David Krantz

First-Trimester Down Syndrome Screening Using Dried Blood Biochemistry and Nuchal Translucency

Objective To assess the effectiveness of free β-hCG, pregnancy-associated plasma protein A, and nuchal translucency in a prospective first-trimester prenatal screening study for Down syndrome and trisomy 18. Methods Risks were calculated for Down syndrome and trisomy 18 based on maternal age and biochemistry only (n = 10,251), nuchal translucency only (n = 5809), and the combination of nuchal translucency and biochemistry (n = 5809). Results The study population included 50 Down syndrome and 20 trisomy 18 cases. Nuchal translucency measurement was done on 33 Down syndrome and 13 trisomy 18 cases. Down syndrome screening using combined biochemistry and ultrasound resulted in a false-positive rate of 4.5% (95% confidence interval [CI] 3.9%, 5.2%) and detection rate of 87.5% (95% CI 47%, 100%) in patients under age 35 years. In older patients, the false-positive rate was 14.3% (95% CI 12.7%, 15.8%) and detection rate was 92% (95% CI 74%, 99%). For trisomy 18 screening, the false-positive rate was 0.4% (95% CI 0.24%, 0.69%) and detection rate was 100% (95% CI 40%, 100%) in younger patients, whereas in older patients the false-positive rate was 1.4% (95% CI 0.9%, 2.0%) and detection rate was 100% (95% CI 66%, 100%). Using modeling, at a fixed 5% false-positive rate, the Down syndrome detection rate was 91%. Conversely, at a fixed 70% Down syndrome detection rate, the false-positive rate was 1.4%. Conclusion First-trimester screening for Down syndrome and trisomy 18 is effective and offers substantial benefits to clinicians and patients.

Measurement of nasal bone length at 11–14 weeks of pregnancy and its potential role in Down syndrome risk assessment

To assess the feasibility of measuring nasal bone length in first‐trimester pregnancy and to confirm if the absence of a fetal nasal bone is a marker for Down syndrome.

First-trimester Down syndrome screening: Free β-human chorionic gonadotropin and pregnancy-associated plasma protein A

OBJECTIVE Our purpose was to determine the feasibility of a first-trimester Down syndrome screening protocol including free beta-human chorionic gonadotropin and pregnancy-associated plasma protein A. STUDY DESIGN First-trimester maternal blood samples from 22 Down syndrome and 483 control cases were assayed for free beta-human chorionic gonadotropin and pregnancy-associated plasma protein A by enzyme-linked immunosorbent assay procedures. False-positive and detection rates were determined on the basis of Down syndrome risks calculated from the levels of biochemical markers and maternal age. Because 11 of the 22 Down syndrome cases were from older pregnancies (> or = 35 years old), rates were recalculated with the United States age distribution of live births to get a more representative estimate of false positives and detection efficiency. RESULTS The median free beta-human chorionic gonadotropin and pregnancy-associated plasma protein A levels in cases of Down syndrome was 2.09 (95% confidence interval 1.69 to 2.62) and 0.405 multiples of the median (95% confidence interval 0.28 to 0.67), respectively. At a 5.0% false-positive rate, 15 (68.2%) Down syndrome cases were detected. By the use of the age distribution of live births, 63% of cases could be expected to be detected at a 5.0% false-positive rate. CONCLUSION First-trimester free beta-human chorionic gonadotropin and pregnancy-associated plasma protein A screening for Down syndrome can achieve detection rates as high as those associated with alpha-fetoprotein and human chorionic gonadotropin or alpha-fetoprotein, human chorionic gonadotropin, and unconjugated estriol screening in the second trimester. Prospective studies are needed to further assess first-trimester screening.

Sequential pathways of testing after first-trimester screening for trisomy 21

OBJECTIVE: To evaluate the performance and use of second-trimester multiple-marker maternal serum screening for trisomy 21 by women who had previously undergone first-trimester combined screening (nuchal translucency, pregnancy-associated plasma protein A, and free β-hCG), with disclosure of risk estimates. METHODS: In a multicenter, first-trimester screening study sponsored by the National Institute of Child Health and Human Development, multiple-marker maternal serum screening with alpha-fetoprotein, unconjugated estriol, and total hCG was performed in 4,145 (7 with trisomy 21) of 7,392 (9 with trisomy 21) women who were first-trimester screen-negative and 180 (7 with trisomy 21) of 813 (52 with trisomy 21) who were first-trimester screen-positive. Second-trimester risks were calculated using multiples of the median and a standardized risk algorithm with a cutoff risk of 1:270. RESULTS: Among the first-trimester screen-negative cohort, 6 of 7 (86%) trisomy 21 cases were detected by second-trimester multiple-marker maternal serum screening with a false-positive rate of 8.9%. Among the first-trimester screen-positive cohort, all 7 trisomy 21 cases were also detected in the second trimester, albeit with a 38.7% false-positive rate. CONCLUSION: Our data demonstrate that a sequential screening program that provides patients with first-trimester results and offers the option for early invasive testing or additional serum screening in the second trimester can detect 98% of trisomy 21–affected pregnancies. However, such an approach will result in 17% of patients being considered at risk and, hence, potentially having an invasive test. LEVEL OF EVIDENCE: II-2

Pregnancy-associated Plasma Protein A, Free β-hcg, Nuchal Translucency, and Risk of Pregnancy Loss

OBJECTIVE: To estimate the likelihood of clinical early and late pregnancy loss as a function of first-trimester maternal serum analytes and fetal nuchal translucency measurements. METHODS: Study subjects were recruited for a National Institute of Child Health and Human Development–sponsored multicenter cohort study initially designed to study the detection of Down syndrome during the first trimester of pregnancy. The cohort consisted of women who had a live fetus between 10 and 14 weeks of gestation and had no significant vaginal bleeding. Women with prior fetal trisomy (T21/18) and those with structural or chromosomal abnormalities in the index pregnancy were excluded. First-trimester screening consisted of pregnancy-associated plasma protein A (PAPP-A), free β-hCG, and nuchal translucency. Pregnancy loss rates in women with various levels of PAPP-A, free β-hCG, or nuchal translucency (less than 1st, less than 5th, more than 95th, and more than 99th percentile) were compared with losses in women with normal values (5th to 95th percentile). RESULTS: The mean gestational age at screening of 7,932 women meeting study criteria was 12.1 weeks. Loss rates were only 0.36% at less than 20 weeks after normal free β-hCG, PAPP-A, and nuchal translucency. Conversely, low levels of PAPP-A and free β-hCG as well as increased nuchal translucency were individually associated with increased early loss. These associations persisted after controlling for maternal age and race using logistic regression analysis. CONCLUSION: Normal values of PAPP-A, free β-hCG, and nuchal translucency are associated with a very low risk of pregnancy loss at less than 20 weeks. LEVEL OF EVIDENCE: II-2

Prenatal maternal dried blood screening with α-fetoprotein and free β-human chorionic gonadotropin for open neural tube defect and Down syndrome

Abstract OBJECTIVE: Our purpose was to evaluate second-trimester prenatal screening for open neural tube defects and Down syndrome by use of dried blood specimen collection and transport. STUDY DESIGN: A prospective study of 7497 dried blood specimens from patients RESULTS: The initial positive rate for open neural tube defect was 4.4% adjusted to 2.7% after ultrasonographic revision and collection of a second sample. The initial positive rate for Down syndrome was 3.6%, adjusted to 2.8% after ultrasonographic revision. All seven cases of open neural tube defect were detected within the increased risk group. Six of 8 (75%) cases of Down syndrome were detected. The median α-fetoprotein multiple of the median was 3.5 in open neural tube defect cases and 0.6 in Down syndrome cases. The median free β-human chorionic gonadotropin multiple of the median was 2.4 in Down syndrome cases. The SD (log e ) of α -fetoprotein and free β -human chorionic gonadotropin in 5868 unaffected white patients was 0.4022 and 0.5635, respectively. CONCLUSION: Second-trimester dried blood screening for open neural tube defects and Down syndrome can achieve screening efficiency comparable to serum-based protocols with distinct advantages over the conventional method of blood collection. (AM J OBSTET GYNECOL 1996;174:566-72.)

Genetic sonography after first‐trimester Down syndrome screening

Approximately 90% of Down syndrome cases are detected during first‐trimester screening. We aimed to determine the potential effectiveness of second‐trimester genetic sonography as a sequential screen for Down syndrome.

Nearly a third of abnormalities found after first‐trimester screening are different than expected:10‐year experience from a single center

This study aimed to assess the efficacy of first‐trimester aneuploidy screening in a single clinical setting.

Cell-free fetal DNA screening in the USA: a cost analysis of screening strategies

To determine whether implementation of primary cell‐free fetal DNA (cffDNA) screening would be cost‐effective in the USA and to evaluate potential lower‐cost alternatives.

First trimester Down syndrome screening with dried blood spots using a dual analyte free beta hCG and PAPP-A immunofluorometric assay.

To determine the effectiveness of first trimester Down syndrome screening with dried blood spots using a dual analyte free beta human chorionic gonadotrophin (hCG)/pregnancy‐associated plasma protein A (PAPP‐A) immunofluorometric assay.