First-trimester Combined Test Research Articles

First- and Second-trimester Down Syndrome Screening: Current Strategies and Clinical Guidelines

Down syndrome (DS) is the most common human disease caused by a structural chromosome defect. The original screening test for DS was maternal age or a history of a previously affected infant. Maternal serum screening has been incorporated into routine prenatal checkup in Taiwan since 1994. We used free beta-human chorionic gonadotropin and alpha-fetoprotein (double test) as the serum markers, and this was carried out between the 15th to 20th week of gestation. The overall detection rate was 56% and was compatible with studies of Caucasian populations. The impact of double tests in Taiwan has shown itself by a dramatic lowering of the rate of DS live birth from 0.63 before screening to 0.16 per 1,000 live births at present. However, because of its relatively low detection rate and poor cost-effectiveness, the double test is not justified as a routine screening tool currently. First-trimester combined test is now becoming more widely available and provides increased sensitivity when detecting DS; it has a detection rate of approximately 85% with a false-positive rate of 5%. Nuchal translucency measurement requires ongoing quality control and sufficient certified obstetricians; therefore, first-trimester ultrasound is limited only in designated centers. The quadruple test, having comparable detection rate, should be considered for incorporation into second-trimester screening in Taiwan in the near future. Other screening approaches and combinations have also been utilized in the Western countries. In this review, we outline the various options with respect to DS screening and hope that this will provide practical information for physicians offering such screenings.

Multi‐centre first‐trimester screening for Down syndrome in the Netherlands in routine clinical practice

This is the first report on the results of a first-trimester combined-test screening programme in the Netherlands in a multi-centre routine clinical setting. Between July 2002 and May 2004, blood samples were taken from subjects in 44 centres in the Netherlands and sent to our laboratory to assay for maternal serum concentrations of fbeta-hCG and PAPP-A. Fetal nuchal translucency (NT) was measured in the participating centres at a gestational age (GA) of 10-14 weeks. Results of those pregnancies for which a combined biochemical and NT risk was calculated were included in the epidemiological analysis of this study. A total of 4033 singleton pregnancies were included in the analysis. The median maternal age of the analysed group was 36.5 years. The distribution of GA was biphasic, with median GA of 10.3 and 12.1 weeks, respectively. The detection rate using the combined ultrasound and serum screening at a cut-off level of 1 in 250 was 71% (15/21), with a screen-positive rate of 4.7%. The results of this study show that the first-trimester combined test is suitable as a prenatal screening test in a multi-centre routine clinical setting in the Netherlands. Strict performance evaluation should identify weaknesses in the organisation that impair the performance of the test. Here, the performance of NT was especially identified as a candidate for improvement.

Historical Perspectives

This month’s Historical Perspectives is in a slightly different format, but should be of considerable interest to readers of NeoReviews. Professor Nicholas Wald is an epidemiologist who has evaluated and written about a variety of topics, but he is best known for his work on screening methods, particularly in the area of maternal serum alpha-fetoprotein (AFP) and fetal abnormalities. Because of his continuing heavy commitments and to minimize the disruption of his schedule, I posed a number of questions to him, to which he responded with detailed answers. Before moving to his responses, some background information seems in order. Shortly before publication of the article highlighted this month, evaluation of amniotic fluid in cases of open spina bifida and other neural tube defects had shown increased levels of AFP. (1) Somewhat later, it was shown that abdominal wall defects, as well as neural tube defects, could contribute to increased levels of amniotic fluid AFP. (2) In his responses, Professor Wald documents the sequence of events that followed, noting that Professor David Brock in Edinburgh described the association of increased levels of maternal serum alpha-fetoprotein (MSAFP) with fetal anencephaly, which triggered the idea that this also might be true of open spina bifida. Thus, MSAFP was used as a screening tool for the detection of neural tube and abdominal wall defects. Elevated MSAFP levels were noted in other “at-risk” pregnancies (3) and twin pregnancies. (4) To provide better standardization, Professor Wald introduced the concept of “multiples of the median” (MoM) at different gestational ages. Approximately a decade passed before the association was made between low MoMs for AFP and chromosomal defects, particularly Down syndrome. Soon thereafter, several other serum markers for Down syndrome were described, and by linking them to maternal age, screening became increasingly valuable. In the early 1980s, Dr …

Pregnancy outcomes in unselected singleton pregnant women with an increased risk of first‐trimester Down's syndrome

The purpose of this study was to assess outcomes in pregnancies with a positive screen of first-trimester combined test (nuchal translucency, pregnancy-associated plasma protein-A and free beta-human chorionic gonadotropin). Using a cut-off level of 1 in 270, 216 (7.1%) women had a positive screen. Among them, 187 delivered their babies in our hospital and the adverse outcomes, such as spontaneous abortion, intrauterine fetal demize, preterm prelabor rupture of the membranes, preterm labor, intrauterine growth restriction, gestational hypertensive disorders, placenta previa, chromosomal abnormalities and fetal structural anomalies, were identified and compared with the 2097 women who screened negative for Down's syndrome. Pregnancies with a positive screen had a significantly higher risk of adverse outcomes than those with negative screens (30.5% versus 15.3%; odds ratio 2.4; p < 0.001), especially for those complicated by spontaneous abortion (odds ratio 11.4; p < 0.05) and placenta previa (odds ratio 4.3; p < 0.05). Besides fetal chromosomal abnormalities and structural abnormalities, pregnancies with a positive screen for Down's syndrome in the first-trimester had a significantly higher incidence of subsequent adverse obstetric outcomes.

First-Trimester Combined Test Screening for Down Syndrome: Results of A Series with 5,036 Cases

Summary Objective To assess the sensitivity of a first-trimester combined screening test for fetal chromosomal abnormalities. Materials and Methods From April 1999 to December 2002, 5,036 unselected women with singleton pregnancies underwent a first-trimester combined test (nuchal translucency thickness, pregnancy-associated plasma protein-A, and free β-human chorionic gonadotropin) screening for Down syndrome. They included 298 (5.9%) women aged 35 years or older and 4,738 (94.1%) women aged below 35 years. A positive result was defined as an estimated Down syndrome risk of greater than 1/270. Results Twenty-five (0.50%) chromosomal abnormalities were identified, with a false-positive rate of 7.1% (333/4,717) in women younger than 35 years and a false-positive rate of 17.3% (51/294) in women of advanced maternal age. The 25 chromosomal abnormalities included trisomy 21 in six fetuses, trisomy 18 and Turner's syndrome in four fetuses each, Klinefelter's syndrome, a marker chromosome and pseudohermaphroditism in one fetus each, and structural rearrangements in eight, including four with balanced translocations. One fetus with trisomy 18 was not discovered at screening, but a fetal ventricular septal defect was found on ultrasound at 30 weeks' gestation. The detection rate for fetal chromosomal abnormalities was 95.2% (20/21). If a cutoff of 1 in 200 was used, the false-positive rate would be 5.6% with the same detection rate, whereas the test still yielded a detection rate of 90.5% (19/21) with a 5% false-positive rate. In 83.3% of cases with trisomy 21 and 5.7% of normal pregnancies, fetal nuchal translucency thickness measurement was above the 95 th percentile, whereas in 0.7% of the study population and in 24% of those with fetal chromosomal abnormalities, the fetal nuchal translucency thickness was at least 3 mm. Conclusion Our results indicate that the first-trimester combined test for Down syndrome is effective in identifying fetal chromosomal abnormalities. Moreover, the measurement of fetal nuchal translucency thickness at 10 to 13 weeks of gestation enables early detection of major fetal structural anomalies.