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Background: Non-invasive prenatal testing (NIPT) is a widely adopted maternal blood test that analyses foetal originating DNA to screen for foetal chromosomal conditions, including Down's syndrome (DS). The introduction of this test, which may have implications for important decisions made during pregnancy, requires continual monitoring and evaluation. This systematic review aims to assess the extent of NIPT introduction into national screening programmes for DS worldwide, its uptake, and impact on pregnancy outcomes. Methods and findings: The study protocol was published in PROSPERO (CRD42022306167). We systematically searched MEDLINE, CINAHL, Scopus, and Embase for population-based studies, government guidelines, and Public Health documents from 2010 onwards. Results summarised the national policies for NIPT implementation into screening programmes geographically, along with population uptake. Meta-analyses estimated the pooled proportions of women choosing invasive prenatal diagnosis (IPD) following a high chance biochemical screening result, before and after NIPT was introduced. Additionally, we meta-analysed outcomes (termination of pregnancy and live births) amongst high chance pregnancies identified by NIPT. Results demonstrated NIPT implementation in at least 27 countries. Uptake of second line NIPT varied, from 20.4% to 93.2% (n = 6). Following NIPT implementation, the proportion of women choosing IPD after high chance biochemical screening decreased from 75% (95% CI 53%, 88%, n = 5) to 43% (95%CI 31%, 56%, n = 5), an absolute risk reduction of 38%. A pooled estimate of 69% (95% CI 52%, 82%, n = 7) of high chance pregnancies after NIPT resulted in termination, whilst 8% (95% CI 3%, 21%, n = 7) had live births of babies with DS. Conclusions: NIPT has rapidly gained global acceptance, but population uptake is influenced by healthcare structures, historical screening practices, and cultural factors. Our findings indicate a reduction in IPD tests following NIPT implementation, but limited pre-NIPT data hinder comprehensive impact assessment. Transparent, comparable data reporting is vital for monitoring NIPT's potential consequences. [ABSTRACT FROM AUTHOR]

This study represents our second investigation into NIPT, involving a more extensive patient cohort with a specific emphasis on the high-risk group. The high-risk group was subsequently divided into two further groups to compare confirmed cases versus unconfirmed via direct methods. The methodology encompassed the analysis of 1400 consecutive cases from a single genetic center in western Romania, where NIPT was used to assess the risk of specific fetal chromosomal abnormalities. All high-risk cases underwent validation through direct analysis of fetal cells obtained via invasive methods, including chorionic villus sampling and amniocentesis. The confirmation process utilized QF-PCR, karyotyping, and SNP-Array methods customized to each case. Results: A high risk of aneuploidy at NIPT was identified in 36 out of 1400 (2.57%) cases and confirmed in 28 cases. The study also detected an increased risk for copy number variations (CNVs) in 1% of cases, confirmed in two instances involving one large microdeletion and one large microduplication. Trisomy 21 was the exclusive anomaly where NIPT confirmed all cases with identified risk. High-risk NIPT results which were not validated by invasive methods, were classified as false positives; parents in these cases determined to continue the pregnancy. In conclusion, NIPT can serve as a screening method for all pregnancies; however, in high-risk cases, an invasive confirmation test is strongly recommended. [ABSTRACT FROM AUTHOR]

To analyze the risk for genetic aberrations and pregnancy outcomes in pregnancies with isolated polyhydramnios. This was a retrospective study of singleton pregnancies complicated by isolated polyhydramnios that underwent genetic amniocentesis between 2016 and 2021. Clinical and laboratory data were collected and reviewed for these cases, including maternal demographics, prenatal sonographic findings, chromosomal microarray results, and pregnancy outcomes. A total of 94 singleton pregnancies were included. Three (3.2%) cases with chromosomal abnormalities were detected, including 2 case of trisomy 21 and 1 of 22q21.1 microdeletion. One case was diagnosed as Prader-Willi syndrome caused by maternal uniparental disomy of chromosome 15. Perinatal death occurred in 1 case with severe polyhydramnios, and was retrospectively diagnosed as Bartter syndrome. Of the 90 infants survived, two were identified to have single gene disorders after birth by whole exome sequencing. We first attempted to determine the value of exome sequencing in pregnancies with isolated polyhydramnios. Our results warrant more studies to evaluate advanced genetic testing technologies used in such pregnancies. [ABSTRACT FROM AUTHOR]

We aimed to evaluate retrospectively associated anomalies and outcome in prenatal aortic arch anomalies (AAAs). We included ninety patients with aberrant right subclavian artery (ARSA), right aortic arch (RAA) with mirror image branching (RAA-mirror) or aberrant left subclavian artery (RAA-ALSA) and double aortic arch (DAA) between 2011 and 2020. In total, 19/90 (21.1%) had chromosomal anomalies, the highest rate being within the ARSA subgroup (17/46, 37%). All (13/13) of the RAA-mirror subgroup, 10/27 (37.0%) of RAA-ALSA, 13/46 (28.3%) of ARSA and 0/4 within the DAA subgroup had additional intracardiac anomaly. The rate of extracardiac anomalies was 30.7% in RAA-mirror, 28.3% in ARSA, 25.0% in DAA and 22.2% in the RAA-ALSA subgroup. A total of 42/90 (46.7%) had isolated AAAs: three (7.1%) with chromosomal anomalies, all trisomy 21 (3/26, 11.5%) within the ARSA subgroup. Out of 90, 19 (21.1%) were lost to follow-up (FU). Two (2.2%) intrauterine deaths occurred, and six (6.7%) with chromosomal anomalies terminated their pregnancy. In total, 63 (70.0%) were liveborn, 3/63 (4.8%) with severe comorbidity had compassionate care and 3/60 (5.0%) were lost to FU. The survival rate in the intention-to-treat cohort was 53/57 (93%). Forty-one (77.4%) presented with vascular ring/sling, two (4.9%) with RAA-ALSA developed symptoms and one (2.4%) needed an operation. We conclude that intervention due to vascular ring is rarely necessary. NIPT could be useful in isolated ARSA cases without higher a priori risk for trisomy 21 and after exclusion of other anomalies. [ABSTRACT FROM AUTHOR]

The Haredi (ultraorthodox Jewish) community in Israel presents distinct views on disability and prenatal testing compared to the pro-testing attitudes of the Israeli general public. Based on qualitative analysis of semi-structured interviews with Haredi parents of children with Down syndrome, this study explores the interplay between their personal experiences and community norms in the creation of views on disability and pregnancy management. The experiences of life with disability carry varied positive and negative aspects, for both secular and religious parents. However, while this variability sometimes led to re-consideration (for better or worse) of views on disability and prenatal testing among secular parents, we demonstrate that parenting a child with disability did not change the views of Haredi parents regarding the futility of prenatal testing and the value of disability. For them, the Haredi model of disability remained the dominant framework through which life is experienced. While the Israeli general public is supportive of tests performed during pregnancy with the aim of selective terminations of pregnancies when anomalies in the fetus are detected, the most religious Jewish (Haredi) community tends to avoid such testing. The study demonstrates the interplay between cultural norms and personal experiences in forming attitudes toward disability. For Haredi parents, life with a child with Down syndrome did not essentially change their positive perceptions of disability and their rejection of testing the fetus in future pregnancies. Haredi parents' critical view of testing during pregnancy reflects their religious perspective, rather than the perspective of people with disabilities and their empowerment. Haredi parents view children with Down syndrome as 'higher souls' sent by God as a test of faith and a mission, thus constructing testing the fetus for Down syndrome as futile. [ABSTRACT FROM AUTHOR]

Aim: Down syndrome is the most common well-known chromosomal disorder. The incidence of congenital heart disease (CHD) in these patients is high and it is the most important cause of mortality. In this study, we reviewed the comorbid CHDs and their characteristics in patients with the diagnosis of Down syndrome. We compared our results with the results of studies conducted in different regions of our country in different years. Materials and Methods: Between January 2020 and December 2022, data from a total of 385 patients (175 females, 210 males) with Down syndrome were evaluated. The age of the mothers at the time of delivery and the availability of prenatal diagnosis information in accessible patients were determined. Results: Of 385 patients with Down syndrome, 38.2% (n=147) had CHD. Among patients with CHD, 57 patients had atrioventricular septal defect (AVSD)(38.7%), 35 patients had perimembranous ventricular septal defect (23.8%), 24 patients had secundum atrial septal defect(16.3%), 8 patients had patent ductus arteriosus(5.4%), and 10 patients without AVSD had CHD with multiple left-to-right shunts (6.8%). The most common cyanotic CHD was tetralogy of Fallot (n=7, 4.7%). Complete AVSD was present in 63.1% of AVSD patients. CHD was present in 36.2% of boys and 40.6% of girls. Among all female patients, 17.1% had AVSD, while this rate was 12.8% among all male patients (p<0.05). The mean maternal age at delivery was 32.59±6.9 (17-48) years. It was found that children with Down syndrome whose mothers had a maternal age of 33.5 years and above had a lower rate of CHD. Of the 170 mothers for whom prenatal diagnosis information was available, 58.2% (n=99) had a prenatal diagnosis. Conclusion: Prenatal diagnosis opportunities have increased and become widespread over the years. However, no significant change was observed in the rates of CHD, which is most frequently responsible for mortality in children with Down syndrome. It is appropriate for every expectant mother with a prenatal diagnosis to be referred for fetal echocardiography or postnatal transthoracic echocardiography. [ABSTRACT FROM AUTHOR]

• Families with a prenatal diagnosis are not eligible for early intervention until their baby is born despite other developmental programs starting during pregnancy. • Families appraisals of their formal, intermediate, and informal supports to meet their desire for a positive, hopeful pregnancy and parenting vision varied. • Early Intervention could support families in meeting their prenatal goals that families' currently existing resources do not. In the United States, families whose infants or toddlers have a diagnosis that results in a high likelihood of developmental delay or disability are automatically eligible for early intervention (EI). When families know prenatally of this diagnosis, they are not eligible for EI until their baby is born despite other developmental programs starting during pregnancy. Seventeen families who had a prenatal diagnosis of Down syndrome shared their experiences with formal, intermediate, and informal resources during their pregnancy. Findings centered on families' appraisals of those resources to meet their desire for a positive, hopeful pregnancy and parenting vision. Implications are discussed for early childhood prenatal home visitors, early childhood professionals overall, and EI systems and professionals. [ABSTRACT FROM AUTHOR]

Background: Tarsometatarsal joint (TMJ) arthrodesis is common method used for correcting hallux abductus valgus (HAV). Its popularity has grown due to studies revealing HAV's triplanar deformity with frontal plane rotation. This case report presents a 28-year-old woman with Down syndrome, congenital heart disease, and a history of knee surgery and plantar fasciitis, with severe HAV deformity and flexible valgus flatfoot associated with ligamentous hyperlaxity. Case Report: Examination revealed severe foot deformities, and radiographic studies confirmed the condition. A surgical intervention was planned, and the patient's cardiologist confirmed she was fit for the procedure. The modified Lapidus technique with frontal plane rotational correction included realigning the metatarsal joint, resecting spurs, osteosynthesis material, and arthrosis in the sinus tarsi. After surgery, the patient underwent a recovery period without support for 8 weeks and received appropriate medical care. Radiographs showed successful alignment, and the patient gradually resumed her daily activities. The patient had an uneventful recovery, and postoperative radiographs showed good alignment in all planes. Conclusions: The hyperlaxity associated with Down syndrome makes the incidence of HAV more frequent, and TMJ fusion is preferable to correction by osteotomy. The modified Lapidus technique with frontal plane rotational correction could be a good technique to achieve satisfactory correction in patients with severe HAV deformity and flexible valgus flatfoot associated with ligamentous hyperlaxity. TMJ fusion is indicated when severe or recurrent rotational component is observed in X-rays. [ABSTRACT FROM AUTHOR]

The increasing popularity and expansion of non-invasive prenatal testing (NIPT) to screen for rare conditions beyond common trisomies prompts evaluation of pre-test counselling currently offered. We conducted a prospective survey to assess women's knowledge of NIPT in those who had undergone NIPT (study group) and those who were planning to have NIPT (control group). Out of the 189 questionnaires analysed, the study group did not show a higher knowledge score compared to the control group (P = 0.097). 44% misunderstood that NIPT can identify more conditions than invasive testing, 69.8% were unaware of the recommended need for nuchal translucency measurement and 52.6% were unaware of the possibility of incidental findings. 31% even considered discussing termination of pregnancy as one of the next steps if NIPT shows high risk for Down syndrome. This study shows that current pre-test counselling is inadequate. Service providers should address these knowledge gaps and assist women to make informed choices. What is already known on this subject? Pre-test counselling for non-invasive prenatal testing (NIPT) should be conducted to assist women in making an informed consent. What do the results of this study add? Our results show that a significant proportion of women are unaware of the limitations of NIPT. What are the implications of these findings for clinical practice and/or further research? Service providers should improve their pre-test counselling focusing on areas of knowledge deficiencies and misunderstanding on NIPT identified in this study. [ABSTRACT FROM AUTHOR]

In this study we wanted to determine the performance of a paired-end sequencing-based noninvasive prenatal testing (NIPT) assay in the detection of common fetal trisomies in twin pregnancy samples. Samples from patients with a twin pregnancy were collected from at least 10 weeks of gestation and analyzed at a single prenatal center in Germany. Results of Anomaly Detected (i.e., high risk) or No Anomaly Detected (i.e., low risk) for trisomy 21, trisomy 18, or trisomy 13 were reported. Follow-up confirmatory outcomes were requested for all cases. A total of 1,658 patients with twin pregnancies submitted samples during the study period; only two of these samples failed resulting in a low failure rate of 0.12%. Of the remaining 1,656 cases, there were 1,625 (98.1%) low-risk and 31 (1.9%) high-risk NIPT samples in our cohort. Of these, follow-up information was available for 301 (18.5%) of the low-risk samples and 19 (61.3%) of the high-risk samples. All of the low-risk cases with follow-up were determined to be true negatives giving an estimated negative predictive value of 100%. Seventeen of the 19 high-risk samples with follow-up were true positives, resulting in an overall positive predictive value of 89.5%. Sensitivities of > 99.9% were noted for both trisomy 21 and trisomy 18, with high specificities of ≥ 99.7% observed for all three trisomies. In conclusion, our study showed strong performance of the NIPT assay in the detection of common fetal trisomies in twin pregnancy samples, with high sensitivities, specificities, and positive predictive values observed based on known clinical outcomes along with a low failure rate. [ABSTRACT FROM AUTHOR]

Objective: A rolling circle amplification (RCA) based commercial methodology using cell-free (cf)DNA to screen for common trisomies became available in 2018. Relevant publications documented high detection but with a higher than expected 1% false positive rate. Preliminary evidence suggested assay variability was an issue. A multi-center collaboration was created to explore this further and examine whether subsequent manufacturer changes were effective. Methods: Three academic (four devices) and two commercial (two devices) laboratories provided run date, chromosome 21, 18, and 13 run-specific standard deviations, number of samples run, and reagent lot identifications. Temporal trends and between-site/device consistency were explored. Proportions of run standard deviations exceeding pre-specified caps of 0.4%, 0.4% and 0.6% were computed. Results: Overall, 661 RCA runs between April 2019 and July 30, 2022 tested 39,756 samples. In the first 24, subsequent 9, and final 7 months, proportions of capped chromosome 21 runs dropped from 39% to 22% to 6.0%; for chromosome 18, rates were 76%, 36%, and 4.0%. Few chromosome 13 runs were capped using the original 0.60%, but capping at 0.50%, rates were 28%, 16%, and 7.6%. Final rates occurred after reformulated reagents and imaging software modifications were fully implemented across all devices. Revised detection and false positive rates are estimated at 98.4% and 0.3%, respectively. After repeat testing, failure rates may be as low as 0.3%. Conclusion: Current RCA-based screening performance estimates are equivalent to those reported for other methods, but with a lower test failure rate after repeat testing. [ABSTRACT FROM AUTHOR]

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]

Objective: We aimed to evaluate the clinical performance of expanded noninvasive prenatal testing (NIPT-Plus) for the detection of aneuploidies and microdeletion/microduplication syndromes. Methods: A total of 7177 pregnant women were enrolled in the study from June 2020 to March 2022 at Xijing Hospital, China. Cases with NIPT-Plus-positive results were further confirmed by chromosomal karyotyping and a chromosomal microarray analysis. Results: A total of 112 positive cases (1.56%) were identified by NIPT-Plus, including 60 chromosome aneuploidies and 52 microdeletion/microduplication syndromes. Ninety-five cases were validated by amniocentesis, and 57 were confirmed with true-positive results, comprising 18 trisomy 21, 4 trisomy 18, 1 trisomy 13, 17 sex chromosome aneuploidies, 1 other aneuploidy, and 16 microdeletion/microduplication syndromes. The positive predictive value of total chromosomal abnormalities was 60% (57/95). For trisomy 21, trisomy 18, trisomy 13, sex chromosome aneuploidies, other aneuploidies and microdeletion/microduplication syndromes, the sensitivity was all 100%, the specificity was 100, 99.986, 100, 99.888, 99.958, and 99.636%, and the positive predictive value was 100, 80, 100, 68, 25, and 38.10%, respectively. For all clinical characteristics, the abnormal maternal serum screening group was found to have the highest prevalence of chromosomal abnormalities (1.54%), and the ultrasound abnormality group presented the highest positive predictive value (73.33%). Conclusions: NIPT-Plus has great potential for the detection of aneuploidies and microdeletion/microduplication syndromes owing to its high sensitivity, safety, and specificity, which greatly reduces unnecessary invasive procedures and the risk of miscarriage and allows informed maternal choice. [ABSTRACT FROM AUTHOR]

Objective The aim of this work was to compare different local cutoff values (LCV) and inline cutoff values (ICV) in pregnant women in the second trimester at high risk for carrying fetuses with trisomy 21. Methods This retrospective cohort study analyzed prenatal screening outcomes in pregnant women (n = 311,561). The receiver operating characteristic curve was used to evaluate the diagnostic significance of the trisomy 21 risk value, alpha-fetoprotein, and free beta human chorionic gonadotropin multiple of the median for predicting trisomy 21 risk. The cutoff value corresponding to the maximal Youden index was taken as the LCV. The screening efficiency of both cutoff values was compared. Results The LCV cutoff value was lower than the ICV cutoff value (1/643 vs 1/270). The sensitivity increased by 19.80%, the positive predictive value decreased by 0.20%, and the false-positive rate increased by 6.50%. Conclusion The LCV should be used to determine trisomy 21 risk, which can increase the detection rate of trisomy 21 in the second trimester. [ABSTRACT FROM AUTHOR]

Background: Down syndrome myeloid hyperplasia includes transient abnormal myelopoiesis (TAM) and the myeloid leukemia associated with Down syndrome (ML-DS). The mutation of GATA1 gene is essential in the development of Down syndrome combined with TAM or ML-DS. Some patients with TAM are asymptomatic and may also present with severe manifestations such as hepatosplenomegaly and hydrops. Case presentation: We report two cases of prenatally diagnosed TAM. One case was a rare placental low percentage 21 trisomy mosiacism, resulting in the occurrence of a false negative NIPT. The final diagnosis was made at 36 weeks of gestation when ultrasound revealed significant enlargement of the foetal liver and spleen and an enlarged heart; the foetus eventually died in utero. We detected a placenta with a low percentage (5–8%) of trisomy 21 mosiacism by Copy Number Variation Sequencing (CNV-seq) and Fluorescence in situ hybridization (FISH). In another case, foetal oedema was detected by ultrasound at 31 weeks of gestation. Two foetuses were diagnosed with Down syndrome by chromosomal microarray analysis via umbilical vein puncture and had significantly elevated cord blood leucocyte counts with large numbers of blasts. The GATA1 Sanger sequencing results suggested the presence of a [NM_002049.4(GATA1):c.220G > A (p. Val74Ile)] hemizygous variant and a [NM_002049.4(GATA1):c.49dupC(p. Gln17ProfsTer23)] hemizygous variant of the GATA1 gene in two cases. Conclusion: It seems highly likely that these two identified mutations are the genetic cause of prenatal TAM in foetuses with Down syndrome. [ABSTRACT FROM AUTHOR]

Negative, ableist discourse challenging the rights of people with Down syndrome to receive support services and even to be born regularly arise on social media. This disability community has retaliated against such hate speech with resistance narratives that promote the value of people with Down syndrome, with few other recourses available. This article explores online free speech versus ableism in Australia through a major case study of 60 Minutes Australia Facebook discussions. Analysis identifies types of ableism expressed, types of harm caused and dimensions of grassroots responses. Using Timothy Garton Ash's 2016 work Free Speech as a basis for contemporary analysis, we discuss: to what extent should harmful and offensive comments directed at vulnerable populations be tolerated in the name of free speech; might negative, ableist discourse contribute to any social good; and what mechanisms beyond grassroots resistance narratives might effectively respond to harmful, online ableist discourses. The article looks at whether the right to free speech is more important than the harmful effects of online hate speech towards people with Down syndrome. We use the ideas in a book on Free Speech by Timothy Garton Ash to think about whether online hate speech should be allowed or silenced. Our analysis is based on a case study of Facebook discussion threads from a 60 Minutes Australia television segment. People in the disability community speaking up to create resistance narratives is the main way that online disability hate speech is challenged. Other ways that could help are laws, government agencies providing support materials, and social media rules. [ABSTRACT FROM AUTHOR]

Background: Combined first‐trimester screening (cFTS) for fetal anomalies involves maternal serum screening for biochemical markers and measurement of the nuchal translucency (NT) by ultrasound. Noninvasive prenatal screening (NIPS) analyses cell‐free DNA present in a maternal blood sample for presence of fetal chromosomal aneuploidies. Aims: To compare NIPS with cFTS as frontline screening in a public hospital in Australia. Materials and methods: Women were offered NIPS in addition to the usual cFTS routinely offered to all women at a public hospital in NSW, Australia. The cFTS sample was collected at ten weeks' gestation and the NIPS sample at 12 weeks' gestation at the ultrasound appointment. Results: In a low‐risk population of 997 women, frontline NIPS had a screen‐positive rate of 0.5% (5/997) vs 4.2% (42/997) with cFTS. cFTS correctly identified one trisomy 21 case and one trisomy 18 case; however, there were two trisomy 18 false negatives. Of five positive NIPS calls, four were correctly identified as trisomy 21 (one) and trisomy 18 (three); there were no NIPS false negatives. Overall, the false‐positive rate with NIPS was 0.1% vs 4.0% by cFTS. Conclusions: The lower screen‐positive rate with NIPS for common trisomies was a result of the significantly lower false‐positive rate with NIPS. Consequently, NIPS as first‐line screening, even if funded by the hospital, may provide cost savings. We believe NIPS should be used from ten weeks' gestation in conjunction with morphology ultrasound for routine first‐trimester prenatal management. [ABSTRACT FROM AUTHOR]

Background: This study aimed to evaluate the clinical application value of noninvasive prenatal testing from DNA (NIPT) and serum screening for screening in detecting fetal trisomy 21 and 18. Methods: As a retrospective analysis, we collected data from 1383 women (singleton pregnancy) who underwent serum screening and noninvasive prenatal testing from DNA (NIPT) in our department from May 2015 to September 2017 and calculated the diagnostic value of the two methods. Results: In 1383 cases, the sensitivity of serum screening to trisomy 21 and 18 was 76.9%, specificity 74.7%, PPV 2.9%, NPV 99.7%, and AUC 0.758 (95% Cl: 0.625- 0.891). The sensitivity of noninvasive prenatal testing from DNA (NIPT) to trisomy 21 and 18 was 100%, specificity 99.8%, PPV 81%, NPV 100%, and AUC 0.999 (95% Cl: 0.000-1.000). Conclusion: Serum screening can detect high-risk pregnant women in time, but the incidence of false positives and negatives is high; the accuracy of noninvasive prenatal testing from DNA (NIPT) is high, which can effectively reduce the rate of defective babies. [ABSTRACT FROM AUTHOR]

Historically, there has been a lack of cost-effectiveness data regarding the inclusion of universal non-invasive prenatal testing (NIPT) for trisomy 21, 18, and 13 in the benefit package of the Universal Health Coverage (UHC) in Thailand. Therefore, this study aimed to perform the cost-benefit analysis of prenatal screening tests and calculate the budget impact that would result from the implementation of a universal NIPT program. A decision-tree model was employed to evaluate cost and benefit of different prenatal chromosomal abnormalities screenings: 1) first-trimester screening (FTS), 2) NIPT, and 3) definitive diagnostic (amniocentesis). The comparison was made between these screenings and no screening in three groups of pregnant women: all ages, < 35 years, and ≥ 35 years. The analysis was conducted from societal and governmental perspectives. The costs comprised direct medical, direct non-medical, and indirect costs, while the benefit was cost-avoidance associated with caring for children with trisomy and the loss of productivity for caregivers. Parameter uncertainties were evaluated through one-way and probabilistic sensitivity analyses. From a governmental perspective, all three methods were found to be cost-beneficial. Among them, FTS was identified as the most cost-beneficial, especially for pregnant women aged ≥ 35 years. From a societal perspective, the definitive diagnostic test was not cost-effective, but the other two screening tests were. The most sensitive parameters for FTS and NIPT strategies were the productivity loss of caregivers and the incidence of trisomy 21. Our study suggested that NIPT was the most cost-effective strategy in Thailand, if the cost was reduced to 47 USD. This evidence-based information can serve as a crucial resource for policymakers when making informed decisions regarding the allocation of resources for prenatal care in Thailand and similar context. [ABSTRACT FROM AUTHOR]

Children with Down syndrome (DS) require multiple sleep studies throughout childhood to diagnose and monitor sleep disordered breathing (SDB). Previous research suggests sensors applied during polysomnography (PSG) are poorly tolerated by children with DS. The Sonomat is a contactless device previously validated in typically developing children, and adult populations. Our study aimed to compare simultaneous Sonomat and PSG recordings in children with DS to determine the suitability of the Sonomat for use in this population. Fifty children with DS undergoing diagnostic PSG were recruited from the Queensland Children's Hospital sleep laboratory. Agreement for sleep and respiratory parameters were assessed using concordance correlation coefficients (CCC), while detection and classification of SDB were assessed using indicators such as sensitivity, specificity, likelihood ratios, and receiver operator characteristic curves. Comparison of parameters including the apnea-hypopnea index (CCC=89%; 95%CI 76, 93), and obstructive events index (CCC=74%; 95%CI 44, 88) showed reasonable agreement between Sonomat and PSG. The Sonomat showed outstanding ability to differentiate between the presence and absence of SDB (area under the curve [AUC]=0.97; 95%CI 0.93, 1.00), though we are uncertain of its ability to classify SDB profile and severity due to sample size limitations resulting in wide confidence intervals. The easy-to-use, non-invasive nature of the Sonomat make it ideal for use in the screening of SDB in children with DS. Further data are needed to determine its suitability for classifying SDB profile and severity, including within the home, and for its use in other neurodevelopmental groups. • Excellent AHI (CCC=89%; 95%CI 76, 93) agreement between Sonomat and PSG. • Reasonable OAHI (CCC=74%; 95%CI 44, 88) agreement between Sonomat and PSG. • Sonomat showed outstanding ability to identify SDB (AUC=0.97; 95%CI 0.93, 1.00). • Ability of Sonomat to classify SDB profile and severity uncertain; more data are required. • Sonomat is a non-invasive tool that appears well suited to SDB screening in children with DS. [ABSTRACT FROM AUTHOR]

Harvey and Gurvir's Law is a bill proposed to the Legislative Assembly of Ontario (Canada) to reduce stigma and bias associated with Down syndrome, by developing and disseminating quality information about Down syndrome in the context of prenatal testing. [ABSTRACT FROM AUTHOR]

Down syndrome (Trisomy 21) is a mild to moderate intellectual disability. Historically, this condition has been a primary target for prenatal testing. However, Down syndrome has not been targeted for prenatal testing because it is an especially severe illness. The condition was just one that could be easily identified prenatally using the techniques first available decades ago. We are moving into an era in which we can prenatally test for a vast range of human traits. I argue that when we can test for anything, there is no longer any reason to continue targeting Down syndrome. I present an argument based on the value of nondiscrimination. It is justified to set limits on access to prenatal information if the information is going to be used for discriminatory purposes. I use the examples of (1) prenatal testing for misogynistic fetal sex selection, and (2) homophobia-motivated prenatal testing for potential homosexuality, as compelling analogies. [ABSTRACT FROM AUTHOR]

Noninvasive prenatal screening with cell-free DNA is now considered a first-line screening for common aneuploidies. Advancements in existing laboratory techniques now allow to interrogate the entirety of the fetal genome, and many commercial laboratories have expanded their screening panels to include screening for rare autosomal aneuploidies and copy number variants. Here, we review the currently available data on the performance of fetal cell-free DNA to detect rare autosomal aneuploidies and copy number variants that are associated with clinically significant microdeletion and microduplication syndromes and the current position of medical societies on routine screening for these syndromes. [ABSTRACT FROM AUTHOR]

Cell-free DNA (cfDNA) screening has high detection for the common fetal autosomal aneuploidies, but is not diagnostic. The positive predictive value should be utilized in counseling after a positive cell-free DNA screen, and diagnostic testing should be offered for confirmation. cfDNA screening does not report a result in ~3% of cases; nonreportable results indicate an increased risk for aneuploidy and some adverse perinatal outcomes. False-positive cfDNA screening occurs due to confined placental mosaicism, maternal copy number variants, mosaicism, and cancer. Pretest education and counseling should be provided with emphasis on the potential benefits, risks, and limitations before cfDNA screening. [ABSTRACT FROM AUTHOR]

Although nearly all noninvasive prenatal testing is currently based on analyzing circulating maternal cell-free DNA, the technical methods usedvary considerably. We review the different methods. Based on validation trials and clinical experience, there are mostly relatively small differences in screening performance for trisomies 21, 18, and 13 in singleton pregnancies. Recent reports show low no-call rates for all methods, diminishing its importance when choosing a laboratory. However, method can be an important consideration for twin pregnancies, screening for sex chromosome abnormalities, microdeletion syndromes, triploidy, molar pregnancies, rare autosomal trisomies, and segmental imbalances, and detecting maternal chromosome abnormalities. [ABSTRACT FROM AUTHOR]

Objectives: Unconjugated estriol (uE3) is used as a marker for fetal aneuploidy in maternal serum screening tests. The goal of this study was to examine the validity of a new immunoassay for uE3 that uses a monoclonal antibody (m-uE3) rather than the more commonly used polyclonal antibody (p-uE3). Setting: Assays were performed in the Special Chemistry laboratory at Women and Infants Hospital of Rhode Island. Methods: Residual fresh (n = 100) and frozen (n = 533) second trimester serum samples from routine clinical care were tested using p-uE3 and/or m-uE3 assays. Assay results were compared between methods using Bland–Altman plots. A median equation was developed for m-uE3 results. Down syndrome risks were compared between the two assays in a case–control sample set (21 cases each matched with five controls for the completed week of gestation, duration of freezer storage and race). Results: Log-transformed serum uE3 levels were highly correlated between the assays (r = 0.93, p < 0.001), with the m-uE3 assay levels yielding, on average, 23% higher (standard deviation of differences in log uE3 concentrations = 0.07) results. Assay and gestation-based median equations were calculated and used to convert m-uE3 concentrations to multiples of the median (MoM). The m-uE3 MoM values fit a log Gaussian distribution well with a log standard deviation of 0.11. Down syndrome risk results were not significantly different between assays. Conclusions: The m-uE3 assay, with results expressed in MoMs, is suitable for screening and as a monoclonal-based assay offers the advantage of a predictable and indefinite supply of antibody to perform the assay. [ABSTRACT FROM AUTHOR]

Objective: The first trimester combined risk of trisomy 21 is obtained by multiplying the risk related to maternal age by the likelihood ratios of nuchal translucency, free beta‐human chorionic gonadotrophin (β‐hCG) and placenta associated plasma protein‐A. Beyond five multiples of the median (MoM) of β‐hCG, the risk of trisomy 21 is truncated. The objective of the present study was to evaluate the evolution of the first trimester combined risk of trisomy 21 in individuals with first‐trimester free‐β‐hCG levels between 5 and 10 MoM. Methods: We conducted a non‐interventional cohort study from a 6‐year database of combined first‐trimester trisomy 21 screening of all individuals who underwent the screening in a French specialized medical analysis center. We included all pregnant individuals who had a serum‐free β‐hCG between 5 and 10 MoM. Patients for whom the status of the fetus, with or without trisomy 21, was not identified by the outcome of the pregnancy or by a karyotype result were excluded from the study. The discriminatory capacity of free‐β‐hCG above 5 MoM was studied by a receiver operating characteristic curve. We used an orthogonal polynomial regression to represent the evolution of likelihood ratios according to free‐β‐hCG in MoM. Results: Among 413 216 combined first‐trimester screens of trisomy 21, 2239 (0.5%) screens met the inclusion criteria. In the selected population, 801 (35.8%) were excluded from the study because of missing fetal or neonatal status, and 46 (3.2%) fetuses out of 1438 included were diagnosed with trisomy 21. For free β‐hCG values between 5 and 10 MoM, the area under the curve is 0.56 (0.46–0.65). The scatterplot of the likelihood ratio of β‐hCG showed an increasing parabolic pattern: the likelihood of trisomy 21 increases with the free‐β‐hCG threshold. Conclusion: To override the truncated risk of trisomy 21 in case of free β‐hCG values between 5 and 10 MoM, the study has allowed us to estimate the adjusted risk of trisomy 21, enabling health professionals to offer appropriate prenatal counseling. Synopsis: Estimation of the adjusted risk of trisomy 21 in pregnant individuals with a free ß‐hCG level between 5 and 10 multiples of the median in the first trimester. [ABSTRACT FROM AUTHOR]

Non-invasive prenatal testing was first discovered in 1988; it was primarily thought to be able to detect common aneuploidies, such as Patau syndrome (T13), Edward Syndrome (T18), and Down syndrome (T21). It comprises a simple technique involving the analysis of cell-free foetal DNA (cffDNA) obtained through maternal serum, using advances in next-generation sequencing. NIPT has shown promise as a simple and low-risk screening test, leading various governments and private organizations worldwide to dedicate significant resources towards its integration into national healthcare initiatives as well as the formation of consortia and research studies aimed at standardizing its implementation. This article aims to review the reliability of NIPT while discussing the current challenges prevalent among different communities worldwide. [ABSTRACT FROM AUTHOR]

The 'expressivist objection' (EO) refers to the notion that using reproductive (genetic) technologies to prevent the birth of future would‐be disabled people contain, and express, a negative valuation of life with disability. Whilst the EO has received increased attention in recent years in line with rapid technological and genomic developments, there remains scant research on how EO concerns are experienced and expressed by disabled people and their families, especially within and between impairment groups. Bringing together two studies—one with adults and family members living with genetic conditions (n = 62) and one with parents of children with Down's syndrome (n = 22)—we argue that disabled people and their families variously embrace, reject or rework the EO across contexts, and yet also frequently situate it within broad support for reproductive technologies. We present three key factors that mediate responses to the EO: (1) the nature of impairment and its integration within identity; (2) social and cultural contexts relating to disability and (3) the (individual and collective) imagined futures of disabled people. In so doing, we blend the conceptual architecture of medical sociology and disability studies, arguing that this allows us to accurately illuminate the nuanced responses of disabled people and their families. [ABSTRACT FROM AUTHOR]

Background: Maternal serum sample screening in the first and second trimesters has been commonly used to identify women who are at risk of fetal trisomy 21. In addition, these serum markers are associated with adverse perinatal outcomes. Hence, the present study was conducted to determine the relationship between false positive screening results of Down syndrome and adverse pregnancy outcomes. Material and Methods: This prospective, two-group, cohort study was conducted on 608 pregnant women who had undergone fetal contingent screening. They were selected through convenience sampling in the twentieth week of pregnancy and were followed up until delivery. The raw Odd Ratios (OR), Relative Risk (RR), and adjusted OR of adverse pregnancy outcomes were calculated in the false positive and true negative groups. Results: The adjusted OR of developing preeclampsia was 1.98 (95% CI: 1.14-3.42), and its RR was 2.13 (95% CI: 1.34-3.38) times higher in the false positive group. Moreover, the adjusted OR of Small for Gestational Age (SGA) was 2.80 (95% CI: 1.76-4.47), and its RR was 2.28 (95% CI: 1.54-3.36) times higher in the false positive group. The adjusted OR of Low Birth Weight (LBW) was 3.34 (95% CI: 1.97-5.64), and its RR was 2.65 (95% CI: 1.72-4.11) times higher in the false positive group. In addition, no significant difference was observed between false positive and true negative groups in terms of preterm birth. Conclusions: Women with a false positive fetal screening test result are more likely to suffer from preeclampsia, SGA, and LBW and require planned prenatal care. [ABSTRACT FROM AUTHOR]

The discovery of cell-free fetal DNA (cffDNA) in maternal blood and the rapid development of massively parallel sequencing have revolutionized prenatal testing from invasive to noninvasive. Noninvasive prenatal screening (NIPS) based on cffDNA enables the detection of fetal trisomy through sequencing, comparison, and bioassays. Its accuracy is better than that of traditional screening methods, and it is the most advanced clinical application of high-throughput sequencing technologies. However, the existing sequencing methods are limited by high costs and complex sequencing procedures. These limitations restrict the availability of NIPS for pregnant women. Many amplification methods have been developed to overcome the limitations of sequencing methods. The rapid development of non-sequencing methods has not been accompanied by reviews to summarize them. In this review, we initially describe the detection principles for sequencing-based NIPS. We summarize the rapidly evolving amplification technologies, focusing on the need to reduce costs and simplify the procedures. To ensure that the testing systems are feasible and that the testing processes are reliable, we expand our vision to the clinic. We evaluate the clinical validity of NIPS in terms of sensitivity, specificity, and positive predictive value. Finally, we summarize the application guidelines and discuss the corresponding quality control methods for NIPS. In addition to cffDNA, extracellular vesicle DNA, RNA, protein/peptide, and fetal cells can also be detected as biomarkers of NIPS. With the development of prenatal testing, NIPS has become increasingly important. Notably, NIPS is a screening test instead of a diagnostic test. The testing methods and procedures used in the NIPS process require standardization. [ABSTRACT FROM AUTHOR]

Trisomy 21 (Down syndrome) is the most common autosomal aneuploidy among newborns. About 90% result from meiotic nondisjunction during oogenesis, which occurs around conception, when also the most profound epigenetic modifications take place. Thus, maternal meiosis is an error prone process with an extreme sensitivity to endogenous factors, as exemplified by maternal age. This contrasts with the missing acceptance of causal exogenous factors. The proof of an environmental agent is a great challenge, both with respect to ascertainment bias, determination of time and dosage of exposure, as well as registration of the relevant individual health data affecting the birth prevalence. Based on a few exemplary epidemiological studies the feasibility of trisomy 21 monitoring is illustrated. In the nearer future the methodical premises will be clearly improved, both due to the establishment of electronic health registers and to the introduction of non-invasive prenatal tests. Down syndrome is a sentinel phenotype, presumably also with regard to other congenital anomalies. Thus, monitoring of trisomy 21 offers new chances for risk avoidance and preventive measures, but also for basic research concerning identification of relevant genomic variants involved in chromosomal nondisjunction. [ABSTRACT FROM AUTHOR]

This article discusses a case of prenatal diagnosis of congenital eyelid eversion in a fetus with trisomy 21. A 27-year-old pregnant woman underwent genetic screening for trisomy 21 and a subsequent ultrasound at 39 weeks and 6 days revealed a soft tissue mass below the right eye of the fetus. The male infant was delivered via cesarean section and was found to have congenital bilateral upper eyelid eversion. The article emphasizes the importance of prompt identification and treatment of congenital eyelid eversion, particularly in cases of trisomy 21, as delays can lead to complications including vision loss. The authors suggest that clinicians should consider the diagnosis of eyelid eversion in fetuses with eyelid masses on ultrasound. [Extracted from the article]

This study evaluated prenatal screening test performance and the prevalence of common aneuploidies at Siriraj Hospital, Thailand. We collected data from screening tests which are first-trimester test, quadruple test, and noninvasive prenatal tests (NIPT) between January 2016 and December 2020. Thirty percent (7,860/25,736) of pregnancies received prenatal screening tests for aneuploidies disorders, and 17.8% underwent prenatal diagnosis tests without screening. The highest percentage of screening tests was first-trimester test (64.5%). The high-risk results were 4% for first-trimester test, 6.6% for quadruple test, and 1.3% for NIPT. The serum screening tests for trisomy 13 and 18 had no true positives; therefore, we could not calculate sensitivity. For the first-trimester test, the sensitivity for trisomy 21 was 71.4% (95% confidence intervals (CI) 30.3–94.9); specificity for trisomy 13 and 18 was 99.9% (95% CI 99.8–99.9); and for trisomy 21 was 96.1% (95% CI 95.6–96.7). For the quadruple test, the specificity for trisomy 18 was 99.6% (95% CI 98.9–99.8), while the sensitivity and specificity for trisomy 21 were 50% (95% CI 26.7–97.3) and 93.9% (95% CI 92.2–95.3), respectively. NIPT had 100% sensitivity and specificity for trisomy 13, 18 and 21, and there were neither false negatives nor false positives. For pregnant women < 35 years, the prevalence of trisomy 13, 18, and 21 per 1,000 births was 0.28 (95% CI 0.12–0.67), 0.28 (95% CI 0.12–0.67), and 0.89 (95% CI 0.54–1.45), respectively. For pregnant women ≥35 years, the prevalence of trisomy 13, 18, and 21 per 1,000 births was 0.26 (95% CI 0.06–1.03), 2.59 (95% CI 1.67–4.01), and 7.25 (95% CI 5.58–9.41), respectively. For all pregnancies, the prevalence of trisomy 13, 18, and 21 per 1,000 births was 0.27 (95% CI 0.13–0.57), 0.97 (95% CI 0.66–1.44), 2.80 (95% CI 2.22–3.52), respectively. [ABSTRACT FROM AUTHOR]

Prenatal screening for aneuploidy has undergone immense changes over the past two decades. In 2013 cell‐free DNA‐based non‐invasive prenatal testing (NIPT) became a new self‐funded option primarily for Down syndrome screening, but also other aneuploidies and genetic conditions. The numbers of Medicare item claims for prenatal diagnostic procedures have halved since the introduction of NIPT, while billings for serum screening fell by 40% over the same period, on a background of steady births. Australia is now observing historically low rates of prenatal diagnostic testing. These data provide an informative snapshot of historic changes in prenatal screening and diagnosis, as our sector prepares for the impending impacts of other advances in genomics on maternity care. They also highlight the need to address equity and quality issues that arise when consumers must bear the full costs of improved genomic tests in the absence of Medicare funding. [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]

Non-invasive prenatal testing (NIPT) has been widely adopted as an approach for foetal aneuploidy screening. This study was to evaluate the performance of NIPT for foetal T21 detection in subgroups of pregnancies and the correlation between Z-score and discordant positive predictive values (PPVs). We retrospectively reviewed the NIPT results among 22361 pregnancies undergoing combined second-trimester screening (cSTS) previously. Sixty-four cases with positive NIPT results for foetal T21 were validated by invasive prenatal diagnosis. In pregnancies with cSTS-T21 low-, intermediate-, and high-risk, the PPVs at NIPT were 14.3%, 64.3%, and 86.4%, respectively. Mean Z-scores of positive NIPT cases with cSTS-T21 high- and intermediate-risk were comparable, while were higher than that of cases with pre-test low-risk. Furthermore, PPVs for positive NIPT cases at 3 < Z < 5, 5 ≤ Z < 9, and Z ≥ 9 were 16.7%, 63.2%, and 100.0%, respectively. This study suggested that Z-score value of positive cases might be associated with discordant PPVs for T21 screening in subgroups of pregnancies. Non-invasive prenatal testing has been offered as a primary screening option to high-risk or general pregnancy. However, the accuracy of non-invasive prenatal testing in patients with various pre-test risks remained unveiled. The current study revealed that the true positive probability for foetal trisomy 21 screening in pregnancies with prior high-risk was higher than that in pregnancies of intermediate-risk, and both of them were much higher than that of those with pre-test low-risk. The average of Z-score for chromosome 21 of positive non-invasive prenatal testing case in high-risk group was comparable with that of intermediate-risk group, while was higher than that of low-risk group. There was also an upward trend for the true positive probability of foetal trisomy 21 screening with the increase of Z-score. Our study revealed that pre-test risk and Z-score for chromosome 21 were helpful for accurately interpreting the reliability of positive results for foetal trisomy 21. [ABSTRACT FROM AUTHOR]

We analyzed patients with isolated, balanced complete atrioventricular septal defects. We identified 71 patients born in Nevada, between January 2008 and December 2020. We also analyzed prenatal detection rates. Of the 71, 61 (85%) had trisomy 21, 1 (1%) had CHARGE syndrome and 22q.11 deletion, and 10 (14%) had no chromosomal abnormalities. Of the 71, 67 had prenatal care, and 43/67 (64%) were prenatally diagnosed. Prenatal detection rate for 2008-2012 was 9/20 (45%) and 18/21 (86%) for 2018-2020, P =.03. Of the 71, 67 underwent surgical repair with 1 current postpulmonary artery banding and 0 surgical deaths. Of the 67, 3 (4%) had heart block. Only 1 (1.5%) patient had reoperation for a mitral valve replacement. Of the 71, 67 (94%) are alive during a 6-year average (range = 0-12 years) follow-up. In conclusion, surgical and long-term outcomes were excellent. Also, high state-wide, general population prenatal detection rates were achieved. [ABSTRACT FROM AUTHOR]

Cardiovascular disease is a leading cause of morbidity and mortality in individuals with Down syndrome. Congenital heart disease is the most common cardiovascular condition in this group, present in up to 50% of people with Down syndrome and contributing to poor outcomes. Additional factors contributing to cardiovascular outcomes include pulmonary hypertension; coexistent pulmonary, endocrine, and metabolic diseases; and risk factors for atherosclerotic disease. Moreover, disparities in the cardiovascular care of people with Down syndrome compared with the general population, which vary across different geographies and health care systems, further contribute to cardiovascular mortality; this issue is often overlooked by the wider medical community. This review focuses on the diagnosis, prevalence, and management of cardiovascular disease encountered in people with Down syndrome and summarizes available evidence in 10 key areas relating to Down syndrome and cardiac disease, from prenatal diagnosis to disparities in care in areas of differing resource availability. All specialists and nonspecialist clinicians providing care for people with Down syndrome should be aware of best clinical practice in all aspects of care of this distinct population. [ABSTRACT FROM AUTHOR]

15q11.2 microdeletion can lead to syndromes affecting the nervous system. However, 15q11.2 microdeletion has large phenotypic differences and incomplete penetrance, which brings challenges to prenatal diagnosis. We reported 21 cases of 15q11.2 microdeletion fetuses in Eastern China and reviewed literature on the prenatal clinical characteristics related to the deletion variants to provide a basis for prenatal genetic counseling. The clinical data of 21 cases of 15q11.2 microdeletion fetuses collected from June 2018 to September 2021 were retrospectively analyzed, and chromosomal microarray analysis was performed. The reported prenatal clinical features of 15q11.2 microdeletion fetuses were reviewed and summarized. A meta-analysis of 20 studies was performed to test heterogeneity, data integration, and sensitivity on the correlation between 15q11.2 microdeletion and neuropsychiatric diseases. The median age of the women was 29.5 years. The median gestational age at interventional examination was 24 weeks. All fetuses showed deletion variants of the 15q11.2 fragment, and the median deletion range was approximately 0.48 MB. Ultrasound of five cases showed no abnormalities; however, four of them showed a high risk of Down's syndrome (risk values were 1/184, 1/128, 1/47, and 1/54, respectively). The remaining 16 fetuses showed congenital heart disease (7/16), elevated nuchal translucency (5/16), abnormal brain structure (2/16) and renal disease (2/16). In a literature review of 82 prenatal cases, 44% (36/82) had abnormal ultrasound features, 31% (11/36) showed abnormal nuchal translucency, approximately 28% (10/36) showed abnormal cardiac structure, and 14% (5/36) had brain structural abnormalities. The meta-analysis revealed that the frequency of the 15q11.2 microdeletion mutation in patients with schizophrenia and epilepsy was significantly higher (odds ratio 2.04, 95% confidence interval: 1.78–2.33, p < 0.00001; odds ratio 5.23, 95% confidence interval: 2.83–9.67, p < 0.00001) than that in normal individuals. More than half of the 15q11.2 microdeletion cases presented no abnormalities in prenatal ultrasound examination. The cases with ultrasound features mainly showed isolated malformations such as elevated nuchal translucency, congenital heart disease, and brain structural abnormalities. Postpartum 15q11.2 microdeletion patients are at an increased risk of suffering from schizophrenia, epilepsy, and other neurological and mental diseases from 15q11.2 microdeletion. Therefore, prenatal diagnosis of 15q11.2 microdeletion not only depends on molecular diagnostic techniques but also requires cautious genetic counseling. [ABSTRACT FROM AUTHOR]

The increasing popularity and expansion of non-invasive prenatal testing (NIPT) to screen for rare conditions beyond common trisomies prompts evaluation of pre-test counselling currently offered. We conducted a prospective survey to assess women's knowledge of NIPT in those who had undergone NIPT (study group) and those who were planning to have NIPT (control group). Out of the 189 questionnaires analysed, the study group did not show a higher knowledge score compared to the control group (P = 0.097). 44% misunderstood that NIPT can identify more conditions than invasive testing, 69.8% were unaware of the recommended need for nuchal translucency measurement and 52.6% were unaware of the possibility of incidental findings. 31% even considered discussing termination of pregnancy as one of the next steps if NIPT shows high risk for Down syndrome. This study shows that current pre-test counselling is inadequate. Service providers should address these knowledge gaps and assist women to make informed choices. What is already known on this subject? Pre-test counselling for non-invasive prenatal testing (NIPT) should be conducted to assist women in making an informed consent. What do the results of this study add? Our results show that a significant proportion of women are unaware of the limitations of NIPT. What are the implications of these findings for clinical practice and/or further research? Service providers should improve their pre-test counselling focusing on areas of knowledge deficiencies and misunderstanding on NIPT identified in this study. [ABSTRACT FROM AUTHOR]

Background: Fetal exposure to maternal anxiety is associated with low birth weight and maternal stress may be led to constriction of uterine arteries. This study compared the relation of anxiety and uterine artery doppler flow indices in pregnant women with the high and low-risk of Down syndrome. Materials and Methods: This prospective cohort study was conducted among pregnant women in the second trimester that were classified as having a high or low risk according to their prenatal aneuploidy screening outcome. The high risk group underwent amniocentesis. Anxiety was initially assessed using the Spielberger State-Anxiety Inventory (STAI) and uterine artery blood flow indices were evaluated 2 times for the both groups. For the high-risk group first: immediately before amniocentesis and second: after two weeks follow up, when receiving the karyotype results and for the low-risk group in the first admission and two weeks later. Results: Totally, 375 pregnant women participated in our study that sorted into 2 risk populations based on the aneuploidy screening test, low-risk=176 and high-risk women=199. The high-risk group for Down syndrome amniocentesis showed abnormal results in the 23 cases (23/199). The mean state (P=0.003) and trait (P=0.033) of the Anxiety Inventory scores were significantly different between the groups. Baseline uterine artery indices were no significant difference between the groups. Baseline Uterine artery indices in the high-risk group was significantly different with follow-up (in both positive-amniocentesis and negative amniocentesis sub-groups) indices. Also, there was a weak and significant correlation in the uterine resistance index and STAI scores (P=0.008, r=0.137) during the follow-up period. Conclusion: All pregnant women experienced high level anxiety, especially in the high-risk group that may reduce after confirmation of prenatal aneuploidy screening test and also affects the Doppler indices. For all pregnant women; Stress management and emotional support training is recommended before and during pregnancy. [ABSTRACT FROM AUTHOR]

Objective: An aberrant right subclavian artery (ARSA) is an aortic arch anomaly isolated or associated with other ultrasound markers and/or congenital anomalies. This study aimed to evaluate the necessity of invasive prenatal tests (PIT) in cases with isolated ARSA (iARSA) in prenatal sonography. Materials and Methods: The presence of ARSA was evaluated retrospectively in 7690 fetuses who underwent a second-trimester ultrasonography evaluation between March 2015 and February 2021. PIT was recommended for patients with non-iARSA. cfDNA test (including 22q11.2 microdeletion/duplication syndrome (MMS) or PIT was suggested for patients with iARSA. Results: The mean week of gestation was 20.26±3.93 in 95 fetuses diagnosed with ARSA. Of the fetuses, fourty-two (44%) had iARSA, and 53 (56%) had additional findings. No chromosomal abnormality was found in any of the isolated cases. Trisomy 21 in 14, Trisomy 18 in one, 47,XX,+i(9)(p10) in one of 53 were found in non-isolated cases. Additional abnormalities and/or soft ultrasound markers were accompanied in all fetuses with chromosomal abnormalities. Conclusion: When iARSA is detected in prenatal ultrasonography, cfDNA testing may be sufficient, including 22q11.2 MMS. However, PIT should be recommended in the presence of structural abnormalities, soft ultrasound markers, or increased risk in the antenatal screening test. [ABSTRACT FROM AUTHOR]

Background: To investigate the prevalence and prenatal diagnosis rate of chromosomal abnormalities (CA) in Zhejiang Province, China. Methods: We estimated the annual changes in the detected prevalence of CA and prenatal diagnosis rate among 681,590 births in Zhejiang Province, China, between 2014 and 2020. Data were derived from the provincial birth defects surveillance system, which represents 30% of annual births in Zhejiang Province. The effect of maternal age was also evaluated. Results: The detected prevalence of sex chromosomal abnormalities (1.70–7.30 per 10,000 births, Ptrend < 0.001) and microdeletion and microduplication (0.30–6.81 per 10,000 births, Ptrend < 0.001) gradually increased, contributing to an upward trend in overall CA (12.09–39.22 per 10,000 births). The diagnosis rate before 22 gestational weeks constantly increased from 20.8 to 70.1% for trisomy 21 (Ptrend = 0.003). The prevalence rate ratio for maternal age of ≥ 35 years was higher than that for maternal age of 25–29 years for trisomy 21 (5.40, 95% confidence interval [CI] 4.59–6.35) and sex chromosomal abnormalities (3.28, 95% CI 2.48–4.33). Conclusions: The rising prevalence of CA in China may be attributable to the elevated maternal age and the innovation of prenatal diagnosis tools, Thus, studies should pay attention to the rare CA that were previously ignored, and select rational screening tools. [ABSTRACT FROM AUTHOR]

The primary aim of this review is to estimate the prevalence of ARSA both in euploid fetuses as well as in fetuses with Down Syndrome. Secondary objectives were to estimate the association of ARSA with cardiac anomalies and chromosomal defects, especially trisomy 21 and 22q11 deletion (DiGeorge Syndrome). The incidence of ARSA in normal population varies from 0.35% to 3.5%, based on different studies. Since the first reported association between ARSA and trisomy 21 in 2015 until today, several studies have emerged to confirm different degrees of this correlation. Indeed, ARSA appears to be a clinically useful prenatal ultrasound marker for trisomy 21. Particularly, most recent studies concluded that ARSA as a non-isolated finding can be used as screening for Down syndrome. However, when ARSA is an isolated finding, various studies proved that there is no significant correlation with Down syndrome. Apart from these, ARSA appears to be associated with other chromosomal abnormalities, such as 22q11 deletion, cardiac defects and other morphological anomalies. As a conclusion ARSA should be characterized as isolated or non-isolated, as the non – isolated ARSA appears to be a clinically useful marker of Down syndrome and thus, additional testing is required when diagnosed. [ABSTRACT FROM AUTHOR]

Objective: We retrospectively analyzed our center’s experience with the prenatal diagnosis of isolated perimembranous ventricular septal defects that underwent primary surgical repair in infancy. Methods: We identified patients born in Southern Nevada, between October 2012 and October 2020, with prenatal care that underwent surgical closure of an isolated large perimembranous ventricular septal defect between 1 and 12 months of age. The description at surgery defined ventricular septal defect morphology. We included only those with situs solitus, levocardia without dextroposition, and without any other cardiovascular abnormality. We analyzed prenatal detection rates for each of the eight years. Results: We identified 81 patients. Of the 81, 35 (43%) had trisomy 21. We identified no other aneuploidies in those that underwent surgical repair; however, 1 had a 15q13.3 deletion syndrome, and 1 had a 22 q11.2 deletion syndrome. Of the 81, 27 (33%) overall were prenatally diagnosed. Increasing prenatal detection rates strongly correlated with time (R = 0.92, p = .002). Conclusions: Trisomy 21 is common in isolated perimembranous ventricular septal defects undergoing primary repair in infancy. Further, prenatal detection rates significantly improved over time, up to 65% detection in the current years. [ABSTRACT FROM AUTHOR]

In the last decades, the screening for Down syndrome brought the 11- to 14-week scan to the forefront of modern pregnancy care. Initially just a nuchal scan as part of the combined test, it upgraded to a detailed anatomy scan that should be done always where the ultrasound machine and the expertise allow, as instructed by current guidelines. Though a lot of the anatomy can be assessed at this age, it is still mainly used only for the measurements necessary for the combined tests or for noninvasive prenatal testing, hence a lot of the structural anomalies are missed. Our paper focuses on cases in which the anatomy scan was not performed, and structural and chromosomal anomalies were missed. [ABSTRACT FROM AUTHOR]

• We investigated interference of anti-alkaline phosphatase antibodies (anti-ALP's). • The anti-ALP's interfered with the unconjugated estriol assay for maternal serum screening. • These efforts identified 17 of 160 samples at increased risk for erroneous results. • Four of the 17 had screen interpretations changes using pseudo-risk calculations. Unconjugated estriol (uE3) is an important biomarker in second trimester prenatal screening. Previous studies from our laboratory identified rare interference in the Beckman uE3 assay due to anti-ALP antibodies, which could be mitigated with a scavenger or heat-inactivated ALP (hALP). In the current study, 160 de-identified patient samples previously submitted for the Quad screen with low uE3 multiples of the median (MoM ≤0.50) were investigated for potential interference. A reagent pack spiking strategy with hALP was employed to understand if the interference could be identified and mitigated in a scalable manner. The 160 samples were measured using uE3 lot #920861 previously known to be subject to interference, lot #920861 spiked with hALP, and the vendor reformulated lot #922579. Samples were suspected to have interference if the percent difference in uE3 measurements was >50%. Pseudo-risks were calculated using a test patient environment to understand the screening impact due to the change in uE3 result. Seventeen of the 160 samples had uE3 results that were >50% different between the hALP spiked and non-spiked reagent pack. Both original lot #920861 with hALP and reformulated lot #922579 identified the same 17 patients as having interference in lot #920861. Analysis of screening risks using a test patient environment showed that assay interference could result in false positives for one trisomy 21 and three trisomy 18 post-test risk calculations. Our experiment of reagent pack spiking with hALP produced similar uE3 results to a reformulated reagent designed to address potential interference, demonstrating that this is a feasible strategy to screen for interference in a scalable manner. The vendor-provided reformulation addressed anti-ALP interference and improved the performance of the screen. [ABSTRACT FROM AUTHOR]

Background: Non-invasive prenatal testing (NIPT) as a screening method for trisomy 21 and other chromosomal abnormalities has been adopted widely across the globe. However, while many clinical validation studies have been performed, less is known regarding the patient experience with NIPT. This study explored how individuals experience NIPT in a pre- and post-test setting, where NIPT is broadly available as a primary screening method with the option of reporting beyond common trisomies.Methods: Participants were recruited using social media with a strategy designed to select individuals who had the option to have NIPT as part of the TRIDENT-2 study (In the Netherlands, NIPT is only available within the TRIDENT studies executed by the NIPT consortium. This research was done independently from the NIPT consortium.) in the Netherlands. The study used online questionnaires and semi-structured interviews. Both were developed around a patient experience framework consisting of seven themes: information, patient as active participant, responsiveness of services, lived experience, continuity of care and relationships, communication, and support.Results: Overall, 4539 questionnaire responses were analyzed and 60% of the respondents had experienced NIPT. Of those, 1.7% received a high-risk result for trisomy or another chromosomal copy number variant (referred to as an "additional finding"). Overall, participants felt they had received sufficient information and had control over their decision regarding whether or not to choose NIPT. The vast majority of respondents who had NIPT were positive about their experience and would use it again. Those with results showing an increased probability for trisomy or additional findings were more likely to report negative feelings such as tension and anxiety, and less likely to feel that they had been sufficiently prepared for the implications of their results.Conclusions: The patient experience with first-tier NIPT in the Netherlands was largely positive. Areas for improvement included counseling on the implications of screening and the different possible outcomes of NIPT, including additional findings that may be uncovered by expanding NIPT beyond the common trisomies. The experiences reported in this study may be useful for other countries intending to implement NIPT. [ABSTRACT FROM AUTHOR]

Objective: To examine the number of cases filed about Down syndrome in terms of its numbers, causes and consequences, to provide an overview of what doctors should pay attention to when informing and consulting patients and during follow-up and recommend solutions for decreasing the number of malpractice cases. (Discussing the legal aspect of the decisions is beyond the scope of this research.) Materials and Methods: 'Down', 'Down sendromu' 'Down's, 'trizomi 21', 'trisomi 21' and 'trisomy 21' was written to 'https:// karararama.yargitay.gov.tr/' and 'https://karararama.danistay.gov.tr/' web addresses search engines and the data was examined with Microsoft Excel or with R version 4.0.5 ( 2021-03-31) for bias and frequency table was used and the results were examined. Results: A total of 53 cases were found. 49 supreme court and 4 Council of State court decisions are found. The cases are from 27.10.2009 to 13.10.2021. Conclusion: A total of 39 different Down syndrome cases were examined, as 6 of the 53 cases were related to the same cases and 8 of them were cases not related to Down syndrome. 28 cases are "doctor negligence", 5 are "reckless killing", 1 "material mixing in the genetic center", 1 "unauthorized use of the child's photo", 1 "stealing money from the child", 1 "intentionally injuring the child", 1 'inheritance request for the child' and 1 on 'guardianship'. [ABSTRACT FROM AUTHOR]