Detection Of Fetal Down Syndrome Research Articles

First trimester genetic sonogram for screening fetal Down syndrome: A population-based study

ObjectiveTo evaluate the performance of first trimester sonomarkers in the detection of fetal Down syndrome among Thai pregnant women. Materials and methodsPregnant women at 11–13+6 weeks’ gestation underwent ultrasound examination for assessment of nuchal translucency (NT), nasal bone (NB), tricuspid regurgitation (TR), and abnormal ductus venosus (aDV) Doppler waveforms. The women were followed up for final outcomes. Fetal abnormalities other than trisomy 21 were excluded. The performances of each sonomarker and their combinations in predicting fetal Down syndrome were calculated. ResultsA total of 7820 pregnant women meeting the inclusion criteria were available for analysis, including 20 cases with fetal Down syndrome and 7800 unaffected cases. Of the four sonomarkers, NT, as a single sonomarker, had the highest detection rate (55.0% at a false positive rate of about 5%), whereas the remaining single sonomarkers had low detection rate (15–20%). The combination of all sonomarkers had the highest detection rate of 70% but the false positive rate was as high as 10.8%. The combination of NT and NB had a detection rate of 60% with an acceptable false positive rate of 6.9%, whereas the other combinations yielded relatively high false positive rates. ConclusionThe first trimester genetic sonogram in screening for Down syndrome among Asian women is acceptably effective and may be offered to some selected groups of the population. NT is the best sonomarker with a detection rate of 55% at 5% false positive rate and its combination with NB can improve performance with minimal increase in false positive rate.

Analysis of Antenatal Sonographic Features of the Fetuses with Trisomy 21

Objectives: To evaluate the second trimester ultrasound findings of the fetuses with Down syndrome. Patients and Methods: We conducted a retrospective analysis of 781 patients who underwent prenatal invasive test between November 2011 and July 2015. Based on the patients’ medical records, the demographic data and second trimester ultrasound findings of the fetuses with Down syndrome were retrospectively analyzed. Results: Trisomy 21 was detected in 26 (3.3%) patients. The median (min-max) maternal age of trisomy 21 cases was 31.9 (17 - 41) years. The karyotype indications were high risk in the combined test, triple test, quadruple test and pathologic findings on the ultrasound examination. One case in the ultrasound group had both of combined test and triple test in the low risk area. In this patient, ultrasound examination revealed talipes equinovarus and delayed chorioamniotic fusion at 27 weeks of gestation. Trisomy 21 was detected in four patients by chorion villus biopsy at the first trimester. Second trimester ultrasound was performed in 22 out of these 26 women. However, there were sonographic findings in only 16 (72.7%) patients. Six (27.2%) fetuses had no minor or major anomaly at the detailed ultrasound examination. The frequency of major cardiac anomaly was 22.7%. Choroid plexus cyst and aberrant right subclavian artery were the single findings in two fetuses at the second trimester ultrasound exam. Conclusion: Although the sensitivity of second trimester genetic ultrasound for detection of fetal Down syndrome at our perinatology unit was rather high, nearly one of three patients with Down syndrome had no detectable sonographic finding. Second trimester ultrasound alone is not strong enough to exclude the diagnosis of Down’s syndrome

High Positive Predictive Value (PPV) of Cell-Free DNA (cfDNA) Testing in a Clinical Study of 10,000 Consecutive Pregnancies

Background: Cell-free DNA (cfDNA) analysis in maternal blood for the detection of fetal Down syndrome is gradually replacing first trimester screening. We present here a large clinical series of 10,000 consecutive pregnancies. Objectives: To study the reliability of cell-free DNA (cfDNA) analysis in maternal blood for the detection of fetal trisomy 21, 18 and 13 in a clinical setting in 10,000 consecutive pregnancies with variable risk. cfDNA testing has been evaluated in an increasing number of pregnancies mainly at high risk for fetal trisomy, and some studies have suggested that its positive predictive value (PPV) might be lower in low-risk populations. Study design: CfDNA testing using the Harmony™ Prenatal Test was performed in 10,000 consecutive pregnancies with high or low a-priori risk for fetal trisomy 21, 18 and 13. Results: In 147 (1.47%) of the 10,000 pregnancies a high-risk cfDNA testing result indicated trisomy 21 (n=121), trisomy 18 (n=15) or trisomy 13 (n=11). It failed to detect 5 trisomies (2 trisomies 21, 2 trisomies 18, and 1 trisomy 13). Five false-positive results were recorded (4 in the high and 1 in the low risk population). The overall positive predictive value (PPV) was 96%, with a PPV of 96% in the high-risk (>1/200) population and 97% in the low risk (<1/200) population. Conclusions: In this large clinical series of 10,000 consecutive pregnancies, cfDNA testing proved very reliable in detecting fetal trisomy 21, 18 and 13, with a very high PPV both in high and low risk populations.

Median levels of serum biomarkers of fetal Down syndrome detected during the first trimester among pregnant Thai women

ObjectiveTo develop Thai-specific medians of serum pregnancy-associated plasma protein A (PAPP-A) and free β-human chorionic gonadotropin (hCG) levels during the first trimester of pregnancy and to compare these values to a Caucasian-specific model for the detection of fetal Down syndrome. MethodsSerum concentrations of PAPP-A and free β-hCG were measured during the first trimester in a group of 2339 Thai women undergoing normal singleton pregnancies. ResultsThai reference ranges of PAPP-A and free β-hCG were established by gestational age (70–98days). The equation of best fit for PAPP-A was: predicted median PAPP-A level=28.767 – 0.781×(gestational age in days)+0.006×(gestational age in days)2; r=0.986. The equation of best fit for free β-hCG was: predicted median free β-hCG level=465.332×10(–0.024×gestational age in days); r=0.881. Weight-corrected models were also derived for each biomarker. The Thai-specific reference ranges gave higher positive screening rates than the Caucasian-specific model, even after weight correction (5.1% versus 4.0%). The Thai-specific models were validated in an independent group of 302 pregnant women. ConclusionEthnic group-specific medians for PAPP-A and free β-hCG should be incorporated during first-trimester screening for fetal Down syndrome.

Non-invasive prenatal diagnosis of down syndrome: a dream come true

Our group discovered the presence of cell-free fetal DNA in plasma of pregnant women. This finding offered opportunities for the development of non-invasive approaches for prenatal diagnosis. However, fetal DNA co-exists with a large background of maternal DNA and amounts to just some 10% of the total DNA in maternal plasma. Despite the technical challenges, we developed an approach based on massively parallel sequencing for the non-invasive detection of fetal Down syndrome by detecting the small increments in chromosome 21 DNA sequences in maternal plasma. We showed in a study of 750 pregnancies that Down syndrome can be accurately identified by direct analysis of maternal plasma DNA. The method could be further adapted for the prenatal detection of trisomy 18 and trisomy 13. A number of groups have since confirmed our findings. Non-invasive prenatal detection of fetal Down syndrome has since been implemented as a routine service at a number of centres around the world. <h3>Acknowledgement</h3> Supported by the University Grants Committee of the Government of the Hong Kong Special Administrative Region, China, under the Areas of Excellence Scheme (AoE/M-04/ 06), the General Research Fund Scheme of the Hong Kong Research Grants Council (CUHK463109), and an Innovation and Technology Fund (ITS/054/09).

Non-invasive prenatal diagnosis of down syndrome: a dream come true

Our group discovered the presence of cell-free fetal DNA in plasma of pregnant women. This finding offered opportunities for the development of non-invasive approaches for prenatal diagnosis. However, fetal DNA co-exists with a large background of maternal DNA and amounts to just some 10% of the total DNA in maternal plasma. Despite the technical challenges, we developed an approach based on massively parallel sequencing for the non-invasive detection of fetal Down syndrome by detecting the small increments in chromosome 21 DNA sequences in maternal plasma. We showed in a study of 750 pregnancies that Down syndrome can be accurately identified by direct analysis of maternal plasma DNA. The method could be further adapted for the prenatal detection of trisomy 18 and trisomy 13. A number of groups have since confirmed our findings. Non-invasive prenatal detection of fetal Down syndrome has since been implemented as a routine service at a number of centres around the world. <h3>Acknowledgement</h3> Supported by the University Grants Committee of the Government of the Hong Kong Special Administrative Region, China, under the Areas of Excellence Scheme (AoE/M-04/ 06), the General Research Fund Scheme of the Hong Kong Research Grants Council (CUHK463109), and an Innovation and Technology Fund (ITS/054/09).

Noninvasive Prenatal Diagnosis of a Case of Down Syndrome due to Robertsonian Translocation by Massively Parallel Sequencing of Maternal Plasma DNA

To the Editor: There has been much recent interest in the use of massively parallel sequencing of maternal plasma DNA for the detection of fetal Down syndrome, or trisomy 21 (1–4). DNA fragments in maternal plasma were sequenced at random to determine if an additional dose of chromosome 21 (chr21)1 sequences was contributed by the fetus. This approach has been shown to be highly robust in distinguishing trisomic and euploid cases. In these studies, however, all recruited trisomy 21 cases possess supernumerary whole chr21, as confirmed by karyotyping. This approach has not been formally shown to be applicable to other forms of the condition. For example, although the ratio of fetal to maternal DNA in maternal plasma has been shown to remain relatively constant across the entire genome for normal chromosomes (5), it is unknown whether an aberrant chromosome (e.g., one containing a chromosomal translocation) would exhibit an atypical genomic representation in the plasma. As a first step in addressing this issue, we applied the sequencing approach to a case of familial robertsonian translocation. This study was approved by the local research ethics committee. Maternal peripheral blood samples …

Integrating AHP in an FMECA framework for ranking Down syndrome tests

Many have argued that good quality health care includes involving patients in decisions about their care. In the case of genetic consultation women make decisions that also concern the next generation. Today, tests for detection of fetal Down syndrome (DS) are readily available. These tests are either diagnostic or screening tests. The result of a diagnostic test is certain, however, it involves the risk of hurting the fetus. The results of a screening test are less certain but do not involve a risk to the fetus. Pregnant women have their own preferences concerning possible losses based on their own beliefs. We developed a model similar to the failure mode, effects, and criticality analysis (FMECA) model to support the pregnant woman's decision making process. The model takes into account information about DS statistics, the risk of hurting the fetus, false diagnostic rates, and possible losses. Analytic hierarchy process (AHP) is used for scaling the subjective scores of the losses. A case study demonstrates the model.

The history of the second‐trimester sonographic markers for detecting fetal Down syndrome, and their current role in obstetric practice

This review summarizes the development, history and use of second-trimester sonographic markers for the detection of fetal Down syndrome over three decades. Starting with the nuchal fold thickening in 1985 and culminating in the genetic sonogram in the 1990 s. The combination of second-trimester serum screening with the ultrasound markers improved the detection rate of affected fetuses but also allowed patients to decrease their risk of carrying a fetus with Down syndrome if the genetic sonogram was normal. More recently the role of the genetic sonogram and its markers have changed with the wide spread use of first-trimester screening. This prior screening ultimately decreases the prevalence of fetal Down syndrome in the second trimester to less than 85% of what it was in the first-trimester as most fetuses with Down syndrome are now identified early. Current interpretation of the second-trimester Down syndrome markers must be based on the result of the first trimester and combined screening to achieve the most accurate risk estimate of an affected fetus.

Diagnosis of fetal acrania during the first trimester nuchal translucency screening for Down syndrome

Objectives: Prenatal screening during the first-trimester using fetal nuchal translucency (NT) measurement and maternal serum levels of free β-human chorionic gonadotropin (hCG) and pregnancy-associated plasma protein-A (PAPP-A) has become an established method for the detection of fetal Down syndrome. Increasing evidence has shown that some of the fetal structural abnormalities could be identified during NT scanning. Second trimester maternal serum alpha-fetoprotein (MSAFP) measurements and ultrasound scans have been widely used in clinical practice to identify fetal neural tube defects (NTDs). In this study, we evaluated the effectiveness of early diagnosis of fetal acrania during NT scanning. Methods: We reviewed the medical records of 5890 pregnancies that were delivered in our hospital between January 1, 1999 and January 31, 2001. Among them, 3600 pregnant women received NT-based Down syndrome screening at 10–13 weeks’ gestation. Pregnancies with fetal NTDs were evaluated and their maternal serum levels of free β-hCG and PAPP-A were compared with those of the normal control pregnancies. Results: Seven of the 3600 pregnancies were identified with fetal acrania and all of them were detected during first-trimester NT scanning. Among the seven cases, five had measurements of maternal serum concentration free β-hCG and PAPP-A concentration, yet there were not significant difference between the pregnancies with fetal acrania and those of the control pregnancies (PAPP-A, 1.13 vs. 0.96; free β-hCG, 1.10 vs. 1.06; P>0.05). Two of the seven affected patients did not have maternal serum biochemical measurements due to the immediate termination of pregnancies. Conclusions: We demonstrated that pregnancies with fetal acrania could be easily identified at the time of NT scanning. Careful ultrasound inspection of fetal structure during NT measurements at 10–13 weeks of gestation provides an encouraging advantage for early diagnosis of fetal acrania.

A novel method for the detection of down syndrome with the use of four serum markers

Objective: The purpose of this study was to evaluate the use of the Lens culinaris agglutinin-reactive α-fetoprotein ratio for the detection of fetal Down syndrome in combination with traditional serum markers. Study Design: We obtained maternal serum from 530 women with unaffected pregnancies and 31 women who were pregnant with a fetus with Down syndrome at 14 to 20 weeks of gestation. Various combinations of Lens culinaris agglutinin-reactive α-fetoprotein ratio, α-fetoprotein, human chorionic gonadotropin, and unconjugated estriol were evaluated by score, without regard for the maternal age-related fetal Down syndrome risk. Results: The best combination of serum markers, according to our scoring method, was a combination of all 4 markers. This combination showed a sensitivity of 83.9%, with a 5.1% false-positive rate for Down syndrome. Moreover, in older women, high sensitivity was obtained without increasing the false-positive rate. Conclusion: The screen using all 4 markers showed high sensitivity in all age groups without increasing the false-positive rate. (Am J Obstet Gynecol 2002;187:197-201.)

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.

Prospective evaluation of free β-subunit of human chorionic gonadotropin and dimeric inhibin A for aneuploidy detection

Objective: Our goal was to prospectively evaluate the use of the free β-subunit of human chorionic gonadotropin and dimeric inhibin A for the detection of fetal Down syndrome and other aneuploidies. Study Design: Women who had a second-trimester multiple-marker screening test (α-fetoprotein, unconjugated estriol, human chorionic gonadotropin) and genetic amniocentesis from August 1996 to August 1998 were included. Serum was also analyzed for inhibin and the free β-subunit of human chorionic gonadotropin. Detection and false-positive rates for 4 analyte combinations at 5 different screening risk cutoff points for Down syndrome were determined and compared. Results: We evaluated 1256 patients, including 23 with aneuploidy (13 with Down syndrome, 10 others). The maternal age was 35.9 ± 4.6 years (mean ± SD). At the optimal risk cutoff point for Down syndrome detection (1:190; false-positive rate, 19%), the multiple-marker screening test plus inhibin was superior, detecting 85% of Down syndrome cases, in comparison with 69% when the multiple-marker screening test alone was used and 62% when the other 2 combinations were used. The multiple-marker screening test plus inhibin also detected 60% of the other aneuploidies. Conclusions: When evaluated prospectively in a high-risk population, the multiple-marker screening test plus inhibin was superior to the traditional multiple-marker screening test and 2 other analyte combinations, with a lower false-positive rate and increased detection of all aneuploidies in a high-risk population. (Am J Obstet Gynecol 1999;181:887-92.)

Elevated Second-Trimester Maternal Urine Free Beta-Human Chorionic Gonadotropin Levels in Asian Pregnancies with Fetal Chromosomal Abnormalities

Objectives: To investigate the second trimester maternal urine free beta-human chorionic gonadotropin (hCG) levels of chromosomally abnormal pregnancies in Asians. Methods: Free beta-hCG levels were analyzed from the urine samples of 110 control and 17 chromosomally abnormal pregnancies, including 11 cases of Down syndrome, 1 case of trisomy 18, and other chromosomal abnormalities (one mosaic deletion and 4 translocations) from the second trimester of pregnancy. Results were normalized to urine creatinine (Cr) concentration and converted to the multiple of the median (MOM) level for the appropriate gestation. Gestational age of all cases was determined by ultrasound parameters. Results: The median free beta-hCG MOM levels of Down syndrome (4.02 MOM) and other chromosomally abnormal pregnancies (2.03 MOM) are significantly higher than that of normal pregnancies (0.99 MOM) (p = 0.002 and p = 0.024, respectively). Nine of 11 (81.8%) Down syndrome cases, one trisomy 18 case, and 2 of 5 (40%) other chromosomally abnormal cases would be expected to be above the 95th centile of the control values (2.95 MOM cut-off). Conclusion: Urine free beta-hCG could be a potential and useful marker in the detection of fetal Down syndrome and other chromosomal abnormalities in Asians.

Schwangerschafts protein 1 (SP1) adds little to the age‐related detection of fetal Down syndrome in the first trimester of pregnancy

Schwangerschafts protein 1 (SP1) adds little to the age‐related detection of fetal Down syndrome in the first trimester of pregnancy

Schwangerschafts protein 1 (SP1) adds little to the age-related detection of fetal Down syndrome in the first trimester of pregnancy

Schwangerschafts Protein 1 (SP1), being a placental protein appearing in the maternal circulation early in pregnancy, has been investigated as a potential marker for Down syndrome in the first trimester. Our study compared SP1 levels in 15 pregnancies with a Down syndrome fetus and 97 matched controls. Although the median MoM in Down syndrome pregnancies (0.49) was lower than in controls, its use as a marker added very little to the detection rate above the maternal age alone.

Schwangerschafts protein 1 (SP1) adds little to the age‐related detection of fetal Down syndrome in the first trimester of pregnancy

Schwangerschafts protein 1 (SP1) adds little to the age‐related detection of fetal Down syndrome in the first trimester of pregnancy

Down syndrome screening in an asian population using alpha-fetoprotein and free β-hcg: a report of the taiwan down syndrome screening group

To evaluate whether the strategy of maternal serum screening for Down syndrome, using alpha-fetoprotein (AFP) and free beta-hCG in combination with maternal age, a technique developed in western countries, is applicable to an Asian population. Alpha-fetoprotein and beta-hCG were measured in serum samples from 23 Down syndrome pregnancies and 1748 unaffected singleton Taiwanese (ethnically Chinese) pregnancies at 14-22 weeks' gestation. Gestational age-specific medians and a maternal weight correction formula were established for our own population. Likelihood ratio for Down syndrome pregnancies in relation to multiples of the median (MoM) levels of these analytes were derived from the overlapping gaussian frequency distribution curves for Down syndrome and unaffected pregnancies. The serum AFP and free beta-hCG median MoM values of Down syndrome pregnancies were significantly abnormal in Asian subjects (0.77 and 2.91, respectively), and similar to those of affected pregnancies in white women. The median value of free beta-hCG:AFP MoM ratio (2.97) in Down syndrome pregnancies was significantly higher than that of unaffected pregnancies (1.09). The mean maternal weight during the second trimester in pregnant Asian women (55.2 kg) was markedly lighter than that of white women. At a 5.8% false-positive rate, free beta-hCG identified 47.8% of Down syndrome pregnancies (likelihood ratio 8.2), AFP detected only 13% of the cases (likelihood ratio 2.2), and free beta-hCG:AFP MoM ratio detected 43.5% of the cases (likelihood ratio 7.4). By using a multivariate risk algorithm involving the combination of AFP, free beta-hCG, and maternal age, 56.5% of Down syndrome cases could be detected with a 5.3% false-positive rate (likelihood ratio 10.7). Maternal serum screening strategy using AFP and free beta-hCG in combination with maternal age is feasible in the detection of fetal Down syndrome among Asian women.

Comparion of multiple-marker screening with amniocentesis for the detection of fetal aneuploidy in women ≥35 years old

OBJECTIVE: Our purpose was to compare the multiple-marker screening test with elective amniocentesis for the detection of fetal Down syndrome and other aneuploidies in women aged ≥35. STUDY DESIGN: Our database included the multiple-marker screening test (maternal serum α-fetoprotein, human chorionic gonadotropin, unconjugated estriol, and maternal age) and genetic amniocentesis results from 1942 women aged ≥35. A Down syndrome risk ≥1:190 was considered screen positive. An algorithm to detect trisomy 18 was also used. RESULTS: The multiple-marker screening test Down syndrome screen-positive rate was 26.1% ( 507 1942 ). The Down syndrome detection rate was 75% ( 33 44 ); the trisomy 18 detection rate was 75% ( 3 4 ). However, the multiple-marker screening test detection rate for all aneuploidies was only 61%. Missed aneuploidies included trisomy 21, sex chromosome abnormalities, trisomy 13, trisomy 22, and trisomy 18. CONCLUSIONS: The multiple-marker screening test fails to detect approximately 39% of all fetal aneuploidies in women aged ≥35. These data should be provided to women considering prenatal diagnosis so that they can make an informed decision regarding the multiple-marker screening test versus amniocentesis for advanced maternal age.