Estimating the risk of Down's syndrome in antenatal screening and the gestation at which this risk applies

Two equations are given to estimate the risk of a woman having a Down's syndrome pregnancy according to maternal age: one for use in estimating antenatal screening performance and the other for use in estimating an individual woman's risk of having an affected pregnancy. Because Down's syndrome pregnancies have an increased tendency to result in a spontaneous fetal loss, the estimation of a woman's risk of having an affected pregnancy will be dependent on gestational age. The best estimates of the prevalence of Down's syndrome are obtained from information relating to births and can reliably be adjusted to prevalence in early second trimester. The most reliable estimates of risk of a Down's syndrome pregnancy using all the currently used markers apply to early in the second trimester. These risks cannot accurately be adjusted to apply to term, because the first trimester markers have not in general been studied in pregnancies that continue to term. Therefore the early second trimester of pregnancy is the gestational age at which all screening performances should be given for the different antenatal screening programmes for Down's syndrome.     

Advances in prenatal screening for Down syndrome: I. general principles and second trimester testing

BACKGROUND: Down syndrome is one of the most important causes of mental retardation in the population. In the absence of prenatal screening and diagnosis, prevalence at birth in the United States would currently exceed 1:600. The purpose of prenatal screening is to identify those women at the increased risk for an affected pregnancy and to maximize the options available to these women. TESTS AVAILABLE: Second trimester serum screening involves combining the maternal age-specific risk for an affected pregnancy with the risks associated with the concentrations of maternal serum alpha-fetoprotein (MSAFP), unconjugated estriol (uE3), and human chorionic gonadotropin (hCG) (triple testing). A forth analyte, inhibin-A (INH-A), is increasingly being utilized (quadruple testing). Optimal second trimester screening requires the integration of a number of clinical variables, the most important of which is an accurate assessment of gestational age. In addition to Down syndrome, the triple and quadruple tests preferentially identify fetal trisomy 18, Turner syndrome, triploidy, trisomy 16 mosaicism, fetal death, Smith-Lemli-Opitz syndrome, and steroid sulfatase deficiency. Some programs modify the Down syndrome risks generated through maternal serum screening tests with fetal biometric data obtained by ultrasound. Other second trimester tests have shown promise, including the analysis of maternal urine and fetal cells in the maternal circulation, but none are in routine clinical use. CONCLUSION: The second trimester triple and quadruple tests provide benchmarks for evaluating new screening protocols. The combination of fetal biometry, new test development as well as clarification of the role of co-factors that affect the concentrations of analytes in existing tests should lead to greater efficacy in second trimester screening for Down syndrome.     

联合检测孕中期血清甲胎蛋白、β-绒毛膜促性腺激素、游离雌三醇筛查出生缺陷的应用研究

目的:评价联合检测孕妇孕中期(14～19+6周)血清标志物甲胎蛋白、β-绒毛膜促性腺激素、游离雌三醇在产前筛查先天出生缺陷中的应用价值。方法:应用化学发光免疫分析技术检测2 149例孕妇孕中期血清标志物,并结合孕妇年龄、孕周、体质量等因素,应用仪器配套的产前筛查风险分析软件计算唐氏综合征、18-三体综合征和开放性脊柱裂的风险率,对高风险孕妇采用B超和/或细胞染色体检查进行确认,根据随访及诊断结果进行评估。结果:2 149例孕妇筛查出出生缺陷高风险136例,筛查阳性率为6.33%,其中唐氏综合征、开放性脊柱裂和18-三体综合征的筛查阳性率分别为4.14%,1.77%,0.42%。唐氏综合征检出率为66.67%,筛查假阳性率为3.75%;开放性脊柱裂检出率为100%,筛查假阳性率为1.85%。结论:化学发光免疫分析技术联合检测孕中期血清甲胎蛋白、β-绒毛膜促性腺激素和游离雌三醇筛查出生缺陷是可靠和有效的,结合产前诊断可减少出生缺陷的发生。     

Down syndrome in India--diagnosis, screening, and prenatal diagnosis

Down syndrome (DS) is the most common genetic cause of mental retardation. Clinical manifestations are variable, and children have psychomotor impairment, multiple malformations, and medical conditions. Confirmation of the diagnosis is by karyotype analysis. The cytogenetic abnormality can be classified into pure trisomy 21, translocation, or mosaicism. Risk of recurrence depends on the primary cytogenetic abnormality in the proband. Prenatal screening is by biochemical and ultrasound markers in the first and second trimester. Definitive prenatal diagnosis is by analysis of fetal chromosomes in fetal chorionic villi, amniocytes, or cord blood. A noninvasive test for trisomy 21 in maternal blood has been developed by massively parallel shotgun sequencing. Therapeutic studies in Ts65Dn mice suggest an exciting prospect of improvement of learning ability and memory deficits.     

我国产前诊断技术发展与质量控制

产前诊断是针对母体所怀胎儿是否异常开展的技术,从母体血清学筛查,到细胞遗传学的染色体核型分析、基因的分子诊断等,是目前防止与减少出生缺陷的主要手段.借鉴欧美发达国家的经验,我国较大规模的产前诊断工作已开展,主要为唐氏综合征血清学筛查,以及染色体病的产前诊断,常见遗传病的基因诊断也已开展,但各地区发展不平衡.作为涉及国家、民族可持续发展的群体性疾病预防工程,尚需建立或完善适合我国国情的产前诊断体系与质量管理规范.     

Rapid aneuploidy screening (FISH or QF-PCR): the changing scene in prenatal diagnosis?

The accuracy of new molecular diagnostics, fluoresence in situ hybridization or quantitative fluorescence-PCR (collectively known as rapid aneuploidy screening), in prenatal diagnosis has already been demonstrated in a number of large studies. The challenge now is how to apply them clinically in the most cost-effective manner. It is now time to appraise whether rapid aneuploidy screening can replace traditional karyotyping when amniocenteses are performed for increased risk of Down's syndrome by maternal serum screening or advanced maternal age in the absence of ultrasound abnormality. The ten most recent studies from the literature within this research theme are reviewed and the pros and cons of this new approach in prenatal diagnosis are discussed, including the suggestion of future studies.     

Down's syndrome: current screening techniques

Antenatal screening for Down's syndrome traditionally relied upon performing amniocentesis for karyotype on pregnant women aged 35 years and older. This method detects approximately 20% of all Down's syndrome pregnancies, with a false-positive rate of 4.3%. By incorporating maternal serum alpha-fetoprotein values as an additional screening parameter to maternal age, 28% of all Down's syndrome pregnancies may be diagnosed, with a 35% reduction in false-positive results. Other screening parameters such as maternal serum unconjugated estriol and human chorionic gonadotropin may eventually make it possible to detect more than 65% of pregnancies with chromosomally abnormal fetuses, without compromise in false-positive rates.     

第二代测序技术与无创产前诊断

孕妇外周血中胎儿游离DNA（cellfreefetalDNA,cffDNA）的发现开辟了无创产前诊断的新篇章,借助各种分子诊断技术针对cffDNA进行胎儿染色体疾病、遗传性疾病以妊娠相关疾病的研究迅速成为热点。以高通量、自动化为显著特征的第二代测序（next—generationsequencing,NGS）技术诞生．极大加速了cffDNA的实验室研究进展。目前基于NGS平台,建立的胎儿21／18／13三体综合征的产前基因诊断技术已应用于临床。其他如性染色体非整倍体、双胎妊娠染色体非整倍体、胎儿染色体结构异常疾病以及孟德尔单基因遗传病的研究也因NGS的出现获得了显著的进步。本文就NGS的基本原理、cffDNA的生理特性及NGS在无创产前诊断研究中的进展进行综述。     

Evaluation of an assay of the free beta-subunit of choriogonadotropin and its potential value in screening for Down's syndrome.

In this study I investigated the analytical and clinical performance of the measurement of the free beta-subunit of choriogonadotropin (hCG) in normal pregnancies and in pregnancies affected by Down's syndrome. Free beta-hCG in maternal serum has been shown to be increased in Down's syndrome-affected pregnancies and is proportionally increased in more cases than is total hCG. This study confirms previous findings of low concentrations of unconjugated estriol and alpha-fetoprotein in maternal serum in Down's syndrome-affected pregnancies. Using a multivariate risk analysis of maternal age and concentrations of alpha-fetoprotein, unconjugated estriol, and hCG in maternal serum, I determined that, at a risk cutoff value of 1 in 300, 52% of Down's cases could be detected with total hCG in the calculation, compared with 66% with the free beta-hCG concentration. The false-positive rate was 5.9% in both cases. Therefore, free beta-hCG can be used effectively in a screening program for Down's syndrome; however, further studies are required to ascertain whether the measurement of free beta-hCG has any advantages over the use of total hCG for detecting Down's syndrome.     

中晚孕期超声筛查胎儿染色体异常的有效性及应用价值研究

目的 研究中晚孕期超声筛查胎儿染色体异常的有效性及应用价值.方法 经超声筛查为结构异常的中晚孕期胎儿和经孕母血清筛查为高风险的中期妊娠胎儿,行羊膜腔或脐静脉穿刺取羊水或脐血,作染色体核型诊断.结果 ①超声筛查接受检查的结构异常胎儿31例,检出异常染色体8例,检出率为25.8%.31例中颈部淋巴囊肿伴水肿3例,全部染色体异常;单纯颈项皮肤增厚3例,其中2例染色体异常;多发畸形、Dandy-Walker畸形及前脑无裂畸形各1例,染色体均异常.②血清筛查接受检查的唐氏综合征和18-三体高风险孕妇516例,检出异常染色体14例,检出率为2.71%.14例中唐氏综合征7例,其他染色体异常7例.③单纯超声筛查和血清筛查共筛查为高危又接受诊断者544(516+28)例,检出异常染色体21(14+7)例,两种方法互补染色体异常检出率为3.86%.互补筛查检出率是血清筛查的1.42倍,比血清筛查提高42.43%.结论 ①中晚孕期超声显示的某些胎儿结构异常是提示胎儿染色体异常的有效指征.②超声和血清两种筛查方法互补,可以提高染色体异常的检出率,对于血清失筛查或筛查低危漏诊孕妇是有效的弥补措施.     

无创基因检测(NIPT)对胎儿染色体异常筛查的临床应用

目的 探讨无创产前基因检测(NIPT)在预测胎儿染色体异常中的临床应用价值。方法 选取2016年4月～2018年4月在福建省宁德市闽东医院行NIPT的单活胎孕妇6 357例,按孕周分为早、中、晚孕期组,按孕龄分为高、低龄组,低龄组又按申请理由分唐氏筛查高风险组、临界风险组、单项指标或中位数倍数(MOM值)异常组,B超软指标异常组和直接选择NIPT组,对于结果异常者签署知情同意书行羊膜腔穿刺术。结果 ①6 357例孕妇共检出染色体异常76例,早、中、晚孕期组阳性率分别为2.17%,1.23%和0.70%,三者之间差异无统计学意义(χ²=2.265～6.052,均P>0.05); ②6 357例孕妇按孕龄和申请理由分组,各组阳性率分别为1.45%,1.07%,0.97%,0.60%,1.29%和1.15%,各组之间差异无统计学意义(χ²=0.017～1.809,均P>0.05); ③76例NIPT结果异常孕妇有64例接受了羊膜腔穿刺羊水细胞染色体检查,其中21,18和13-三体的诊断率分别为90%,100%和100%,符合率分别为88.9%,88.9%和50%; 性染色体的诊断率为83.9%,符合率61.5%; 其它染色体异常诊断率为58.3%,符合率为0。结论 ①不同孕期NIPT的阳性率之间无差异,孕妇可以尽早行NIPT,为后续介入性诊断争取时间; ②不同申请理由NIPT的阳性率之间无差异,高龄和错过唐筛时间的孕妇可将NIPT作为筛查胎儿染色体异常的首选,而唐筛高风险、临界风险、单项指标或MOM值异常的孕妇可将NIPT作为二线筛查,从而避免不必要的羊膜腔穿刺; ③NIPT不仅对21和18-三体具有较高的特异度和敏感度,对13-三体、性染色体也有一定的预示作用,可作为产前检测胎儿染色体异常的辅助手段。     

Advances in prenatal screening for Down syndrome: II first trimester testing,integrated testing,and future directions

BACKGROUND: The acceptability of prenatal screening and diagnosis of Down syndrome is dependent, in part, on the gestational age at which the testing is offered. First trimester screening could be advantageous if it has sufficient efficacy and can be effectively delivered. ISSUES: Two first trimester maternal serum screening markers, pregnancy-associated plasma protein-A (PAPP-A) and free beta-human chorionic gonadotropin (beta-hCG), are useful for identifying women at increased risk for fetal Down syndrome. In addition, measurement of an enlarged thickness of the subcutaneous fluid-filled space at the back of the neck of the developing fetus (referred to as nuchal translucency or NT) has been demonstrated to be an indicator for these high-risk pregnancies. When these three parameters are combined, estimates for Down syndrome efficacy exceed those currently attainable in the second trimester. Women who are screen-positive in the first trimester can elect to receive cytogenetic testing of a chorionic villus biopsy. The first trimester tests could also, theoretically, be combined with the second trimester maternal serum screening tests (integrated screening) to obtain even higher levels of efficacy. There are, however, several practical limitations to first trimester and integrated screening. These include scheduling of testing within relatively narrow gestational age intervals, availability of appropriately trained ultrasonographers for NT measurement, risks associated with chorionic villus biopsy, and costs. There is also increasing evidence that an enlarged NT measurement is indicative of a high risk for spontaneous abortion and for fetal abnormalities that are not detectable by cytogenetic analysis. Women whose fetuses show enlarged NT, therefore, need first trimester counseling regarding their Down syndrome risks and the possibility of other adverse pregnancy outcomes. Follow-up ultrasound and fetal echocardiography in the second trimester are also indicated. CONCLUSION: First trimester screening appears to be a highly effective method to screen for Down syndrome. Women with screen-positive results based on NT measurement appear to be at increased risk for diverse fetal abnormalities. The finding of a normal fetal karyotype may not, therefore, carry a high level of reassurance for a normal baby.     

Risk prediction for Down's syndrome in young pregnant women using maternal serum biomarkers: determination of cut-off risk from receiver operating characteristic curve analysis

OBJECTIVE: The aim of this study was to establish a predictive model for Down's syndrome using maternal age as well as maternal serum levels of alpha-fetoprotein (AFP) and human chorionic gonadotropin (hCG), and to identify an optimal cut-off risk in women under the age of 35 years to improve sensitivity. METHODS: Logistic regression models were utilized to predict fetal Down's syndrome as a function of maternal age and logarithm of levels of AFP as well as hCG using training data of 20 pregnancies with fetal Down's syndrome and 9730 unaffected pregnancies. Validation was performed using data of another nine affected pregnancies and 3496 unaffected pregnancies. Receiver operating characteristic (ROC) curves were plotted. RESULTS: Based on the newly established logistic regression equations, the optimal cut-off risk from the ROC curve analysis was at 1:499, with a 17.8% false-positive rate and a 90.0% sensitivity. A suboptimal cut-off risk was estimated at 1:332, with a 12.0% false-positive rate and an 80% sensitivity. CONCLUSION: A predictive model for Down's syndrome was developed using logistic regression. By ROC curve analysis and clinical consideration, the cut-off risk for young pregnant women could be determined.     

Isolated echogenic foci in the fetal heart as marker of chromosomal abnormality.

OBJECTIVE: To assess the effect of echogenic foci in the fetal heart on the risk for Down's syndrome. DESIGN: Prospective evaluation of fetal echocardiograms at a fetal cardiology referral center and systematic postnatal follow-up. A relative risk was calculated from the prevalence of echogenic foci in fetuses subsequently demonstrated to have trisomy 21 divided by that in normal fetuses. For a subgroup of 548 fetuses with echogenic foci but otherwise normal detailed anomaly scans, the expected number of trisomy 21 fetuses calculated from maternal age risks was compared with the observed number to derive a relative risk for isolated echogenic foci. RESULTS: Echogenic foci occurred in 905 of 6904 fetuses scanned, but after excluding those referred specifically because of an echogenic focus and those with heart defects, the incidence was 9.5%. Overall, echogenic foci were more frequent in fetuses with trisomy 21 than those without by a factor of 2.93. For the 548 fetuses with echogenic foci but otherwise normal detailed anomaly scans, the actual number of trisomy 21 fetuses exceeded that expected on the basis of maternal age risks by a factor of 5.54. Combination with data from several previous studies suggests a consensus relative risk of about 3.0. CONCLUSIONS: Echogenic foci are associated with increased risk of trisomy 21 even when present as an isolated finding. Their significance in an individual should be interpreted in the light of prior risk assessment based on maternal age and results of any first-trimester screening tests. We suggest that the prior risk is increased by a factor of 3.0.     

Maternal serum screening for Down's syndrome, open neural tube defects and trisomy 18.

Maternal serum screening identifies women at an increased risk of a pregnancy with Down's syndrome or trisomy 18 or an open neural tube defect. The triple test, consisting of maternal serum alpha-fetoprotein, unconjugated estriol and human chorionic gonadotropin was carried out by a chemiluminescence immunoassay method in our laboratory. The study consisted of 373 pregnant women. The gestational range for the study group was 14-22 weeks. The mean maternal age for the study group was 28.53 +/- 5.46 years (range 17.4 to 43.5 years); 9.1% of the women were considered at high risk for Down's syndrome based on the test results. In our study the detection rate for Down's syndrome by prenatal karyotyping was 66.6%. Maternal serum screening allows reduction of the number of women requiring amniocentesis without a significant decrease in the detection rate.     

Screening for Down syndrome based on maternal age or fetal nuchal translucency: a randomized controlled trial in 39,572 pregnancies.

OBJECTIVES: Nuchal translucency (NT) screening increases antenatal detection of Down syndrome (DS) compared to maternal age-based screening. We wanted to determine if a change in policy for prenatal diagnosis would result in fewer babies born with DS. METHODS: A total of 39,572 pregnant women were randomized to a scan at 12-14 gestational weeks including NT screening for DS (12-week group) or to a scan at 15-20 weeks with screening for DS based on maternal age (18-week group). Fetal karyotyping was offered if risk according to NT was > or = 1:250 in the 12-week group and if maternal age was > or = 35 years in the 18-week group. Both policies included the offer of karyotyping in cases of fetal anomaly detected at any scan during pregnancy or when there was a history of fetal chromosomal anomaly. The number of babies born with DS and the number of invasive tests for fetal karyotyping were compared. RESULTS: Ten babies with DS were born alive with the 12-week policy vs. 16 with the 18-week policy (P = 0.25). More fetuses with DS were spontaneously lost or terminated in the 12-week group (45/19,796) than in the 18-week group (27/19 776; P = 0.04). All women except one with an antenatal diagnosis of DS at < 22 weeks terminated the pregnancy. For each case of DS detected at < 22 weeks in a living fetus there were 16 invasive tests in the 12-week group vs. 89 in the 18-week group. NT screening detected 71% of cases of DS for a 3.5% test-positive rate whereas maternal age had the potential of detecting 58% for a test-positive rate of 18%. CONCLUSIONS: The number of newborns with DS differed less than expected between pregnancies that had been screened at 12-14 weeks' gestation by NT compared with those screened at 15-20 weeks by maternal age. One explanation could be that NT screening--because it is performed early in pregnancy--results in the detection and termination of many pregnancies with a fetus with DS that would have resulted in miscarriage without intervention, and also by many cases of DS being detected because of a fetal anomaly seen on an 18-week scan. The major advantage of the 12-week scan policy is that many fewer invasive tests for fetal karyotyping are needed per antenatally detected case of DS.     

Sonographic screening for fetal aneuploidy: first trimester.

Screening for fetal aneuploidy is now possible during the first trimester using sonographic and biochemical markers. The aim of this review was to summarize the efficacy and use of nuchal translucency in screening for fetal aneuploidy, especially fetal Down syndrome, and other anomalies. We reviewed available literature regarding first‐trimester screening. This includes more than 16 studies of nuchal translucency as a marker for fetal aneuploidy published since 1995. Although early studies showed wide variation in detection of fetal Down syndrome when using nuchal translucency, more recent studies showed sensitivities of approximately 70% to 80%, for a 5% false‐positive rate. Increased nuchal translucency has also been found to be a marker for other aneuploidies, including trisomy 18, trisomy 13, and Turner syndrome. Maternal serum biochemical screening can be used as a test for aneuploidy during the first trimester The 2 maternal serum markers that appear to be most useful in the late first trimester are the free beta subunit of human chorionic gonadotropin and pregnancy‐associated plasma protein A. Together with maternal age, these markers yield a detection rate for trisomy 21 of approximately 60%, for a 5% false‐positive rate. Because sonographic and biochemical markers appear to be largely independent, their combined risk results in improved detection rates compared with either method alone. As a result, the combination of nuchal translucency, biochemical markers, and maternal age has achieved a detection rate of approximately 85%, for a 5% false‐positive level for detection of trisomy 21. A newly proposed "integrated" approach using a panel of first‐ and second‐trimester markers suggests that further improvement in the screening performance is possible. A number of questions regarding first‐trimester screening remain. We address some of these questions: is first‐trimester screening more effective than second‐trimester screening? How to account for intrauterine lethality? Is earlier diagnosis important, and will it be accepted by patients? Is first‐trimester screening cost‐effective? How should first‐trimester screening be interpreted with second‐trimester tests? Despite encouraging data and general enthusiasm for first‐trimester screening for fetal Down syndrome and other aneuploidies, a number of questions remain about its implementation in the United States. Multicenter studies currently under way should help answer some of these questions.     

基于胎源遗传物质的唐氏综合征无创性产前诊断研究进展

唐氏综合征是常见且严重的染色体异常类出生缺陷,迄今无有效治疗方法,在产前进行筛查与诊断,减少和避免患儿出生是唯一预防措施.目前常用的侵入性诊断方式因存在诸多弊端而被部分孕妇拒绝接受,因此寻找并建立准确且无创的唐氏综合征产前诊断方法是亟待解决的重要临床问题.利用存在于母体外周血中的胎儿遗传物质是近年来开展的无创性产前诊断...     

Nasal Bone Measurement To Diagnose Down Syndrome

Down syndrome occurs in 1 of 1000 live births and in most cases occurs in families with no previous history of the syndrome. Ultrasound and maternal blood samples are screening tests used to identify women with an increased risk of carrying a baby with Down syndrome. In the past 30 years, extensive progress has been made in fetal ultrasound technology, as well as in Down syndrome detection. However, Down syndrome detection continues to be one of the main challenges of perinatal medicine. It is important to keep in mind that even the best combination of ultrasound findings and other screening tests are only predictive and not diagnostic. Amniocentesis or chorionic villus sampling is necessary for true diagnosis; however, nasal bone measurement appears to be an encouraging marker for earlier detection of Down syndrome.     

Application of fetal DNA in maternal plasma for noninvasive prenatal diagnosis

Prenatal diagnosis of fetal genetic conditions is a standard part of modern obstetric care. Many of the current methods rely on invasive methods and are associated with an inherent risk of fetal loss. Consequently, there has been a long-term goal for development of noninvasive prenatal diagnostic methods. In 1997, the presence of fetal DNA in maternal plasma was first discovered through the detection of Y-chromosome-specific sequences in the plasma of women conceived with male fetuses. This discovery has opened up new possibilities in the development of noninvasive prenatal diagnostic methods through a source of fetal genetic material that could be conveniently accessible simply through the collection of a maternal peripheral blood sample. To date, there have been numerous reported applications, including fetal RhD genotyping, prenatal diagnosis of sex-linked disorders, paternally inherited genetic diseases and some pregnancy-associated conditions, including preeclampsia. More recently, there have been significant new developments with expanding number of potential applications.