conditions that should or should not be tested for - and covered or not covered by the healthcare system - and the regulation of FWGS introduction, among others. Further research needs to be performed to address these concerns and hence guide the discussion about the clinical implementation of FWGS through NIPT. [ABSTRACT FROM AUTHOR]

Abstract Background Non-invasive prenatal testing (NIPT) using cell-free fetal DNA in maternal plasma is a high accurate test for prenatal screening for Down syndrome. Although it has been reported to be cost effective as a contingent test, evidence about its budget impact is lacking. Objective To evaluate, using computer simulations, the budget impact of implementing NIPT as a contingent test in the Quebec Program of screening for Trisomy 21. Methods A semi-Markov analytic model built to simulate the budget impact of implementing NIPT into the current Quebec Trisomy 21 public Prenatal Screening, Serum Integrated prenatal screening (SIPS). Comparisons were made for a virtual population similar to that of expected Quebec pregnant women in 2015 in terms of size and age. Data input parameters were retrieved from a thorough literature search and in government databases, especially data from Quebec Program of screening for Trisomy 21. The 2015–2016 fiscal year budget impact was estimated from the Quebec healthcare system perspective and was expressed as the difference in the overall costs between the two alternatives (SIPS minus SPS + NIPT). Results Our study found that, at a baseline cost for NIPT of CAD$ 795, NIPT as a second-tier test offered to high-risk women identified by current screening program (SIPS + NIPT) may be affordable for Quebec health care system. Compared to the current screening program, it would be implemented at a neutral cost, considering a modest annual savings of $ 80,432 (95% CI $ 79, $ 874–$ 81,462). Results were sensitive to the NIPT costs and the uptake-rate of invasive diagnostic tests. Conclusion Introducing NIPT as a contingent test in the Quebec Trisomy 21 screening program is an affordable strategy compared to the current practice. Further research is needed to confirm if our results can be reproduced in other healthcare jurisdictions.

Abstract Background Non-invasive prenatal testing (NIPT) has revolutionized the prenatal screening landscape with its high accuracy and low false positive rate for detecting Trisomy 21, 18 and 13. Good understanding of its benefits and limitations is crucial for obstetricians to provide effective counselling and make informed decisions about its use. This study aimed to evaluate obstetrician knowledge and attitudes regarding NIPT for screening for the common trisomies, explore how obstetricians integrated NIPT into first-line and contingent screening, and determine whether expanded use of NIPT to screen for sex chromosome aneuploidies (SCAs) and microdeletion/microduplication syndromes (CNVs) was widespread. Methods A questionnaire was designed and administered with reference to the CHERRIES criteria for online surveys. Doctors on the Obstetrics & Gynaecology trainee and specialist registers were invited to participate. Medians and 95% confidence intervals (CI) were reported for confidence and knowledge scores. Results 94/306 (30.7%) doctors responded to the survey. First trimester screening (FTS) remained the main method offered to screen for the common trisomies. 45.7% (43/94) offered NIPT as an alternative first-line screen for singletons and 30.9% (29/94) for monochorionic diamniotic twins. A significant proportion offered concurrent NT and NIPT (25/94, 26.6%), or FTS and NIPT (33/94, 35.1%) in singletons. Varying follow up strategies were offered at intermediate, high and very-high FTS risk cut-offs for Trisomy 21. Respondents were likely to offer screening for SCAs and CNVs to give patients autonomy of choice (53/94, 56.4% SCAs, 47/94, 50% CNVs) at no additional cost (52/94, 55.3% SCAs, 39/94, 41.5% CNVs). Median clinical knowledge scores were high (10/12) and did not differ significantly between specialists (95% CI 10–11) and non-specialists (95% CI 9.89–11). Lower scores were observed for scenarios in which NIPT would be more likely to fail. Conclusions Our findings show the diversity of clinical practice with regard to the incorporation of NIPT into prenatal screening algorithms, and suggest that the use of NIPT both as a first-line screening tool in the general obstetric population, and to screen for SCAs and CNVs, is becoming increasingly prevalent. Clear guidance and continuing educational support are essential for providers in this rapidly evolving field.

Introduction: Non-invasive prenatal testing (NIPT) allows for genetic testing of a fetus through the analysis of cell-free DNA from the mother’s plasma. NIPT is easy and safe for the fetus, since it only requires a blood draw from the mother and therefore holds no risk of miscarriage. It is considered superior to other prenatal screening tests and can also be performed earlier in the pregnancy. NIPT has the future potential for fetal whole genome sequencing (FWGS) for an expanded range of conditions, such as late onset genetic conditions and carrier status. Objective: To review ethical, legal, social, and policy implications of the potential use of non-invasive prenatal testing for FWGS. Methods: This study is a critical interpretive literature review exploring and reporting ethical, legal, social, and policy implications of potential future implementation of NIPT for FWGS, which will be referred to as non-invasive prenatal whole genome sequencing (NIPW). Database and reference list searching was conducted between 2010 and 2019 for terms related to “non-invasive prenatal testing” AND “fetal whole genome sequencing” and derivatives. Results: Following screening, 32 articles were included. Data were grouped into four thematic categories: 1) ethical implications for the future child concerning autonomy and harms, as well as for prospective parents involving autonomy, informed consent concerns, and harms; 2) legal implications including privacy concerns; 3) social implications including changes in family dynamics, altered societal perceptions and disability concerns, justice and equity in accessing the test, and social pressure to use the test; and 4) policy implications including cost and funding concerns, limiting the scope of testing, as well as counseling, education, and support. Discussion: The discussion of results highlights several ethical, legal, social, and policy implications of NIPT use for FWGS. These findings have implications on NIPT implementation for FWGS including how the autonomy of the future child should be balanced with the autonomy of prospective parents, the scope of conditions that should or should not be tested for – and covered or not covered by the healthcare system – and the regulation of FWGS introduction, among others. Further research needs to be performed to address these concerns and hence guide the discussion about the clinical implementation of FWGS through NIPT.

Introduction: The presence of an unbalanced familial translocation can be reliably assessed in the cytotrophoblast of chorionic villi. However, carriers of a balanced translocation often decline invasive testing. This study aimed to investigate whether an unbalanced translocation can also be diagnosed in cell free DNA by whole‐genome non‐invasive prenatal screening (NIPS). Material and methods: Pregnant women carrying a fetus with an unbalanced familial translocation, for whom NIPS as well as microarray data were available, were included in this retrospective assessment. NIPS was performed in the course of the TRIDENT study. Results: In 12 cases, both NIPS and microarray data were available. In 10 of 12 cases the unbalanced translocation was correctly identified by NIPS without prior knowledge on parental translocation. One was missed because the fetal fraction was too low. One was missed because of technical restrictions in calling 16p gains. Conclusions: This study supports the hypothesis that routine NIPS may be used for prenatal diagnosis of unbalanced inheritance of familial translocations, especially with prior knowledge of the translocation allowing focused examination of the involved chromosomal regions. Our study showed that routine shallow sequencing designed for aneuploidy detection in cell free DNA may be sufficient for higher resolution NIPS, if specialized copy number software is used and if sufficient fetal fraction is present. [ABSTRACT FROM AUTHOR]

The increasing prevalence of advanced paternal age (APA) has mirrored the rise in maternal age. APA is associated with an increased risk of de novo pathogenic single-nucleotide variants, but this topic has been much less frequently discussed than advanced maternal age (AMA). To explore the awareness of pregnant women regarding paternal age effect (PAE) disorders, a self-administered questionnaire survey was conducted for pregnant women at their first prenatal visit before 17 weeks of gestation. A total of 120 valid respondents (95.2%) were included in the analyses. Of these, 63.3% of pregnant women were aware of PAE disorders. This was markedly lower than the 90.8% recognition of maternal age effect (MAE) disorders. One-third of women with awareness of MAE disorders were not aware of PAE disorders. Pregnant women who were parous, older than their male partners, with knowledge of prenatal testing prior to this pregnancy, and with experience of prenatal testing in a prior pregnancy were significantly more aware of PAE disorders than others. Awareness of PAE disorders was not associated with undergoing prenatal testing during the present pregnancy. Our results show that the prevalence of pregnant women's awareness of PAE disorders was lower than that of MAE disorders. The current study served as a preliminary baseline of information about pregnant women's awareness of PAE disorders. With the introduction of non-invasive prenatal testing, which has the potential to identify PAE disorders, these findings will help the development of a framework for comprehensive prenatal genetic counseling for APA pregnancies. [ABSTRACT FROM AUTHOR]

Introduction: Following the wide distribution of non-invasive prenatal genetic screening (NIPS), numerous studies have reported a decline in total invasive tests in the recent years, up to 50–70% in some countries. However, in Denmark and Israel we have not experienced these declines. The objective of our study was to evaluate the trends in NIPS and chromosomal microarray analysis (CMA) use in Denmark and Israel.Methods: This retrospective study was performed by data acquisition from the Danish Cytogenetics Central Registry throughout the years 2000–2019, and Israeli Public Health Services, Ministry of Health computerized database (from 2011).Results: Of the 1,243,956 live births registered in Denmark over the years 2000–2019, a relatively steady level of invasive testing around 6% was noted since 2004, as opposed to 13.0% in Israel based on 1,594,962 live births between 2011 and 2019. The average uptake of NIPS was 1.1 ± 0.5% in Denmark vs. 4.3% in Israel (2013–2019). Relatively steady rates of invasive testing were noted in both countries, compared to a slight decline in NIPS in the recent years.Discussion: The recent decrease in the rates of invasive testing in the NIPS era was not observed in Denmark or in Israel. These results imply that Danish and Israeli women and/or health providers might favor the high resolution and yield of CMA testing over the non-invasiveness of NIPS. We explore and discuss this phenomenon, based on five central factors.

ObjectiveTo evaluate the effectiveness of non-invasive prenatal screening (NIPS) in prenatal screening of fetal pathogenic copy number variants (CNVs).Materials and MethodsWe evaluated the prenatal screening capacity using traditional and retrospective approaches. For the traditional method, we evaluated 24,613 pregnant women who underwent NIPS; cases which fetal CNVs were suggested underwent prenatal diagnosis with chromosomal microarray analysis (CMA). For the retrospective method, we retrospectively evaluated 47 cases with fetal pathogenic CNVs by NIPS. A systematic literature search was performed to compare the evaluation efficiency.ResultsAmong the 24,613 pregnant women who received NIPS, 124 (0.50%) were suspected to have fetal CNVs. Of these, 66 women underwent prenatal diagnosis with CMA and 13 had true-positive results. The positive predictive value (PPV) of NIPS for fetal CNVs was 19.7%. Among 1,161 women who did not receive NIPS and underwent prenatal diagnosis by CMA, 47 were confirmed to have fetal pathogenic CNVs. Retesting with NIPS indicated that 24 of these 47 cases could also be detected by NIPS, representing a detection rate (DR) of 51.1%. In total, 10 publications, namely, six retrospective studies and four prospective studies, met our criteria and were selected for a detailed full-text review. The reported DRs were 61.10–97.70% and the PPVs were 36.11–80.56%. The sizes of CNVs were closely related to the accuracy of NIPS detection. The DR was 41.9% (13/31) in fetuses with CNVs ≤ 3 Mb, but was 55.0% (11/20) in fetuses with CNVs > 3 Mb. Finally, to intuitively show the CNVs accurately detected by NIPS, we mapped all CNVs to chromosomes according to their location, size, and characteristics. NIPS detected fetal CNVs in 2q13 and 4q35.ConclusionThe DR and PPV of NIPS for fetal CNVs were approximately 51.1% and 19.7%, respectively. Follow-up molecular prenatal diagnosis is recommended in cases where NIPS suggests fetal CNVs.

Introduction: To evaluate the effect of repeating test failures using an automated, non-sequencing based non-invasive prenatal testing test on a general-risk population in Finland.Material and Methods: A total of 545 samples from women who represent the average-risk population in Oulu, Finland were analyzed with Vanadis® non-invasive prenatal testing. Repeat testing of test failures was performed using a second sample. Results before and after repeat testing were compared with the reference outcome, as determined by clinical examination of neonates.Results: There were eight test failures after first-pass analysis, representing 1.5% of samples (95% CI 0.6%-2.9%). Seven out of eight failures could be resolved by analysis of a second sample, thereby reducing the test failure rate from 1.5% to 0.2% (95% CI 0.0%-1.0%).Conclusions: Repeating test failures with a second plasma sample could significantly reduce the effective failure rate, thereby providing a way to effectively minimize test failures and further improving clinical utility and test performance. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effectiveness of non-invasive prenatal screening (NIPS) in prenatal screening of fetal pathogenic copy number variants (CNVs). Materials and Methods: We evaluated the prenatal screening capacity using traditional and retrospective approaches. For the traditional method, we evaluated 24,613 pregnant women who underwent NIPS; cases which fetal CNVs were suggested underwent prenatal diagnosis with chromosomal microarray analysis (CMA). For the retrospective method, we retrospectively evaluated 47 cases with fetal pathogenic CNVs by NIPS. A systematic literature search was performed to compare the evaluation efficiency. Results: Among the 24,613 pregnant women who received NIPS, 124 (0.50%) were suspected to have fetal CNVs. Of these, 66 women underwent prenatal diagnosis with CMA and 13 had true-positive results. The positive predictive value (PPV) of NIPS for fetal CNVs was 19.7%. Among 1,161 women who did not receive NIPS and underwent prenatal diagnosis by CMA, 47 were confirmed to have fetal pathogenic CNVs. Retesting with NIPS indicated that 24 of these 47 cases could also be detected by NIPS, representing a detection rate (DR) of 51.1%. In total, 10 publications, namely, six retrospective studies and four prospective studies, met our criteria and were selected for a detailed full-text review. The reported DRs were 61.10–97.70% and the PPVs were 36.11–80.56%. The sizes of CNVs were closely related to the accuracy of NIPS detection. The DR was 41.9% (13/31) in fetuses with CNVs ≤ 3 Mb, but was 55.0% (11/20) in fetuses with CNVs > 3 Mb. Finally, to intuitively show the CNVs accurately detected by NIPS, we mapped all CNVs to chromosomes according to their location, size, and characteristics. NIPS detected fetal CNVs in 2q13 and 4q35. Conclusion: The DR and PPV of NIPS for fetal CNVs were approximately 51.1% and 19.7%, respectively. Follow-up molecular prenatal diagnosis is recommended in cases where NIPS suggests fetal CNVs. [ABSTRACT FROM AUTHOR]

To evaluate the clinical efficiency of non-invasive prenatal screening (NIPS) for fetal aneuploidies in low-risk and twin pregnancies, patients who received NIPS in a tertiary university hospital were enrolled, and their clinical data, NIPS results and pregnancy outcomes were collected. Patients were divided into singleton and twin pregnancies, and then those with singleton pregnancies were divided into low- and high-risk pregnancies. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were estimated. Comparisons were made on the clinical efficiency of NIPS between singleton and twin pregnancies, as well as between low- and high-risk pregnancies. Of 66,172 patients enrolled, 59,962 were eligible for analysis. The sensitivity, specificity and NPV were ≥ 99% in singleton and twin pregnancies. The PPVs were 90.4, 56.6, and 13.0% in singleton pregnancies, while 100, 33.3, and 0% in twin pregnancies for trisomy 21 (T21), trisomy 18 (T18) and trisomy 13 (T13), respectively (P > 0.05 for all). The PPVs were 97.4 and 90.0% in high-risk pregnancies, while 78.6 and 16.7% in low-risk pregnancies for T21 and T18, respectively (P < 0.05 for all). In summary, the performance of NIPS in singleton pregnancies was similar to that in twin pregnancies. NIPS can be recommended for all pregnancies regardless of the risks.

BackgroundOur aim was to provide a theoretical basis for clinicians to conduct genetic counseling and choose further prenatal diagnosis methods for pregnant women who failed non-invasive prenatal screening (NIPS).MethodsA retrospective analysis was performed on pregnant women who had failed NIPS tests.ResultsAmong the 123,291 samples, 394 pregnant women did not obtain valid results due to test failures. A total of 378 pregnant women were available for follow-up, while 16 patients were lost to follow-up. Of these 378, 135 pregnant women chose further prenatal diagnosis through amniocentesis, and one case of dysplasia was recalled for postpartum chromosome testing. The incidence rate of congenital chromosomal abnormalities in those who failed the NIPS was 3.97% (15/378), which was higher than that of the chromosomal abnormalities in the common population (1.8%). Among the pregnant women who received prenatal diagnosis, the positive rates of chromosomal abnormalities in the chromosomal microarray analysis/copy number variation sequencing (CMA/CNV-seq) group and in the karyotyping group were 15.28 and 4.76%, respectively.ConclusionPrenatal diagnosis should be strongly recommended in posttest genetic counseling for pregnant women with NIPS failures. Further, high-resolution detection methods should be recommended for additional prenatal diagnoses.

Background: Our aim was to provide a theoretical basis for clinicians to conduct genetic counseling and choose further prenatal diagnosis methods for pregnant women who failed non-invasive prenatal screening (NIPS). Methods: A retrospective analysis was performed on pregnant women who had failed NIPS tests. Results: Among the 123,291 samples, 394 pregnant women did not obtain valid results due to test failures. A total of 378 pregnant women were available for follow-up, while 16 patients were lost to follow-up. Of these 378, 135 pregnant women chose further prenatal diagnosis through amniocentesis, and one case of dysplasia was recalled for postpartum chromosome testing. The incidence rate of congenital chromosomal abnormalities in those who failed the NIPS was 3.97% (15/378), which was higher than that of the chromosomal abnormalities in the common population (1.8%). Among the pregnant women who received prenatal diagnosis, the positive rates of chromosomal abnormalities in the chromosomal microarray analysis/copy number variation sequencing (CMA/CNV-seq) group and in the karyotyping group were 15.28 and 4.76%, respectively. Conclusion: Prenatal diagnosis should be strongly recommended in posttest genetic counseling for pregnant women with NIPS failures. Further, high-resolution detection methods should be recommended for additional prenatal diagnoses. [ABSTRACT FROM AUTHOR]

To evaluate the clinical efficiency of non-invasive prenatal screening (NIPS) for fetal aneuploidies in low-risk and twin pregnancies, patients who received NIPS in a tertiary university hospital were enrolled, and their clinical data, NIPS results and pregnancy outcomes were collected. Patients were divided into singleton and twin pregnancies, and then those with singleton pregnancies were divided into low- and high-risk pregnancies. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were estimated. Comparisons were made on the clinical efficiency of NIPS between singleton and twin pregnancies, as well as between low- and high-risk pregnancies. Of 66,172 patients enrolled, 59,962 were eligible for analysis. The sensitivity, specificity and NPV were ≥ 99% in singleton and twin pregnancies. The PPVs were 90.4, 56.6, and 13.0% in singleton pregnancies, while 100, 33.3, and 0% in twin pregnancies for trisomy 21 (T21), trisomy 18 (T18) and trisomy 13 (T13), respectively (P > 0.05 for all). The PPVs were 97.4 and 90.0% in high-risk pregnancies, while 78.6 and 16.7% in low-risk pregnancies for T21 and T18, respectively (P < 0.05 for all). In summary, the performance of NIPS in singleton pregnancies was similar to that in twin pregnancies. NIPS can be recommended for all pregnancies regardless of the risks. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the utility of expanded non-invasive prenatal screening (NIPS), compared with chromosomal microarray analysis (CMA), for the detection of chromosomal abnormalities in high-risk pregnancies.Methods: This was a multicenter retrospective study of singleton pregnancies at high risk for chromosomal abnormality. Patients who underwent expanded NIPS and CMA sequentially during pregnancy from 2015 to 2019 were included in the analysis. Pregnancies with a positive result for sex chromosome aneuploidy were excluded as the full details could not be retrieved. The utility of expanded NIPS and CMA for detection of chromosomal abnormalities in this cohort was compared by assessing the concordance between the results.Results: Of the 774 included high-risk pregnancies, 550 (71.1%) had a positive NIPS result, while a positive CMA result was detected in 308 (39.8%) cases. The rate of full or partial concordance between NIPS and CMA was 82.2%, 59.6% and 25.0% for trisomies 21, 18 and 13, respectively. For rare aneuploidies and segmental imbalances, NIPS and CMA results were fully or partially concordant in 7.5% and 33.3% of cases, respectively. Copy-number variants < 5 Mb were detected more often by CMA, with an incidence of 7.9% (61/774) compared with 3.1% (24/774) by NIPS. A genetic aberration was detected by CMA in 1 in 17 (5.8%) high-risk pregnancies that had a negative or non-reportable NIPS result.Conclusion: CMA allows for comprehensive detection of genome-wide chromosomal abnormalities in high-risk pregnancies. CMA should be offered instead of expanded NIPS for high-risk pregnancies. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

Non-invasive prenatal screening provides a risk assessment for aneuploidies by utilizing cell-free DNA (cfDNA). It is recommended that cell-free DNA screening (cfDNA screening) be offered to all pregnant people regardless of a priori risk for aneuploidy. In the absence of an increased risk, alternative motives for electing cfDNA screening and different levels of informed decision making may arise. Therefore, our study aimed to characterize low-risk patients' motivations for cfDNA screening election, determine how often informed decisions are being made, and compare motivations between informed and uninformed decision makers. A survey that included a modified, validated measure of informed choice (MMIC) and questions to assess patients' motivations for cfDNA screening was offered at four MFM clinics following genetic counseling. It was found that 44% of participants (n = 100) made an uninformed decision about testing. Participants with private insurers were 4.25 times more likely to make an informed decision (95% CI = 1.10-16.37). Informed decision makers scored avoiding invasive procedures higher (p = 0.007) and ranked doing what family/friends desire lower (p = 0.005) than uninformed decision makers. While most participants scored receiving information about genetic conditions highest, 12% of participants reported fetal sex disclosure as a priority. However, this was not found to be associated with uninformed decision making. This study ultimately established that following genetic counseling, a low-risk population shared motivations with high-risk populations which highlights the importance of complete pre-test counseling for all. Future research should investigate the effect of modifying variables, such as socioeconomic status, on the performance of informed choice measures and critically evaluate the parameters that determine informed choice., (© 2024 National Society of Genetic Counselors.)

Abstract Background The non‐invasive prenatal screening (NIPS) has been introduced into clinical practice with a high sensitivity and specificity. Although the false‐negative results are inevitable and important, limited false‐negative NIPS results have been reported and studied previously. In this study, we aim to report and analyze false‐negative results detected in the NIPS cases with a low‐risk result. Methods NIPS was performed using whole‐genome massively parallel shotgun sequencing for screening common trisomies, rare autosomal aneuploidies, and subchromosome copy number variants. All the NIPS cases with a low‐risk result performed in our center in 2017 were followed‐up using medical records and telephone interview at 3 months after delivery. Fetal ultrasound results and available genetic diagnostic testing results were collected for pregnancies with adverse outcomes. The genetic diagnostic testing referred to chromosomal microarray analysis or fluorescent in situ hybridization on amniotic fluid cells, fetal skin tissue, neonatal peripheral blood, or available placental biopsies. Results By following‐up 10,975 low‐risk results, we found 166 NIPS cases with adverse pregnancy outcomes, in which eight cases had diagnostic testing. Among them, four false‐negative cases were confirmed, including one trisomy 18 caused by placental mosaicism, one mosaic tetrasomy 12p, and 2 microdeletion/microduplication cases. Conclusion Our results revealed that mosaicism contributes to a major cause of false negative in NIPS, and highlighted the importance of ultrasound in identifying these false‐negative results.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a new coronavirus, was first identified in December 2019 in Wuhan, China and spread rapidly, affecting many other countries. The disease is now referred to as coronavirus disease 2019 (COVID-19).The Italian government declared a state of emergency on 31st January 2020 and on 11th March World Health Organization (WHO) officially declared the COVID-19 outbreak a global pandemic. Although the COVID-19 incidence remained considerably lower in Sardinia than in the North Italy regions, which were the most affected, the field of prenatal screening and diagnosis was modified because of the emerging pandemic. Data on COVID-19 during pregnancy are so far limited. Since the beginning of the emergency, our Ob/Gyn Department at Microcitemico Hospital, Cagliari offered to pregnant patients all procedures considered essential by the Italian Ministry of Health. To evaluate the influence of the COVID-19 pandemic on the activities of our center, we compared the number of procedures performed from 10th March to 18th May 2020 with those of 2019. Despite the continuous local birth rate decline, during the 10-week pandemic period, we registered a 20% increment of 1st trimester combined screening and a slight rise of the number of invasive prenatal procedures with a further increase in chorionic villi sampling compared to amniocentesis. Noninvasive prenatal testing remained unvariated. The request for multifetal pregnancy reduction as a part of the growing tendency of voluntary termination of pregnancy in Sardinia increased. The COVID-19 pandemic provides many scientific opportunities for clinical research and study of psychological and ethical issues in pregnant women. [ABSTRACT FROM AUTHOR]

Objective: To describe our clinical experience across the entire range of fetal-fraction (FF) measurements of a non-invasive prenatal screen (NIPS) that uses whole- genome sequencing (WGS).Methods: We analyzed retrospectively results from 58 105 singleton pregnancies that underwent NIPS on a customized WGS platform during an 8-month period and assessed clinical test performance for trisomy 21, trisomy 18 and trisomy 13. Pregnancy outcomes were sought for all screen-positive patients and for 18% of screen-negative patients. As differences in outcome-collection response rates could artificially impact test-performance calculations, we computed inferred sensitivity, specificity, positive predictive values (PPV) and negative predictive values adjusted for ascertainment bias.Results: The screening test yielded a result for 99.9% (n = 58 048) of patients, meaning that approximately 1 in 1000 patients received a test failure (i.e. test failure rate = 0.1%). Of pregnancies with a test result, 572 (1%) screened positive for one of the common aneuploidies (362 for trisomy 21, 142 for trisomy 18 and 68 for trisomy 13). Informative outcomes were received for 237 (41.4%) patients with a screen-positive result and 3258 (5.7%) of those with a screen-negative result. In the full cohort, inferred sensitivities for trisomy 21, trisomy 18 and trisomy 13 were 99.7%, 96.8% and 94.3%, respectively, and PPVs were 93.1%, 85.2% and 48.4%, respectively. If a FF threshold of 4% had been employed to guard against false negatives, calculated sensitivities for the three aneuploidies would not have changed significantly, yet, importantly, the overall test-failure rate would have increased to 6.6% (n = 3829), impacting 1 in 15 women.Conclusions: Our clinical experience demonstrates that a customized WGS-based NIPS without a FF threshold achieves high accuracy while maintaining a low test-failure rate of 0.1%. As such, alternative strategies to ensure high accuracy of detection of common aneuploidies in samples with low FF (such as redraw after test failure, redrawing at a later gestational age, risk scoring based on FF) are not necessary for this screening approach. © 2019 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]

Background: The non‐invasive prenatal screening (NIPS) has been introduced into clinical practice with a high sensitivity and specificity. Although the false‐negative results are inevitable and important, limited false‐negative NIPS results have been reported and studied previously. In this study, we aim to report and analyze false‐negative results detected in the NIPS cases with a low‐risk result. Methods: NIPS was performed using whole‐genome massively parallel shotgun sequencing for screening common trisomies, rare autosomal aneuploidies, and subchromosome copy number variants. All the NIPS cases with a low‐risk result performed in our center in 2017 were followed‐up using medical records and telephone interview at 3 months after delivery. Fetal ultrasound results and available genetic diagnostic testing results were collected for pregnancies with adverse outcomes. The genetic diagnostic testing referred to chromosomal microarray analysis or fluorescent in situ hybridization on amniotic fluid cells, fetal skin tissue, neonatal peripheral blood, or available placental biopsies. Results: By following‐up 10,975 low‐risk results, we found 166 NIPS cases with adverse pregnancy outcomes, in which eight cases had diagnostic testing. Among them, four false‐negative cases were confirmed, including one trisomy 18 caused by placental mosaicism, one mosaic tetrasomy 12p, and 2 microdeletion/microduplication cases. Conclusion: Our results revealed that mosaicism contributes to a major cause of false negative in NIPS, and highlighted the importance of ultrasound in identifying these false‐negative results. [ABSTRACT FROM AUTHOR]