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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]

When an increased nuchal translucency (>3.00 mm) is observed during the echographic examination of a foetus in the first trimester of pregnancy, an increased risk of chromosomopathy is considered, and the pregnant woman is offered the possibility of an invasive investigation. Here, we focused our attention on prenatal diagnosis issues in cases of foetuses with cytogenetically balanced reciprocal translocations. We report the finding of a cytogenetically balanced, de facto genomically unbalanced translocation that poses a challenge in a case of prenatal diagnosis, changing the risk of Down syndrome in a Zellweger syndromic spectrum risk (PEX3 deletion). At term, a healthy baby was born. This case teaches that prenatal diagnosis in cases of foetuses at increased risk of chromosomal abnormality imperatively requires molecular investigation in addition to a morphological karyotype. [ABSTRACT FROM AUTHOR]

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]

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]

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]

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]

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: 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]

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]

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]

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]

This article, titled "Prenatal detection of Down syndrome based on second and third trimester ultrasound scan," examines the incidence of Down Syndrome suspected on late trimester scans. The study analyzed the medical records of pregnant women who gave birth to babies with confirmed Down Syndrome. Out of 126 mothers, 80 had at least one prenatal scan, and 50 of them had abnormal findings on the scans. 15 fetuses were suspected with Down Syndrome, and further genetic testing confirmed the diagnosis in some cases. The article suggests that early prenatal diagnosis through first trimester screening programs could be beneficial for counseling and support. [Extracted from the article]

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]

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 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]

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]

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]

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: 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]

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: 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]

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]

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]

The 2022 Lasker-DeBakey Clinical Medical Research Award is presented to Yuk Ming Dennis Lo of the Chinese University of Hong Kong for the discovery of fetal DNA in maternal blood, leading to development of noninvasive prenatal testing for Down syndrome. [ABSTRACT FROM AUTHOR]

Background: A fast adoption of a non-invasive prenatal testing (NIPT) in clinical practice is a global tendency last years. Firstly, in Russia according a new regulation it was possible to perform a widescale testing of pregnant women in chromosomal abnormality risk. The aim of the study-to assess efficiency of using NIPT as a second-line first trimester screening test in Moscow.Methods: Based on the first trimester combined prenatal screening results 12,700 pregnant women were classified as a high-risk (cut-off ≥ 1:100) and an intermediate-risk (cut-off 1:101 - 1:2500) groups followed by whole genome NIPT. Women from high-risk group and those who had positive NIPT results from intermediate-risk group were considered for invasive prenatal diagnostic.Results: 258 (2.0%) samples with positive NIPT results were detected including 126 cases of trisomy 21 (T21), 40 cases of T18, 12 cases of T13, 41 cases of sex chromosome aneuploidies (SCAs) and 39 cases of rare autosomal aneuploidies (RAAs) and significant copy number variations (CNVs). Statistically significant associations (p < 0.05) were revealed for fetal fraction (FF) and both for some patient's (body mass index and weight) and fetus's (sex and high risk of aneuploidies) characteristics. NIPT showed as a high sensitivity as specificity for common trisomies and SCAs with an overall false positive rate 0.3%.Conclusions: NIPT demonstrated high sensitivity and specificity. As a second-line screening test it has shown a high efficiency in detecting fetus chromosomal anomalies as well as it could potentially lower the number of invasive procedures in pregnant women. [ABSTRACT FROM AUTHOR]

Since the infamous Supreme Court decision, Roe v. Wade, the United States has remained divided, each side unyielding to the other regarding the legal and moral issues surrounding abortion. The issues surrounding abortion have become progressively more politicized, thus threatening a woman's right to a safe and healthy termination of her pregnancy. Restrictions on a woman's ability to terminate a child with a genetic disorder, such as Down syndrome, highlight this concern. State restrictions on abortion that prohibit abortions based on a diagnosis of Down syndrome seek to prevent the stigmatization of the Down syndrome community. Regulations, such as these, that prevent a woman from electing a medically sound procedure based solely on her reason for doing so are unconstitutional. This Note explains the history of abortion jurisprudence and genetic abnormalities generally. Further, it discusses abortion law as it pertains to the exceedingly political regulation of abortions that follow a Down Syndrome diagnosis. Lastly, this Note addresses the released early draft opinion, written by Justice Samuel Alito that expressed the Court's intention to overturn Roe v. Wade. [ABSTRACT FROM AUTHOR]

Here we report a case of a 16q24.3 microdeletion KBG syndrome (KBGS) in a fetus. The absence of a well‐defined phenotype poses a challenge for genetic diagnosis. This report demonstrated that the high‐risk chromosome 21 trisomy could be the first manifestation of KBGS, as observed in this case. [ABSTRACT FROM AUTHOR]

Non-invasive prenatal testing ('NIPT') enables quick, safe and generally reliable screening during early pregnancy. NIPT is currently available in Australia for screening for conditions such as trisomy 21 ('Down Syndrome') which are immediately apparent at birth. NIPT may also be used in the future to detect adult-onset disorders and risk profiles for conditions which manifest later in life. Although expanded prenatal testing has the potential to enhance reproductive choice, the use of NIPT to detect adult-onset conditions raises significant ethical concerns about the welfare of the future child. In this article, we explore the legal and ethical issues raised by NIPT for adult-onset conditions. We make some preliminary proposals for regulating access to NIPT, which encourage prospective parents to consider the interests of the future child through careful genetic counselling. [ABSTRACT FROM AUTHOR]

Background: Down syndrome (DS), also known as trisomy 21 (T21), is the most common genetic disorder associated with intellectual disability. There are two methods commonly used for prenatal testing of DS: serum screening (SS) for biomarkers in maternal serum and noninvasive prenatal testing (NIPT) for aneuploidy by cell-free DNA (cfDNA) in maternal plasma. However, cost-effectiveness analyses of these two methods are mostly based on data derived from simulations with various models, with theoretical values calculated. In this study, we statistically analyzed clinical DS screening data and pregnancy outcomes during the follow-up of pregnant women in Zhuhai City, China. The economics of the two mainstream prenatal DS screening methods was evaluated from a public health perspective. Methods: A retrospective analysis was performed on the data of 17,363 pregnant women who received SS and NIPT during gestation in Zhuhai from 2018 to 2019, and a cost-effectiveness analysis was performed with four screening strategies. In strategy I, all pregnant women received SS, and those with T21 risk ≥1/270 had invasive prenatal diagnosis (IPD). In strategy II, all pregnant women received SS, those with T21 risk ≥ 1/270 had IPD, and those with 1/270 > T21 risk ≥ 1/1,000 had NIPT; then, women at high risk based on NIPT also had IPD. In strategy III, all pregnant women received SS, and those with T21 risk ≥1,000 had NIPT; then, women at high risk based on NIPT results had IPD. In strategy IV, all pregnant women received NIPT and those at high risk based on NIPT results had IPD. Finally, to assess the cost and effectiveness of DS screening, the total costs were calculated as the sum of screening and diagnosis as well as the direct and indirect economic burden during the average life cycle of DS patients. Results: A total of 22 of the 17,363 (1/789) pregnant women had DS, of which only one woman was over 35 years of age. SS detected 1,024 cases at high risk of T21 (≥1/270), 8 cases were true positive, with a positive predictive value of 0.78% and a detection rate of 36.4%. NIPT detected 27 cases at high risk of T21 (Z ≥ 3) and 22 cases of DS, with a positive predictive value of 81.5% and a detection rate of 100%. Strategy I had the largest total cost of 65.54 million CNY, strategy II and III had similar total costs of 40 million CNY, and strategy IV had the lowest total cost of 14.91 million CNY. By comparison, the screening strategy with NIPT alone had the highest health economic value for DS. Conclusions: SS was greatly affected by nuchal translucency and the accuracy of gestational age measured by ultrasonography. Unstandardized ultrasonography was an important reason for the low DS detection rate with SS. The influence of interfering factors on NIPT was much lower than in SS. NIPT can be used as an alternative to SS and as a primary screening strategy of prenatal DS screening for secondary prevention and control of birth defects. NIPT greatly decreased the frequency of IPD and the miscarriages associated with IPD, saved the limited medical and health resources, and greatly increased DS detection rate. Therefore, NIPT has great social and economic benefits. [ABSTRACT FROM AUTHOR]

Introduction: Fetal nasal bone hypoplasia has been proven to be a strong marker for trisomy 21 during second trimester ultrasonography. Rather than evaluating the nasal bone hypoplasia according to the nomograms, it may be possible to evaluate it with a more practical and specific method.Material and methods: Retrospectively collected data were provided from the saved and stored patient data between 2012 and 2017. Nasal bone length and nasal tip length were measured and the ratio was calculated. The ratio ≤ 1/3 was defined as the threshold ratio for the definition of the marker. Nasal bone nasal tip length (NB/NL) ratio values were compared among groups with trisomy 21 and euploid fetuses.Results: A total of 59 fetuses had trisomy 21 and 2304 euploid fetuses were included in the study. The ratio of nasal bone to nasal tip length was 1/3 and below in 21/59 (35.5%) of fetuses with trisomy 21 whereas this ratio was 31/2304 (1.3%) in euploid fetuses. The difference was statistically significant (p < 0.001). Sensitivity, specificity, positive likelihood ratio and negative likelihood ratio of nasal bone/nasal tip ratio ≤ 1/3 were 35.5%, 98.6%, 26.4 and 0.6 for Down syndrome, respectively.Conclusions: This study suggested that the nasal bone to nasal tip length ratio may be a new promising and practical sonographic marker in the second trimester genetic sonography. Although its sensitivity is not high, it seems to be more practical and specific than the evaluation of fetal nasal bone length. [ABSTRACT FROM AUTHOR]

Background: Down Syndrome (DS) can be diagnosed with prenatal invasive diagnostic tests to the risky population. In this study, it was aimed to propound the status of the oxidant/antioxidant system and interleukin-6 (IL-6)/interleukin-10 (IL-10) levels in the amniotic fluids of pregnant women with DS diagnosed child by amniocentesis method. Methods: According to the results of the genetic examination of the amniotic fluid obtained from the pregnant women who have been admitted to Zekai Tahir Burak Women's Health Training and Research Hospital, Genetic Center, and have undergone amniocentesis, amniotic fluid of 18 pregnant women who are carrying babies with DS and amniotic fluid of 36 pregnant women with healthy babies were included in the study under two groups. Study group (Group 1) consists of the amniotic fluid of the pregnant women carrying babies with DS while control group (Group 2) consists of the amniotic fluid of the pregnant women carrying healthy babies. In the samples taken, malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and xanthine oxidase (XO), catalase (CAT), adenosine deaminase (ADA), nitric oxide (NO), nitric oxide synthase (NOS) have been determined by spectrophotometric methods, as the measurements of IL-6 and IL-10 tests were carried out by ELISA method. In statistical evaluation, Student's t test and spearman correlation analysis were used. Results for P <0.05 were considered statistically significant. Results: According to the findings of the study, SOD level in Group 1 increased statistically significantly when compared to Group 2 (p <0.05). However, CAT and IL-6 in Group 1 were found to be statistically significantly reduced compared to Group 2 (p <0.05). There was no significant difference between the two groups in terms of MDA, GSH-Px, XO, NO, NOS, ADA and IL-10 levels (p> 0.05). Conclusion: Consequently, SOD enzyme activity was found to be increased in the group with DS. We think that SOD gene localized on the 21st chromosome caused this result. In addition, compared to the control group, the absence of CAT and GSH-Px in the amniotic fluids of pregnant women carrying babies with DS, that can eliminate the excessive amount of H2O2 caused by the activity of the SOD enzyme causes a serious oxidative stress. In parallel with these data, using the SOD enzyme as a marker in prenatal diagnosis can be a useful approach. For this purpose, further studies should be carried out with higher numbers. [ABSTRACT FROM AUTHOR]

Purpose: Women with high-risk pregnancies are often required to make choices about further prenatal testing for Down syndrome, but the decisional conflict they face is poorly understood. This study aimed to test the validity and reliability of the Mandarin version of the decisional conflict scale (M-DCS) in Chinese women with high-risk pregnancies making choices about further prenatal testing for Down syndrome. Patients and Methods: A methodological study was conducted to determine the psychometric properties of the M-DCS, specially, reliability and content, construct, and concurrent validity. The convenience sample comprised 240 pregnant women with high risk for Down syndrome attending the out-patient clinic of the study hospital in Guangzhou, China. Results: The five-factor model of M-DCS was supported by confirmatory factor analysis with a satisfactory fit to the data (RMSEA < 0.08, RMR < 0.05, GFI, CFI, NFI, and IFI all > 0.90, except AGFI=0.88 PNFI = 0.76). The internal consistency of the M-DCS was high, with Cronbach's ? of 0.94. Conclusion: The reliability and validity (content, construct, and concurrent) of the M-DCS were all demonstrated as good. This instrument is an important tool for researchers and health-care providers working with women with high-risk pregnancies who need to make choices about further prenatal testing for Down syndrome. [ABSTRACT FROM AUTHOR]

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

The objective of the study was to identify the types of studies and the most investigated topics in the population with Down syndrome in Chile and to describe the type of sample used and the age range during the period from 2011 to 2020. A documentary study was carried out (systematic review). The Scopus database was used to search for information. The key words used were: Down Syndrome and Chile. The period was 2011 to 2020. The information was recorded on an observation sheet. Thirty studies were identified. A total of 56,7 % (n = 17) were descriptive (cross-sectional) studies, 10,0 % (n = 3) were experimental studies. The study topics mostly cover social issues (8 studies) and anthropometric aspects (7 studies), followed by physiological, psychological, hematological, biomechanical, prenatal tests and sleep disorders. The age range of the sample used by the studies ranges from prenatal to 28 years and the sample size ranges from one to 1922 participants. The results of the study suggest the urgent need to develop experimental and longitudinal studies, the inclusion of middle-aged and older adults, as well as prenatal samples, to explore issues related to physiological, psychological, hematological, biomechanical variables and prenatal diagnostic tests, since they are relevant to the independence and autonomy of people with Down syndrome. [ABSTRACT FROM AUTHOR]

Background: To examine disparities by maternal place of birth in the opportunity to make an informed choice about Down syndrome screening, in France, where the national guidelines recommend that physicians offer it to all pregnant women.Methods: We used population-based data from the nationally representative French Perinatal Surveys in 2010 and 2016 (N=24,644 women) to analyze the opportunity for an informed choice for prenatal screening, measured by a composite indicator.Results: Among the 24 644 women in the study, 20 612 (83.6%) were born in France, 861 (3.5%) elsewhere in Europe, 1550 (6.3%) in North Africa, and 960 (3.9%) in sub-Saharan Africa. The probability of screening was lower for women born outside France. After adjustment for survey year, maternal age, parity, education level, and the maternity unit's level of perinatal care, women born outside France had the opportunity to make an informed choice less often than women born in France. This association remained essentially the same even after excluding women without adequate prenatal care.Conclusions: Women born outside France, including those with adequate prenatal care, had less opportunity than women born in France to make an informed choice about prenatal screening for Down syndrome. [ABSTRACT FROM AUTHOR]

Background/aim: Although cutting edge procedures such as cell-free fetal DNA isolation from maternal blood are now available, invasive prenatal tests are still being used extensively for prenatal diagnosis. The study aims to evaluate the demographic data, indications, and cytogenetic results of 9297 results of patients who underwent prenatal invasive testing for genetic analysis that were referred for the last 20 years in a University Medical Genetics Center. Materials and methods: The records of 8363 amniocenteses, 626 chorionic villus, and 308 cordocenteses samples were retrospectively evaluated and analyzed regarding referral reasons, indications and their cytogenetic results. The total numbers and the percentages of each group were recorded; Chi-square and logistic regression analyses were performed to give the statistical likelihood of different events. Results: The number of referrals decreased significantly after 2009. Risk of having trisomy 21 as well as trisomy 13 and 18 significantly increased in parallel with advanced maternal age. When the 21–25 age group was compared to the older age groups in terms of having a trisomy 21 pregnancy, the risk doubled in the 36–40, 5 times higher in 41–45 and 10-fold in 46–50 age groups. No significant linear correlation between maternal serum screening test results and trisomy 21 was found, however the difference between the pregnancies whom cut-off value above and below 1/250 in maternal serum screening test were significant. Conclusion: These data have provided useful information on the frequency of referrals to the reference genetics department, and the feasibility of genetic services. By reviewing the indications and their corresponding results, we can offer invaluable insights that will be useful in genetic counseling and also in the development of more effective genetic strategies. [ABSTRACT FROM AUTHOR]

Background: Down syndrome is characterized by trisomy 21 or partial duplication of chromosome 21. Extensive studies have focused on the identification of the Down Syndrome Critical Region (DSCR). We aim to provide evidence that duplication of 21q21.1-q21.2 should not be included in the DSCR and it has no clinical consequences on the phenotype. Case presentation: Because serological screening was not performed at the appropriate gestational age, noninvasive prenatal testing (NIPT) analysis was performed for a pregnant woman with normal prenatal examinations at 22 weeks of gestation. The NIPT results revealed a 5.8 Mb maternally inherited duplication of 21q21.1-q21.2. To assess whether the fetus also carried this duplication, ultrasound-guided amniocentesis was conducted, and the result of chromosomal microarray analysis (CMA) with amniotic fluid showed a 6.7 Mb duplication of 21q21.1-q21.2 (ranging from position 18,981,715 to 25,707,009). This partial duplication of 21q21.1-q21.2 in the fetus was maternally inherited. After genetic counseling, the pregnant woman and her family decided to continue the pregnancy. Conclusion: Our case clearly indicates that 21q21.1-q21.2 duplication is not included in the DSCR and most likely has no clinical consequences on phenotype. [ABSTRACT FROM AUTHOR]

Background: Fetoplacental discrepancies occur in approximately 1–2% of analyzed prenatal cases. They are typically due to confined placental mosaicism, where an aberration is observed in the placental cells but not found in the fetal cells. Confined placental mosaicism usually involves aneuploidies and more sparsely structural chromosomal aberrations. To the best of our knowledge, this is the first reported case of a discrepancy in the analyses of chorionic villus sampling and amniocentesis involving two different structural chromosomal aberrations of chromosome 21. Case presentation: We report a 33-year-old woman who was referred for a non-invasive prenatal testing due to an increased risk of trisomy 21 gleaned from a combined ultrasound and blood test. The non-invasive prenatal testing showed an increased risk of trisomy 21 with a normalized coverage signal that did not match the fetal cell-free DNA fraction. Rapid aneuploidy detection performed on uncultured chorionic villi indicated mosaicism for trisomy 21. The follow-up analyses revealed discordant chromosomal aberrations: 46,XY,der(21)t(10;21)(p11.21;q10) in the analysis of the chorionic villus sampling and 46,XY, + 21,der(21;21)(q10;q10) in the analysis of the amniocentesis. Thus, the analyses indicated mosaicism for a cell line containing trisomy 21 and a cell line containing a partially duplicated short arm of chromosome 10 in the chorionic villi and complete trisomy 21 resulting from an isochromosome 21 in the amniotic fluid. The analyses of the lymphocytes and the fibroblasts of the woman were normal. Conclusions: We propose a multiple-step mechanism as a possible theoretical explanation for the formation of these discordant structural chromosomal aberrations in the chorionic villi and amniotic fluid. With this case report, we want to highlight the importance of understanding the possible underlying embryological mechanisms when interpreting results from different prenatal analyses. [ABSTRACT FROM AUTHOR]

Background: Small supernumerary marker chromosomes (sSMCs) are chromosomal fragments with abnormal structures found in patients with fertility problems and developmental delay. They may be detected in amniotic cell karyotypes. sSMCs are categorized as hereditary or de novo. Here, we describe a case of prenatal de novo 4q11q12 sSMC and its molecular cytogenetic features which had no apparent phenotypic abnormality. Case: The fetus of a 36-yr-old pregnant woman was detected positive for Down's syndrome (trisomy 21) at the 16th wk of gestation. Quantitative fluorescent polymerase chain reaction technique was applied for the rapid detection of numerical aneuploidy of chromosomes X, Y, 13, 18, and 21 microsatellites. Array comparative genomic hybridization (array CGH) technique was also conducted following the karyotype analysis of amniotic cells. The karyotype analysis was also done for the parents. Quantitative fluorescent polymerase chain reaction result revealed a male fetus with a normal chromosomal pattern, while the amniocentesis karyotype analysis identified a male fetus with a marker chromosome (47, XY, +mar), and the sSMC were existing in 100% of amniocyte metaphase spreads. The parents' normal karyotypes indicated that the sSMC was de novo. Array CGH analysis revealed a 6.48-Mb duplication at 4q11q12. Eventually, the parents decided to terminate the pregnancy by legal abortion. Conclusion: Our study highlights the importance of the application of array CGH in combination with karyotype analysis for rapid and precise prenatal diagnosis of partial aneuploidy region. [ABSTRACT FROM AUTHOR]

Background: This paper describes the clinical practice and performance of cell-free DNA sequencing-based non-invasive prenatal testing (NIPT) as a screening method for fetal trisomy 21, 18, and 13 (T21, T18, and T13) and sex chromosome aneuploidies (SCA) in a general Italian pregnancy population. Methods: The AMES-accredited laboratory offers NIPT in maternal blood as a screening test for fetal T21, T18, T13 and SCA. Samples were sequenced on a NextSeq 550 (Illumina) using the VeriSeq NIPT Solution v1 assay. Results: A retrospective analysis was performed on 36,456 consecutive maternal blood samples, including 35,650 singleton pregnancies, 800 twin pregnancies, and 6 triplet pregnancies. Samples were tested between April 2017 and September 2019. The cohort included 46% elevated-risk and 54% low-risk patients. A result indicative of a classic trisomy was found in 356 (1%) of singleton or twin samples: 254 T21, 69 T18, and 33 T13. In addition, 145 results (0.4%) were indicative of a SCA. Of the combined 501 screen-positive cases, 484 had confirmatory diagnostic testing. NIPT results were confirmed in 99.2% (247/249) of T21 cases, 91.2% (62/68) of T18 cases, 84.4% (27/32) of T13 cases, and 86.7% (117/135) of SCA cases. In the 35,955 cases reported as unaffected by a classic trisomy or SCA, no false negative cases were reported. Assuming that false negative results would be reported, the sensitivity of NIPT was 100.00% for T21 (95% Cl 98.47–100.0), T18 (95% Cl 94.17–100.0), and T13 (95% Cl 87.54–100.0). The specificities were 99.99% (95% Cl 99.98–100.0), 99.98% (95% Cl 99.96–100.0), 99.99% (95% Cl 99.97–100.0), and 99.95% (95% Cl 99.92–99.97) for T21, T18, T13, and SCA, respectively. Conclusion: This retrospective analysis of a large cohort of consecutive patients who had whole-genome sequencing-based NIPT for classic trisomies and SCA shows excellent detection rates and low false positive rates. [ABSTRACT FROM AUTHOR]

Background: This paper describes the clinical practice and performance of cell-free DNA sequencing-based non-invasive prenatal testing (NIPT) as a screening method for fetal trisomy 21, 18, and 13 (T21, T18, and T13) and sex chromosome aneuploidies (SCA) in a general Italian pregnancy population. Methods: The AMES-accredited laboratory offers NIPT in maternal blood as a screening test for fetal T21, T18, T13 and SCA. Samples were sequenced on a NextSeq 550 (Illumina) using the VeriSeq NIPT Solution v1 assay. Results: A retrospective analysis was performed on 36,456 consecutive maternal blood samples, including 35,650 singleton pregnancies, 800 twin pregnancies, and 6 triplet pregnancies. Samples were tested between April 2017 and September 2019. The cohort included 46% elevated-risk and 54% low-risk patients. A result indicative of a classic trisomy was found in 356 (1%) of singleton or twin samples: 254 T21, 69 T18, and 33 T13. In addition, 145 results (0.4%) were indicative of a SCA. Of the combined 501 screen-positive cases, 484 had confirmatory diagnostic testing. NIPT results were confirmed in 99.2% (247/249) of T21 cases, 91.2% (62/68) of T18 cases, 84.4% (27/32) of T13 cases, and 86.7% (117/135) of SCA cases. In the 35,955 cases reported as unaffected by a classic trisomy or SCA, no false negative cases were reported. Assuming that false negative results would be reported, the sensitivity of NIPT was 100.00% for T21 (95% Cl 98.47–100.0), T18 (95% Cl 94.17–100.0), and T13 (95% Cl 87.54–100.0). The specificities were 99.99% (95% Cl 99.98–100.0), 99.98% (95% Cl 99.96–100.0), 99.99% (95% Cl 99.97–100.0), and 99.95% (95% Cl 99.92–99.97) for T21, T18, T13, and SCA, respectively. Conclusion: This retrospective analysis of a large cohort of consecutive patients who had whole-genome sequencing-based NIPT for classic trisomies and SCA shows excellent detection rates and low false positive rates. [ABSTRACT FROM AUTHOR]

Background: Trisomy 19q is a recognizable syndrome and associated with a wide spectrum of clinical phenotypes in clinic. The purpose of this study was to explore the prenatal phenotypes of 19q13.42 duplication, which was rarely reported in clinic. Case presentation: Three pregnant women presenting diverse indications for prenatal diagnosis accepted amniocentesis: increased nuchal translucency and fetal pyelic separation (case 2) and high risk of maternal serum screening for Down syndrome (case 1 and case 3). Case 1 and case 2 shared similar duplicated locus in the region of 19q13.42, encompassing part NLRP12 gene. The latter inherited the chromosomal duplication from the mother with normal phenotypes. Case 3 carried a 1.445 Mb duplication in the 19q13.42q13.43 region. It was proposed that evolutionary duplication of NLRP12 gene could have a causative role in autoinflammatory diseases development. The genotype–phenotype correlation depends mainly on the duplicated size and functional genes involved, which is still yet to be determined. All pregnant women chose to continue the pregnancy and delivered healthy children with no apparent abnormalities. Conclusions: The 19q13.42 microduplications in our study were the smallest fragments compared to previous literature. Our findings enriched the prenatal phenotypes for this chromosomal microscopic imbalance. It was proposed that long term follow up analysis should be guaranteed till adulthood to determine whether there will be other emerging clinical symptoms and developmental-behavioral disorders for such carriers. [ABSTRACT FROM AUTHOR]

Objective: To investigate factors associated with fetal fraction and to develop a new predictive method for low fetal fraction before noninvasive prenatal testing. Methods: The study was a retrospective cohort analysis based on the results of noninvasive prenatal testing, complete blood count, thyroxin test, and Down's syndrome screening during the first or second trimester in 14,043 pregnant women. Random forests algorithm was applied to predict the low fetal fraction status (fetal fraction < 4%) through individual information and laboratory records. The performance of the model was evaluated and compared to predictions using maternal weight. Results: Of 14,043 cases, maternal weight, red blood cell, hemoglobin, and free T3 were significantly negatively correlated with fetal fraction while gestation age, free T4, pregnancy-associated plasma protein-A, alpha-fetoprotein, unconjugated estriol, and β-human chorionic gonadotropin were significantly positively correlated with fetal fraction. Compared to predictions using maternal weight as an isolated parameter, the model had a higher area under the curve of receiver operating characteristic and overall accuracy. Conclusions: The comprehensive predictive method based on combined multiple factors was more effective than a single-factor model in low fetal fraction status prediction. This method can provide more pretest quality control for noninvasive prenatal testing. [ABSTRACT FROM AUTHOR]

Background: Massively parallel sequencing of maternal cell-free DNA (cfDNA) is widely used to test fetal genetic abnormalities in non-invasive prenatal testing (NIPT). However, sequencing-based approaches are still of high cost. Building upon previous knowledge that placenta, the main source of fetal circulating DNA, is hypomethylated in comparison to maternal tissue counterparts of cfDNA, we propose that targeting either unmodified or 5-hydroxymethylated CG sites specifically enriches fetal genetic material and reduces numbers of required analytical sequencing reads thereby decreasing cost of a test. Methods: We employed uTOPseq and hmTOP-seq approaches which combine covalent derivatization of unmodified or hydroxymethylated CG sites, respectively, with next generation sequencing, or quantitative real-time PCR. Results: We detected increased 5-hydroxymethylcytosine (5hmC) levels in fetal chorionic villi (CV) tissue samples as compared with peripheral blood. Using our previously developed uTOP-seq and hmTOP-seq approaches we obtained whole-genome uCG and 5hmCG maps of 10 CV tissue and 38 cfDNA samples in total. Our results indicated that, in contrast to conventional whole genome sequencing, such epigenomic analysis highly specifically enriches fetal DNA fragments from maternal cfDNA. While both our approaches yielded 100% accuracy in detecting Down syndrome in fetuses, hmTOP-seq maintained such accuracy at ultra-low sequencing depths using only one million reads. We identified 2164 and 1589 placenta-specific differentially modified and 5-hydroxymethylated regions, respectively, in chromosome 21, as well as 3490 and 2002 Down syndrome-specific differentially modified and 5-hydroxymethylated regions, respectively, that can be used as biomarkers for identification of Down syndrome or other epigenetic diseases of a fetus. Conclusions: uTOP-seq and hmTOP-seq approaches provide a cost-efficient and sensitive epigenetic analysis of fetal abnormalities in maternal cfDNA. The results demonstrated that T21 fetuses contain a perturbed epigenome and also indicated that fetal cfDNA might originate from fetal tissues other than placental chorionic villi. Robust covalent derivatization followed by targeted analysis of fetal DNA by sequencing or qPCR presents an attractive strategy that could help achieve superior sensitivity and specificity in prenatal diagnostics. [ABSTRACT FROM AUTHOR]

Objective: To determine the outcome of chorionic villus sampling for prenatal diagnosis of inherited diseases. Methodology: This descriptive study was conducted on 70 antenatal ladies having 11 to 14 weeks singleton pregnancy and with history of genetic disorders in family or children. It was carried in the Department of Obstetrics and Gynaecology, Lady Reading Hospital, Peshawar. Chorionic villus sampling (CVS) was performed by Obstetrics and Gynae consultants via transabdominal route under local anaesthesia and ultrasound guidance. Written informed consent was taken from all the participating couples before starting the process. By using SPSS version 23, statistical analysis was done. Results: A total of 70 samplings were done. Miscarriage as a result of the procedure occurred in 1/70 (1.42%), significant pain requiring intramuscular analgesia occurred in 40 (57%) patients and there were no reported cases of infection. Failure to retrieve sample occurred in 4 (5.7%) patients requiring repeat procedure after 10 days. 3 (4.2%) patients reported vaginal bleeding within a week after the procedure. After DNA analysis of the submitted samples, it showed thalassemia major 15 (21.42%), thalassemia minor 30 (42.85%), no mutation 22 (31.42%) and down syndrome 1 (1.42%). Conclusion: Chorionic villus sampling was found to be a safe procedure for prenatal diagnosis of genetic disorders in first trimester. [ABSTRACT FROM AUTHOR]