Down Syndrome Screening Research Articles

Triple test screening for Down syndrome: an Egyptian-tailored study.

BackgroundThe incidence of Down syndrome (DS) in Egypt varies between 1∶555 and 1∶770 and its screening by triple test is becoming increasingly popular nowadays. Results, however, seem inaccurate due to the lack of Egyptian-specific information needed for risk calculation and a clear policy for programme implementation. Our study aimed at calculation and validation of the triple marker medians used in screening Egyptian females as well as to recommend programme conventions to unify screening in this country.MethodsThe study was conducted on 668 Egyptian women, in weeks 15–20 of pregnancy as proven by sonar. Chorionic gonadotropin (CG), α-fetoprotein (AFP) and unconjugated oestriol (uE3) were measured on Siemens Immulite analyzer. Medians of the three parameters were calculated, regressed against gestational age (GA) and weighted by the number of participants/week. Equations were derived to adjust each parameter to the maternal weight and were centered on the median Egyptian weight. Prisca software was fed with the above data, multiples-of-median (MoM) and DS risks were calculated and the screening performance was evaluated at a mid-trimester risk cutoff of 1∶270.ResultsLog-linear [AFP/uE3 = 10(A+B*GA)] and exponential equations [CG = A*e (B*GA)] were derived and the regressed medians were found to follow similar patterns to other Asian and Western medians. Oestriol was always lowest (even halved) while CG and AFP were intermediate. A linear reciprocal model best fitted weight distribution among Egyptians and successfully adjusted each parameter to a weight of 78.2 kg. Epidemiological monitoring of these recommendations revealed satisfactory performance in terms of 6.7% initial positive rate and 1.00 grand MoM.ConclusionsAdoption of the above recommendations is hoped to pave the way to a successful DS screening programme tailored to Egyptian peculiarities.

Serological prenatal screening and diagnosis for Down syndrome

Objective: This study aimed to review and summarize the recent first-trimester and second-trimester prenatal screening and sequential prenatal screening to analyze the role of the existing prenatal screening system in the secondary prevention of birth defects. Materials and Methods: This study included 3,665 cases of 14~20-week pregnant women that underwent prenatal screening using double serum alphafetoprotein (AFP) and beta-human chorionic gonadotropin (β-hCG) and ultrasound screening; 512 cases of 9~12-week pregnant women underwent triple serological detection of serum β-hCG, pregnancy-associated plasma protein A (PAPP-A), and nuchal translucency (NT) for early screening. Results: The overall screening was with a high-risk rate of 8.52%. Among 356 cases of high-risk pregnant women, a total of 308 cases underwent karyotype analysis of fetal amniotic fluid cells. Of these, five cases of trisomy 21, one case of trisomy 18 and one case of “47, XXY” were diagnosed; among 37 cases of neural tube defect (NTD)-affected high-risk pregnant women, one case of anencephalus, and one case of open spina bifida were diagnosed. Conclusion: The overall detection rate for chromosome abnormalities was about 3.25% in the existing screening system, which could effectively prevent these seriously teratogenic fetuses from being born.

Major congenital anomalies in babies born with Down syndrome: a EUROCAT population-based registry study.

Previous studies have shown that over 40% of babies with Down syndrome have a major cardiac anomaly and are more likely to have other major congenital anomalies. Since 2000, many countries in Europe have introduced national antenatal screening programs for Down syndrome. This study aimed to determine if the introduction of these screening programs and the subsequent termination of prenatally detected pregnancies were associated with any decline in the prevalence of additional anomalies in babies born with Down syndrome. The study sample consisted of 7,044 live births and fetal deaths with Down syndrome registered in 28 European population-based congenital anomaly registries covering seven million births during 2000-2010. Overall, 43.6% (95% CI: 42.4-44.7%) of births with Down syndrome had a cardiac anomaly and 15.0% (14.2-15.8%) had a non-cardiac anomaly. Female babies with Down syndrome were significantly more likely to have a cardiac anomaly compared to male babies (47.6% compared with 40.4%, P < 0.001) and significantly less likely to have a non-cardiac anomaly (12.9% compared with 16.7%, P < 0.001). The prevalence of cardiac and non-cardiac congenital anomalies in babies with Down syndrome has remained constant, suggesting that population screening for Down syndrome and subsequent terminations has not influenced the prevalence of specific congenital anomalies in these babies.

Contingent screening for Down syndrome: A pilot study

ObjectiveTo evaluate the efficacy and practicality of Contingent screening model for detection of Down syndrome and other aneuploidies. MethodsFive hundred women with singleton pregnancies between gestational ages 11.3–13.6 weeks at a crown rump length (CRL) 45–84 mm were enrolled. A one step approach comprising of nuchal translucency (NT) measurement along with assessment of serum analytes for plasma associated placental protein A (PAPP-A) and free beta human chorionic gonadotrophin (β-HCG) was followed. Based on these values, women were categorized as high risk, intermediate risk or low risk. Women with low risk were classified as screen negative and no further testing was offered to them. Those in the high risk category were classified as screen positive and were offered immediate chorionic villus sampling. Women in the intermediate risk group went through second trimester triple test, and after incorporating first trimester risk along with triple test risk, they were finally categorized as screen positive (risk ≥ 1 in 250) or negative (risk < 1 in 250). Those with risk ≥ 1 in 250 underwent amniocentesis. Pregnancies were followed up till the birth of the baby. All newborns were examined for features of chromosomal disorders. ResultsContingent screening had a detection rate (DR) of 97.9% at a false positive rate (FPR) of 2.04% for Down syndrome (Trisomy 21), and overall DR of 98% at an FPR of 2.02% for all aneuploidies. ConclusionContingent model of screening is feasible, practical and cost effective in developing countries with comparable Detection Rate and False Positive Rate to Integrated screening model.

MacKellar, C. and Bechtel, C. (eds) The Ethics of the New Eugenics. New York: Berghahn. 2014. 242pp £60.00 (hbk) ISBN: ISBN 978–1‐78238–120–4 £60.00 (ebk) ISBN: 978–1‐78238–121–1

Acknowledgments A Note on the Text Abbreviations and Acronyms Introduction Chapter 1. The History of Eugenics Chapter 2. General Introduction to Eugenic Procedures Chapter 3. General Ethical Discussion Chapter 4. Arguments Supporting the New Eugenics Chapter 5. Arguments Opposing the New Eugenics Conclusion Appendix I: Past and Present Personalities Supporting Eugenic Policies Appendix II: Scottish Council on Human Bioethics Recommendations on Eugenics Glossary of Terms Bibliography

First-Trimester Screening for Down Syndrome with Serum Sampling at Different Gestational Ages: The Effect on Screening Performance

Introduction: The objective of this study was to evaluate the performance of first-trimester Down syndrome (DS) screening with serum sampling at different weeks of gestation. Material and Methods: We studied 35,431 singleton pregnancies (2005-2011), including 145 DS cases. Screening performance was determined in different maternal age groups with serum sampling between weeks 9 + 0 and 13 + 6. Results: No significant differences were found between the detection rates at different gestational weeks. The false-positive rate (FPR) in week 9 (6%) was comparable to the FPR in week 10 (6.5%; p = 0.214), whereas it was significantly lower compared to weeks 11 (7.2%; p = 0.007), 12 (7.4%; p = 0.003) and 13 (8.5%; p < 0.001). The odds of receiving a false-positive result was significantly increased with serum sampling in week 11 (OR 1.32, 95% CI 1.08-1.63; p = 0.008) for women ≥36 years and from week 12 onwards (OR 1.28, 95% CI 1.01-1.61; p = 0.04) for women <36 years. There were no differences in mean log₁₀ multiple of the median values of pregnancy-associated plasma protein-A, free β-human chorionic gonadotrophin or nuchal translucency between both age groups, nor in mean maternal age between the different gestational weeks in either age group. Discussion: Early serum sampling (<11 weeks) resulted in higher screening performance. The impact of the increase in the FPR was highest in women ≥36 years.

Screening for Down syndrome

Screening for Down Syndrome was initially only related to maternal age and has successively developed by introducing biochemical markers and algorithms to estimate the risk for particularly trisomy 21 and 18. We now have a long experience of screening with four biochemical markers, alpha-fetoprotein, total hCG, unconjugated estriol and free β-hCG during the second trimester. Screening is now moving towards screening in the first trimester using a combination of ultrasound (Nuchal Translucency) and the maternal serum biochemical markers free β-hCG and Pregnancy Associated Plasma Protein-A (PAPP-A). This has become known as the combined test. Several maternal and pregnancy factors which can influence the concentrations of biochemical markers are discussed. The possibilities of screening for other aneuploidies in the first trimester and an outline of recent methods to improve overall screening performance are highlighted and the review will suggest some possible options for the future in which Cell Free DNA techniques may become part of an improved overall screening strategy. In conclusion it is emphasized that the time has come to invert the Pyramid of Antenatal Care to focus on the 11–13 week assessment.

Inhibin at 90: from discovery to clinical application, a historical review.

When it was initially discovered in 1923, inhibin was characterized as a hypophysiotropic hormone that acts on pituitary cells to regulate pituitary hormone secretion. Ninety years later, what we know about inhibin stretches far beyond its well-established capacity to inhibit activin signaling and suppress pituitary FSH production. Inhibin is one of the major reproductive hormones involved in the regulation of folliculogenesis and steroidogenesis. Although the physiological role of inhibin as an activin antagonist in other organ systems is not as well defined as it is in the pituitary-gonadal axis, inhibin also modulates biological processes in other organs through paracrine, autocrine, and/or endocrine mechanisms. Inhibin and components of its signaling pathway are expressed in many organs. Diagnostically, inhibin is used for prenatal screening of Down syndrome as part of the quadruple test and as a biochemical marker in the assessment of ovarian reserve. In this review, we provide a comprehensive summary of our current understanding of the biological role of inhibin, its relationship with activin, its signaling mechanisms, and its potential value as a diagnostic marker for reproductive function and pregnancy-associated conditions.

Evaluation of non-invasive prenatal testing (NIPT) for aneuploidy in an NHS setting: a reliable accurate prenatal non-invasive diagnosis (RAPID) protocol.

BackgroundNon-invasive prenatal testing (NIPT) for aneuploidies is now available through commercial companies in many countries, including through private practice in the United Kingdom (UK). Thorough evaluation of service delivery requirements are needed to facilitate NIPT being offered more widely within state funded healthcare systems such as the UK’s National Health Service (NHS). Successful implementation will require the development of laboratory standards, consideration of stakeholder views, an analysis of costs and development of patient and health professional educational materials.Methods/DesignNIPT will be offered in an NHS setting as a contingent screening test. Pregnant woman will be recruited through six maternity units in England and Scotland. Women eligible for Down’s syndrome screening (DSS) will be informed about the study at the time of booking. Women that choose routine DSS will be offered NIPT if they have a screening risk ≥1:1000. NIPT results for trisomy 21, 18, 13 will be reported within 7–10 working days. Data on DSS, NIPT and invasive testing uptake, pregnancy outcomes and test efficacy will be collected. Additional data will be gathered though questionnaires to a) determine acceptability to patients and health professionals, b) evaluate patient and health professional education, c) assess informed choice in women accepting or declining testing and d) gauge family expenses. Qualitative interviews will also be conducted with a sub-set of participating women and health professionals.DiscussionThe results of this study will make a significant contribution to policy decisions around the implementation of NIPT for aneuploidies within the UK NHS. The laboratory standards for testing and reporting, education materials and counselling strategies developed as part of the study are likely to underpin the introduction of NIPT into NHS practice.NIHR Portfolio Number13865

Male Partners’ Involvement Towards Prenatal Screening And Diagnostic Testing For Down Syndrome

Introduction: Now, male partners’ involvement in prenatal screening and diagnostic testing for Down syndrome is becoming increasingly recognized as well to ensure that parents are well informed of the risks and benefits of screening. The aim of study was to understand the degree of male partners’ involvement during pregnancy in Singapore population. Methods: A cross-sectional survey of male partners’ attending prenatal counseling was performed. The instrument used to measure the level of involvement is a self-assessment questionnaire that identifies the role of male partners with a Likert scale. Descriptive statistics was used to analyze data gained. Result: A total of 107 participants completed the questionnaire. Sixty-seven percent of male partners were found to have a highlevel of involvement while 32.7% was found to have a medium level of involvement. Most of them stated that women can pursue prenatal testing without their permission. Male partners found it more important for them to accompany their spouse to amniocentesis or CVS than to the Down syndrome screening test. When participants were asked about how much information about Down syndrome they sought prior to the appointment, how much discussion they had with their spouse about Down syndrome testing, and about whether they or their spouse should be the first person to receive test results, most stated that they were undecided. Conclusion: These results revealed that male partners were very well involved in the Down syndrome testing during pregnancy and future studies should assess possible underlying factors that influence male partners’ involvement.

Screening for Down syndrome – incidental diagnosis of other aneuploidies

Down syndrome screening programmes lead to the prenatal diagnosis of other chromosomal abnormalities, some of which would not be detected by the secondary use of cell-free (cf)DNA testing in screen positives. This study aims to assess the number of these incidental diagnoses. This study is a systematic review of the literature to identify large prospective screening studies that reported diagnoses other than trisomies 21 and 18. There were ten informative prospective studies in which a total of 1,500,999 women were screened, and there were 3689 aneuploidy cases detected in the screen positives. Trisomy 21 was estimated to comprise only 58% of detected aneuploidies, trisomies 21 and 18 comprised 72%, and the common trisomies - 21, 18 and 13 - comprised 76%. Common trisomies and sex chromosome abnormalities, now included in all commercial cfDNA tests, were estimated to comprise 87% of aneuploidies in the Down syndrome screen positives. All these proportions were higher for second trimester protocols compared with those carried out wholly or partly in the first trimester. Secondary use of cfDNA testing will lead to about one-fifth reduction in diagnoses, taking account of both undetectable aneuploidies and false-negatives. This loss might be overcome by contingent cfDNA testing.

Mother's awareness and attitudes towards prenatal screening for Down syndrome in Muslim Moroccans

Abortion is prohibited and penalized in Morocco. On the other hand, there is no strategy or consensus for prenatal screening for Down syndrome (DS) included into the Moroccan pregnancy monitoring national program. This study aims to explore the awareness and attitudes of women who have a child with DS regarding prenatal screening for DS. This is an observational study based on a knowledge, attitude, and practice survey. Fifty women who have a child with DS agreed to participate in this survey. Although nearly two-thirds of women had not heard of DS or knew what prenatal screening is prior to the birth of the affected child, the majority felt that screening for DS would be useful in the first (84%) or second (90%) trimester. In line with this, most responders would agree to undergo first trimester (84%) or second trimester (80%) screening in a future pregnancy. Most (94%) of the women felt that information on DS screening should be provided to all Moroccan women in early pregnancy and that a public health program for prenatal screening should be established (94%). Deficit in knowledge was detected in awareness that first trimester ultrasound may allow screening for DS. Women who have a child with DS have low awareness of existing screening tests for the condition but have a positive attitude towards them.

Noninvasive prenatal screening by next-generation sequencing.

Noninvasive prenatal screening (NIPS) has emerged as a highly accurate method of screening for fetal Down syndrome, with a detection rate and specificity approaching 100%. Challenging the widespread use of this technology are cost and the paradigm shift in counseling that accompanies any emerging technology. The expense of the test is expected to decrease with increased utilization, and well beyond the current NIPS technology, its components (fetal genome measurements, sequencing technology, and bioinformatics) will be utilized alone or in combinations to interrogate the fetal genome. The end goal is simple: to offer patients information early in pregnancy about fetal genomes without incurring procedural risks. This will allow patients an opportunity to make informed reproductive and pregnancy management decisions based on precise fetal genomic information.

Factors that affect the decision to undergo amniocentesis in women with normal Down syndrome screening results: it is all about the age.

Risk for foetal Down syndrome (DS) increases as maternal age increases. Non-invasive screening (maternal serum triple test) for DS is routinely offered to pregnant women to provide risk estimates and suggest invasive amniocentesis for definitive pre-natal diagnosis to high-risk women. We examined women's decision process with regard to pre-natal screening, and specifically, the degree to which they take into account triple serum screening results when considering whether or not to undergo amniocentesis. Semi-structured phone interviews were conducted to assess recall of DS screening results, understanding of risk estimates and their effect on women's decision whether to undergo amniocentesis. The study included 60 pregnant Israeli women (half younger than 35 and half advanced maternal age - AMA), with normal DS screening results and no known ultrasound abnormalities. Age appeared to determine the decision process. The vast majority of AMA women had amniocentesis, many of them before receiving their DS screening results. Most AMA participants knew that their risk estimate was 'normal', but still considered themselves at high risk due to their age. Procedure-related risk (miscarriage) and other factors only had a minor effect on their decision. A minority of younger women had amniocentesis. Younger women mentioned procedure-related risk and having normal screening results as the main factors affecting their decision not to have amniocentesis. Age 35 is an anchor for the pre-determination regarding performing or avoiding amniocentesis. AMA women mention 'age' as their main reason to have amniocentesis and considered it an independent risk factor.

Methods for the joint meta-analysis of multiple tests.

Existing methods for meta-analysis of diagnostic test accuracy focus primarily on a single index test. We propose models for the joint meta-analysis of studies comparing multiple index tests on the same participants in paired designs. These models respect the grouping of data by studies, account for the within-study correlation between the tests' true-positive rates (TPRs) and between their false-positive rates (FPRs) (induced because tests are applied to the same participants), and allow for between-study correlations between TPRs and FPRs (such as those induced by threshold effects). We estimate models in the Bayesian setting. We demonstrate using a meta-analysis of screening for Down syndrome with two tests: shortened humerus (arm bone), and shortened femur (thigh bone). Separate and joint meta-analyses yielded similar TPR and FPR estimates. For example, the summary TPR for a shortened humerus was 35.3% (95% credible interval (CrI): 26.9, 41.8%) versus 37.9% (27.7, 50.3%) with joint versus separate meta-analysis. Joint meta-analysis is more efficient when calculating comparative accuracy: the difference in the summary TPRs was 0.0% (-8.9, 9.5%; TPR higher for shortened humerus) with joint versus 2.6% (-14.7, 19.8%) with separate meta-analyses. Simulation and empirical analyses are needed to refine the role of the proposed methodology.

First-Trimester Combined Screening Is Effective for the Detection of Unbalanced Chromosomal Translocations at 11 to 12 Weeks of Gestation

The first trimester combined screening, which analyzes fetal nuchal translucency and levels of free β-human chorionic gonadotropin (β-hCG) and pregnancy-associated plasma protein A (PAPP-A) in maternal serum, is routinely used to detect abnormal pregnancies associated with Down syndrome and other trisomy aneuploidies. Based on the hypothesis that major chromosomal translocations could lead to similar biochemical and developmental outcomes during early embryo development, we compared these markers among pregnancies with normal, balanced, or unbalanced fetal karyotypes. Among the parents, 71 (73%) carry balanced reciprocal translocation and 26 (27%) have Robertsonian translocation. Of the 97 pregnancies tested, 39 (40%), 37 (37%), and 22 (23%) fetuses had normal karyotype, balanced chromosomal translocations, and unbalanced chromosomal translocations, respectively. Importantly, we found that pregnancies with an unbalanced translocation had significantly higher free β-hCG multiple of the median (MoM) and larger nuchal translucency thickness than those with normal karyotype or balanced translocations. Analysis showed that the area under a receiver operating characteristic curve (AUC) is 0.716, 0.820, and 0.936 for free β-hCG MoM, PAPP-A MoM, and fetal nuchal translucency, respectively. When these 3 independent factors were combined, the AUC reached 0.976. In addition, logistic regression showed that the most optimal model for predicting an unbalanced chromosomal translocation is a combination of PAPP-A and nuchal translucency with an AUC of 0.980. Therefore, the first trimester combined screening is not only effective in the screening of Down syndrome and other trisomy abnormalities but also has high sensitivity for the detection of unbalanced chromosomal translocations in fetuses.

Will the introduction of non-invasive prenatal testing for Down's syndrome undermine informed choice?

To investigate whether the introduction of non-invasive pre-natal testing for Down's syndrome (DS) has the potential to undermine informed choice. Three hundred and ninety-three health professionals; 523 pregnant women. A cross-sectional questionnaire study across nine maternity units and three conferences in the UK designed to assess opinions regarding test delivery and how information should be communicated to women when offered Down's syndrome screening (DSS) or diagnosis using invasive (IDT) or non-invasive testing (NIPT). Both pregnant women and health professionals in the NIPT and DSS groups were less likely than the IDT group to consider that testing should take place at a return visit or that obtaining written consent was necessary, and more likely to think testing should be carried out routinely. Compared to health professionals, pregnant women expressed a stronger preference for testing to occur on the same day as pre-test counselling (P = 0.000) and for invasive testing to be offered routinely (P = 0.000). They were also more likely to indicate written consent as necessary for DSS (P = 0.000) and NIPT (P < 0.05). Health professionals and pregnant women view the consenting process differently across antenatal test types. These differences suggest that informed choice may be undermined with the introduction of NIPT for DS into clinical practice. To maintain high standards of care, effective professional training programmes and practice guidelines are needed which prioritize informed consent and take into account the views and needs of service users.

PT/NBL ratio assessment at mid-trimester in prenatal screening for Down syndrome in a Chinese population

Objective: To investigate the ratio of prenasal thickness (PT) to nasal bone length (NBL) in normal and trisomy 21 fetuses in the second and third trimester in Chinese population.Methods: The NBL and PT were measured blindly by using 3D volumes in 143 normal fetuses and 31 trisomy 21 fetuses.Results: The mean PT (r = 0.83, p = 0.004) and NBL (r = 0.87, p = 0.0062) both increased with the gestation age, while the PT/NBL ratio (r = 0.12, p > 0.10) remained stable. There was significant difference between normal and trisomy 21 fetuses (p < 0.001). If we took the 95th of the normal fetuses as the cut-off value, the detection rate was only 46%. By using ROC curve to evaluate the screening value of PT/NBL ratio, the area under receiver operating characteristic (ROC) curve was 0.88 (95% confidence interval 0.81 to 0.94, p < 0.0001).Conclusions: In Chinese population, the PT/NBL ratio is not a very strong ultrasound marker to predict trisomy 21 fetuses. However, it can be used as an ultrasound marker for Down syndrome screening during the second and third trimester of pregnancy.

Role of the second‐trimester ‘genetic sonogram’ for Down syndrome screen in the era of first‐trimester screening and noninvasive prenatal testing

Ultrasonography for the screening of Down syndrome was first introduced about 25 years ago. Different combinations of markers detectable at second-trimester ultrasonography have been proposed under the banner of 'genetic sonogram'. In recent years, several developments in first-trimester screening and the recent introduction of noninvasive prenatal testing for aneuploidy screening have had important implications for the prevalence of these conditions in the second-trimester and the screening performance of a genetic sonogram. Several second-trimester sonographic markers for Down syndrome have been reported; meta-analysis has shown that the most powerful predictors are mild ventriculomegaly, increased nuchal fold, hyperechoic bowel, and absent or hypoplastic nasal bone. Whereas use of individual markers should be discouraged and scoring systems of multiple markers are now obsolete, use of combined likelihood ratio and logistic regression analysis formulae provides better accuracy. However, there is significant heterogeneity in results among studies. Despite such limitations, the genetic sonogram will continue to have a place in prenatal screening, particularly in twin and higher-order multiple pregnancies, in countries with limited access to the most recent genetic screening tests, in cases with borderline results at maternal serum screening tests, and as noninvasive supplementary test for high-risk women reluctant to undergo invasive diagnostic testing.

Effect of smoking status on inhibin‐A in second‐trimester prenatal screening for Down syndrome

What's already known about this topic? Inhibin‐A is a useful marker in screening for Down syndrome in the second trimester of pregnancy. It is known to be about 50% higher among women who state they smoke compared with women who state they do not smoke. A single adjustment factor has been used in antenatal screening programmes.What does this study add? This study shows that the extent of the effect of smoking on Inhibin‐A is dependent on the gestational age of the pregnancy. The extent of the effect increases from about 20% higher at early gestation (14 weeks) to about 70% higher at later gestations (20 weeks). An equation allowing the effect of gestation to be considered is presented.