Evaluation of Down syndrome screening strategies

Women contemplating pregnancy today have many different Down syndrome screening protocols from which to choose. Sensitive and specific first and second trimester screening protocols are now widely available, and strategies that combine first and second trimester markers are moving from investigational use into the clinical arena. Modeling indicates that a high detection rate (85%) associated with a very low screen positive rate (1.3%) can be achieved with contingent screening, in which all women undergo first trimester screening and only a portion (25%) go on to second trimester screening.     

First-trimester screening for Down syndrome in singleton pregnancies achieved by intrauterine insemination

Purpose : To evaluate whether achieving a singleton pregnancy by IUI affects the results of first-trimester screening for Down syndrome compared to naturally conceived pregnancy. Methods : Forty-nine IUI and 3059 naturally conceived singleton pregnancies were included in the study. Ovulation in IUI pregnancies was induced by clomiphene and human menopausal gonadotropin. Progesterone was given after insemination for 2 weeks. Down syndrome screening was performed using a combination of maternal age, fetal nuchal translucency, and maternal serum concentrations of free -hCG and PAPP-A during the period of 10–14 weeks' gestation. Results : In IUI pregnancies, nuchal translucency thickness and the levels of PAPP-A were significantly higher. The values of free -hCG were not statistically different between the two groups. The screen-positive rate in IUI pregnancies was significantly higher (14.3% vs. 7.1%). Conclusions : Singleton pregnancies achieved by IUI have a higher screen-positive rate. Not only elder maternal age but also exogenous hormones given during the process of ovulation induction and after conception may play an important factor influencing positive screening results.     

Patient and provider attitudes toward screening for Down syndrome in a Latin American country where abortion is illegal

Objective

To examine patient and provider attitudes toward first trimester nuchal translucency (NT) screening for Down syndrome and to assess how patients consent to screening in a country where abortion is illegal.

Methods

Patients presenting for first trimester ultrasound including NT screening in two obstetric units in Chile completed a questionnaire about their attitudes toward NT screening and perspectives on the consent process. A follow-up questionnaire assessed satisfaction with the test. Prenatal care providers also completed a questionnaire ascertaining their perspectives on NT screening.

Results

A total of 107 patients completed the initial questionnaire and 78 completed the follow-up questionnaire. Although 98 (94%) patients desired NT screening only 38 (38%) indicated that they would undergo diagnostic testing if they received screen positive results. Only 3 patients screened positive; however, 15 (20%) participants experienced increased anxiety after the test. Almost all of the 36 providers surveyed indicated that they counsel their patients thoroughly, but 38 (39%) patients reported that they received adequate information.

Conclusion

NT screening is often performed without patients’ full understanding of the implications of potential results and may cause anxiety. Providers should elicit patients’ preferences regarding prenatal testing and engage them in shared decision making about whether to undergo screening, particularly when abortion is not an option.     

The performance of second trimester long bone ratios for Down syndrome screening is influenced by gestational age

Objective.?To determine if gestational age (GA) at the time of ultrasound impacts the positive predictive value of shortened femur and humerus lengths (FL, HL) for trisomy 21 (T21).

Methods.?Sonograms from 14 to 21 and 6/7 weeks’ gestation were collected over a 28 month period. Multiple gestations or fetuses with major structural anomalies were excluded. Biometric data and GA were obtained; the expected HL (or FL): observed HL (or FL) ratios were calculated using two regression formulas (Benacerraf and Nyberg). A HL ratio <0.90 and a FL ratio <0.91 were considered shortened. T21 fetuses were identified through database and chart review. Positive predictive values (PPV) for T21 of the shortened bone ratios were determined, then stratified by GA.

Results.?Of the 2606 ultrasounds, 8.9% and 18.9% of fetuses had shortened HL and FL ratios, respectively, using the Benacerraf formula. Shortened ratios were noted significantly less commonly (2.3 and 4.4%, respectively, P?<?0.001 for each) using the Nyberg formula. With either formula, abnormal bone ratios were more frequently documented with a GA less than 17 weeks (P?<?0.001). There were 17 T21 pregnancies.

Conclusions.?GA and formula selection influence the performance of long bone ratios as soft markers for T21 in the second trimester.     

Quality assurance of nuchal translucency for prenatal fetal Down syndrome screening

Objective: To assess the quality of nuchal translucency, (NT) measurements were performed at four public institutions performing routine first trimester combined prenatal screening for Down syndrome. Methods: The median of the NT-MoM distribution and standard deviation (SD) of the log₁₀ NT-MoM were determined. Sonographers and screening centres distributions were assessed for measures of central tendency (median) and dispersion (log₁₀ SD). Cumulative Sum (CUSUM) charts were created to assess whether screening centres and individual sonographers who had performed at least 30 NT measurements exhibited any systematic bias by checking whether their CUSUM scores exceeded predefined upper and lower control limits. Results: Of the 36 sonographers, only 67% (n?=?24) had performed 30 or more scans. The median NT-MOM at each screening centre ranged from 1.02 to 1.09. Screening centre standard deviations ranged from 0.073 to 0.099. CUSUM charts indicated that only one screening centre remained within the predefined control limits throughout the assessment period. Analysis of variance indicated that a statistically significant difference existed between the log NT-MoM distributions of the individual sonographers (F?=?10.7; p <0.0001). Inspection of the individual sonographer CUSUM charts indicated that 11 (45%) of the 24, with more than 30 NT measurements were either under or over measuring the NT. Conclusion: Prospective monitoring and feedback of quality assurance assessment results of sonographers and screening centres should be routinely reported as both are responsible, if equity of screening performance is to be maintained.     

From Down syndrome screening to noninvasive prenatal testing: 20 years' experience in Taiwan

Down syndrome is the most common autosomal chromosome aneuploidy. The prenatal Down syndrome screening protocol has been known in Taiwan for the past 20 years. The maternal serum double markers required for the screening test was first implemented into the general prenatal check-up back in 1994, where it had around a 60% detection rate at a 5% false positive rate. The first trimester combined test was started in 2005, and the maternal serum quadruple test was introduced in 2008 to replace the previous double test. The overall detection rate for the current screening strategies (first trimester combined or second trimester quadruple test) in Taiwan ranges between 80% and 85% at a fixed 5% false positive rate. Noninvasive prenatal testing (NIPT) is the latest powerful fetal aneuploidy detection method and has become commercially available in Taiwan starting from 2013. The sensitivity and specificity for NIPT are very high (both over 99%) according to large worldwide studies. Our preliminary data for NIPT from 11 medical centers in Taiwan have also shown a 100% detection rate for Down syndrome and Edwards syndrome, respectively. Invasive chromosome studies such as amniocentesis or chorionic villus sampling cannot be replaced by NIPT, and all prenatal screening and NIPT results require confirmation using invasive testing. This review discusses the Down syndrome screening method assessments and the progress of NIPT in Taiwan.     

妊娠中期唐氏综合征筛查中风险人群的回顾性分析

目的 回顾分析妊娠中期唐氏综合征( Down syndrome,DS)筛查中风险的孕妇人群,探讨如何对其进行合理的指导和管理.方法 研究对象为2009年9月至2011年5月期间,在浙江省宁波市辖区内的所有妇幼保健机构产前门诊建卡的孕妇,均为单胎妊娠,预产年龄＜35周岁.采用血清三联指标(甲胎蛋白十游离β-人绒毛膜促性腺激素+游离雌三醇)进行妊娠中期DS筛查,风险值＜1/1000为低风险,1/1000≤风险值＜1/270为中风险,≥1/270为高风险.高风险孕妇行羊膜腔穿刺及染色体核型分析,中、低风险孕妇行常规产科检查,并随访妊娠结局.采用Fisher确切概率法和x2检验比较不同风险值孕妇人群的DS发生率.结果 86 874例孕妇进行血清学筛查,86 126例随访到妊娠结局,其中高、中、低风险孕妇分别为4342例、8196例和73 588例,DS发生率在高风险组为6.22‰(27/4342),中风险组为0.73‰(6/8196),低风险组为0.04‰(3/73 588),高风险组显著高于中风险组(Fisher确切概率法,P=0.000),中风险组显著高于低风险组(Fisher确切概率法,P=0.000).将中风险孕妇按不同风险值分为3个亚组,比较组间DS发生率,差异无统计学意义(x2 =0.047,P=0.977).结论 应对中风险孕妇予以重视,通过超声诊断,产前咨询等方法对其进行合理妊娠管理.     

Follow up and evaluation of the Victorian first-trimester combined screening programme for Down syndrome and trisomy 18

Objective  The objective of this study was to follow up and evaluate the statewide first-trimester combined screening programme for Down syndrome and trisomy 18 at Genetic Health Services Victoria, Australia.
Design  Retrospective population cohort.
Setting  Maternal Serum Screening Laboratory records.
Sample  All women screened between February 2000 and June 2002 (16 153 pregnancies).
Methods  Screening results were matched to Victorian perinatal and birth defect data via record linkage, with an ascertainment of 96.8% of pregnancy outcomes. Manual follow up with health professionals increased ascertainment to more than 99%.
Main outcome measures  Fetal Down syndrome or trisomy 18, and combined screen results, to calculate test characteristics.
Results  Using a risk threshold of 1 in 300 at time of ultrasound, the sensitivities for standard first-trimester combined screening and augmented 13-week combined screening for Down syndrome were 87.3 and 90.5% and the false-positive rates (FPR) were 4.1 and 3.9%, respectively. The sensitivity for trisomy 18 was 66.7% (10/15, 95% CI 42.8–90.5%) with a 0.4% FPR and 15.2% positive predictive value (1 in 250 risk threshold).
Conclusions  The combined use of record linkage and manual follow-up techniques was effective in ascertaining more than 99% of pregnancy outcomes for calculations of accurate test characteristics of the combined screen. The sensitivity for Down syndrome at Genetic Health is comparable to similar populations. However, the sensitivity for trisomy 18 is lower than that elsewhere, which may reflect the overall low birth prevalence of trisomy 18 and associated small numbers in this particular cohort.     

抑制素A在妊娠中期唐氏综合征筛查中的价值

目的 建立广东地区正常妊娠人群血清抑制素A在妊娠15～20+6周的参考值范围,评估抑制素A在四联唐氏综合征筛查中的价值. 方法 选择2008年3月至2010年12月在广州市妇女儿童医疗中心接受妊娠中期三联唐氏综合征筛查的单胎妊娠孕妇2802例.采用酶联免疫化学发光分析法检测孕妇血清中抑制素A水平,将检测值转换为中位数的倍数(multiples of the median, MoM),并根据母亲体重和孕周进行校正.采用SURUSS相关参数重新计算风险值并统计不同切割值水平的筛查效果.通过受试者工作特性曲线及曲线下面积评估单项和各标志物组合的筛查效果.结果 (1)正常单胎孕妇(对照组,2790例)妊娠15～20+6周时各孕周血清抑制素A浓度的中位数分别为286.60、267.10、249.10、243.40、242.30和256.60 pg/ml,各孕周浓度相对稳定.12例胎儿为唐氏综合征的孕妇血清中抑制素A的MoM值及平均浓度均显著高于对照组[MoM值:2.82与1;平均浓度:(852.83±370.04)pg/ml与(293.28±149.46)pg/ml,差异有统计学意义(t=5.37,P＜0.05)].(2)假阳性率为5.8％时,游离人绒毛膜促性腺激素-β、甲胎蛋白、未结合雌三醇和抑制素A组成的四联唐氏综合征筛查检出率为83.3％(10/12);当检出率为83.3％时,妊娠中期四联唐氏综合征筛查的假阳性率(5.8％)较游离人绒毛膜促性腺激素-β、甲胎蛋白和未结合雌三醇组成的三联唐氏综合征筛查(7.7％)降低了1.9％.受试者工作特性曲线上,假阳性率为5.0％时,抑制素A、甲胎蛋白、游离人绒毛膜促性腺激素-β和未结合雌三醇的曲线下面积分别为63.7％、20.5％、46.1％和4.8％;传统三联和四联唐氏综合征筛查的曲线下相对面积分别为45.5％和63.1％. 结论 建立了广东地区正常妊娠人群血清抑制素A在妊娠15～20+6周的参考值范围.证实抑制素A是最佳的妊娠中期血清筛查标志物,可结合现有标志物——游离人绒毛膜促性腺激素-β、甲胎蛋白和末结合雌三醇,用于我国人群妊娠中期唐氏综合征的筛查.     

Down syndrome screening using race-specific femur length

OBJECTIVE: The study was undertaken to evaluate the influence of maternal race on fetal femur length when screening for Down syndrome. STUDY DESIGN: We reviewed our patient databases to obtain fetal biometry from 15 to 22 weeks' gestation, maternal race, and cases of Down syndrome. Institution and race-specific regression lines for femur length (FL) to biparietal diameter (BPD) were created. The efficiency of using published expected FL was compared with our institution and race-specific regression in screening for Down syndrome. RESULTS: There were 4350 African American, 4271 white, 2315 Hispanic, and 654 Asian subjects and 42 cases of Down syndrome (1:276) included in the study. Our institutionally derived regression for FL by BPD had an R(2) of 0.82. Regression lines for FL by BPD generated by race had an R(2) of 0.86, 0.84, 0.83, and 0.80 for African American, Hispanic, Asian, and white subjects, respectively. The race-specific regression was no better than institution-specific data. CONCLUSION: Using institution-specific FL was more efficient in screening for Down syndrome than published expected FL; race-specific analysis did not improve efficiency.     

Optimal risk cut-offs for Down syndrome contingent maternal serum screening

Objectives: The objective of this study is to identify the optimal cut-off points of contingent serum screening excluding nuchal translucency (NT) measurement, to categorize the risk level in the first trimester.

Methods: A prospective database of women undergoing contingent serum screening, without NT measurement, was reviewed. In conventional categorization, the results of first-trimester screening were categorized into high risk (>1:30) (invasive diagnosis was offered); intermediate risk (1:30–1:1500) (second-trimester screening was needed); and low risk (<1:1500) (no further test). We recategorized the risk levels using various upper and lower cut-offs and compared detection rates, false-positive rates, and rates of intermediate risk.

Results: Among 24,874 women, the prevalence of Down syndrome was 1:691. The previously agreed cut-offs had a detection rate of 88.9% and a false-positive rate of 8.5% with high rate of intermediate risk (38.2%). Re-categorization provided the optimal lower and upper cut-offs 1/900 and 1/50, respectively, giving a detection rate of 86.1%, a false-positive rate of 8.1%, and a rate of intermediate risk of 24.8%.

Conclusions: This is the first study on contingent serum screening without NT measurement which shows a high detection rate with an acceptable false-positive rate. The optimal cut-offs to categorize the risk levels of the upper and the lower cut-off was 1:30–1:50 and 1:900, respectively.     

A sensitive enzyme immunoassay for pregnancy-associated plasma protein A (PAPP-A): a possible first trimester method of screening for down syndrome and other trisomies

Pregnancy-associated plasma protein A (PAPP-A) is a large glycoprotein produced mainly by the trophoblast during pregnancy and released into the maternal circulation. Its biological function is unknown. In the second trimester i.e. when Down syndrome (DS) screening is routinely performed, the level of maternal serum PAPP-A was found to be within the normal range in pregnancies affected by fetal trisomy 21. However, PAPP-A was shown to be a potent marker for DS before 14 weeks of gestation. Only radioimmunoassays (RIAs) based on labelled antigen competition reached the required sensitivity for early pregnancy PAPP-A determinations; but they have a very short shelf life due to inherent tracer half-life and, in the case of PAPP-A, instability of the labelled antigen after three weeks. We describe a convenient and novel enzyme immunoassay (ELISA) with high sensitivity and a long shelf life.     

Patient and health professional acceptance of integrated serum screening for Down syndrome

Integrated testing for Down syndrome combines first trimester maternal serum and nuchal translucency (NT) measurements with second trimester maternal serum measurements into a single second trimester Down syndrome risk. A variant of integrated testing, the integrated serum test, requires only the serum measurements and may be more suitable for widespread use in the general pregnancy population. Concern has been voiced that women will find the delay associated with waiting for screening results unacceptable for either fully integrated (including NT measurements) or integrated serum testing. To address this issue, we surveyed 60 women from a population of 8773 women enrolled in an integrated serum screening intervention trial in Maine. The women all had also undergone traditional second trimester screening 1 to 2 years earlier. All 60 women remembered having the integrated serum test, and 59 remembered having a prenatal test in their previous pregnancy. Three-quarters of women did not experience anxiety relating to the wait for final results in the second trimester, and 95% would consider being screened by the integrated serum test in a future pregnancy. Women receiving prenatal care at the primary care level are prepared to wait until the second trimester for more accurate Down syndrome risk estimates on which to base their decision-making.     

Down syndrome screening in the first and/or second trimester: model predicted performance using meta-analysis parameters

OBJECTIVE: To predict the screening performance for 17 policies currently in use or being considered for the near future. METHODS: Multivariate Gaussian modeling using parameters derived from published meta-analyses and new meta-analyses for gestation-specific nuchal translucency and between trimester correlations. RESULTS: For a 1% to 5% false-positive rate, first trimester screening achieved detection rates up to 16% to 25% higher than the best second trimester combination. Screening in both trimesters sequentially could yield an even greater increase in detection of 24% to 35%. The most efficient sequential policy was contingent screening, which has a high detection rate with only 15% of women needing second trimester tests. CONCLUSION: Modeling with meta-analysis derived parameters provides a reliable guide for policy and favors a contingent screening policy. The widespread practice of calculating first and second trimester risks separately should be abandoned.     

New Down syndrome screening algorithm: Ultrasonographic biometry and multiple serum markers combined with maternal age

Objective: We compared the Down syndrome screening efficiency of a new algorithm that combines humerus length measurement and serum analytes versus that of the traditional triple-analyte serum screen. Study Design: Humerus length measurements were obtained prospectively in 1743 midtrimester (14 to 24 weeks) singleton fetuses before genetic amniocentesis. All patients had triple-marker serum screening before amniocentesis. Data on humerus length were expressed as multiples of the median, and were normalized by log transformation. Backward multiple stepwise logistic regression analysis was performed to determine which combination of biometry and serum markers best predicted fetal Down syndrome. The screening efficiency of the traditional triple-analyte algorithm was compared with that of a new multivariate gaussian algorithm that combined biometry and serum markers. Results: There were 31 (1.8%) fetuses with Down syndrome in the study population. In the regression analysis humerus length, human chorionic gonadotropin, α-fetoprotein, and maternal age were significant predictors of Down syndrome, but unconjugated estriol was not. The combined algorithm (humerus length, human chorionic gonadotropin, and α-fetoprotein and age) was superior to the traditional triple screen for Down syndrome detection. The sensitivities at fixed false-positive rates were consistently higher in the combination than in the triple-screen protocol. For example, at a 10% false-positive rate the sensitivities were 65.0% and 52.3%, respectively. Similarly, at a 15% false-positive rate the sensitivities were 73.5% and 55.0%, respectively. Conclusion: A new screening algorithm combining humerus length and serum analytes was superior to the traditional triple screen. Although we used a high-risk population in this study, it is expected that the observed superiority of the combination screen would persist in a population of younger women. The development of a combined biometric and serum analyte screening algorithm for estimating individual odds could represent an advance in prenatal Down syndrome screening. (Am J Obstet Gynecol 1998;179:1627-31.)     

First-trimester screening for preeclampsia: impact of maternal parity on modeling and screening effectiveness

Objective: The impact of maternal parity on screening efficiency for preeclampsia (PE) has been poorly studied. Our objective was to investigate the effect of maternal parity on models for screening for PE in the first-trimester and their effectiveness.

Study design: A secondary analysis of a prospective cohort study of women present between 11 and 14 weeks gestation. Maternal risk factors, uterine artery Doppler, mean arterial pressure (MAP) and serum markers including PAPP-A, ADAM12, PP13 in the first-trimester were used to create multi-parameter screening models for PE. The best models for screening in nulliparous versus parous women were developed using backward stepwise logistic regression approach. The area under the receiver operating characteristic curves (AUC) and the sensitivity for fixed false positive rates of 10% and 20%, respectively, were compared using non-parametric statistics.

Results: Among 1177 women with complete outcome data (503 (42.7%) nulliparous and 674 (57.3%) multiparous), PE occurred in 102 (8.7%). There were significant differences in predicting variables in the final optimal models when stratified by parity; and screening performance also varied by parity. The AUC for the model for nulliparous women was 0.88(95% CI 0.80–0.95); and for multiparous was 0.84 (95% CI, 0.75–0.91). For fixed false positive rate of 10%, the sensitivity for predicting PE was 70% and 68% for nulliparous and multiparous, respectively. The screening performance for the models were however not statistically or clinically significantly different.

Conclusion: We found significant differences in prediction model parameters between nulliparous and multiparous women, but these did not significantly impact screening performance for PE in the first-trimester.