Philip D. Buchanan

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.

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.

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.)

URINE FREE BETA hCG AND BETA CORE IN PREGNANCIES AFFECTED BY DOWN'S SYNDROME

Urine beta core was shown in recent studies to be markedly elevated in pregnancies affected by Downs syndrome in the late second trimester. Free beta human chorionic gonadotropin (hCG) has also been shown to be the most discriminatory maternal serum marker of Downs syndrome. Since free beta hCG is rapidly cleared from the maternal circulation, we have carried out a study to evaluate whether free beta hCG is elevated in the urine of pregnancies affected by Downs syndrome and to investigate whether urine beta core or urine free beta hCG may be used as possible screening markers. Urine samples from 29 cases of Downs syndrome, three cases of trisomy 18, and 400 control pregnancies were analysed for the two prospective markers. Results were corrected for urine concentration by expressing marker concentrations at a fixed creatinine concentration and then expressing the results as multiples of the median for unaffected pregnancies of the same gestation. The median value of beta core in the Downs syndrome pregnancies was 2·35 compared with 2·47 for free beta hCG. Free beta hCG distributions were closely similar to those in maternal serum. Using free beta hCG, we predict Downs syndrome detection rates of 58 per cent at a 5 per cent false‐positive rate. Using beta core, however, this rate fell to 41 per cent. Measurement of free beta hCG in urine may present a feasible route for screening pregnant populations, particularly where community‐based obstetric care is the norm and/or if early first‐trimester screening becomes a reality.

Prenatal diagnosis of a mosaic extra structurally-abnormal chromosome by spectral karyotyping

A de novo mosaic extra structurally abnormal chromosome (ESAC) was detected in 33 per cent of cultured amniotic fluid cells from a pregnant woman. Neither Q‐banding nor fluorescence in situ hybridization (FISH) employing a DNA probe for nucleolar organizer region demonstrated the presence of satellites on the ESAC. Spectral karyotyping (SKY) was performed in this prenatal case and led to a quick and accurate determination of the ESAC as chromosome 14 in origin. The SKY finding was confirmed by conventional FISH analysis using a chromosome 14 specific painting probe. Subsequent hybridizations with a centromeric probe and a 14q subtelomeric probe were also performed to further characterize the ESAC. Absence of (TTAGGG)n sequence on the ESAC, determined postnatally, suggested it is a ring chromosome 14. Genetic counselling concerning these findings was provided to the parents who chose to continue the pregnancy. The male infant had no apparent abnormal phenotype at birth. Copyright

Free beta hCG screening of hydropic and non-hydropic turner syndrome pregnancies

Fourteen cases of Turner syndrome (45,X), two cases of mosaic Turner syndrome (45,X/47,% and 45,X/46,XX), and one case of Turner syndrome involving an isochromosome X [46,X,i(X)(q10)] were ascertained by prenatal maternal serum alpha‐fetoprotein (MSAFP) and free beta human chorionic gonadotropin (hCG) screening or by ultrasound. Patient‐specific risks for Down syndrome were calculated and used as the criteria to determine offering further testing. Eleven of the 17 cases had hydrops and presented with an increased Down syndrome risk based on MSAFP and free beta hCG screening. The median MOM level was 0·98 and 4·04 for MSAFP and free beta hCG, respectively. Three cases had hydrops but screened negative. The two cases of mosaic Turner syndrome were non‐hydropic and screened positive. The 46,X,i(X)(q10) case was non‐hydropic but had elevated MSAFP and free beta hCG levels. These data suggest that Turner syndrome pregnancies do not appear to screen positive due to hydrops alone, but screening may also be influenced by the inherent genetic imbalance in the fetus and placenta. Because the MSAFP levels in our series were within the normative range in all except one case with an elevated MSAFP, free beta hCG alone was the most effective screening marker for Turner syndrome pregnancies.

Accuracy of a home-based device for giving an early estimate of pregnancy duration compared with reference methods

OBJECTIVE To assess a home pregnancy tests accuracy to concurrently detect pregnancy and determine pregnancy duration. DESIGN Multicenter, prospective study. SETTING Study sites in the United States. PATIENT(S) Women actively attempting to conceive who have menstrual bleeds (18-45 years). INTERVENTION(S) Volunteers collected early morning urine samples (three or fewer menstrual cycles). Pregnant volunteers underwent ultrasound dating scans. Ovulation day (LH surge +1 day) during pregnancy-resulting cycles was determined by quantitative measurement of LH. Random urine samples were tested with the hCG-measuring pregnancy test from 4 days before the expected period until 4 weeks later. MAIN OUTCOME MEASURE(S) A home pregnancy tests accuracy in determining pregnancy duration compared with ultrasound and ovulation day. RESULT(S) Agreement between pregnancy test results and time since ovulation was 93% (confidence interval [CI], 91.5-94.4). Agreement with ultrasound was dependent on the formula: there was 99% agreement when calculated with adjustment for Hadlock formula bias (Pexsters; CI, 98.2-99.4) or using a nonbias formula (Wu; CI, 98.6-99.6), when ultrasound error was accommodated. Agreement was lower when bias/measurement errors were not accounted for (Wu, 86%, CI, 83.9-88; Hadlock, 80.8, CI, 78.2-83.3). CONCLUSION(S) This home pregnancy test provides an accurate estimation of pregnancy duration in weeks categories, 1-2, 2-3, 3+ weeks since ovulation, thereby showing utility in dating pregnancy.